BNF for Children 2011-2012

Medicines information servicesInformation on any aspect of drug therapy can beobtained from Regional and District Medicines InformationServices. Details regarding the local services providedwithin your Region can be obtained by telephoningthe following numbers.EnglandBirmingham (0121) 424 7298Bristol (0117) 342 2867Ipswich (01473) 704 431Leeds (0113) 206 5377Leicester (0116) 255 5779Liverpool (0151) 794 8113/4/5/7(0151) 794 8206LondonGuy’s Hospital (020) 7188 8750(020) 7188 3849(020) 7188 3855Northwick Park Hospital (020) 8869 2761(020) 8869 3973Newcastle (0191) 282 4631Southampton (023) 8079 6908/9WalesCardiff (029) 2074 2979(029) 2074 2251ScotlandAberdeen (01224) 552 316Dundee (01382) 632 351(01382) 660 111Extn 32351Edinburgh (0131) 242 2920Glasgow (0141) 211 4407UK Teratology Information ServiceInformation on drug and chemicalexposures in pregnancy 0844 892 0909Medicines for Children information leafletsMedicines information for parents and carers.www.medicinesforchildren.org.ukPatient Information LinesNHS Direct 0845 4647Poisons Information ServicesUK National Poisons InformationService 0844 892 0111Travel ImmunisationUp-to-date information on travel immunisationrequirements may be obtained from:National Travel Health Network and Centre (forhealthcare professionals only) 0845 602 6712(09.00–12.00 and 14.00–16.30 hours weekdays)Travel Medicine Team, Health Protection Scotland(0141) 300 1130 (14.00–16.00 hours weekdays)www.travax.nhs.uk (for registered users of the NHSwebsite Travax only)Welsh Assembly Government (029) 2082 1318(09.00–17.30 hours weekdays)Department of Health and Social Services (Belfast)(028) 9052 2118 (weekdays)Information on drug therapy relating to dentaltreatment can be obtained by telephoning:Liverpool (0151) 794 8206Northern IrelandBelfast (028) 9063 2032(028) 9063 3847Republic of IrelandDublin Dublin 473 0589Dublin 453 7941Extn 2348SportInformation on substances currently permitted orprohibited is provided in a card supplied by UK Anti-Doping.Further information regarding medicines in sport isavailable from: www.ukad.org.ukTel: (020) 7766 7350information@ukad.org.ukUnited Kingdom Medicines Information PharmacistsGroup (UKMIPG) websitewww.ukmi.nhs.ukTelephone numbers and email addresses of manufacturerslisted in BNF Publications are shown in theIndex of Manufacturers

BNFfor children2011–2012

Published byBMJ GroupTavistock Square, London WC1H 9JP, UKPharmaceutical PressPharmaceutical Press is the publishing division of theRoyal Pharmaceutical Society1 Lambeth High Street, London, SE1 7JN, UKRCPCH Publications Ltd5–11 Theobalds Road, London WC1X 8SH, UKCopyright # BMJ Group, the Royal PharmaceuticalSociety of Great Britain, and RCPCH Publications Ltd2011ISBN: 978 0 85369 959 0ISSN: 1747–5503Printed by CPI Clausen & Bosse, Leck, GermanyTypeset by XpageA catalogue record for this book is available from theBritish Library.All rights reserved. No part of this publication may bereproduced, stored in a retrieval system, or transmittedin any form or by any means, without the prior writtenpermission of the copyright holder.Material published in the BNF for Children may notbe used for any form of advertising, sales or publicitywithout prior written permission. Each of the classificationand the text are protected by copyright and/or database rightPaper copies may be obtained through any bookseller ordirect from:Distribution of BNFCsThe UK health departments distribute BNFCs to NHShospitals, doctors, and community pharmacies.In England, BNFCs are mailed individually to NHSdoctors, pharmacists, and non-medical prescriberswho have prescribing responsibility for children; forextra copies or changes relating to mailed BNFCs,contact the DH Publications Orderline:Tel: 0300 123 1002In Scotland email:nss.psd-bnf@nhs.netIn Wales, telephone the Business Services Centre:Tel: (01495) 332 000In Northern Ireland email:ni.bnf@hscni.netThe BNF for Children is for use by health professionalsengaged in prescribing, dispensing, andadministering medicines to children. It has beenprepared under the guidance of the PaediatricFormulary Committee.BNF for Children has been constructed using robustprocedures for gathering, assessing and assimilatinginformation on paediatric drug treatment. It is, however,expected that the reader will be relying onappropriate professional knowledge and expertiseto interpret the contents in the context of the circumstancesof the individual child. BNF for Childrenshould be used in conjunction with other appropriateand up-to-date literature and, where necessary, supplementedby expert advice. Information is alsoavailable from Medicines Information Services (seeinside front cover).Special care is required in managing childhoodconditions with unlicensed medicines or withlicensed medicines for unlicensed uses. Responsibilityfor the appropriate use of medicines lies solelywith the individual health professional.Pharmaceutical Pressc/o Macmillan Distribution (MDL)Brunel RoadHoundmillsBasingstokeRG21 6XSUKTel: +44 (0) 1256 302 692Fax: +44 (0) 1256 812 521Email: direct@macmillan.co.ukwww.pharmpress.comFor all bulk orders of more than 20 copies:Email: pharmpress@rpharms.comTel: +44 (0) 207 572 2266Pharmaceutical Press also supplies BNF for Children indigital formats suitable for standalone computers andintranets, and for use on mobile devices.

BNFC 2011–2012ContentsiiiPreface.................................................................................................................................. ivAcknowledgements................................................................................................................ vBNF Staff............................................................................................................................... viHow BNF for Children is constructed.................................................................................... ixHow to use BNF for Children................................................................................................. xiChanges for this edition .................................................................................................... xviiGeneral guidance...................................................................................................................1Prescription writing................................................................................................................4Supply of medicines ..............................................................................................................6Emergency supply of medicines ............................................................................................8Prescribing Controlled Drugs .................................................................................................9Adverse reactions to drugs................................................................................................. 12Prescribing in hepatic impairment...................................................................................... 14Prescribing in renal impairment ......................................................................................... 14Prescribing in pregnancy .................................................................................................... 16Prescribing in breast-feeding.............................................................................................. 16Prescribing in palliative care .............................................................................................. 17Prescribing in dental practice ............................................................................................. 22Drugs and sport.................................................................................................................. 23Emergency treatment of poisoning .................................................................................... 24Notes on drugs and Preparations1: Gastro-intestinal system........................................................................................ 352: Cardiovascular system ........................................................................................... 733: Respiratory system .............................................................................................. 1334: Central nervous system ....................................................................................... 1695: Infections ............................................................................................................. 2426: Endocrine system................................................................................................. 3487: Obstetrics, gynaecology, and urinary-tract disorders ......................................... 3938: Malignant disease and immunosuppression ....................................................... 4149: Nutrition and blood.............................................................................................. 44210: Musculoskeletal and joint diseases .................................................................... 49911: Eye ....................................................................................................................... 51712: Ear, nose, and oropharynx ................................................................................... 53413: Skin...................................................................................................................... 55014: Immunological products and vaccines................................................................. 59915: Anaesthesia ......................................................................................................... 628Appendices and indicesAppendix 1: Interactions.................................................................................................. 655Appendix 2: Borderline substances................................................................................. 743Appendix 3: Cautionary and advisory labels for dispensed medicines........................... 788Appendix 4: Intravenous infusions for neonatal intensive care ...................................... 791Dental Practitioners’ Formulary ........................................................................................ 794Nurse Prescribers’ Formulary............................................................................................ 796Non-medical prescribing ................................................................................................... 799Index of manufacturers..................................................................................................... 800Index................................................................................................................................. 811Medical emergencies in the community .................................................... Inside back cover

iv BNFC 2011–2012PrefaceBNF for Children aims to provide prescribers, pharmacistsand other healthcare professionals with sound upto-dateinformation on the use of medicines for treatingchildren.A joint publication of the British Medical Association,the Royal Pharmaceutical Society of Great Britain, theRoyal College of Paediatrics and Child Health, and theNeonatal and Paediatric Pharmacists Group, BNF forChildren (‘BNFC’) is published under the authority of aPaediatric Formulary Committee.Many areas of paediatric practice have suffered frominadequate information on effective medicines. BNFCaddresses this significant knowledge gap by providingpractical information on the use of medicines in childrenof all ages from birth to adolescence. Medicines forChildren (RCPCH Publications Ltd) and the BritishNational Formulary itself form the basis for BNFC.Information in BNFC has been validated against emergingevidence, best-practice guidelines, and crucially,advice from a network of clinical experts.Drawing information from manufacturers’ literaturewhere appropriate, BNFC also includes a great deal ofadvice that goes beyond marketing authorisations (productlicences). This is necessary because licensed indicationsfrequently do not cover the clinical needs ofchildren; in some cases, products for use in childrenneed to be specially manufactured or imported. Carefulconsideration has been given to establishing the clinicalneed for unlicensed interventions with respect to theevidence and experience of their safety and efficacy;local paediatric formularies, clinical literature andnational information resources have been invaluable inthis process.BNFC has been designed for rapid reference and theinformation presented has been carefully selected to aiddecisions on prescribing, dispensing and administrationof medicines. Less detail is given on areas such asmalignant disease and the very specialist use of medicinesgenerally undertaken in tertiary centres. BNFCshould be interpreted in the light of professional knowledgeand it should be supplemented as necessary byspecialised publications. Information is also availablefrom Medicines Information Services (see inside frontcover).It is vital to use the most recent edition of BNFC formaking clinical decisions. The more important changesfor this edition are listed on p. xvii.The website (bnfc.org) includes additional informationof relevance to healthcare professionals. Other digitalformats of BNFC—including intranet and versions formobile devices—are produced in parallel with theprinted version.BNFC aims to provide information suited to theneeds of the clinician and recognises that, althoughthis edition represents a considerable advance in thecontent and presentation of information on thepaediatric use of medicines, further changes will benecessary. Comments from healthcare professionalsare therefore very welcome and should be sent to:British National Formulary Publications, Royal PharmaceuticalSociety of Great Britain, 1 Lambeth HighStreet, London SE1 7JN.bnfc@bnf.orgThe contact email for manufacturers or pharmaceuticalcompanies wishing to contact BNF publicationsis manufacturerinfo@bnf.org

BNFC 2011–2012AcknowledgementsThe Paediatric Formulary Committee is grateful toindividuals and organisations that have provided adviceand information to the BNF for Children.The principal contributors for this edition were:I.H. Ahmed-Jushuf, M.N. Badminton, S. Bailey, T.G.Barrett, D.N. Bateman, G.D.L. Bates, H. Bedford, M.W.Beresford, R.M. Bingham, I.W. Booth, L. Brook, K.G.Brownlee, R.J. Buckley, M. Burch, I.F. Burgess, A. Cant,L.J. Carr, R. Carr, E.A. Chalmers, T.D. Cheetham, A.J.Cotgrove, J.B.S. Coulter, B.G. Craig, S.M. Creighton, J.H.Cross, A. Dhawan, P.N. Durrington, A. Durward, A.B.Edgar, J.A. Edge, D.A.C. Elliman, N.D. Embleton, P.J.Goadsby, P.W. Golightly, J. Gray, J.W. Gregory, P. Gringras,J.P. Harcourt, P.J. Helms, C. Hendriksz, R.F.Howard, R.G. Hull, H.R. Jenkins, S. Jones, B.A. Judd,C.J.H. Kelnar, P.T. Khaw, J.M.W. Kirk, P.J. Lee, T.H. Lee,S. Lewis-Jones, E.G.H. Lyall, A. MacDonald, D.J.Macrae, P.S. Malone, A.Y. Manzur, S.D. Marks, D.F.Marsh, A.G. Marson, K.A. Matyka, P.J. McKiernan,L.M. Melvin, E. Miller, R.E. Morton, C. Moss, P. Mulholland,C. Nelson-Piercy, J.M. Neuberger, K.K. Nischal,C.Y. Ng, L.P. Omerod, J.Y. Paton, G.A. Pearson, M.M.Ramsay, I.A.G. Roberts, J. Rogers, K.E. Rogstad, P.C.Rubin, J.W. Sander, N.J. Scolding, M.R. Sharland, N.J.Shaw, G.J. Shortland, O.F.W. Stumper, M.R.J. Sury, A.G.Sutcliffe, A. Sutherland, A.M. Szarewski, E.A. Taylor,A.H. Thomson, M.A. Thomson, J.A. Vale, J.O. Warner,D.A. Warrell, N.J.A. Webb, A.D. Weeks, R. Welbury, W.P.Whitehouse, C.E. Willoughby, C. Wren, A. Wright, M.M.Yaqoob, Z. Zaiwalla, and S.M. Zuberi.vThe BNF for Children has valuable access to the Martindaledata banks by courtesy of S. Sweetman and staff.J. E. Macintyre and staff provided valuable technicalassistance.C. Adetola, N. Bansal, J.J. Coleman, S. Foad, E.H.Glover, T. Hamp, A. Holmes, J. Humphreys, J.M.James, E. Laughton, H.M.N. Brady, R.M. Patel, J. Reynolds,and E.J. Tong provided considerable assistanceduring the production of this edition of BNF for Children.Xpage have provided assistance with typesetting developmentand related production processes.Members of the British Association of Dermatologists’Therapy & Guidelines Subcommittee, D.A. Buckley, L.C.Fuller, J. Hughes, S.E. Hulley, J. Lear, A.J. McDonagh, J.McLelland, N. Morar, I. Nasr, S. Punjabi, M.J. Tidman,S.E. Haveron (Secretariat), and M.F. Mohd Mustapa(Secretariat) have provided valuable advice.Members of the Advisory Committee on Malaria Prevention,R.H. Behrens, P.L. Chiodini, F. Genasi, L. Goodyer,A. Green, D. Hill, G. Kassianos, D.G. Lalloo, G.Pasvol, S. Patel, M. Powell, D.V. Shingadia, C.J.M.Whitty, M. Blaze (Secretariat), and V. Smith (Secretariat)have provided valuable advice.Members of the UK Ophthalmic Pharmacy Group havealso provided valuable advice.R. Suvarna and colleagues at the MHRA have providedvaluable assistance.Correspondents in the pharmaceutical industry haveprovided information on new products and commentedon products in the BNF for Children. NHS PrescriptionServices has supplied the prices of products in the BNFfor Children.Numerous doctors, pharmacists, nurses and others havesent comments and suggestions.

vi BNFC 2011–2012BNF StaffDigital Development EditorPhilip D. Lee BSc, PhDManaging Editor: Knowledge CreationJohn Martin BPharm, PhD, MRPharmSAssistant EditorsLeigh-Anne Claase BSc, PhDBryony Jordan BSc, DipPharmPract, MRPharmSColin R. Macfarlane BPharm, MSc, MRPharmSPaul S. Maycock MPharm, DipPharmPract,MRPharmSClaire L. Preston BPharm, PGDipMedMan,MRPharmSRachel S. M. Ryan BPharm, MRPharmSShama M. S. Wagle BPharm, DipPharmPract,MRPharmSStaff EditorsSejal Amin BPharm, MScAngela K. Bennett MPharm, DipPharmPractShena S. Chauhan BPharm, MRPharmSSusan E. Clarke BPharm, DipClinPharm, MRPharmSKristina Fowlie MPharm, PGCertPharmPract,MRPharmSBelén Granell Villen BSc, PGDipClinPharmManjula Halai BScChem, MPharmEmma E. Harris MPharm, DipPharmPract,MRPharmSAmy E. Harvey MPharm, PGDipCommPharmAmber F. Lauder BPharm, PGCertPharmAngela M. G. McFarlane BSc, DipClinPharm,MRPharmSSarah Mohamad MPharmElizabeth Nix DipPharm(NZ), MRPharmSSanjay Patel BPharmVinaya K. Sharma BPharm, MSc, PGDipPIM,MRPharmSKatie E. Walters MPharm, PGCertPharmPract,MRPharmSDigital Development AssistantsRobert C. Buckingham BScMichelle CartwrightJennifer L. Palmer FdScTerminologistSarah Peck BScHead of ProductionJohn WilsonSenior Production EditorLinda PaulusBNF Publishing DirectorDuncan S.T. Enright MA, PGCE, MInstP, FIDMManaging Director, Pharmaceutical PressRobert Bolick BA, MASenior Medical AdviserMartin J. Kendall OBE, MB, ChB, MD, FRCP, FFPMEditorial AssistantsRebecca S. Bastable BA, BTECCristina Lopez-Bueno BASenior BNF AdministratorHeidi Homar BAManaging Editor: Digital Development and DeliveryCornelia Schnelle MPhil

BNFC 2011–2012Paediatric FormularyCommittee2010–2011Dental AdvisoryGroup2010–2011viiChairWarren LenneyMD, FRCP, FRCPCH, DCHCommittee MembersJeffrey K. AronsonMA, MBChB, DPhil, FRCP, FBPharmacolS, FFPMNeil A. CaldwellBSc, MSc, MRPharmSIan CostelloBPharm, MSc, MRPharmSMartin G. Duerden BMedSci, MB BS, DRCOG,MRCGP, DipTher, DPHSimon KeadyBSc, MRPharmS, SPMartin J. KendallOBE, MB, ChB, MD, FRCP, FFPM (Chair, ContentStrategy Committee)James H. LarcombeMB, ChB, FRCGP, DipAdvGPE. David G. McIntoshMB BS, MPH, PhD, FAFPHM, FRACP, FRCPCH,FFPM, DRCOG, DCH, DipPharmMedNeena ModiMB, ChB, MD, FRCP, FRCPCHMatthew J. ThatcherMB BS, FRCS, DRCOG, DMRDDavid Tuthill MB, BCh, FRCPCHWilliam G. van’t HoffBSc, MB, MD, FRCPCH, FRCPEdward R. WozniakBSc, MB BS, FRCP, FRCPCH, DCHExecutive SecretaryHeidi HomarBAChairDavid WrayMD, BDS, MB ChB, FDSRCPS, FDSRCS Ed,F MedSciCommittee MembersChristine ArnoldBDS, DDPHRCS, MCDHBarry CockcroftBDS, FFDS (Eng)Duncan S.T. EnrightMA, PGCE, MInstP, FIDMAmy E. HarveyMPharm, PGDipCommPharmMartin J. KendallOBE, MB, ChB, MD, FRCP, FFPMLesley P. LongmanBSc, BDS, FDSRCS Ed, PhDSarah MantonBDS, FDSRCS Ed, FHEA, PhDJohn MartinBPharm, PhD, MRPharmSMichelle MoffatBDS, MFDS RCS Ed, M Paed Dent RPCS, FDS (PaedDent) RSC EdRachel S.M. RyanBPharm, MRPharmSSecretaryArianne J. MatlinMA, MSc, PhDExecutive SecretaryHeidi HomarBAAdvice on dental practiceThe British Dental Association has contributed tothe advice on medicines for dental practice throughits representatives on the Dental Advisory Group.

viii BNFC 2011–2012Nurse Prescribers’Advisory Group2010–2011ChairNicky A. Cullum (until November 2010)PhD, RGNMolly Courtenay (from December 2010)PhD, MSc, Cert Ed, BSc, RGNCommittee MembersFiona CulleyLLM, RN, BSc, Cert EdDuncan S.T. EnrightMA, PGCE, MInstP, FIDMPenny M. FranklinRN, RCN, RSCPHN(HV), MA, PGCEBelén Granell VillenBSc, PGDipClinPharmMargaret F. HelliwellMB, BS, BSc, MFPHMBryony JordanBSc, DipPharmPract, MRPharmSMartin J. KendallOBE, MB, ChB, MD, FRCP, FFPMFiona LynchBSc, MSc, RGN, RSCNJohn MartinBPharm, PhD, MRPharmSWendy J. NicholsonBSc, MA, Cert Ed, RGN, RSCNJill M. ShearerBSc, RGN, RMRabina TindaleRN, RSCN, BSc, DipAEN, PGCEVicky VidlerMA, RGN, RSCNJohn WrightExecutive SecretaryHeidi HomarBA

BNFC 2011–2012How BNF for Childrenis constructedBNF for Children (BNFC) is unique in bringing togetherauthoritative, independent guidance on best practicewith clinically validated drug information, enablinghealthcare professionals to select safe and effectivemedicines for individual children.Information in BNFC has been validated against emergingevidence, best-practice guidelines, and advice froma network of clinical experts. BNFC includes a great dealof advice that goes beyond marketing authorisations(product licences or summaries of product characteristics).This is necessary because licensed indicationsfrequently do not cover the clinical needs of children;in some cases, products for use in children need to bespecially manufactured or imported. Careful considerationhas been given to establishing the clinical need forunlicensed interventions with respect to the evidenceand experience of their safety and efficacy.Hundreds of changes are made between editions, andthe most clinically significant changes are listed at thefront of each edition.Paediatric Formulary CommitteeThe Paediatric Formulary Committee (PFC) is responsiblefor the content of BNFC. The PFC includes aneonatologist and paediatricians appointed by theRoyal College of Paediatrics and Child Health, paediatricpharmacists appointed by the Royal PharmaceuticalSociety of Great Britain and the Neonatal andPaediatric Pharmacists Group, doctors appointed bythe BMJ Publishing Group, a GP appointed by theRoyal College of General Practitioners, and representativesfrom the Medicines and Healthcare products RegulatoryAgency (MHRA) and the UK health departments.The PFC decides on matters of policy andreviews amendments to BNFC in the light of newevidence and expert advice. The Committee meetsevery 6 months and each member also receives proofsof all BNFC chapters for review before publication.Dental Advisory GroupThe Dental Advisory Group oversees the preparation ofadvice on the drug management of dental and oralconditions; the group includes representatives fromthe British Dental Association.Editorial teamBNFC staff editors are pharmacists with a sound understandingof how drugs are used in clinical practice,including paediatrics. Each staff editor is responsiblefor editing, maintaining, and updating specific chaptersof BNFC. During the publication cycle the staff editorsreview information in BNFC against a variety of sources(see below).Amendments to the text are drafted when the editorsare satisfied that any new information is reliable andrelevant. The draft amendments are passed to expertadvisers for comment and then presented to the PaediatricFormulary Committee for consideration. Additionally,for each edition, sections are chosen from everyixchapter for thorough review. These planned reviews aimto verify all the information in the selected sections andto draft any amendments to reflect current best practice.Staff editors prepare the text for publication and undertakea number of checks on the knowledge at variousstages of the production.Expert advisersBNFC uses about 80 expert clinical advisers (includingdoctors, pharmacists, nurses, and dentists) throughoutthe UK to help with the production of each edition. Therole of these expert advisers is to review existing textand to comment on amendments drafted by the staffeditors. These clinical experts help to ensure that BNFCremains reliable by:. commenting on the relevance of the text in thecontext of best clinical practice in the UK;. checking draft amendments for appropriate interpretationof any new evidence;. providing expert opinion in areas of controversy orwhen reliable evidence is lacking;. advising on areas where BNFC diverges from summariesof product characteristics;. advising on the use of unlicensed medicines or oflicensed medicines for unlicensed uses (‘off-label’use);. providing independent advice on drug interactions,prescribing in hepatic impairment, renal impairment,pregnancy, breast-feeding, neonatal care, palliativecare, and the emergency treatment of poisoning.In addition to consulting with regular advisers, BNFCcalls on other clinical specialists for specific developmentswhen particular expertise is required.BNFC also works closely with a number of expert bodiesthat produce clinical guidelines. Drafts or pre-publicationcopies of guidelines are routinely received forcomment and for assimilation into BNFC.Sources of BNFC informationBNFC uses a variety of sources for its information; themain ones are shown below.Summaries of product characteristics BNFCreceives summaries of product characteristics (SPCs)of all new products as well as revised SPCs for existingproducts. The SPCs are a key source of product informationand are carefully processed, despite the everincreasingvolume of information being issued by thepharmaceutical industry. Such processing involves:. verifying the approved names of all relevant ingredientsincluding ‘non-active’ ingredients (BNFC iscommitted to using approved names and descriptionsas laid down by the Medicines Act);. comparing the indications, cautions, contra-indications,and side-effects with similar existing drugs.Where these are different from the expected pattern,justification is sought for their inclusion orexclusion;. seeking independent data on the use of drugs inpregnancy and breast-feeding;

x BNFC 2011–2012. incorporating the information into BNFC usingestablished criteria for the presentation and inclusionof the data;. checking interpretation of the information by twostaff editors before submitting to a senior editor;changes relating to doses receive an extra check;. identifying potential clinical problems or omissionsand seeking further information from manufacturersor from expert advisers;. careful validation of any areas of divergence ofBNFC from the SPC before discussion by the Committee(in the light of supporting evidence);. constructing, with the help of expert advisers, acomment on the role of the drug in the context ofsimilar drugs.Much of this processing is applicable to the followingsources as well.Expert advisers The role of expert clinical advisers inproviding the appropriate clinical context for all BNFCinformation is discussed above.Literature Staff editors monitor core medical, paediatric,and pharmaceutical journals. Research papersand reviews relating to drug therapy are carefully processed.When a difference between the advice in BNFCand the paper is noted, the new information is assessedfor reliability and relevance to UK clinical practice. Ifnecessary, new text is drafted and discussed with expertadvisers and the Paediatric Formulary Committee.BNFC enjoys a close working relationship with a numberof national information providers.Systematic reviews BNFC has access to variousdatabases of systematic reviews (including theCochrane Library and various web-based resources).These are used for answering specific queries, forreviewing existing text and for constructing new text.Staff editors receive training in critical appraisal, literatureevaluation, and search strategies. Reviews publishedin Clinical Evidence are used to validate BNFCadvice.Consensus guidelines The advice in BNFC ischecked against consensus guidelines produced byexpert bodies. A number of bodies make drafts or prepublicationcopies of the guidelines available to BNFC; itis therefore possible to ensure that a consistent messageis disseminated. BNFC routinely processes guidelinesfrom the National Institute for Health and ClinicalExcellence (NICE), the Scottish Medicines Consortium(SMC), and the Scottish Intercollegiate Guidelines Network(SIGN).Reference sources Paediatric formularies and referencesources are used to provide background informationfor the review of existing text or for the constructionof new text. The BNFC team works closely with theeditorial team that produces Martindale: The CompleteDrug Reference. BNFC has access to Martindale informationresources and each team keeps the otherinformed of significant developments and shifts in thetrends of drug usage.Statutory information BNFC routinely processesrelevant information from various Government bodiesincluding Statutory Instruments and regulations affectingthe Prescription only Medicines Order. Official compendiasuch as the British Pharmacopoeia and itsaddenda are processed routinely to ensure that BNFCcomplies with the relevant sections of the MedicinesAct.BNFC maintains close links with the Home Office (inrelation to controlled drug regulations) and the Medicinesand Healthcare products Regulatory Agency(including the British Pharmacopoeia Commission).Safety warnings issued by the Commission on HumanMedicines (CHM) and guidelines on drug use issued bythe UK health departments are processed as a matter ofroutine.Relevant professional statements issued by the RoyalPharmaceutical Society of Great Britain are included inBNFC as are guidelines from bodies such as the RoyalCollege of Paediatrics and Child Health.BNFC reflects information from the Drug Tariff, theScottish Drug Tariff, and the Northern Ireland DrugTariff.Pricing information NHS Prescription Servicesprovide information on prices of medicinal productsand appliances in BNFC. BNFC also receives and processesprice lists from product suppliers.Comments from readers Readers of BNFC areinvited to send in comments. Numerous letters andemails are received during the preparation of eachedition. Such feedback helps to ensure that BNFCprovides practical and clinically relevant information.Many changes in the presentation and scope of BNFChave resulted from comments sent in by users.Comments from industry Close scrutiny of BNFC bythe manufacturers provides an additional check andallows them an opportunity to raise issues about BNFC’spresentation of the role of various drugs; this is yetanother check on the balance of BNFC advice. Allcomments are looked at with care and, where necessary,additional information and expert advice are sought.Virtual user groups BNFC has set up virtual usergroups across various healthcare professions (e.g. doctors,pharmacists, nurses). The aim of these groups willbe to provide feedback to the editors and publishers toensure that BNF publications continue to serve theneeds of its users.Market research Market research is conducted atregular intervals to gather feedback on specific areas ofdevelopment, such as drug interactions or changes tothe way information is presented in digital formats.BNFC is an independent professional publicationthat is kept up-to-date and addresses the day-todayprescribing information needs of healthcareprofessionals treating children. Use of this resourcethroughout the health service helps to ensure thatmedicines are used safely, effectively, and appropriatelyin children.

BNFC 2011–2012xiHow to use BNF for ChildrenBNF for Children (BNFC) provides information onthe use of medicines in children ranging from neonates(including preterm neonates) to adolescents.The terms infant, child, and adolescent are not usedconsistently in the literature; to avoid ambiguityactual ages are used in the dose statements inBNFC. The term neonate is used to describe a newborninfant aged 0–28 days. The terms child orchildren are used generically to describe the entirerange from infant to adolescent in BNFC.In order to achieve the safe, effective, and appropriateuse of medicines in children, healthcare professionalsmust be able to use BNFC effectively, and keep up todate with significant changes in each new edition ofBNFC that are relevant to their clinical practice. How toUse BNF for Children is aimed as a quick refresher forall healthcare professionals involved with prescribing,monitoring, supplying, and administering medicines forchildren, and as a learning aid for students training tojoin these professions. While How to Use BNF forChildren is linked to the main elements of rationalprescribing, the generic structure of this section meansthat it can be adapted for teaching and learning indifferent clinical settings.Finding information in BNFCBNFC includes a number of aids to help access relevantinformation:. Index (p. 811), where entries are included in alphabeticalorder of non-proprietary drug names, proprietarydrug names, clinical conditions, and prescribingtopics. A specific entry for ‘DentalPrescribing’ brings together topics of relevance todental surgeons. The page reference to the drugmonograph is shown in bold type. References todrugs in Appendices 1 and 3 are not included in themain Index;. Contents (p. iii), provides a hierarchy of how informationin BNFC is organised;. The beginning of each chapter includes a classifiedhierarchy of how information is organised in thatchapter;. Running heads, located next to the page number onthe top of each page, show the section of BNFC thatis being used;. Thumbnails, on the outer edge of each page, showthe chapter of BNFC that is being used;. Cross-references, lead to additional relevant informationin other parts of BNFC.Structure of BNFCThe Contents list (on p. iii) shows that information inBNFC is divided into:. How BNF for Children is Constructed (p. ix);. Changes for this Edition (p. xvii);. General Guidance (p. 1), which provides practicalinformation on many aspects of prescribing fromwriting a prescription to prescribing in palliativecare;. Emergency Treatment of Poisoning (p. 24), whichprovides an overview on the management of acutepoisoning;. Classified notes on clinical conditions, drugs, andpreparations, these notes are divided into 15 chapters,each of which is related to a particular systemof the body (e.g. chapter 3, Respiratory System) orto an aspect of paediatric care (e.g. chapter 5,Infections). Each chapter is further divided intoclassified sections. Each section usually beginswith prescribing notes followed by relevant drugmonographs and preparations (see fig. 1). Drugsare classified in a section according to their pharmacologyand therapeutic use;. Appendices and Indices, includes 4 Appendices(providing information on drug interactions, borderlinesubstances, cautionary and advisory labels fordispensed medicines, and intravenous infusions forneonatal intensive care), the Dental Practitioners’Formulary, the Nurse Prescribers’ Formulary, NonmedicalPrescribing, Index of Manufacturers, andthe main Index. The information in the Appendicesshould be used in conjunction with relevant informationin the chapters.Finding dental information in BNFCExtra signposts have been added to help access dentalinformation in BNFC:. Prescribing in Dental Practice (p. 22), includes acontents list dedicated to drugs and topics of relevanceto dentists, together with cross-references tothe prescribing notes in the appropriate sections ofBNFC. For example, a review of this list shows thatinformation on the local treatment of oral infectionsis located in chapter 12 (Ear, Nose, and Oropharynx)while information on the systemic treatmentof these infections is found in chapter 5 (Infections).Further guidance for dental practice can befound in the BNF.. Side-headings, in the prescribing notes, side-headingsfacilitate the identification of advice on oralconditions (e.g. Dental and Orofacial Pain, p. 199);. Dental prescribing on NHS, in the body of BNFC,preparations that can be prescribed using NHS formFP10D (GP14 in Scotland, WP10D in Wales) can beidentified by means of a note headed ‘Dental prescribingon NHS’ (e.g. Aciclovir Oral Suspension,p. 323).Identifying effective drug treatmentsThe prescribing notes in BNFC provide an overview ofthe drug management of common conditions and facilitaterapid appraisal of treatment options (e.g. epilepsy,p. 215). For ease of use, information on the managementof certain conditions has been tabulated (e.g. acuteasthma, p. 136).Advice issued by the National Institute for Health andClinical Excellence (NICE) is integrated within BNFC

xii BNFC 2011–2012prescribing notes if appropriate. Summaries of NICEtechnology appraisals, and relevant short guidelines,are included in pink panels. BNFC also includes adviceissued by the Scottish Medicines Consortium (SMC)when a medicine is restricted or not recommended foruse within NHS Scotland.In order to select safe and effective medicines forindividual children, information in the prescribingnotes must be used in conjunction with other prescribingdetails about the drugs and knowledge of thechild’s medical and drug history.Figure 1 Illustrates the typical layout of a drug monograph and preparationrecords in BNFCBNFC How to use BNFC xiiDRUG NAME UCautions details of precautions required and alsoany monitoring requiredCounselling Verbal explanation to the patient of specificdetails of the drug treatment (e.g. posture whentaking a medicine)Contra-indications circumstances when a drugshould be avoidedHepatic impairment advice on the use of a drugin hepatic impairmentRenal impairment advice on the use of a drug inrenal impairmentPregnancy advice on the use of a drug duringpregnancyBreast-feeding advice on the use of a drug duringbreast-feedingSide-effects very common (greater than 1 in 10)and common (1 in 100 to 1 in 10); less commonly(1 in 1000 to 1 in 100); rarely (1 in 10 000 to 1 in1000); very rarely (less than 1 in 10 000); alsoreported, frequency not knownLicensed use shows if drug unlicensed in theUK, or ‘off-label’ use of drug licensed in the UKIndication and doseDetails of uses and indications. By routeChild dose and frequency of administration(max. dose) for specific age group. By alternative routeChild dose and frequencyAdministration practical advice on the administrationof a drug1Approved Name (Non-proprietary) APharmaceutical form, sugar-free, active ingredientmg/mL, net price, pack size = basic NHSprice. Label: (as in Appendix 3)1. Exceptions to the prescribing status are indicated by anote or footnote.Proprietary Name (Manufacturer) ADPharmaceutical form, colour, coating, activeingredient and amount in dosage form, net price,pack size = basic NHS price. Label: (as inAppendix 3)Excipients include clinically important excipientsElectrolytes clinically significant quantities of electrolytesNote Specific notes about the product e.g. handlingPreparationsPreparations are included under a non-proprietarytitle, if they are marketed under such a title, if theyare not otherwise prescribable under the NHS, or ifthey may be prepared extemporaneously.In the case of compound preparations, the indications,cautions, contra-indications, side-effects, andinteractions of all constituents should be taken intoaccount for prescribing.When no suitable licensed preparation is available,details of preparations that may be imported orformulations available as manufactured specials orextemporaneous preparations are included.DrugsDrugs appear under pharmacopoeial or other nonproprietarytitles. When there is an appropriatecurrent monograph (Medicines Act 1968, Section65) preference is given to a name at the head of thatmonograph; otherwise a British Approved Name(BAN), if available, is used.The symbol U is used to denote those preparationsconsidered to be less suitable for prescribing.Although such preparations may not be consideredas drugs of first choice, their use may be justifiablein certain circumstances.Prescription-only medicines AThis symbol has been placed against preparationsthat are available only on a prescription from anappropriate practitioner. For more detailed informationsee Medicines, Ethics and Practice, London,Pharmaceutical Press (always consult latestedition).The symbols 23KL indicate that thepreparations are subject to the prescription requirementsof the Misuse of Drugs Act. For advice onprescribing such preparations see Prescribing ControlledDrugs, p. 9.Preparations not available for NHSprescription DThis symbol has been placed against preparationsthat are not prescribable under the NHS. Thoseprescribable only for specific disorders have afootnote specifying the condition(s) for which thepreparation remains available. Some preparationswhich are not prescribable by brand name underthe NHS may nevertheless be dispensed using thebrand name provided that the prescription showsan appropriate non-proprietary name.PricesPrices have been calculated from the basic costused in pricing NHS prescriptions, see also Pricesin BNFC, p. xvi for details.How to use BNFC

BNFC 2011–2012A brief description of the clinical uses of a drug canusually be found in the Indication and Dose section of itsmonograph (e.g. ibuprofen, p. 503); a cross-reference isprovided to any indications for that drug that are coveredin other sections of BNFC.The symbol U is used to denote preparations that areconsidered by the Joint Formulary Committee to be lesssuitable for prescribing. Although such preparationsmay not be considered as drugs of first choice, theiruse may be justifiable in certain circumstances.Drug management of medicalemergenciesGuidance on the drug management of medical emergenciescan be found in the relevant BNFC chapters (e.g.treatment of anaphylaxis is included in section 3.4.3). Asummary of drug doses used for Medical Emergenciesin the Community can be found in the glossy pages atthe back of BNFC. Algorithms for Newborn, PaediatricBasic, and Paediatric Advanced Life Support can also befound within these pages.Minimising harm in children with comorbiditiesThe drug chosen to treat a particular condition shouldhave minimal detrimental effects on the child’s otherdiseases and minimise the child’s susceptibility toadverse effects. To achieve this, the Cautions, Contraindications,and Side-effects of the relevant drug shouldbe reviewed, and can usually be found in the drugmonograph. However, if a class of drugs (e.g. tetracyclines,p. 274) share the same cautions, contra-indications,and side-effects, these are amalgamated in theprescribing notes while those unique to a particular drugin that class are included in its individual drug monograph.Occasionally, the cautions, contra-indications,and side-effects may be included within a preparationrecord if they are specific to that preparation or if thepreparation is not accompanied by a monograph.The information under Cautions can be used to assessthe risks of using a drug in a child who has co-morbiditiesthat are also included in the Cautions for thatdrug—if a safer alternative cannot be found, the drugmay be prescribed while monitoring the child foradverse-effects or deterioration in the co-morbidity.Contra-indications are far more restrictive than Cautionsand mean that the drug should be avoided in achild with a condition that is contra-indicated.The impact that potential side-effects may have on achild’s quality of life should also be assessed. Forinstance, in a child who has constipation, it may bepreferable to avoid a drug that frequently causes constipation.The prescribing notes in BNFC may highlightimportant safety concerns and differences betweendrugs in their ability to cause certain side-effects.xiiiPrescribing for children with hepatic orrenal impairmentDrug selection should aim to minimise the potential fordrug accumulation, adverse drug reactions, and exacerbationof pre-existing hepatic or renal disease. If it isnecessary to prescribe drugs whose effect is altered byhepatic or renal disease, appropriate drug dose adjustmentsshould be made, and the child should be monitoredadequately. The general principles for prescribingare outlined under Prescribing in Hepatic Impairment(p. 14) and Prescribing in Renal Impairment (p. 14).Information about drugs that should be avoided orused with caution in hepatic disease or renal impairmentcan be found in drug monographs under HepaticImpairment and Renal Impairment (e.g. fluconazole,p. 301). However, if a class of drugs (e.g. tetracyclines,p. 274) share the same recommendations for use inhepatic disease or renal impairment, this advice ispresented in the prescribing notes under HepaticImpairment and Renal Impairment and any advicethat is unique to a particular drug in that class isincluded in its individual drug monograph.Prescribing for patients who arepregnant or breast-feedingDrug selection should aim to minimise harm to thefetus, nursing infant, and mother. The infant should bemonitored for potential side-effects of drugs used by themother during pregnancy or breast-feeding. The generalprinciples for prescribing are outlined under Prescribingin Pregnancy (p. 16) and Prescribing in Breast-feeding(p. 16). The prescribing notes in BNFC chapters provideguidance on the drug treatment of common conditionsthat can occur during pregnancy and breast-feeding (e.g.asthma, p. 133). Information about the use of specificdrugs during pregnancy and breast-feeding can befound in their drug monographs under Pregnancy andBreast-feeding (e.g. fluconazole, p. 301). However, if aclass of drugs (e.g. tetracyclines, p. 274) share the samerecommendations for use during pregnancy or breastfeeding,this advice is amalgamated in the prescribingnotes under Pregnancy and Breast-feeding while anyadvice that is unique to a particular drug in that class isincluded in its individual drug monograph.Minimising drug interactionsDrug selection should aim to minimise drug interactions.If it is necessary to prescribe a potentially seriouscombination of drugs, children should be monitoredappropriately. The mechanisms underlying drug interactionsare explained in Appendix 1 (p. 655).Details of drug interactions can be found in Appendix 1of BNFC (p. 656). Drugs and their interactions are listedin alphabetical order of the non-proprietary drug name,and cross-references to drug classes are provided whereappropriate. Each drug or drug class is listed twice: inthe alphabetical list and also against the drug or classwith which it interacts. The symbol . is placed againstinteractions that are potentially serious and where combinedadministration of drugs should be avoided (oronly undertaken with caution and appropriate monitoring).Interactions that have no symbol do not usuallyhave serious consequences.If a drug or drug class has interactions, a cross referenceto where these can be found in Appendix 1 is providedunder the Cautions of the drug monograph or prescribingnotes.

Branded oral liquid preparations that do not containfructose, glucose, or sucrose are described as ‘sugarfree’in BNFC. Preparations containing hydrogenatedglucose syrup, mannitol, maltitol, sorbitol, or xylitol arealso marked ‘sugar-free’ since there is evidence that theydo not cause dental caries. Children receiving medicinescontaining cariogenic sugars, or their carers, should beadvised of appropriate dental hygiene measures to prexivBNFC 2011–2012Selecting the doseThe drug dose is usually located in pink panels withinthe Indication and Dose section of the drug monographor within the Dose section of the preparation record.Doses are linked to specific indications and routes ofadministration. The dose of a drug may vary accordingto different indications, routes of administration, age,body-weight, and body-surface area. When the dose of adrug varies according to different indications, eachindication and its accompanying dose is included in aseparate pink panel (e.g. aciclovir, p. 322). The dose islocated within the preparation record when the dosevaries according to different formulations of that drug(e.g. amphotericin, p. 305) or when a preparation has adose different to that in its monograph. Occasionally,drug doses may be included in the prescribing notes forpractical reasons (e.g. doses of drugs in Helicobacterpylori eradication regimens, p. 42). The right doseshould be selected for the right age and body-weight(or body surface area) of the child, as well as for the rightindication, route of administration, and preparation.Doses in BNFC are usually assigned to specific ageranges; neonatal doses are preceded by the wordNeonate, all other doses are preceded by the wordChild. Age ranges in BNFC are described as shownin the following example:Child 1 month–4 years refers to a child from 1month old up to their 4 th birthday;Child 4–10 years refers to a child from the day oftheir 4 th birthday up to their 10 th birthday.However, a pragmatic approach should be applied tothese cut-off points depending on the child’s physiologicaldevelopment, condition, and if weight isappropriate for the child’s age.For some drugs (e.g. gentamicin, p. 278) the neonataldose varies according to the postmenstrual age of theneonate. Postmenstrual age is the neonate’s total ageexpressed in weeks from the start of the mother’s lastmenstrual period. For example, a 3 week old baby bornat 27 weeks gestation is treated as having a postmenstrualage of 30 weeks. A term baby has a postmenstrualage of 37–42 weeks when born. For most other drugs,the dose can be based on the child’s actual date of birthirrespective of postmenstrual age. However, the degreeof prematurity, the maturity of renal and hepatic function,and the clinical properties of the drug need to beconsidered on an individual basis.Many children’s doses in BNFC are standardised bybody-weight. To calculate the dose for a given childthe weight-standardised dose is multiplied by the child’sweight (or occasionally by the child’s ideal weight forheight). The calculated dose should not normallyexceed the maximum recommended dose for an adult.For example, if the dose is 8 mg/kg (max. 300 mg), achild of 10 kg body-weight should receive 80 mg, but achild of 40 kg body-weight should receive 300 mg(rather than 320 mg). Calculation by body-weight inthe overweight child may result in much higher dosesbeing administered than necessary; in such cases, thedose should be calculated from an ideal weight forheight.Occasionally, some doses in BNFC are standardised bybody surface area because many physiological phenomenacorrelate better with body surface area. Inthese cases, to calculate the dose for a given child, thebody surface area-standardised dose is multiplied by thechild’s body surface area. The child’s body surface areacan be estimated from his or her weight using the tablesfor Body Surface Area in Children located in the glossypages at the back of the print version of BNFC.The doses of some drugs may need to be adjusted iftheir effects are altered by concomitant use with otherdrugs, or in patients with hepatic or renal impairment(see Minimising Drug Interactions, and Prescribing forChildren with Hepatic or Renal Impairment).Wherever possible, doses are expressed in terms of adefinite frequency (e.g. if the dose is 1 mg/kg twicedaily, a child of body-weight 9 kg would receive 9 mgtwice daily). Occasionally, it is necessary to includedoses in the total daily dose format (e.g. 10 mg/kgdaily in 3 divided doses); in these cases the total dailydose should be divided into individual doses (in thisexample a child of body-weight 9 kg would receive30 mg 3 times daily).Most drugs can be administered at slightly irregularintervals during the day. Some drugs, e.g. antimicrobials,are best given at regular intervals. Some flexibilityshould be allowed in children to avoid waking themduring the night. For example, the night-time dose maybe given at the child’s bedtime.Special care should be taken when converting dosesfrom one metric unit to another, and when calculatinginfusion rates or the volume of a preparation to administer.Conversions for imperial to metric measures canbe found in the glossy pages at the back of BNFC.Where possible, doses should be rounded to facilitateadministration of suitable volumes of liquid preparations,or an appropriate strength of tablet or capsule.Selecting a suitable preparationChildren should be prescribed a preparation that complementstheir daily routine, and that provides the rightdose of drug for the right indication and route ofadministration.In BNFC, preparations usually follow immediately afterthe monograph for the drug which is their main ingredient.The preparation record (see fig. 1) provides informationon the type of formulation (e.g. tablet), theamount of active drug in a solid dosage form, and theconcentration of active drug in a liquid dosage form.The legal status is shown for prescription only medicinesand controlled drugs; any exception to the legalstatus is shown by a Note immediately after the preparationrecord or a footnote. If a proprietary preparationhas a distinct colour, coating, scoring, or flavour,this is shown in the preparation record. If a proprietarypreparation includes excipients usually specified inBNFC (see p. 2), these are shown in the Excipientsstatement, and if it contains clinically significant quantitiesof electrolytes, these are usually shown in theElectrolytes statement.

BNFC 2011–2012vent caries. Sugar-free preparations should be usedwhenever possible.Where a drug has several preparations, those of asimilar type may be grouped together under a heading(e.g. ‘Modified-release’ for theophylline preparations,p. 143). Where there is good evidence to show thatthe preparations for a particular drug are not interchangeable,this is stated in a Note either in the Dosesection of the monograph or by the group of preparationsaffected. When the dose of a drug varies accordingto different formulations of that drug, the right doseshould be prescribed for the preparation selected.In the case of compound preparations, the prescribinginformation of all constituents should be taken intoaccount for prescribing.Unlicensed preparations that are available from ‘Specialorder’ manufacturers and specialist importing companiesare included (e.g. midazolam buccal liquid, p. 639).The availability of an extemporaneous formulation of adrug is shown after its other preparations (e.g. captopril,p. 102).Writing prescriptionsGuidance is provided on writing prescriptions that willhelp to reduce medication errors, see p. 4. Prescriptionrequirements for controlled drugs are also specified onp. 9.Administering drugsBasic information on the route of administration isprovided in the Indication and Dose section of a drugmonograph or the Dose section of a preparation record.Further details, such as masking the bitter taste of somemedicines, may be provided in the Administration sectionof a drug monograph (e.g. proguanil, p. 336). Practicalinformation is also provided on the preparation ofintravenous drug infusions, including compatibility ofdrugs with standard intravenous infusion fluids, methodof dilution or reconstitution, and administration rates(e.g. co-amoxiclav, p. 263). The Administration sectionis located within preparation records when this informationvaries according to different preparations of thatdrug (e.g. amphotericin, p. 305). If a class of drugs (e.g.topical corticosteroids, p. 559) share the same administrationadvice, this may be presented in the prescribingnotes.Information on intravenous infusions for neonatal intensivecare can also be found in Appendix 4, p. 791.Advising children (and carers)The prescriber, the child’s carer, and the child (if appropriate)should agree on the health outcomes desired andon the strategy for achieving them (see Taking Medicinesto Best Effect, p. 1). Taking the time to explain tothe child (and carers) the rationale and the potentialadverse effects of treatment may improve adherence.For some medicines there is a special need for counselling(e.g. recognising signs of blood, liver, or skin disorderswith carbamazepine); this is shown in Counsellingstatements, usually in the Cautions or Indicationand Dose section of a monograph, or within a preparationrecord if it is specific to that preparation.xvChildren and their carers should be advised if treatmentis likely to affect their ability to perform skilled tasks(e.g. driving).Cautionary and advisory labels that pharmacists arerecommended to add when dispensing are included inthe preparation record (see fig. 1). Details of these labelscan be found in Appendix 3 (p. 788).Monitoring drug treatmentChildren should be monitored to ensure they are achievingthe expected benefits from drug treatment withoutany unwanted side-effects. The prescribing notes or theCautions in the drug monograph specify any specialmonitoring requirements. Further information on monitoringthe plasma concentration of drugs with a narrowtherapeutic index can be found in the Pharmacokineticssection or as a Note under the Dose section of the drugmonograph.Identifying and reporting adverse drugreactionsClinically relevant Side-effects for most drugs areincluded in the monographs. However, if a class ofdrugs (e.g. tetracyclines, p. 274) share the same sideeffects,these are presented in the prescribing noteswhile those unique to a particular drug in that classare included in its individual drug monograph. Occasionally,side-effects may be included within a preparationrecord if they are specific to that preparation or ifthe preparation is not accompanied by a monograph.Side-effects are generally listed in order of frequencyand arranged broadly by body systems. Occasionally arare side-effect might be listed first if it is considered tobe particularly important because of its seriousness. Thefrequency of side-effects is described in fig. 1.An exhaustive list of side-effects is not included fordrugs that are used by specialists (e.g. cytotoxic drugsand drugs used in anaesthesia). Recognising that hypersensitivityreactions can occur with virtually all medicines,this effect is generally not listed, unless the drugcarries an increased risk of such reactions. BNFC alsoomits effects that are likely to have little clinical consequence(e.g. transient increase in liver enzymes).The prescribing notes in BNFC may highlight importantsafety concerns and differences between drugs in theirability to cause certain side-effects. Safety warningsissued by the Commission on Human Medicines(CHM) or Medicines and Healthcare products RegulatoryAgency (MHRA) can also be found here or in thedrug monographs.Adverse Reactions to Drugs (p. 12) provides advice onpreventing adverse drug reactions, and guidance onreporting adverse drug reactions to the MHRA. Theblack triangle symbol T identifies those preparations inBNFC that are monitored intensively by the MHRA.

xvi BNFC 2011–2012Finding significant changes in a neweditionBNFC is published in July each year and includes lists ofchanges in a new edition that are relevant to clinicalpractice:. The print version includes an Insert that summarisesthe background to several key changes. Acopy of the Insert can also be found at bnfc.org inthe section on Updates under ‘What’s new inBNFC?’;. Changes for this edition (p. xvii), provides a list ofsignificant changes, dose changes, classificationchanges, new names, and new preparations thathave been incorporated into a new edition, as wellas a list of preparations that have been discontinuedsince the last edition. For ease of identification, themargins of these pages are marked in pink;. E-newsletter, the BNF & BNFC e-newsletter serviceis available free of charge. It alerts healthcare professionalsto details of significant changes in theclinical content of these publications and to the waythat this information is delivered. Newsletters alsoreview clinical case studies and provide tips onusing these publications effectively. To sign up fore-newsletters go to bnf.org/newsletter. To visitthe e-newsletter archive, go to bnfc.org/bnfc/bnfcextra/current/450066.htm.So many changes are made to each new edition ofBNFC, that not all of them can be accommodated inthe Insert and the Changes section. We encouragehealthcare professionals to review regularly the prescribinginformation on drugs that they encounter frequently.NutritionAppendix 2 (p. 743) includes tables of ACBS-approvedenteral feeds and nutritional supplements based on theirenergy and protein content. There are separate tablesfor specialised formulae for specific clinical conditions.Classified sections on foods for special diets and nutritionalsupplements for metabolic diseases are alsoincluded.Licensed status of medicinesBNFC includes advice on the use of unlicensed medicinesor of licensed medicines for unlicensed applications(‘off-label’ use). Such advice reflects careful considerationof the options available to manage a givencondition and the weight of evidence and experience ofthe unlicensed intervention. Limitations of the marketingauthorisation should not preclude unlicensed usewhere clinically appropriate.The Licensed Use statement in a drug monograph isused to indicate that:. a drug is not licensed in the UK (e.g. pyrazinamide,p. 293);. a drug is licensed in the UK, but not for use inchildren (e.g. lansoprazole, p. 45);. BNFC advice for certain indications, age groups ofchildren, routes of administration, or preparationsfalls outside a drug’s marketing authorisation (e.g.naproxen, p. 505).The absence of the Licensed Use statement from a drugmonograph indicates that the drug is licensed for allindications given in the monograph (e.g. zanamivir,p. 327).Prescribing unlicensed medicines or medicines outsidetheir marketing authorisation alters (and probablyincreases) the prescriber’s professional responsibilityand potential liability. The prescriber should be able tojustify and feel competent in using such medicines.Further information can be found in BNF for Childrenand Marketing Authorisation, p. 2.Prices in BNFCBasic net prices are given in BNFC to provide anindication of relative cost. Where there is a choice ofsuitable preparations for a particular disease or conditionthe relative cost may be used in making a selection.Cost-effective prescribing must, however, take intoaccount other factors (such as dose frequency andduration of treatment) that affect the total cost. Theuse of more expensive drugs is justified if it will result inbetter treatment of the patient, or a reduction of thelength of an illness, or the time spent in hospital. Priceshave generally been calculated from the net cost used inpricing NHS prescriptions in October 2010. Prices generallyreflect whole dispensing packs; prices for injectionsare stated per ampoule, vial, or syringe. The pricefor an extemporaneously prepared preparation has beenomitted where the net cost of the ingredients used tomake it would give a misleadingly low impression of thefinal price.BNFC prices are not suitable for quoting to patientsseeking private prescriptions or contemplating over-thecounterpurchases because they do not take intoaccount VAT, professional fees, and other overheads.A fuller explanation of costs to the NHS may beobtained from the Drug Tariff. Separate drug tariffsare applicable to England and Wales, Scotland, andNorthern Ireland; prices in the different tariffs may vary.Extra resources on the BNFC websiteWhile the BNFC website (bnfc.org) hosts the digitalcontent of BNFC proper, it also provides additionalresources such as Frequently Asked Questions andonline calculators.

BNFC 2011–2012Changes for thiseditionSignificant changesThe BNF for Children is revised yearly and numerouschanges are made between issues. All copies of BNF forChildren 2010–2011 should therefore be withdrawn andreplaced by BNF for Children 2011–2012. Significantchanges have been made in the following sections forBNF for Children 2011–2012:How to use BNFC, p. xiNew symbols introduced throughout BNF for Childrento identify Controlled Drug preparations in Schedules 2,3, and 4, Prescribing Controlled DrugsIbuprofen poisoning, Emergency treatment of poisoningParacetamol poisoning [calculating the potentially toxicdose ingested by obese children], Emergency treatmentof poisoningInfliximab for Crohn’s Disease [NICE guidance], section1.5Formoterol [MHRA/CHM advice], section 3.1.1.1Omalizumab [NICE guidance], section 3.4.2Fentanyl [counselling for the use of patches], section4.7.2Epilepsy in pregnancy, section 4.8.1Neonatal seizures, section 4.8.1Febrile convulsions, section 4.8.3Nicotine dependence, section 4.10.2Summary of antibacterial therapy [advice reformatted],section 5.1, Table 1Cystic Fibrosis, section 5.1, Table 1Meningitis, section 5.1, Table 1Erysipelas and cellulitis, section 5.1, Table 1Prevention of pertussis, section 5.1, Table 2Prevention of pneumococcal infection in asplenia or inpatients with sickle-cell disease, section 5.1, Table 2Prevention of infection in open fractures, section 5.1,Table 2Urinary-tract infections [culture and sensitivity testing],section 5.1.13Treatment of fungal infections: aspergillosis, section 5.2HIV infection [initiation of treatment], section 5.3.1Antiretroviral drugs [doses included in their monographs],section 5.3.1Palivizumab [respiratory syncytial virus], section 5.3.5Prophylaxis against malaria [recommendations for Moroccoand Turkmenistan removed], section 5.4.1Dexamethasone [parenteral doses expressed as dexamethasonebase], section 6.3.2Somatropin for the treatment of growth failure in children[NICE guidance], section 6.5.1Recurrent vulvovaginal candidiasis [updated treatmentregimens], section 7.2.2Combined hormonal contraceptive interactions, section7.3.1xviiCombined oral contraceptives [preparations tabulated],section 7.3.1Progestogen-only contraceptive interactions, section7.3.2.1 and section 7.3.2.2Nocturnal enuresis, section 7.4.2Rapamune c tablets [0.5 mg tablet not bioequivalent toother strengths], section 8.2.2G6PD deficiency [rasburicase and risk of haemolysis],section 9.1.5Calcium gluconate injection [MHRA advice], section9.5.1.1Drugs unsafe for use in acute porphyrias, section 9.8.2Aqueous cream [skin reactions when used as a leave-onemollient], section 13.2.1Nappy rash, section 13.2.2Sunscreens [International Nomenclature for CosmeticIngredients, table added], section 13.8.1Immunisation Schedule, section 14.1Haemophilus type B conjugate vaccine and meningococcalvaccines [in asplenia, splenic dysfunction, orcomplement deficiency], section 14.4Influenza vaccines, section 14.4Meningococcal vaccines, section 14.4Pertussis vaccine [management of contacts], section14.4Sedative and analgesic peri-operative drugs, section15.1.4Local anaesthesia [section updated and reorganised],section 15.2Dose changesChanges in dose statements introduced into BNF forChildren 2011–2012:Aciclovir [herpes simplex suppression], p. 322Actiq c , p. 206ACWY Vax c , p. 615AmBisome c , p. 306Amitriptyline [neuropathic pain], p. 185Ampicillin, p. 262Atorvastatin, p. 126Atropine [premedication by intravenous injection inneonates and intra-operative bradycardia in neonates],p. 635Azathioprine [severe ulcerative colitis and Crohn’s disease],p. 54Bendroflumethiazide, p. 77Cervarix c [alternative schedule], p. 611Cetirizine [dose and dose in renal impairment], p. 154Ciprofloxacin, p. 254Co-amoxiclav [intravenous dose], p. 263Colistimethate sodium (Colistin), p. 288Dexamethasone, p. 374Dexamfetamine, p. 189Diazepam [intravenous dose for status epilepticus],p. 232

xviii BNFC 2011–2012Epilim Chronosphere c , p. 228Fersamal c , p. 444Flucloxacillin [staphylococcal lung infection in cysticfibrosis], p. 259Fludrocortisone acetate [mineralocorticoid replacementin adrenocortical insufficiency in neonates], p. 369Flumazenil [intravenous injection dose for reversal ofsedative effects of benzodiazepines], p. 647Foradil c [dose for children under 12 years], p. 138Fresh frozen plasma, p. 125Fungizone c [neonatal dose], p. 306Glycopyrronium [premedication at induction in children12–18 years and control of muscarinic side-effects ofneostigmine in children 12–18 years], p. 636Hydralazine [intravenous infusion in neonates], p. 93Hydrocortisone [congenital adrenal hyperplasia andadrenal hypoplasia, Addison’s disease, chronic maintenanceor replacement therapy], p. 375Hydrocortisone [paediatric severe or life-threateningacute asthma], p. 134 and p. 136Indometacin [symptomatic ductus arteriosus], p. 130Ipratropium [dose frequency for severe or life-threateningacute asthma in children 12–18 years], p. 134 andp. 136Itraconazole [tinea capitis], p. 303Isoniazid, p. 255Lansoprazole [dose in hepatic impairment], p. 45Levetiracetam [no dose adjustment when switchingbetween intravenous and oral therapy], p. 222Macrogol Oral Powder, Compound [faecal impaction],p. 62Menveo c , p. 615Mercaptamine, p. 492Meropenem, p. 273Metronidazole, p. 296Midazolam [neonatal dose for sedation in intensivecare], p. 638Modigraf c , p. 437Morphine [intravenous injection and oral dose in children12–18 years], p. 207Movicol c [faecal impaction], p. 62Movicol c -Half [faecal impaction], p. 62Naloxone [intravenous infusion dose for overdosagewith opioids], p. 29Nifedipine [hypertensive crisis, acute angina in Kawasakidisease or progeria], p. 107Nitrous oxide [maintenance of anaesthesia], p. 635Paracetamol [severe postoperative pain by mouth andby rectum], p. 200Phenytoin sodium, p. 235Prednisolone [corticosteroid replacement therapy],p. 376Prograf c , p. 437Propranolol [migraine prophylaxis], p. 88Retapamulin, p. 586Salofalk c tablets, granules, and rectal foam, p. 51Selenium sulphide [pityriasis versicolor], p. 584Sodium valproate, p. 227Sumatriptan [cluster headache], p. 213Symbicort c 100/6 [dose for children 6–12 years], p. 149Temazepam, p. 639Tiagabine [adjunctive treatment for focal seizures anddose in hepatic impairment], p. 226Topiramate [focal seizures and Lennox-Gastautsyndrome, migraine prophylaxis, and dose in renalimpairment], p. 226Tranexamic acid [prevention of excessive bleeding afterdental procedures by intravenous injection and menorrhagia],p. 123Trimethoprim, p. 255Valaciclovir, p. 323Xylometazoline nasal spray, p. 542Zydol SR c , p. 211Classification changesClassification changes have been made in the followingsections of BNF for Children 2011–2012:Section 2.1.2 Phosphodiesterase type-3 inhibitors [titlechange]Section 4.7.1 Non-opioid analgesics and compoundanalgesic preparations [title change]Section 4.10.2 Nicotine dependence [new section]Section 5.2.1 Triazole antifungals [new sub-section]Section 5.2.2 Imidazole antifungals [new sub-section]Section 5.2.3 Polyene antifungals [new sub-section]Section 5.2.4 Echinocandin antifungals [new sub-section]Section 5.2.5 Other antifungals [new sub-section]Section 6.1.2 Antidiabetic drugs [title change]Section 10.3 Drugs for the relief of soft-tissue inflammationand topical pain relief [title change]Section 10.3.2 Rubefacients, topical NSAIDs, capsaicin,and poultices [title change]Section 13.2.1.1 Emollient bath additives and showerpreparations [title change]Section 15.1.4.1 Anxiolytics [title change]New NamesColistimethate sodium [formerly Colistin], p. 288Dulcolax c Pico Liquid and Pico Perles [formerlyDulcolax c Liquid and Perles], p. 61Hydrocortisone mucoadhesive buccal tablets [formerlyCorlan c ], p. 544Laxido c Orange [formerly Laxido c ], p. 62Oilatum c Junior bath additive [formerly Oilatum cJunior emollient bath additive], p. 555

BNFC 2011–2012Deleted preparationsPreparations listed below have been discontinued duringthe compilation of BNF for Children 2011–2012, orare still available but are not considered suitable forinclusion by the Paediatric Formulary Committee (seefootnote):Andropatch cAtropine eye ointmentAtrovent Aerocaps cBaxan cBeclometasone Cyclocaps cBetnesol-N c eye ointmentBudesonide Cyclocaps cChlorohex cCitanest c 4%Crixivan c1Dexedrine cDimercaprol 1Ditropan c elixirDopram c1Dovonex c scalp solutionDoxapram 1Exelderm cFlixotide c DiskhalerHewletts cIndinavir 1Ledermycin cLinola c GammaLoceryl c creamMetrotop cMixtard c 30Neosporin cNorvir c capsulesOctagam cPharmorubicin c rapid dissolution injectionPolytar AF cPosalfilin cProtirelinPulmicort c aerosol inhalationSalbutamol Cyclocaps cSalinum cSelect-A-Jet c DopamineSpectraBan cSulconazoleTriclofosZantac c effervescent tabletsZeffix c oral solution1. Not considered suitable for inclusion by the PaediatricFormulary CommitteeNew preparations included in thiseditionPreparations included in the relevant sections of BNFfor Children 2011–2012:Adoport c [tacrolimus], p. 436Anthelios c , p. 582Aquamol c , p. 552Calcichew-D 3c500 mg/400 unit caplets [calcium carbonatewith colecalciferol], p. 484Capimune c [ciclosporin], p. 435Carmize c [carmellose sodium], p. 530Catacrom c [sodium cromoglicate], p. 523Crestor c [rosuvastatin], p. 127Cyanokit c [hydroxocobalamin], p. 32Dermatonics Heel Balm c , p. 553Diovan c [valsartan], p. 104Dovobet c [betamethasone with calcipotriol], p. 568Dovonex c ointment [calcipotriol], p. 568Eczmol c , p. 554Epiduo c [adapalene with benzoyl peroxide], p. 577FlebogammaDIF c [normal immunoglobulin], p. 624Fulsovin c [griseofulvin], p. 309Gammanorm c [normal immunoglobulin], p. 623Gammaplex c [normal immunoglobulin], p. 624Gynoxin c intravaginal cream [fenticonazole], p. 395Humulin I KwikPen c [isophane insulin], p. 355Humulin M3 KwikPen c [biphasic isophane insulin],p. 356Hyabak c [sodium hyaluronate], p. 531Hydromol HC Intensive c , p. 560Hylo-Care c [sodium hyaluronate], p. 531Insuman c Comb 25 Solostar [biphasic isophane insulin],p. 356Jext c [adrenaline], p. 161Kalcipos-D c [calcium carbonate with colecalciferol],p. 484Lescol c XL [fluvastatin], p. 127Lopresor SR c [metoprolol], p. 91Lumecare c Long Lasting Tear Gel [carbomers], p. 530Lumecare c Preservative Free Tear Drops [hypromellose],p. 531Lumecare c Sodium Hyaluronate [sodium hyaluronate],p. 531Marol c [tramadol], p. 211Miphtel c [acetylcholine chloride], p. 532Moxivig c [moxifloxacin], p. 520Nebusal c [hypertonic sodium chloride], p. 166Neokay c [phytomenadione], p. 487Nexplanon c [etonogestrel], p. 405Nicorette Quickmist c [nicotine], p. 240Nivestim c [filgrastim], p. 456Norvir c tablets [ritonavir], p. 318xix

xx BNFC 2011–2012Tears Naturale c Single Dose [hypromellose], p. 531Tevagrastim c [filgrastim], p. 456Tobravisc c [tobramycin], p. 520Vismed c Gel [sodium hyaluronate], p. 531Vivadex c [tacrolimus], p. 438VPRIV c [velaglucerase alfa], p. 491Wellvone c [atovaquone], p. 343Xenical c [orlistat], p. 191Zerocream c , p. 553Zeroguent c , p. 553Zerolatum c , p. 555Zerolatum c Plus, p. 556Zeroneum c , p. 555Zerozole c , p. 556

BNFC 2011–2012 1General guidanceMedicines should be given to children only when theyare necessary, and in all cases the potential benefit ofadministering the medicine should be considered inrelation to the risk involved. This is particularly importantduring pregnancy, when the risk to both mother andfetus must be considered (for further details see Prescribingin Pregnancy, p. 16).It is important to discuss treatment options carefullywith the child and the child’s carer (see also TakingMedicines to Best Effect, below). In particular, the childand the child’s carer should be helped to distinguish theadverse effects of prescribed drugs from the effects ofthe medical disorder. When the beneficial effects of themedicine are likely to be delayed, this should be highlighted.Taking medicines to best effect Difficulties inadherence to drug treatment occur regardless of age.Factors that contribute to poor compliance with prescribedmedicines include:. difficulty in taking the medicine (e.g. inability toswallow the medicine);. unattractive formulation (e.g. unpleasant taste);. prescription not collected or not dispensed;. purpose of medicine not clear;. perceived lack of efficacy;. real or perceived adverse effects;. carers’ or child’s perception of the risk and severityof side-effects may differ from that of the prescriber;. instructions for administration not clear.The prescriber, the child’s carer, and the child (if appropriate)should agree on the health outcomes desired andon the strategy for achieving them (‘concordance’). Theprescriber should be sensitive to religious, cultural, andpersonal beliefs of the child’s family that can affectacceptance of medicines.Taking the time to explain to the child (and carers) therationale and the potential adverse effects of treatmentmay improve adherence. Reinforcement and elaborationof the physician’s instructions by the pharmacistand other members of the healthcare team can beimportant. Giving advice on the management of adverseeffects and the possibility of alternative treatments mayencourage carers and children to seek advice ratherthan merely abandon unacceptable treatment.Simplifying the drug regimen may help; the need forfrequent administration may reduce adherence,although there appears to be little difference in adherencebetween once-daily and twice-daily administration.Combination products reduce the number ofdrugs taken but at the expense of the ability to titrateindividual doses.Drug treatment in children Children, and particularlyneonates, differ from adults in their response todrugs. Special care is needed in the neonatal period (first28 days of life) and doses should always be calculatedwith care; the risk of toxicity is increased by a reducedrate of drug clearance and differing target organ sensitivity.For guidance on selecting doses of drugs in children seeHow to Use BNF for Children, p. xiv.Administration of medicines to children Childrenshould be involved in decisions about taking medicinesand encouraged to take responsibility for using themcorrectly. The degree of such involvement will dependon the child’s age, understanding, and personal circumstances.Occasionally a medicine or its taste has to be disguisedor masked with small quantities of food. However,unless specifically permitted (e.g. some formulationsof pancreatin), a medicine should not be mixed withlarge quantities of food because the full dose might notbe taken and the child might develop an aversion tofood if the medicine imparts an unpleasant taste. Medicinesshould not be mixed or administered in a baby’sfeeding bottle.Children under 5 years (and some older children) find aliquid formulation more acceptable than tablets or capsules.However, for long-term treatment it may bepossible for a child to be taught to take tablets orcapsules.An oral syringe (see below) should be used for accuratemeasurement and controlled administration of an oralliquid medicine. The unpleasant taste of an oral liquidcan be disguised by flavouring it or by giving a favouritefood or drink immediately afterwards, but the potentialfor food-drug interactions should be considered.Advice should be given on dental hygiene to thosereceiving medicines containing cariogenic sugars forlong-term treatment; sugar-free medicines should beprovided whenever possible.Children with nasal feeding tubes in place for prolongedperiods should be encouraged to take medicines bymouth if possible; enteric feeding should generally beinterrupted before the medicine is given (particularly ifenteral feeds reduce the absorption of a particular drug).Oral liquids can be given through the tube provided thatprecautions are taken to guard against blockage; thedose should be washed down with warm water. When amedicine is given through a nasogastric tube to aneonate, sterile water must be used to accompanythe medicine or to wash it down.The intravenous route is generally chosen when amedicine cannot be given by mouth; reliable access,often a central vein, should be used for children whosetreatment involves irritant or inotropic drugs or whoneed to receive the medicine over a long period or forhome therapy. The subcutaneous route is used mostcommonly for insulin administration. Intramuscularinjections should preferably be avoided in children,particularly neonates, infants, and young children. However,the intramuscular route may be advantageous foradministration of single doses of medicines when intravenouscannulation would be more problematic orGeneral guidance

2 General guidance BNFC 2011–2012General guidancepainful to the child. Certain drugs, e.g. some vaccines,are only administered intramuscularly.The intrathecal, epidural and intraosseous routes shouldbe used only by staff specially trained to administermedicines by these routes. Local protocols for themanagement of intrathecal injections must be in place(section 8.1).Managing medicines in school Administration of amedicine during schooltime should be avoided if possible;medicines should be prescribed for once or twicedailyadministration whenever practicable. If the medicineneeds to be taken in school, this should be discussedwith parents or carers and the necessaryarrangements made in advance; where appropriate,involvement of a school nurse should be sought. ManagingMedicines in Schools and Early Years Settingsproduced by the Department of Health provides guidanceon using medicines in schools (www.dh.gov.uk).Patient information leaflets Manufacturers’ patientinformation leaflets that accompany a medicine, coveronly the licensed use of the medicine (see BNF forChildren and Marketing Authorisation, below). Therefore,when a medicine is used outside its licence, it maybe appropriate to advise the child and the child’s parentor carer that some of the information in the leaflet mightnot apply to the child’s treatment. Where necessary,inappropriate advice in the patient information leafletshould be identified and reassurance provided about thecorrect use in the context of the child’s condition.Biosimilar medicines A biosimilar medicine is a newbiological product that is similar to a medicine that hasalready been authorised to be marketed (the biologicalreference medicine) in the European Union. The activesubstance of a biosimilar medicine is similar, but notidentical, to the biological reference medicine. Biologicalproducts are different from standard chemical productsin terms of their complexity and although theoreticallythere should be no important differences betweenthe biosimilar and biological reference medicine interms of safety or efficacy, when prescribing biologicalproducts, it is good practice to use the brand name. Thiswill ensure that substitution of a biosimilar medicinedoes not occur when the medicine is dispensed.Biosimilar medicines have black triangle status (T, seep. 12) at the time of initial marketing. It is important toreport suspected adverse reactions to biosimilar medicinesusing the Yellow Card Scheme (p. 12). For biosimilarmedicines, adverse reaction reports should clearlystate the brand name of the suspected medicine.Complementary and alternative medicine Anincreasing amount of information on complementaryand alternative medicine is becoming available. Whereappropriate, the child and the child’s carers should beasked about the use of their medicines, including dietarysupplements and topical products. The scope of BNFfor Children is restricted to the discussion of conventionalmedicines but reference is made to complementarytreatments if they affect conventional therapy (e.g.interactions with St John’s wort—see Appendix 1).Further information on herbal medicines is available atwww.mhra.gov.uk.BNF for Children and marketing authorisationWhere appropriate the doses, indications, cautions,contra-indications, and side-effects in BNF for Childrenreflect those in the manufacturers’ Summaries of ProductCharacteristics (SPCs) which, in turn, reflect thosein the corresponding marketing authorisations (formerlyknown as Product Licences). BNF for Children does notgenerally include proprietary medicines that are notsupported by a valid Summary of Product Characteristicsor when the marketing authorisation holder has notbeen able to supply essential information. When apreparation is available from more than one manufacturer,BNF for Children reflects advice that is the mostclinically relevant regardless of any variation in themarketing authorisation. Unlicensed products can beobtained from ‘special-order’ manufacturers or specialistimporting companies, see p. 809.As far as possible, medicines should be prescribed withinthe terms of the marketing authorisation. However,many children require medicines not specificallylicensed for paediatric use. Although medicines cannotbe promoted outside the limits of the licence, theMedicines Act does not prohibit the use of unlicensedmedicines.BNF for Children includes advice involving the use ofunlicensed medicines or of licensed medicines for unlicenseduses (‘off-label’ use). Such advice reflects carefulconsideration of the options available to manage a givencondition and the weight of evidence and experience ofthe unlicensed intervention (see also Unlicensed Medicines,p. 6). Where the advice falls outside a drug’smarketing authorisation, BNF for Children shows thelicensing status in the drug monograph. However, limitationsof the marketing authorisation should not precludeunlicensed use where clinically appropriate.Prescribing unlicensed medicinesPrescribing unlicensed medicines or medicines outsidethe recommendations of their marketingauthorisation alters (and probably increases) theprescriber’s professional responsibility and potentialliability. The prescriber should be able to justify andfeel competent in using such medicines.Drugs and skilled tasks Prescribers and otherhealthcare professionals should advise children andtheir carers if treatment is likely to affect their abilityto perform skilled tasks (e.g. driving). This applies especiallyto drugs with sedative effects; patients should bewarned that these effects are increased by alcohol.General information about a patient’s fitness to driveis available from the Driver and Vehicle LicensingAgency at www.dvla.gov.uk.Oral syringes An oral syringe is supplied when oralliquid medicines are prescribed in doses other thanmultiples of 5 mL. The oral syringe is marked in 0.5-mL divisions from 1 to 5 mL to measure doses of lessthan 5 mL (other sizes of oral syringe may also beavailable). It is provided with an adaptor and an instructionleaflet. The 5-mL spoon is used for doses of 5 mL(or multiples thereof).Excipients Branded oral liquid preparations that donot contain fructose, glucose, or sucrose are describedas ‘sugar-free’ in BNF for Children. Preparations containinghydrogenated glucose syrup, mannitol, maltitol,sorbitol, or xylitol are also marked ‘sugar-free’ sincethey do not cause dental caries. Children receiving

BNFC 2011–2012 General guidance 3medicines containing cariogenic sugars, or their carers,should be advised of dental hygiene measures to preventcaries. Sugar-free preparations should be usedwhenever possible, particularly if treatment is requiredfor a long period.Where information on the presence of alcohol, aspartame,gluten, sulphites, tartrazine, arachis (peanut) oilor sesame oil is available, this is indicated in BNF forChildren against the relevant preparation.Information is provided on selected excipients in skinpreparations (section 13.1.3), in vaccines (section 14.1),and on selected preservatives and excipients in eyedrops and injections.The presence of benzyl alcohol and polyoxyl castor oil(polyethoxylated castor oil) in injections is indicated inBNF for Children. Benzyl alcohol has been associatedwith a fatal toxic syndrome in preterm neonates, andtherefore, parenteral preparations containing the preservativeshould not be used in neonates. Polyoxylcastor oils, used as vehicles in intravenous injections,have been associated with severe anaphylactoid reactions.The presence of propylene glycol in oral or parenteralmedicines is indicated in BNF for Children; it can causeadverse effects if its elimination is impaired, e.g. in renalfailure, in neonates and young children, and in slowmetabolisers of the substance. It may interact withmetronidazole.The lactose content in most medicines is too small tocause problems in most lactose-intolerant children.However in severe lactose intolerance, the lactose contentshould be determined before prescribing. Theamount of lactose varies according to manufacturer,product, formulation, and strength.ImportantIn the absence of information on excipients in BNFfor Children and in the product literature (availableat www.emc.medicines.org.uk), contact the manufacturer(see Index of Manufacturers) if it is essentialto check details.Health and safety When handling chemical or biologicalmaterials particular attention should be given tothe possibility of allergy, fire, explosion, radiation, orpoisoning. Care is required to avoid sources of heat(including hair dryers) when flammable substances areused on the skin or hair. Substances, such as corticosteroids,some antimicrobials, phenothiazines, and manycytotoxics, are irritant or very potent and should behandled with caution; contact with the skin and inhalationof dust should be avoided. Healthcare professionalsand carers should guard against exposure to sensitising,toxic or irritant substances if it is necessary to crushtablets or open capsules.whether the prescriber is a doctor or dentist, and shouldbe signed by the prescriber.Security and validity of prescriptions The Councilsof the British Medical Association and the RoyalPharmaceutical Society have issued a joint statement onthe security and validity of prescriptions.In particular, prescription forms should:. not be left unattended at reception desks;. not be left in a car where they may be visible; and. when not in use, be kept in a locked drawer withinthe surgery and at home.Where there is any doubt about the authenticity of aprescription, the pharmacist should contact the prescriber.If this is done by telephone, the number should beobtained from the directory rather than relying on theinformation on the prescription form, which may befalse.Patient group direction (PGD) In most cases, themost appropriate clinical care will be provided on anindividual basis by a prescriber to a specific child.However, a Patient Group Direction for supply andadministration of medicines by other healthcare professionalscan be used where it would benefit the child’scare without compromising safety.A Patient Group Direction is a written direction relatingto the supply and administration (or administrationonly) of a licensed prescription-only medicine by certainclasses of healthcare professionals; the Direction issigned by a doctor (or dentist) and by a pharmacist.Further information on Patient Group Directions isavailable in Health Service Circular HSC 2000/026(England), HDL (2001) 7 (Scotland), and WHC (2000)116 (Wales) and at www.nelm.nhs.uk/en/Communities/NeLM/PGDs.NICE and Scottish Medicines Consortium Adviceissued by the National Institute for Health and ClinicalExcellence (NICE) and by the Scottish Medicines Consortium(SMC) is included in BNF for Children whenrelevant. If advice within a NICE Single TechnologyAppraisal differs from SMC advice, the Scottish Executiveexpects NHS Boards within NHS Scotland to complywith the SMC advice. Details of the advice togetherwith updates can be obtained from www.nice.org.uk andfrom www.scottishmedicines.org.General guidanceEEA and Swiss prescriptions Pharmacists candispense prescriptions issued by doctors and dentistsfrom the European Economic Area (EEA) or Switzerland(except prescriptions for controlled drugs in Schedules1, 2, or 3, or for drugs without a UK marketing authorisation).Prescriptions should be written in ink or otherwiseso as to be indelible, should be dated, should statethe name of the patient, should state the address of theprescriber, should contain particulars indicating

4 Prescription writing BNFC 2011–2012Prescription writingPrescription writingShared careIn its guidelines on responsibility for prescribing(circular EL (91) 127) between hospitals and generalpractitioners, the Department of Health has advisedthat legal responsibility for prescribing lies with thedoctor who signs the prescription.Prescriptions 1 should be written legibly in ink or otherwiseso as to be indelible 2 , should be dated, should statethe full name and address of the patient, and should besigned in ink by the prescriber 3 . The age and the date ofbirth of the child should preferably be stated, and it is alegal requirement in the case of prescription-only medicinesto state the age for children under 12 years.Wherever appropriate the prescriber should state thecurrent weight of the child to enable the dose prescribedto be checked. Consideration should also be given toincluding the dose per unit mass e.g. mg/kg or the doseper m 2 body-surface area e.g. mg/m 2 where this wouldreduce error.The following should be noted:(a) The unnecessary use of decimal points should beavoided, e.g. 3 mg, not 3.0 mg.Quantities of 1 gram or more should be written as1 g, etc.Quantities less than 1 gram should be written inmilligrams, e.g. 500 mg, not 0.5 g.Quantities less than 1 mg should be written inmicrograms, e.g. 100 micrograms, not 0.1 mg.When decimals are unavoidable a zero should bewritten in front of the decimal point where there isno other figure, e.g. 0.5 mL, not .5 mL.Use of the decimal point is acceptable to express arange, e.g. 0.5 to 1 g.(b) ‘Micrograms’ and ‘nanograms’ should not be abbreviated.Similarly ‘units’ should not be abbreviated.(c) The term ‘millilitre’ (ml or mL) 4 is used in medicineand pharmacy, and cubic centimetre, c.c., or cm 3should not be used.(d) Dose and dose frequency should be stated; in thecase of preparations to be taken ‘as required’ aminimum dose interval should be specified.Care should be taken to ensure the child receivesthe correct dose of the active drug. Therefore, thedose should normally be stated in terms of the massof the active drug (e.g. ‘125 mg 3 times daily’); termssuch as ‘5 mL’ or ‘1 tablet’ should be avoided exceptfor compound preparations.When doses other than multiples of 5 mL are prescribedfor oral liquid preparations the dosevolumewill be provided by means of an oralsyringe, see p. 2 (except for preparations intendedto be measured with a pipette).1. These recommendations are acceptable for prescriptiononlymedicines (A). For items marked 2, 3, K,and L, see also Prescribing Controlled Drugs, p. 9.2. It is permissible to issue carbon copies of NHS prescriptionsas long as they are signed in ink.3. Computer-generated facsimile signatures do not meet thelegal requirement.4. The use of capital ‘L’ in mL is a printing conventionthroughout BNF for Children; both ‘mL’ and ‘ml’ arerecognised SI abbreviations.(e) For suitable quantities of dermatological preparations,see section 13.1.2.(f) The names of drugs and preparations should bewritten clearly and not abbreviated, using approvedtitles only (see also advice in box on p. 5 to avoidcreating generic titles for modified-release preparations).(g) The quantity to be supplied may be stated byindicating the number of days of treatment requiredin the box provided on NHS forms. In most casesthe exact amount will be supplied. This does notapply to items directed to be used as required—ifthe dose and frequency are not given then thequantity to be supplied needs to be stated.When several items are ordered on one form thebox can be marked with the number of days oftreatment provided the quantity is added for anyitem for which the amount cannot be calculated.(h) Although directions should preferably be in Englishwithout abbreviation, it is recognised that someLatin abbreviations are used (for details see InsideBack Cover).For a sample prescription, see below.Abbreviation of titles In general, titles of drugs andpreparations should be written in full. Unofficial abbreviationsshould not be used as they may be misinterpreted.Non-proprietary titles Where non-proprietary (‘generic’)titles are given, they should be used for prescribing.This will enable any suitable product to bedispensed, thereby saving delay to the patient andsometimes expense to the health service. The onlyFP10NC0105

BNFC 2011–2012 Prescription writing 5exception is where there is a demonstrable difference inclinical effect between each manufacturer’s version ofthe formulation, making it important that the childshould always receive the same brand; in such cases,the brand name or the manufacturer should be stated.Non-proprietary names of compound preparationsNon-proprietary names of compound preparationswhich appear in BNF for Children are those thathave been compiled by the British PharmacopoeiaCommission or another recognised body; wheneverpossible they reflect the names of the active ingredients.Prescribers should avoid creating their own compoundnames for the purposes of generic prescribing;such names do not have an approveddefinition and can be misinterpreted.Special care should be taken to avoid errors whenprescribing compound preparations; in particularthe hyphen in the prefix ‘co-’ should be retained.Special care should also be taken to avoid creatinggeneric names for modified-release preparationswhere the use of these names could lead to confusionbetween formulations with different duration ofaction.Strengths and quantities The strength or quantityto be contained in capsules, lozenges, tablets, etc.should be stated by the prescriber. In particular,strengths of liquid preparations should be clearly stated(e.g. 125 mg/5 mL).Prescription writing

6 Supply of medicines BNFC 2011–2012Supply of medicinesSupply of medicinesWhen supplying a medicine for a child, the pharmacistshould ensure that the child and the child’s carer understandthe nature and identity of the medicine and how itshould be used. The child and the carer should beprovided with appropriate information (e.g. how longthe medicine should be taken for and what to do if adose is missed or the child vomits soon after the dose isgiven).Safety in the home Carers and relatives of childrenmust be warned to keep all medicines out of the reachand sight of children. Tablets, capsules and oral andexternal liquid preparations must be dispensed in areclosable child-resistant container unless:. the medicine is in an original pack or patient packsuch as to make this inadvisable;. the child’s carer will have difficulty in opening achild-resistant container;. a specific request is made that the product shall notbe dispensed in a child-resistant container;. no suitable child-resistant container exists for aparticular liquid preparation.All patients should be advised to dispose of unwantedmedicines by returning them to a pharmacy for destruction.Strength and quantities If a pharmacist receives anincomplete prescription for a systemically administeredpreparation 1 and considers it would not be appropriatefor the patient to return to the prescriber, the followingprocedures will apply:(a) an attempt must always be made to contact theprescriber to ascertain the intention;(b) if the attempt is successful the pharmacist must,where practicable, subsequently arrange for detailsof quantity, strength where applicable, and dosageto be inserted by the prescriber on the incompleteform;(c) where, although the prescriber has been contacted,it has not proved possible to obtain the writtenintention regarding an incomplete prescription,the pharmacist may endorse the form ‘p.c.’ (prescribercontacted) and add details of the quantityand strength where applicable of the preparationsupplied, and of the dose indicated. The endorsementshould be initialled and dated by the pharmacist;(d) where the prescriber cannot be contacted and thepharmacist has sufficient information to make aprofessional judgement the preparation may bedispensed. If the quantity is missing the pharmacistmay supply sufficient to complete up to 5 days’treatment; except that where a combination pack(i.e. a proprietary pack containing more than onemedicinal product) or oral contraceptive is prescribedby name only, the smallest pack shall bedispensed. In all cases the prescription must beendorsed ‘p.n.c.’ (prescriber not contacted), thequantity, the dose, and the strength (where applic-1. With the exception of temazepam, an incomplete prescriptionis not acceptable for controlled drugs in schedules 2and 3 of the Misuse of Drugs Regulations 2001.able) of the preparation supplied must be indicated,and the endorsement must be initialled and dated;(e) if the pharmacist has any doubt about exercisingdiscretion, an incomplete prescription must bereferred back to the prescriber.Unlicensed medicines A drug or formulation that isnot covered by a marketing authorisation (see also BNFfor Children and Marketing Authorisation) may beobtained from a pharmaceutical company, importedby a specialist importer, manufactured by a commercialor hospital licensed manufacturing unit (see SpecialorderManufacturers, p. 809), or prepared extemporaneously(see below) against a prescription.The safeguards that apply to products with marketingauthorisation should be extended, as far as possible, tothe use of unlicensed medicines. The safety, efficacy,and quality (including labelling) of unlicensed medicinesshould be assured by means of clear policies on theirprescribing, purchase, supply, and administration. Extracare is required with unlicensed medicines because lessinformation may be available on the drug and anyformulation of the drug.The following should be agreed with the supplier whenordering an unlicensed or extemporaneously preparedmedicine:. the specification of the formulation;. documentation confirming the specification andquality of the product supplied (e.g. a certificate ofconformity or of analysis);. for imported preparations product and licensinginformation should be supplied in English.Extemporaneous preparations A product should bedispensed extemporaneously only when no productwith a marketing authorisation is available. Every effortshould be made to ensure that an extemporaneouslyprepared product is stable and that it delivers therequisite dose reliably; the child should be providedwith a consistent formulation regardless of where themedicine is supplied to minimise variations in quality.Where there is doubt about the formulation, adviceshould be sought from a medicines information centre,the pharmacy at a children’s hospital, a hospital productionunit, a hospital quality control department, or themanufacturer.In many cases it is preferable to give a licensed productby an unlicensed route (e.g. an injection solution givenby mouth) than to prepare a special formulation. Whentablets or capsules are cut, dispersed, or used for preparingliquids immediately before administration, it isimportant to confirm uniform dispersal of the activeingredient, especially if only a portion of the solidcontent (e.g. a tablet segment) is used or if only analiquot of the liquid is to be administered.In some cases the child’s clinical condition may requirea dose to be administered in the absence of full informationon the method of administration. It is importantto ensure that the appropriate supporting information isavailable at the earliest opportunity.Preparation of products that produce harmful dust (e.g.cytotoxic drugs, hormones, or potentially sensitising

BNFC 2011–2012 Supply of medicines 7drugs such as neomycin) should be avoided or undertakenwith appropriate precautions to protect staff andcarers (see also Safety in the Home, above).The BP direction that a preparation must be freshlyprepared indicates that it must be made not more than24 hours before it is issued for use. The direction that apreparation should be recently prepared indicates thatdeterioration is likely if the preparation is stored forlonger than about 4 weeks at 15–25 o C.The term water used without qualification means eitherpotable water freshly drawn direct from the publicsupply and suitable for drinking or freshly boiled andcooled purified water. The latter should be used if thepublic supply is from a local storage tank or if thepotable water is unsuitable for a particular preparation.See also Water for Injections, section 9.2.2.Labelling medicines The name of the medicineshould appear on the label unless the prescriber indicatesotherwise; the name shown on the label should bethat written on the prescription. The strength shouldalso be stated on the label in the case of preparationsthat are available in different strengths.Labels should indicate the total quantity of the productdispensed in the container to which the label refers. Thisrequirement applies equally to solid, liquid, internal, andexternal preparations. If a product is dispensed in morethan one container, the reference should be to theamount in each container.Supply of medicines

8 Emergency supply of medicines BNFC 2011–2012Emergency supply of medicinesEmergency supply of medicinesEmergency supply requested bymember of the publicPharmacists are sometimes called upon by members ofthe public to make an emergency supply of medicines.The Prescription Only Medicines (Human Use) Order1997 allows exemptions from the Prescription Onlyrequirements for emergency supply to be made by aperson lawfully conducting a retail pharmacy businessprovided:(a) that the pharmacist has interviewed the personrequesting the prescription-only medicine and issatisfied:(i) that there is immediate need for the prescription-onlymedicine and that it is impracticablein the circumstances to obtain a prescriptionwithout undue delay;(ii) that treatment with the prescription-only medicinehas on a previous occasion been prescribedfor the person requesting it;(iii) as to the dose that it would be appropriate forthe person to take;(b) that no greater quantity shall be supplied than willprovide 5 days’ treatment of phenobarbital, phenobarbitalsodium, or Controlled Drugs in Schedules 4or 5, 1 or 30 days’ treatment for other prescriptiononlymedicines, except when the prescription-onlymedicine is:(i) insulin, an ointment or cream, or a preparationfor the relief of asthma in an aerosol dispenserwhen the smallest pack can be supplied;(ii) an oral contraceptive when a full cycle may besupplied;(iii) an antibiotic in liquid form for oral administrationwhen the smallest quantity that willprovide a full course of treatment can be supplied;(c) that an entry shall be made by the pharmacist in theprescription book stating:(i) the date of supply;(ii) the name, quantity, and, where appropriate, thepharmaceutical form and strength;(iii) the name and address of the patient;(iv) the nature of the emergency;(d) that the container or package must be labelled toshow:(i) the date of supply;(ii) the name, quantity, and, where appropriate, thepharmaceutical form and strength;(iii) the name of the patient;(iv) the name and address of the pharmacy;(v) the words ‘Emergency supply’;(vi) the words ‘Keep out of the reach of children’ (orsimilar warning);1. Doctors or dentists from the European Economic Area andSwitzerland, or their patients, cannot request an emergencysupply of Controlled Drugs in schedules 1, 2, or 3, ordrugs that do not have a UK marketing authorisation.(e) that the prescription-only medicine is not a substancespecifically excluded from the emergencysupply provision, and does not contain a ControlledDrug specified in Schedules 1, 2, or 3 to the Misuseof Drugs Regulations 2001 except for phenobarbitalor phenobarbital sodium for the treatment of epilepsy:for details see Medicines, Ethics and Practice,No. 34, London, Pharmaceutical Press, 2010(and subsequent editions as available). 1Emergency supply requested byprescriberEmergency supply of a prescription-only medicine mayalso be made at the request of a doctor, a dentist, asupplementary prescriber, a community practitionernurse prescriber, a nurse, pharmacist or optometristindependent prescriber, or a doctor or dentist from theEuropean Economic Area or Switzerland, provided:(a) that the pharmacist is satisfied that the prescriber byreason of some emergency is unable to furnish aprescription immediately;(b) that the prescriber has undertaken to furnish aprescription within 72 hours;(c) that the medicine is supplied in accordance with thedirections of the prescriber requesting it;(d) that the medicine is not a Controlled Drug specifiedin Schedules 1, 2, or 3 to the Misuse of DrugsRegulations 2001 except for phenobarbital or phenobarbitalsodium for the treatment of epilepsy: fordetails see Medicines, Ethics and Practice, No. 34,London, Pharmaceutical Press, 2010 (and subsequenteditions as available); 1(e) that an entry shall be made in the prescription bookstating:(i) the date of supply;(ii) the name, quantity, and, where appropriate, thepharmaceutical form and strength;(iii) the name and address of the practitionerrequesting the emergency supply;(iv) the name and address of the patient;(v) the date on the prescription;(vi) when the prescription is received the entryshould be amended to include the date onwhich it is received.Royal Pharmaceutical Society’sguidelines1. The pharmacist should consider the medical consequencesof not supplying a medicine in an emergency.2. If the pharmacist is unable to make an emergencysupply of a medicine the pharmacist should advisethe patient how to obtain essential medical care.For conditions that apply to supplies made at therequest of a patient, see Medicines, Ethics and Practice,No. 34, London Pharmaceutical Press, 2010 (and subsequenteditions).

BNFC 2011–2012 Prescribing Controlled Drugs 9Prescribing Controlled DrugsThe Misuse of Drugs Act, 1971 prohibits certain activitiesin relation to ‘Controlled Drugs’, in particular theirmanufacture, supply, and possession. The penaltiesapplicable to offences involving the different drugs aregraded broadly according to the harmfulness attributableto a drug when it is misused and for this purpose thedrugs are defined in the following three classes:Class A includes: alfentanil, cocaine, diamorphine(heroin), dipipanone, lysergide (LSD), methadone,methylenedioxymethamfetamine (MDMA,‘ecstasy’), morphine, opium, pethidine, phencyclidine,remifentanil, and class B substances whenprepared for injectionClass B includes: oral amfetamines, barbiturates,cannabis, cannabis resin, codeine, ethylmorphine,glutethimide, nabilone, pentazocine, phenmetrazine,and pholcodineClass C includes: certain drugs related to the amfetaminessuch as benzfetamine and chlorphentermine,buprenorphine, diethylpropion, mazindol,meprobamate, pemoline, pipradrol, most benzodiazepines,zolpidem, androgenic and anabolic steroids,clenbuterol, chorionic gonadotrophin (HCG),non-human chorionic gonadotrophin, somatotropin,somatrem, and somatropinThe Misuse of Drugs Regulations 2001 define theclasses of person who are authorised to supply andpossess controlled drugs while acting in their professionalcapacities and lay down the conditions underwhich these activities may be carried out. In the regulationsdrugs are divided into five schedules each specifyingthe requirements governing such activities asimport, export, production, supply, possession, prescribing,and record keeping which apply to them.Schedule 1 includes drugs such as cannabis andlysergide which are not used medicinally. Possessionand supply are prohibited except in accordancewith Home Office authority.Schedule 2 includes drugs such as diamorphine(heroin), morphine, nabilone, remifentanil, pethidine,secobarbital, glutethimide, amfetamine, andcocaine and are subject to the full controlled drugrequirements relating to prescriptions, safe custody(except for secobarbital), the need to keep registers,etc. (unless exempted in Schedule 5).Schedule 3 includes the barbiturates (except secobarbital,now Schedule 2), buprenorphine, diethylpropion,mazindol, meprobamate, midazolam,pentazocine, phentermine, and temazepam. Theyare subject to the special prescription requirements(except for temazepam) and to the safe custodyrequirements (except for any 5,5 disubstituted barbituricacid (e.g. phenobarbital), mazindol, meprobamate,midazolam, pentazocine, phentermine, orany stereoisomeric form or salts of the above).Records in registers do not need to be kept(although there are requirements for the retentionof invoices for 2 years).Schedule 4 includes in Part I benzodiazepines(except temazepam and midazolam which are inSchedule 3) and zolpidem, which are subject tominimal control. Part II includes androgenic andanabolic steroids, clenbuterol, chorionic gonadotrophin(HCG), non-human chorionic gonadotrophin,somatotropin, somatrem, and somatropin. ControlledDrug prescription requirements do notapply (but see Department of Health Guidance,p. 10) and Schedule 4 Controlled Drugs are notsubject to safe custody requirements.Schedule 5 includes those preparations which,because of their strength, are exempt from virtuallyall Controlled Drug requirements other than retentionof invoices for two years.Prescriptions Preparations in Schedules 2, 3, and 4 ofthe Misuse of Drugs Regulations 2001 (and subsequentamendments) are identified throughout BNF for Childrenusing the following symbols:. 2 for preparations in Schedule 2;. 3 for preparations in Schedule 3;. K for preparations in Schedule 4 (Part I);. L for preparations in Schedule 4 (Part II).The principal legal requirements relating to medicalprescriptions are listed below (see also Department ofHealth Guidance, p. 10).Prescription requirementsPrescriptions for Controlled Drugs that are subjectto prescription requirements 1 must be indelible 2 andmust be signed by the prescriber, be dated, andspecify the prescriber’s address. The prescriptionmust always state:. The name and address of the patient;. In the case of a preparation, the form 3 andwhere appropriate the strength 4 of the preparation;. either the total quantity (in both words andfigures) of the preparation, 5 or the number (inboth words and figures) of dosage units, asappropriate, to be supplied; in any other case,the total quantity (in both words and figures) ofthe Controlled Drug to be supplied;. The dose; 6. The words ‘for dental treatment only’ if issuedby a dentist.A pharmacist is not allowed to dispense a ControlledDrug unless all the information required by law is givenon the prescription. In the case of a prescription for aControlled Drug in Schedule 2 or 3, a pharmacist canamend the prescription if it specifies the total quantityonly in words or in figures or if it contains minortypographical errors, provided that such amendmentsare indelible and clearly attributable to the pharmacist. 7Failure to comply with the regulations concerning the1. All preparations in Schedules 2 and 3, except temazepam.2. A machine-written prescription is acceptable. The prescriber’ssignature must be handwritten.3. The dosage form (e.g. tablets) must be included on aControlled Drugs prescription irrespective of whether it isimplicit in the proprietary name (e.g. MST Continus) orwhether only one form is available.4. When more than one strength of a preparation exists thestrength required must be specified.5. The Home Office has advised that quantities of liquidpreparations such as methadone mixture should be writtenin millilitres.6. The instruction ‘one as directed’ constitutes a dose but ‘asdirected’ does not.7. Implementation date for N. Ireland not confirmed.Prescribing Controlled Drugs

10 Prescribing Controlled Drugs BNFC 2011–2012Trusts in England, Health Boards in Scotland, LocalHealth Boards in Wales or the Northern Ireland CentralServices Agency; in addition, prescriptions must specifythe prescriber’s identification number. Prescriptions tobe supplied by a pharmacist in hospital are exempt fromthe requirement for private prescriptions.Prescribing Controlled DrugsDepartment of Health guidance Guidance (June2006) issued by the Department of Health in England onprescribing and dispensing of Controlled Drugsrequires:. in general, prescriptions for Controlled Drugs inSchedules 2, 3, and 4 to be limited to a supply ofup to 30 days’ treatment; exceptionally, to cover ajustifiable clinical need and after consideration ofany risk, a prescription can be issued for a longerperiod, but the reasons for the decision should berecorded on the patient’s notes;. the patient’s identifier to be shown on NHS andprivate prescriptions for Controlled Drugs in Schedules2 and 3.Further information is available at www.dh.gov.uk.For a sample prescription, see above.FP10NC0105writing of prescriptions will result in inconvenience topatients and carers and delay in supply of the necessarymedicine. A prescription for a Controlled Drug in Schedules2, 3, or 4 is valid for 28 days from the date statedthereon. 1Instalments and ‘repeats’ A prescription may ordera Controlled Drug to be dispensed by instalments; theamount of instalments and the intervals to be observedmust be specified. 2Instalment prescriptions must be dispensed in accordancewith the directions in the prescription. However,the Home Office has approved specific wording whichmay be included in an instalment prescription to covercertain situations; for example, if a pharmacy is closedon the day when an instalment is due. For details seeMedicines, Ethics and Practice, No. 34, London, PharmaceuticalPress, 2010 (and subsequent editions asavailable) or see Drug Misuse and Dependence: UKGuidelines on Clinical Management (2007), available atwww.nta.nhs.uk/uploads/clinical_guidelines_2007.pdf.Prescriptions ordering ‘repeats’on the same form arenot permitted for Controlled Drugs in Schedules 2 or 3.Private prescriptions Private prescriptions for ControlledDrugs in Schedules 2 and 3 must be written onspecially designated forms provided by Primary Care1. The prescriber may forward-date the prescription; the startdate may also be specified in the body of the prescription.2. A total of 14 days’ treatment by instalment of any druglisted in Schedule 2 of the Misuse of Drugs Regulations,buprenorphine and diazepam may be prescribed inEngland. In England, forms FP10(MDA) (blue) andFP10H(MDA) (blue) should be used. In Scotland, formsGP10 (peach), HBP (blue), or HBPA (pink) should be used.In Wales a total of 14 days’ treatment by instalment of anydrug listed in Schedules 2–5 of the Misuse of DrugsRegulations may be prescribed. In Wales, formWP10(MDA) or form WP10HP(AD) should be used.Dependence and misuse The most serious drugs ofaddiction are cocaine, diamorphine (heroin), morphine,and the synthetic opioids.Despite marked reduction in the prescribing of amfetaminesthere is concern that abuse of illicit amfetamineand related compounds is widespread.Benzodiazepines are commonly misused. However,the misuse of barbiturates is now uncommon becauseof their declining medicinal use and consequent availability.Cannabis (Indian hemp) has no approved medicinal useand cannot be prescribed by doctors. Its use is illegal butwidespread. Cannabis is a mild hallucinogen seldomaccompanied by a desire to increase the dose; withdrawalsymptoms are unusual. Lysergide (lysergic aciddiethylamide, LSD) is a much more potent hallucinogen;its use can lead to severe psychotic states which can belife-threatening.There are concerns over increases in the availability andthe misuse of other drugs with variously combinedhallucinogenic, anaesthetic, or sedative properties.These include ketamine and gamma-hydroxybutyrate(sodium oxybate, GHB).Prescribing drugs likely to cause dependence ormisuse The prescriber has three main responsibilities:. to avoid creating dependence by introducing drugsto patients without sufficient reason. In this context,the proper use of the morphine-like drugs is wellunderstood. The dangers of other Controlled Drugsare less clear because recognition of dependence isnot easy and its effects, and those of withdrawal, areless obvious;. to see that the patient does not gradually increasethe dose of a drug, given for good medical reasons,to the point where dependence becomes morelikely. The prescriber should keep a close eye onthe amount prescribed to prevent patients or theircarers from accumulating stocks. A minimalamount should be prescribed in the first instance,or when seeing a new patient for the first time;

BNFC 2011–2012 Prescribing Controlled Drugs 11. to avoid being used as an unwitting source of supplyfor addicts and being vigilant to methods for obtainingmedicines which include visiting more than onedoctor, fabricating stories, and forging prescriptions.Patients under temporary care should be given onlysmall supplies of drugs unless they present an unequivocalletter from their own doctor. It is sensible toreduce dosages steadily or to issue weekly or evendaily prescriptions for small amounts if dependence issuspected.The stealing and misuse of prescription forms could beminimised by the following precautions:(a) do not leave unattended if called away from theconsulting room or at reception desks; do not leavein a car where they may be visible; when not in use,keep in a locked drawer within the surgery and athome;(b) draw a diagonal line across the blank part of theform under the prescription;(c) the quantity should be shown in words and figureswhen prescribing drugs prone to abuse; this isobligatory for controlled drugs (see Prescriptions,above);(d) alterations are best avoided but if any are made theyshould be clear and unambiguous; add initialsagainst altered items;(e) if prescriptions are left for collection they should beleft in a safe place in a sealed envelope.Travelling abroad Prescribed drugs listed in Schedule4 Part II (CD Anab) and Schedule 5 of the Misuse ofDrugs Regulations 2001 are not subject to export orimport licensing. However, patients intending to travelabroad for more than 3 months carrying any amount ofdrugs listed in Schedules 2, 3, or 4 Part I (CD Benz) willrequire a personal export/import licence. Furtherdetails can be obtained at www.homeoffice.gov.uk/drugs/licensing/personal, or from the Home Office bycontacting licensing_enquiry.aadu@homeoffice.gsi.gov.uk(in cases of emergency, telephone (020) 7035 0484).Applications must be supported by a covering letterfrom the prescriber and should give details of:. the patient’s name and current address;. the quantities of drugs to be carried;. the strength and form in which the drugs will bedispensed;. the country or countries of destination;. the dates of travel to and from the United Kingdom.Applications for licences should be sent to the HomeOffice, Drugs Licensing, Peel Building, 2 MarshamStreet, London, SW1P 4DF. Alternatively, completedapplication forms can be emailed to licensing_enquiry.aadu@homeoffice.gsi.gov.ukwith a scanned copy ofthe covering letter from the prescriber. A minimum oftwo weeks should be allowed for processing the application.Patients travelling for less than 3 months do not requirea personal export/import licence for carrying ControlledDrugs, but are advised to carry a letter fromthe prescribing doctor. Those travelling for more than 3months are advised to make arrangements to have theirmedication prescribed by a practitioner in the countrythey are visiting.Doctors who wish to take Controlled Drugs abroadwhile accompanying patients may similarly be issuedwith licences. Licences are not normally issued todoctors who wish to take Controlled Drugs abroadsolely in case a family emergency should arise.Personal export/import licences do not have any legalstatus outside the UK and are issued only to complywith the Misuse of Drugs Act and facilitate passagethrough UK Customs and Excise control. For clearancein the country to be visited it would be necessary toapproach that country’s consulate in the UK.Notification of drug misusersDoctors should report cases of drug misuse to theirregional or national drug misuse database or centre—for further advice and contact telephone numbers consultthe BNF.Prescribing Controlled Drugs

Adverse reactions to drugs12 Adverse reactions to drugs BNFC 2011–2012Adverse reactions to drugsAny drug may produce unwanted or unexpectedadverse reactions. Rapid detection and recording ofadverse drug reactions is of vital importance so thatunrecognised hazards are identified promptly andappropriate regulatory action is taken to ensure thatmedicines are used safely. Healthcare professionals andcoroners (see also Self-reporting, below) are urged toreport suspected adverse drug reactions directly to theMedicines and Healthcare products Regulatory Agency(MHRA) through the Yellow Card Scheme using theelectronic form at www.yellowcard.gov.uk. Alternatively,prepaid Yellow Cards for reporting are availablefrom the address below and are also bound in this book(inside back cover).Send Yellow Cards to:FREEPOST YELLOW CARD(No other address details required)Tel: 0800 731 6789Suspected adverse drug reactions to any therapeuticagent should be reported, including drugs (self-medicationas well as those prescribed), blood products, vaccines,radiographic contrast media, complementary andherbal products.The reporting of all suspected adverse drug reactions,no matter how minor, in children under 18 years,including those relating to unlicensed or off-label useof medicines, is strongly encouraged through the YellowCard Scheme even if the intensive monitoringsymbol (T, see below) has been removed. This isbecause experience in children may still be limited.The identification and reporting of adverse reactions todrugs in children is particularly important because:. the action of the drug and its pharmacokinetics inchildren (especially in the very young) may bedifferent from that in adults;. drugs may not be extensively tested in children;. children may be more susceptible to developmentaldisorders or they may have delayed adverse reactionswhich do not occur in adults;. many drugs are not specifically licensed for use inchildren and are used ‘off-label’;. suitable formulations may not be available to allowprecise dosing in children;. the nature and course of illnesses and adverse drugreactions may differ between adults and children.Spontaneous reporting is particularly valuable forrecognising possible new hazards rapidly. An adversereaction should be reported even if it is not certain thatthe drug has caused it, or if the reaction is well recognised,or if other drugs have been given at the sametime. Reports of overdoses (deliberate or accidental) cancomplicate the assessment of adverse drug reactions,but provide important information on the potentialtoxicity of drugs.A 24-hour Freefone service is available to all parts of theUK for advice and information on suspected adversedrug reactions; contact the National Yellow Card InformationService at the MHRA on 0800 731 6789. Outsideoffice hours a telephone-answering machine will takemessages.The following Yellow Card Centres can be contacted forfurther information:Yellow Card Centre, NorthWestFreepost SW299170 Pembroke PlaceLiverpool L69 3GFTel: (0151) 794 8122Yellow Card Centre,Northern & YorkshireFreepost SW2991Wolfson UnitClaremont PlaceNewcastle uponTyne NE2 4HHTel: (0191) 260 6181Yellow Card Centre, ScotlandFreepost NAT3271CARDS, Royal Infirmaryof EdinburghEdinburgh EH16 4SATel: (0131) 242 2919Yellow Card Centre, WalesFreepost SW2991University Hospital ofWalesCardiff CF4 1ZZTel: (029) 2074 4181Yellow Card Centre, WestMidlandsFreepost SW2991City HospitalBirmingham B18 7QHTel: (0121) 507 5672The MHRA’s database facilitates the monitoring ofadverse drug reactions.More detailed information on reporting and a list ofproducts currently under intensive monitoring can befound on the MHRA website:www.mhra.gov.uk.MHRA Drug Safety UpdateDrug Safety Update is a monthly newsletter from theMHRA and the Commission on Human Medicines(CHM); it is available at www.mhra.gov.uk/drugsafetyupdate.Self-reporting Patients and their carers can alsoreport suspected adverse drug reactions to theMHRA. Reports can be submitted directly to theMHRA through the Yellow Card Scheme using theelectronic form at www.yellowcard.gov.uk or by telephoneon 0808 100 3352. Alternatively, patient YellowCards are available from pharmacies and GP surgeries,or can be downloaded from www.mhra.gov.uk, wheremore detailed information on patient reporting is available.Information for patients about the Yellow CardScheme is available in other languages atwww.yellowcard.gov.uk.Prescription-event monitoring In addition to theMHRA’s Yellow Card Scheme, an independent schememonitors the safety of new medicines using a differentapproach. The Drug Safety Research Unit identifiespatients who have been prescribed selected new medicinesand collects data on clinical events in thesepatients. The data are submitted on a voluntary basisby general practitioners on green forms. More informationabout the scheme and the Unit’s educational materialis available from www.dsru.org.Newer drugs and vaccines Only limited informationis available from clinical trials on the safety of newmedicines. Further understanding about the safety of

BNFC 2011–2012 Adverse reactions to drugs 13medicines depends on the availability of informationfrom routine clinical practice.The black triangle symbol (T) identifies newly licensedmedicines that are monitored intensively by the MHRA.Such medicines include new active substances, biosimilarmedicines, medicines that have been licensed foradministration by a new route or drug delivery system,or for significant new indications which may alter theestablished risks and benefits of that drug, or thatcontain a new combination of active substances.There is no standard time for which products retain ablack triangle; safety data are usually reviewed after 2years.Adverse reactions to medical devices Suspectedadverse reactions to medical devices including dental orsurgical materials, intra-uterine devices, and contactlens fluids should be reported. Information on reportingthese can be found at:www.mhra.gov.uk.Side-effects in the BNF for Children The BNF forChildren includes clinically relevant side-effects formost drugs; an exhaustive list is not included fordrugs that are used by specialists (e.g. cytotoxic drugsand drugs used in anaesthesia). Where causality has notbeen established, side-effects in the manufacturers’ literaturemay be omitted from the BNF for Children.In the product literature the frequency of side-effects isgenerally described as follows:Very common greater than 1 in 10Common 1 in 100 to 1 in 10Uncommon [‘less commonly’ in 1 in 1000 to 1 in 100BNF for Children]Rare 1 in 10 000 to 1 in 1000Very rare less than 1 in 10 000Special problemsSymptoms Children may be poor at expressing thesymptoms of an adverse drug reaction and parentalopinion may be required.Delayed drug effects Some reactions (e.g. cancersand effects on development) may become manifestmonths or years after exposure. Any suspicion of suchan association should be reported directly to the MHRAthrough the Yellow Card Scheme.Congenital abnormalities When an infant is bornwith a congenital abnormality or there is a malformedaborted fetus doctors are asked to consider whether thismight be an adverse reaction to a drug and to report alldrugs (including self-medication) taken duringpregnancy.. allergy and idiosyncrasy are important causes ofadverse drug reactions. Ask if the child has hadprevious reactions to the drug or formulation;. prescribe as few drugs as possible and give veryclear instructions to the child, parent, or carer;. whenever possible use a familiar drug; with a newdrug be particularly alert for adverse reactions orunexpected events;. consider if excipients (e.g. colouring agents) may becontributing to the adverse reaction. If the reactionis minor, a trial of an alternative formulation of thesame drug may be considered before abandoningthe drug;. obtain a full drug history including asking if thechild is already taking other drugs including overthe-countermedicines; interactions may occur;. age and hepatic or renal disease may alter themetabolism or excretion of drugs, particularly inneonates, which can affect the potential for adverseeffects. Genetic factors may also be responsible forvariations in metabolism, and therefore for theadverse effects of the drug;. warn the child, parent, or carer if serious adversereactions are liable to occur.Defective medicinesDuring the manufacture or distribution of a medicine anerror or accident may occur whereby the finished productdoes not conform to its specification. While such adefect may impair the therapeutic effect of the productand could adversely affect the health of a patient, itshould not be confused with an Adverse Drug Reactionwhere the product conforms to its specification.The Defective Medicines Report Centre assists with theinvestigation of problems arising from licensed medicinalproducts thought to be defective and co-ordinatesany necessary protective action. Reports on suspectdefective medicinal products should include the brandor the non-proprietary name, the name of the manufactureror supplier, the strength and dosage form of theproduct, the product licence number, the batch numberor numbers of the product, the nature of the defect, andan account of any action already taken in consequence.The Centre can be contacted at:The Defective Medicines Report CentreMedicines and Healthcare products Regulatory Agency151 Buckingham Palace RoadLondon, SW1W 9SZTel: (020) 3080 6588info@mhra.gsi.gov.ukAdverse reactions to drugsPrevention of adverse reactionsAdverse reactions may be prevented as follows:. never use any drug unless there is a good indication.If the patient is pregnant do not use a drugunless the need for it is imperative;

Prescribing in hepatic impairment14 Prescribing in hepatic impairment BNFC 2011–2012Prescribing in hepatic impairmentChildren have a large reserve of hepatic metaboliccapacity and modification of the choice and dosage ofdrugs is usually unnecessary even in apparently severeliver disease. However, special consideration is requiredin the following situations:. liver failure characterised by severe derangement ofliver enzymes and profound jaundice; the use ofsedative drugs, opioids, and drugs such as diureticsand amphotericin which produce hypokalaemiamay precipitate hepatic encephalopathy;. impaired coagulation, which can affect response tooral anticoagulants;. in cholestatic jaundice elimination may be impairedof drugs such as fusidic acid and rifampicin whichare excreted in the bile;Prescribing in renal impairment. in hypoproteinaemia, the effect of highly proteinbounddrugs such as phenytoin, prednisolone, warfarin,and benzodiazepines may be increased;. use of hepatotoxic drugs is more likely to causetoxicity in children with liver disease; such drugsshould be avoided if possible;. in neonates, particularly preterm neonates, and alsoin infants metabolic pathways may differ from olderchildren and adults because liver enzyme pathwaysmay be immature.Where care is needed when prescribing in hepaticimpairment, this is indicated under the relevant drugin BNF for Children.The use of drugs in children with reduced renal functioncan give rise to problems for several reasons:. reduced renal excretion of a drug or its metabolitesmay produce toxicity;. sensitivity to some drugs is increased even if eliminationis unimpaired;. many side-effects are tolerated poorly by childrenwith renal impairment;. some drugs are not effective when renal function isreduced;. neonates, particularly preterm, may have immaturerenal function.Many of these problems can be avoided by reducing thedose or by using alternative drugs.Principles of dose adjustment in renalimpairmentThe level of renal function below which the dose of adrug must be reduced depends on the proportion of thedrug eliminated by renal excretion and its toxicity.For many drugs with only minor or no dose-related sideeffects,very precise modification of the dose regimen isunnecessary and a simple scheme for dose reduction issufficientFor more toxic drugs with a small safety margin doseregimens based on glomerular filtration rate should beused. When both efficacy and toxicity are closely relatedto plasma-drug concentration, recommended regimensshould be regarded only as a guide to initial treatment;subsequent doses must be adjusted according to clinicalresponse and plasma-drug concentration.The total daily maintenance dose of a drug can bereduced either by reducing the size of the individualdoses or by increasing the interval between doses. Forsome drugs, although the size of the maintenance doseis reduced it is important to give a loading dose if animmediate effect is required. This is because it takesabout five times the half-life of the drug to achievesteady-state plasma concentration. Because the plasmahalf-life of drugs excreted by the kidney is prolonged inrenal impairment, it can take many doses at the reduceddosage to achieve a therapeutic plasma concentration.The loading dose should usually be the same as theinitial dose for a child with normal renal function.Nephrotoxic drugs should, if possible, be avoided inchildren with renal disease because the consequences ofnephrotoxicity are likely to be more serious when therenal reserve is already reduced.Glomerular filtration rate is low at birth and increasesrapidly during the first 6 months. Thereafter, glomerularfiltration rate increases gradually to reach adult levels by1–2 years of age, when standardised to a typical adultbody surface area (1.73 m 2 ). In the first weeks after birth,serum creatinine falls; a single measure of serum creatinineprovides only a crude estimate of renal functionand observing the change over days is of more use. Inthe neonate, a sustained rise in serum creatinine or alack of the expected postnatal decline, is indicative of areduced glomerular filtration rate.Dose recommendations are based on the severity ofrenal impairment. This is expressed in terms of glomerularfiltration rate (mL/minute/1.73 m 2 ).The following equations provide a guide to glomerularfiltration rate.Child over 1 year:Estimated glomerular filtration rate (mL/minute/1.73 m 2 )= 40 1 height (cm)/serum creatinine (micromol/litre)Neonate:Estimated glomerular filtration rate (mL/minute/1.73 m 2 )= 30 1 height (cm)/serum creatinine (micromol/litre)The serum-creatinine concentration is sometimes usedas a measure of renal function but is only a rough guideeven when corrected for age, weight, and sex.1. The values used in these formulas may differ according tolocality or laboratory.

BNFC 2011–2012 Prescribing in renal impairment 15ImportantThe information on dose adjustment in BNF forChildren is expressed in terms of estimated glomerularfiltration rate.Renal function in adults is increasingly beingreported as estimated glomerular filtration rate(eGFR) normalised to a body surface area of1.73 m 2 ; however, eGFR is derived from the MDRD(Modification of Diet in Renal Disease) formulawhich is not validated for use in children. eGFRderived from the MDRD formula should not beused to adjust drug doses in children with renalimpairment.In BNF for Children, values for measures of renalfunction are included where possible. However, wheresuch values are not available, the BNF for Childrenreflects the terms used in the published information.Chronic kidney disease in adults: UK guidelines foridentification, management and referral (March2006) defines renal function as follows:Degree of impairment eGFR 1 mL/minute/1.73 m 2Normal: Stage 1More than 90 (with otherevidence of kidney damage)Mild: Stage 260–89 (with other evidenceof kidney damage)Moderate 2 : Stage 3 30–59Severe: Stage 4 15–29Established renal failure: Less than 15Stage 51. Estimated glomerular filtration rate (eGFR) derived fromthe Modification of Diet in Renal Disease (MDRD) formulafor use in patients over 18 years2. NICE clinical guideline 73 (September 2008)—Chronickidney disease: Stage 3A eGFR = 45–59, Stage 3B eGFR =30–44Prescribing in renal impairmentDialysisFor prescribing in children on renal replacementtherapy consult specialist literature.Drug prescribing should be kept to the minimum in allchildren with severe renal disease.If even mild renal impairment is considered likely onclinical grounds, renal function should be checkedbefore prescribing any drug which requires dose modification.Where care is needed when prescribing in renal impairment,this is indicated under the relevant drug in BNFfor Children.

Prescribing in pregnancy16 Prescribing in pregnancy BNFC 2011–2012Prescribing in pregnancyDrugs can have harmful effects on the fetus at any timeduring pregnancy. It is important to bear this in mindwhen prescribing for a female of childbearing age or formen trying to father a child.During the first trimester drugs may produce congenitalmalformations (teratogenesis), and the period of greatestrisk is from the third to the eleventh week ofpregnancy.During the second and third trimesters drugs may affectthe growth and functional development of the fetus orhave toxic effects on fetal tissues; and drugs givenshortly before term or during labour may have adverseeffects on labour or on the neonate after delivery.BNF for Children identifies drugs which:. may have harmful effects in pregnancy and indicatesthe trimester of risk;. are not known to be harmful in pregnancy.The information is based on human data but informationon animal studies has been included for somedrugs when its omission might be misleading. Maternaldrug doses may require adjustment during pregnancydue to changes in maternal physiology but this isbeyond the scope of BNF for Children.Where care is needed when prescribing in pregnancy,this is indicated under the relevant drug in BNF forChildren.Prescribing in breast-feedingBreast-feeding is beneficial; the immunological andnutritional value of breast milk to the infant is greaterthan that of formula feeds.Although there is concern that drugs taken by themother might affect the infant, there is very little informationon this. In the absence of evidence of an effect,the potential for harm to the infant can be inferred from:. the amount of drug or active metabolite of the drugdelivered to the infant (dependent on the pharmacokineticcharacteristics of the drug in the mother);. the efficiency of absorption, distribution and eliminationof the drug by the infant (infant pharmacokinetics);. the nature of the effect of the drug on the infant(pharmacodynamic properties of the drug in theinfant).Most medicines given to a mother cause no harm tobreast-fed infants and there are few contra-indicationsto breast-feeding when maternal medicines are necessary.However, administration of some drugs to nursingmothers can harm the infant. In the first week of life,some such as preterm or jaundiced infants are at aslightly higher risk of toxicity.Toxicity to the infant can occur if the drug enters themilk in pharmacologically significant quantities. Theconcentration in milk of some drugs (e.g. fluvastatin)may exceed the concentration in maternal plasma sothat therapeutic doses in the mother can cause toxicityto the infant. Some drugs inhibit the infant’s suckingreflex (e.g. phenobarbital) while others can affect lactation(e.g. bromocriptine). Drugs in breast milk may, atleast theoretically, cause hypersensitivity in the infantImportantDrugs should be prescribed in pregnancy only if theexpected benefit to the mother is thought to begreater than the risk to the fetus, and all drugs shouldbe avoided if possible during the first trimester.Drugs which have been extensively used inpregnancy and appear to be usually safe should beprescribed in preference to new or untried drugs;and the smallest effective dose should be used.Few drugs have been shown conclusively to beteratogenic in humans but no drug is safe beyondall doubt in early pregnancy. Screening proceduresare available where there is a known risk of certaindefects.Absence of information does not imply safety.It should be noted that BNF for Children providesindependent advice and may not always agree withthe product literature.Information on drugs and pregnancy is also availablefrom the UK Teratology Information Service.Tel: 0844 892 0909 (08:30–17:00 Monday to Friday)Fax: (0191) 260 6193Outside of these hours, urgent enquiries onlywww.uktis.orgeven when concentration is too low for a pharmacologicaleffect. BNF for Children identifies drugs:. which should be used with caution or which arecontra-indicated in breast-feeding for the reasonsgiven above;. which, on present evidence, may be given to themother during breast-feeding, because they appearin milk in amounts which are too small to beharmful to the infant;. which are not known to be harmful to the infantalthough they are present in milk in significantamounts.Where care is needed when prescribing in breast-feeding,this is indicated under the relevant drug in BNF forChildren.ImportantFor many drugs insufficient evidence is available toprovide guidance and it is advisable to administeronly essential drugs to a mother during breast-feeding.Because of the inadequacy of information ondrugs in breast milk information in BNF for Childrenshould be used only as a guide; absence of informationdoes not imply safety.

BNFC 2011–2012 Prescribing in palliative care 17Prescribing in palliative carePalliative care is the active total care of children andyoung adults who have incurable, life-limiting conditionsand are not expected to survive beyond youngadulthood.The child may be cared for in a hospice or at homeaccording to the needs of the child and the child’s family.In all cases, children should receive total care of theirphysical, emotional, social, and spiritual needs, and theirfamilies should be supported throughout. In particular,specialist palliative care is essential for end-of-life careof the child and for supporting the family through deathand bereavement.Drug treatment The number of drugs should be asfew as possible. Oral medication is usually appropriateunless there is severe nausea and vomiting, dysphagia,weakness, or coma, when parenteral medication may benecessary.PainAnalgesics are more effective in preventing pain than inthe relief of established pain; it is important that they aregiven regularly.Paracetamol (p. 200) or a NSAID (section 10.1.1) givenregularly will often make the use of opioid analgesicsunnecessary. A NSAID may also control the pain ofbone secondaries. Radiotherapy and bisphosphonates(section 6.6.2) may also be useful for pain due to bonemetastases.An opioid analgesic (section 4.7.2) such as codeine(p. 204), alone or in combination with a non-opioidanalgesic at adequate dosage, may be helpful in thecontrol of moderate pain if non-opioid analgesics aloneare not sufficient. If these preparations do not controlthe pain, morphine (p. 207) is the most useful opioidanalgesic. Alternatives to morphine, including transdermalfentanyl (see below and p. 206), are best initiatedby those with experience in palliative care. Initiation ofan opioid analgesic should not be delayed by concernover a theoretical likelihood of psychological or physicaldependence (addiction).Equivalent single doses of opioid analgesicsThese equivalences are intended only as an approximateguide; patients should be carefully monitored after anychange in medication and dose titration may be requiredAnalgesicDoseMorphine salts (oral)10 mgDiamorphine hydrochloride (subcutaneous) 3 mgHydromorphone hydrochloride1.3 mgOxycodone (oral)5 mgOral route Morphine (p. 207) is given by mouth as anoral solution or as standard (‘immediate release’) tabletsregularly every 4 hours, the initial dose dependinglargely on the patient’s previous treatment. If the firstdose of morphine is no more effective than the previousanalgesic, the next dose should be increased by 30–50%,the aim being to choose the lowest dose that preventspain. The dose should be adjusted with careful assessmentof the pain, and the use of adjuvant analgesics(such as NSAIDs) should also be considered. Althoughlow doses of morphine are usually adequate thereshould be no hesitation in increasing the dose stepwiseaccording to response if necessary.When the pain is controlled and the patient’s 24-hourmorphine requirement is established, the daily dose canbe given as a single dose or in 2 divided doses as amodified-release preparation. The first dose of themodified-release preparation is given with, or within 4hours of, the last dose of the oral solution. The childshould be reviewed regularly for treatment efficacy andside-effects.MST Continus c tablets or suspension (p. 209) aredesigned for twice daily administration; MXL c capsules(p. 209) allow administration of the total daily morphinerequirement as a single dose.Alternatively, a modified-release preparation may becommenced immediately and the dose adjusted accordingto pain control. The starting dose of modifiedreleasepreparations designed for twice daily administrationis usually 200–800 micrograms/kg every 12hours if no other analgesic (or only paracetamol) hasbeen taken previously, but to replace a weaker opioidanalgesic (such as codeine) the starting dose is usuallyhigher. Increments should be made to the dose, not tothe frequency of administration, which should remain atevery 12 hours.If pain occurs between regular doses of morphine(‘breakthrough pain’), an additional dose (‘rescuedose’) should be given. An additional dose should alsobe given 30 minutes before an activity that causes pain(e.g. wound dressing). Morphine, as oral solution orstandard formulation tablets, should be prescribed forbreakthrough pain. The standard dose of a strong opioidfor breakthrough pain is usually one-tenth to one-sixthof the regular 24 hour total daily dose, repeated every 4hours if necessary (review pain management if analgesicrequired more frequently). Each child should beassessed on an individual basis.Children often require a higher dose of morphine inproportion to their body-weight compared to adults.Children are more susceptible to certain adverse effectsof opioids such as urinary retention (which can be easedby carbachol or bethanechol), and opioid-induced pruritus.Oxycodone (p. 209) is used in a child who requires anopioid but cannot tolerate morphine. If the child isalready receiving an opioid, oxycodone should bestarted at a dose equivalent to the current analgesic(see above).Parenteral route Diamorphine (p. 205) is preferredfor injection because, being more soluble, it can be givenin a smaller volume. The equivalent subcutaneous doseis approximately a third of the oral dose of morphine.Subcutaneous infusion of diamorphine via a continuousinfusion device can be useful (for details, see p. 19).If the child can resume taking medicines by mouth, thenoral morphine may be substituted for subcutaneousinfusion of diamorphine. See table of approximateequivalent doses of morphine and diamorphine, p. 21.Prescribing in palliative care

18 Prescribing in palliative care BNFC 2011–2012Prescribing in palliative careRectal route Morphine (p. 209) is also available forrectal administration as suppositories.Transdermal route Transdermal preparations offentanyl (p. 206) are available; they are not suitable foracute pain or in those children whose analgesic requirementsare changing rapidly because the long time tosteady state prevents rapid titration of the dose. Prescribersshould ensure that they are familiar with thecorrect use of transdermal preparations (see underfentanyl, p. 206) because inappropriate use has causedfatalities.The following 24-hour doses of morphine by mouth areconsidered to be approximately equivalent to thefentanyl patches shown:Morphine salt 45 mg daily : fentanyl ‘12’ patchMorphine salt 90 mg daily : fentanyl ‘25’ patchMorphine salt 180 mg daily : fentanyl ‘50’ patchMorphine salt 270 mg daily : fentanyl ‘75’ patchMorphine salt 360 mg daily : fentanyl ‘100’ patchMorphine (as oral solution or standard formulationtablets) is given for breakthrough pain.Gastro-intestinal pain The pain of bowel colic maybe reduced by loperamide (p. 47). Hyoscine hydrobromide(p. 198) may also be helpful in reducing thefrequency of spasms; it is given sublingually at a dose of10 micrograms/kg (max. 300 micrograms) 3 times dailyas Kwells c tablets. For the dose by subcutaneousinfusion, see p. 20.Gastric distension pain due to pressure on the stomachmay be helped by a preparation incorporating an antacidwith an antiflatulent (p. 36) and a prokinetic such asdomperidone (p. 41) before meals.Muscle spasm The pain of muscle spasm can behelped by a muscle relaxant such as diazepam (p. 515)or baclofen (p. 514).Neuropathic pain Patients with neuropathic pain(p. 212) may benefit from a trial of a tricyclic antidepressant,most commonly amitriptyline (p. 185), for severalweeks. An anticonvulsant, such as carbamazepine(p. 218), may be added or substituted if pain persists.Ketamine is sometimes used under specialist supervisionas an adjuvant for neuropathic pain that respondspoorly to opioid analgesics.Pain due to nerve compression may be reduced by acorticosteroid such as dexamethasone, which reducesoedema around the tumour, thus reducing compression.Nerve blocks can be considered when pain is localisedto a specific area. Transcutaneous electrical nervestimulation (TENS) may also help.Miscellaneous conditionsUnlicensed indications or routesSeveral recommendations in this section involveunlicensed indications or routes.Anorexia Anorexia may be helped by prednisolone ordexamethasone.Anxiety Anxiety can be treated with a long-actingbenzodiazepine such as diazepam, or by continuousinfusion of the short-acting benzodiazepine midazolam.Interventions for more acute episodes of anxiety (suchas panic attacks) include short-acting benzodiazepinessuch as lorazepam given sublingually or midazolamgiven subcutaneously. Temazepam provides usefulnight-time sedation in some children.Capillary bleeding Capillary bleeding can be treatedwith tranexamic acid (p. 123) by mouth; treatment isusually continued for one week after the bleeding hasstopped but it can be continued at a reduced dose ifbleeding persists. Alternatively, gauze soaked in tranexamicacid 100 mg/mL or adrenaline (epinephrine) solution1 mg/mL (1 in 1000) can be applied to the affectedarea.Vitamin K may be useful for the treatment and preventionof bleeding associated with prolonged clotting inliver disease. In severe chronic cholestasis, absorptionof vitamin K may be impaired; either parenteral orwater-soluble oral vitamin K should be considered (section9.6.6).Constipation Constipation is a common cause ofdistress and is almost invariable after administration ofan opioid analgesic. It should be prevented if possible bythe regular administration of laxatives. Suitable laxativesinclude osmotic laxatives (p. 61) (such as lactuloseor macrogols), stimulant laxatives (p. 59) (such as codanthramerand senna) or the combination of lactuloseand a senna preparation. Naloxone given by mouth mayhelp relieve opioid-induced constipation; it is poorlyabsorbed but opioid withdrawal reactions have beenreported.Convulsions Intractable seizures are relatively commonin children dying from non-malignant conditions.Phenobarbital by mouth or as a continuous subcutaneousinfusion may be beneficial; continuous infusion ofmidazolam is an alternative. Both cause drowsiness, butthis is rarely a concern in the context of intractableseizures. For breakthrough convulsions diazepam(p. 232) given rectally (as a solution), buccal midazolam(p. 234), or paraldehyde (p. 234) as an enema may beappropriate.For the use of midazolam by subcutaneous infusionusing a continuous infusion device, see p. 20.Dry mouth Dry mouth may be caused by certainmedications including opioid analgesics, antimuscarinicdrugs (e.g. hyoscine), antidepressants and some antiemetics;if possible, an alternative preparation should beconsidered. Dry mouth may be relieved by good mouthcare and measures such as chewing sugar-free gum,sucking ice or pineapple chunks, or the use of artificialsaliva (p. 548); dry mouth associated with candidiasiscan be treated by oral preparations of nystatin (p. 546)or miconazole (p. 545); alternatively, fluconazole(p. 301) can be given by mouth.Dysphagia A corticosteroid such as dexamethasonemay help, temporarily, if there is an obstruction due totumour. See also Dry Mouth, above.Dyspnoea Breathlessness at rest may be relieved byregular oral morphine in carefully titrated doses. Diazepammay be helpful for dyspnoea associated with

BNFC 2011–2012 Prescribing in palliative care 19anxiety. Sublingual lorazepam or subcutaneous orbuccal midazolam are alternatives. A nebulised shortactingbeta 2agonist (section 3.1.1.1) or a corticosteroid(section 3.2), such as dexamethasone or prednisolone,may also be helpful for bronchospasm or partialobstruction.Excessive respiratory secretion Excessive respiratorysecretion (death rattle) may be reduced by hyoscinehydrobromide patches (p. 198) or by subcutaneousor intravenous injection of hyoscinehydrobromide 10 micrograms/kg (max. 600 micrograms)every 4 to 8 hours; however, care must betaken to avoid the discomfort of dry mouth. Alternatively,glycopyrronium (p. 636) may be given.For the administration of hyoscine hydrobromide bysubcutaneous or intravenous infusion using a continuousinfusion device, see p. 20.Fungating tumours Fungating tumours can be treatedby regular dressing and antibacterial drugs; systemictreatment with metronidazole (p. 296) is often requiredto reduce malodour, but topical metronidazole (p. 587)is also used.Hiccup Hiccup due to gastric distension may be helpedby a preparation incorporating an antacid with an antiflatulent(p. 37).Hypercalcaemia See section 9.5.1.2.Insomnia Children with advanced cancer may notsleep because of discomfort, cramps, night sweats, jointstiffness, or fear. There should be appropriate treatmentof these problems before hypnotics (p. 169) are used.Benzodiazepines, such as temazepam, may be useful.Metoclopramide has a prokinetic action and is used bymouth for nausea and vomiting associated with gastritis,gastric stasis, and functional bowel obstruction. Drugswith antimuscarinic effects antagonise prokinetic drugsand, if possible, should not therefore be used concurrently.Haloperidol (p. 174) is used by mouth or by continuousintravenous or subcutaneous infusion for most metaboliccauses of vomiting (e.g. hypercalcaemia, renal failure).Cyclizine (p. 193) is used for nausea and vomiting due tomechanical bowel obstruction, raised intracranial pressure,and motion sickness.Ondansetron (p. 197) is most effective when the vomitingis due to damaged or irritated gut mucosa (e.g. afterchemotherapy or radiotherapy).Antiemetic therapy should be reviewed every 24 hours;it may be necessary to substitute the antiemetic or toadd another one.Levomepromazine (p. 175) can be used if first-line antiemeticsare inadequate. Dexamethasone by mouth canbe used as an adjunct.For the administration of antiemetics by subcutaneousinfusion using a continuous infusion device, see below.For the treatment of nausea and vomiting associatedwith cancer chemotherapy, see section 8.1.Pruritus Pruritus, even when associated with obstructivejaundice, often responds to simple measures suchas application of emollients (p. 552). Ondansetron maybe effective in some children. Where opioid analgesicscause pruritus it may be appropriate to review the doseor to switch to an alternative opioid analgesic. In thecase of obstructive jaundice, further measures includeadministration of colestyramine (p. 70).Prescribing in palliative careIntractable cough Intractable cough may be relievedby moist inhalations or by regular administration of oralmorphine every 4 hours. Methadone linctus should beavoided because it has a long duration of action andtends to accumulate.Mucosal bleeding Mucosal bleeding from the mouthand nose occurs commonly in the terminal phase,particularly in a child suffering from haemopoeiticmalignancy. Bleeding from the nose caused by a singlebleeding point can be arrested by cauterisation or bydressing it. Tranexamic acid (p. 123) may be effectiveapplied topically or given systemically.Nausea and vomiting Nausea and vomiting arecommon in children with advanced cancer. Ideally, thecause should be determined before treatment with anantiemetic (section 4.6) is started.Nausea and vomiting with opioid therapy are less commonin children than in adults but may occur particularlyin the initial stages and can be prevented by givingan antiemetic. An antiemetic is usually necessary onlyfor the first 4 or 5 days and therefore combined preparationscontaining an opioid with an antiemetic arenot recommended because they lead to unnecessaryantiemetic therapy (and associated side-effects whenused long-term).Raised intracranial pressure Headache due toraised intracranial pressure often responds to a highdose of a corticosteroid, such as dexamethasone, for 4to 5 days, subsequently reduced if possible; dexamethasoneshould be given before 6 p.m. to reduce therisk of insomnia. Treatment of headache and of associatednausea and vomiting should also be considered.Restlessness and confusion Restlessness and confusionmay require treatment with haloperidol (p. 174)10–20 micrograms/kg by mouth every 8–12 hours.Levomepromazine (p. 175) is also used occasionallyfor restlessness. See also p. 20.Continuous infusion devicesAlthough drugs can usually be administered by mouthto control symptoms in palliative care, the parenteralroute may sometimes be necessary. Repeated administrationof intramuscular injections should be avoided inchildren, particularly if cachectic. This has led to the useof portable continuous infusion devices such as syringedrivers to give a continuous subcutaneous infusion,

20 Prescribing in palliative care BNFC 2011–2012Prescribing in palliative carewhich can provide good control of symptoms with littlediscomfort or inconvenience to the patient.Syringe driver rate settingsStaff using syringe drivers should be adequatelytrained and different rate settings should be clearlyidentified and differentiated; incorrect use ofsyringe drivers is a common cause of medicationerrors.Indications for the parenteral route are:. inability to take medicines by mouth owing tonausea and vomiting, dysphagia, severe weakness,or coma;. malignant bowel obstruction for which surgery isinappropriate (avoiding the need for an intravenousinfusion or for insertion of a nasogastric tube);. refusal by the child to take regular medication bymouth.Bowel colic and excessive respiratory secretionsHyoscine hydrobromide (p. 198) effectively reducesrespiratory secretions and is sedative (but occasionallycauses paradoxical agitation); it is given in a subcutaneousor intravenous infusion dose of 40–60 micrograms/kg/24hours. Glycopyrronium (p. 636) mayalso be used.Hyoscine butylbromide (p. 40) is effective in bowelcolic, is less sedative than hyoscine hydrobromide, butis not always adequate for the control of respiratorysecretions; it is given by subcutaneous infusion (important:hyoscine butylbromide must not be confused withhyoscine hydrobromide, above).should not be mixed) does not apply to the use ofsyringe drivers in palliative care. Provided that there isevidence of compatibility, selected injections can bemixed in syringe drivers. Not all types of medicationcan be used in a subcutaneous infusion. In particular,chlorpromazine, prochlorperazine, and diazepam arecontra-indicated as they cause skin reactions at theinjection site; to a lesser extent cyclizine and levomepromazinealso sometimes cause local irritation.In theory injections dissolved in water for injections aremore likely to be associated with pain (possibly owing totheir hypotonicity). The use of physiological saline (sodiumchloride 0.9%) however increases the likelihood ofprecipitation when more than one drug is used; moreoversubcutaneous infusion rates are so slow (0.1–0.3 mL/hour) that pain is not usually a problem whenwater is used as a diluent.Diamorphine can be given by subcutaneous infusion ina strength of up to 250 mg/mL; up to a strength of40 mg/mL either water for injections or physiologicalsaline (sodium chloride 0.9%) is a suitable diluent—above that strength only water for injections is used (toavoid precipitation).The following can be mixed with diamorphine:Cyclizine 1Hyoscine hydrobromideDexamethasone 2LevomepromazineHaloperidol 3 Metoclopramide 4Hyoscine butylbromide MidazolamSubcutaneous infusion solution should be monitoredregularly both to check for precipitation (and discoloration)and to ensure that the infusion is running at thecorrect rate.Convulsions If a child has previously been receivingan antiepileptic drug or has a primary or secondarycerebral tumour or is at risk of convulsion (e.g. owing touraemia) antiepileptic medication should not bestopped. Midazolam (p. 234) is the benzodiazepine antiepilepticof choice for continuous subcutaneous infusion.Nausea and vomiting Levomepromazine (p. 175)causes sedation in about 50% of patients. Haloperidol(p. 174) has little sedative effect.Cyclizine (p. 193) is particularly likely to precipitate ifmixed with diamorphine or other drugs (see underMixing and Compatibility); it is given by subcutaneousinfusion.Pain control Diamorphine (p. 205) is the preferredopioid since its high solubility permits a large dose to begiven in a small volume (see under Mixing and Compatibility).The table on p. 21 shows approximate equivalentdoses of morphine and diamorphine.Restlessness and confusion Haloperidol has littlesedative effect. Levomepromazine (p. 175) has a sedativeeffect. Midazolam is a sedative and an antiepilepticthat may be suitable for a very restless patient.Mixing and compatibility The general principle thatinjections should be given into separate sites (andProblems encountered with syringe drivers Thefollowing are problems that may be encountered withsyringe drivers and the action that should be taken:. if the subcutaneous infusion runs too quickly checkthe rate setting and the calculation;. if the subcutaneous infusion runs too slowly checkthe start button, the battery, the syringe driver, thecannula, and make sure that the injection site is notinflamed;. if there is an injection site reaction make sure thatthe site does not need to be changed—firmness orswelling at the site of injection is not in itself anindication for change, but pain or obvious inflammationis.1. Cyclizine may precipitate at concentrations above 10 mg/mL or in the presence of sodium chloride 0.9% or as theconcentration of diamorphine relative to cyclizine increases;mixtures of diamorphine and cyclizine are alsolikely to precipitate after 24 hours.2. Special care is needed to avoid precipitation of dexamethasonewhen preparing it.3. Mixtures of haloperidol and diamorphine are likely toprecipitate after 24 hours if haloperidol concentration isabove 2 mg/mL.4. Under some conditions, infusions containing metoclopramidebecome discoloured; such solutions should bediscarded.

BNFC 2011–2012 Prescribing in palliative care 21Equivalent doses of morphine sulphate anddiamorphine hydrochloride given over 24hoursThese equivalences are approximate only and mayneed to be adjusted according to responseOralmorphinesulphateMORPHINESubcutaneousinfusion ofmorphine sulphatePARENTERALDIAMORPHINESubcutaneousinfusion ofdiamorphinehydrochlorideover 24 hours over 24 hours over 24 hours30 mg 15 mg 10 mg60 mg 30 mg 20 mg90 mg 45 mg 30 mg120 mg 60 mg 40 mg180 mg 90 mg 60 mg240 mg 120 mg 80 mg360 mg 180 mg 120 mg480 mg 240 mg 160 mg600 mg 300 mg 200 mg780 mg 390 mg 260 mg960 mg 480 mg 320 mg1200 mg 600 mg 400 mgIf breakthrough pain occurs give a subcutaneousinjection equivalent to one-tenth to one-sixth of thetotal 24-hour subcutaneous infusion dose. With anintermittent subcutaneous injection absorption issmoother so that the risk of adverse effects at peakabsorption is avoided (an even better method is to usea subcutaneous butterfly needle).To minimise the risk of infection no subcutaneousinfusion solution should be used for longer than 24hours.Prescribing in palliative care

22 Prescribing in dental practice BNFC 2011–2012Prescribing in dental practiceAdvice on the drug management of dental and oralconditions is covered in the main text. For ease ofaccess, guidance on such conditions is usually identifiedby means of a relevant heading (e.g. Dental andOrofacial Pain) in the appropriate sections.Prescribing in dental practiceThe following is a list of topics of particular relevance todental surgeons.General guidancePrescribing by dental surgeons, see BNFOral side-effects of drugs, see BNFMedical emergencies in dental practice, see BNFMedical problems in dental practice, see BNFDrug management of dental and oral conditionsDental and orofacial pain, p. 199Neuropathic pain, p. 212Non-opioid analgesics and compound analgesicpreparations, p. 199Opioid analgesics, p. 204Non-steroidal anti-inflammatory drugs, p. 500Oral infectionsBacterial infections, p. 244Phenoxymethylpenicillin, p. 258Broad-spectrum penicillins (amoxicillin andampicillin), p. 261Cephalosporins (cefalexin and cefradine),p. 266Tetracyclines, p. 274Macrolides (clarithromycin, erythromycin andazithromycin), p. 280Clindamycin, p. 283Metronidazole, p. 296Fusidic acid p. 587Fungal infections, p. 545Local treatment, p. 545Systemic treatment, p. 300Viral infections, p. 545Herpetic gingivostomatitis, local treatment,p. 545Herpetic gingivostomatitis, systemic treatment,p. 321 and p. 545Herpes labialis, p. 591Anaesthetics, anxiolytics and hypnoticsAnaesthesia, sedation, and resuscitation in dentalpractice, p. 629Hypnotics, p. 170Sedation for dental procedures, p. 637Local anaesthesia, p. 649Oral ulceration and inflammation, p. 543Mouthwashes and gargles, p. 546Dry mouth, p. 548MineralsFluorides, p. 476Aromatic inhalations, p. 166Nasal decongestants, p. 541Dental Practitioners’ Formulary, p. 794

BNFC 2011–2012 Drugs and sport 23Drugs and sportUK Anti-Doping, the national body responsible for theUK’s anti-doping policy, advises that athletes are personallyresponsible should a prohibited substance bedetected in their body. An advice card listing examplesof permitted and prohibited substances is availablefrom:UK Anti-DopingOceanic House1a Cockspur StreetLondon SW1Y 5BGTel: (020) 7766 7350information@ukad.org.ukwww.ukad.org.ukGeneral Medical Council’s adviceDoctors who prescribe or collude in the provision ofdrugs or treatment with the intention of improperlyenhancing an individual’s performance in sport contravenethe GMC’s guidance, and such actions wouldusually raise a question of a doctor’s continuedregistration. This does not preclude the provisionof any care or treatment where the doctor’s intentionis to protect or improve the patient’s health.Drugs and sport

Emergency treatment of poisoning24 BNFC 2011–2012Emergency treatment ofpoisoningThese notes provide only an overview of the treatmentof poisoning and it is strongly recommended that eitherTOXBASE or the UK National Poisons InformationService (see below) be consulted when there is doubtabout the degree of risk or about appropriate management.Most childhood poisoning is accidental. Other causesinclude intentional overdose, drug abuse, iatrogenic anddeliberate poisoning. The drugs most commonlyinvolved in childhood poisoning are paracetamol, ibuprofen,orally ingested creams, aspirin, iron preparations,cough medicines, and the contraceptive pill.Hospital admission Children who have features ofpoisoning should generally be admitted to hospital.Children who have taken poisons with delayed actionsshould also be admitted, even if they appear well.Delayed-action poisons include aspirin, iron, paracetamol,tricyclic antidepressants, and co-phenotrope(diphenoxylate with atropine, Lomotil c ); the effects ofmodified-release preparations are also delayed. A noteof all relevant information, including what treatment hasbeen given, should accompany the patient to hospital.Further information and adviceTOXBASE, the primary clinical toxicology database ofthe National Poisons Information Service, is available onthe Internet to registered users at www.toxbase.org (abackup site is available at www.toxbasebackup.org if themain site cannot be accessed). It provides informationabout routine diagnosis, treatment, and management ofpatients exposed to drugs, household products, andindustrial and agricultural chemicals.the course of events. All relevant information should besought from the poisoned child and from their carers.However, such information should be interpreted withcare because it may not be complete or entirely reliable.Sometimes symptoms arise from other illnesses, andchildren should be assessed carefully. Accidents mayinvolve a number of domestic and industrial products(the contents of which are not generally known). TheNational Poisons Information Service should be consultedwhen there is doubt about any aspect of suspectedpoisoning.RespirationRespiration is often impaired in unconscious children.An obstructed airway requires immediate attention. Inthe absence of trauma, the airway should be openedwith simple measures such as chin lift or jaw thrust. Anoropharyngeal or nasopharyngeal airway may be usefulin children with reduced consciousness to preventobstruction, provided ventilation is adequate. Intubationand ventilation should be considered in children whoseairway cannot be protected or who have respiratoryacidosis because of inadequate ventilation; such childrenshould be monitored in a critical care area.Most poisons that impair consciousness also depressrespiration. Assisted ventilation (either mouth-to-mouthor using a bag-valve-mask device) may be needed.Oxygen is not a substitute for adequate ventilation,although it should be given in the highest concentrationpossible in poisoning with carbon monoxide and irritantgases.The potential for pulmonary aspiration of gastric contentsshould be considered.Specialist information and advice on the treatmentof poisoning is available day and night from the UKNational Poisons Information Service on the followingnumber:Tel: 0844 892 0111Advice on laboratory analytical services can beobtained from TOXBASE or from the National PoisonsInformation Service.Help with identifying capsules or tablets may be availablefrom a regional medicines information centre (seeinside front cover) or (out of hours) from the NationalPoisons Information Service.General careIt is often impossible to establish with certainty theidentity of the poison and the size of the dose. This isnot usually important because only a few poisons (suchas opioids, paracetamol, and iron) have specific antidotes;few children require active removal of the poison.In most children, treatment is directed at managingsymptoms as they arise. Nevertheless, knowledge ofthe type and timing of poisoning can help in anticipatingBlood pressureHypotension is common in severe poisoning with centralnervous system depressants; if severe this may leadto irreversible brain damage or renal tubular necrosis.Hypotension should be corrected initially by raising thefoot of the bed and administration of either sodiumchloride intravenous infusion or a colloidal infusion.Vasoconstrictor sympathomimetics (section 2.7.2) arerarely required and their use may be discussed with theNational Poisons Information Service.Fluid depletion without hypotension is common afterprolonged coma and after aspirin poisoning due tovomiting, sweating, and hyperpnoea.Hypertension, often transient, occurs less frequentlythan hypotension in poisoning; it may be associatedwith sympathomimetic drugs such as amfetamines,phencyclidine, and cocaine.HeartCardiac conduction defects and arrhythmias can occurin acute poisoning, notably with tricyclic antidepres-

BNFC 2011–2012 Emergency treatment of poisoning 25sants, some antipsychotics, and some antihistamines.Arrhythmias often respond to correction of underlyinghypoxia, acidosis, or other biochemical abnormalities,but ventricular arrhythmias that cause serious hypotensionmay require treatment (section 2.3.1). If theQT interval is prolonged, specialist advice should besought because the use of some anti-arrhythmic drugsmay be inappropriate. Supraventricular arrhythmias areseldom life-threatening and drug treatment is best withhelduntil the child reaches hospital.Body temperatureHypothermia may develop in patients of any age whohave been deeply unconscious for some hours, particularlyfollowing overdose with barbiturates or phenothiazines.It may be missed unless core temperature ismeasured using a low-reading rectal thermometer or bysome other means. Hypothermia should be managed byprevention of further heat loss and appropriate rewarmingas clinically indicated.Hyperthermia can develop in children taking CNSstimulants; children are also at risk when taking therapeuticdoses of drugs with antimuscarinic properties.Hyperthermia is initially managed by removing allunnecessary clothing and using a fan. Sponging withtepid water will promote evaporation. Advice should besought from the National Poisons Information Serviceon the management of severe hyperthermia resultingfrom conditions such as the serotonin syndrome.Both hypothermia and hyperthermia require urgenthospitalisation for assessment and supportive treatment.ConvulsionsSingle short-lived convulsions do not require treatment.If convulsions are protracted or recur frequently, lorazepam100 micrograms/kg (max. 4 mg) or diazepam (preferablyas emulsion) 300–400 micrograms/kg (max.20 mg) should be given by slow intravenous injectioninto a large vein. Benzodiazepines should not be givenby the intramuscular route for convulsions. If the intravenousroute is not readily available, midazolam [unlicenseduse] can be given by the buccal route or diazepamcan be administered as a rectal solution (section4.8.2).Active elimination techniques Repeated doses ofactivated charcoal by mouth may enhance the eliminationof some drugs after they have been absorbed;repeated doses are given after overdosage with:CarbamazepineDapsonePhenobarbitalQuinineTheophyllineVomiting should be treated (e.g. with an antiemeticdrug) since it may reduce the efficacy of charcoaltreatment. In cases of intolerance, the dose may bereduced and the frequency increased but this maycompromise efficacy.Other techniques intended to enhance the elimination ofpoisons after absorption are only practicable in hospitaland are only suitable for a small number of severelypoisoned patients. Moreover, they only apply to a limitednumber of poisons. Examples include:. haemodialysis for ethylene glycol, lithium, methanol,phenobarbital, salicylates, and sodium valproate. alkalinisation of the urine for salicylates.Removal from the gastro-intestinal tract Gastriclavage is rarely required as benefit rarely outweighs risk;advice should be sought from the National PoisonsInformation Service if a significant quantity of iron orlithium has been ingested within the previous hour.Whole bowel irrigation (by means of a bowel cleansingpreparation) has been used in poisoning with certainmodified-release or enteric-coated formulations, insevere poisoning with lithium salts, and if illicit drugsare carried in the gastro-intestinal tract (‘body-packing’).However, it is not clear that the procedure improvesoutcome and advice should be sought from a poisonsinformation centre.The administration of laxatives alone has no role in themanagement of the poisoned child and is not a recommendedmethod of gut decontamination. The routineuse of a laxative in combination with activated charcoalhas mostly been abandoned. Laxatives should not beadministered to young children because of the likelihoodof fluid and electrolyte imbalance.Emergency treatment of poisoningRemoval and eliminationPrevention of absorptionGiven by mouth, activatedcharcoal can adsorb many poisons in the gastro-intestinalsystem, thereby reducing their absorption.The sooner it is given the more effective it is, but it maystill be effective up to 1 hour after ingestion of thepoison—longer in the case of modified-release preparationsor of drugs with antimuscarinic (anticholinergic)properties. It is particularly useful for the prevention ofabsorption of poisons that are toxic in small amountssuch as antidepressants.A second dose may occasionally be required whenblood-drug concentration continues to rise suggestingdelayed drug release or delayed gastric emptying.For the use of charcoal in active elimination techniques,see below.CHARCOAL, ACTIVATEDCautions drowsy or comatose child (risk of aspiration—ensureairway protected); reduced gastrointestinalmotility (risk of obstruction); not for poisoningwith petroleum distillates, corrosive substances,alcohols, malathion, and metal salts including iron andlithium saltsSide-effects black stoolsIndication and doseReduction of absorption of poisons. By mouthNeonate 1 g/kgChild 1 month–12 years 1 g/kg (max. 50 g)Child 12–18 years 50 g

26 Emergency treatment of poisoning BNFC 2011–2012Emergency treatment of poisoningActive elimination of poisons. By mouthNeonate 1 g/kg every 4 hoursChild 1 month–12 years 1 g/kg (max. 50 g) every4 hoursChild 12–18 years 50 g every 4 hoursAdministration suspension or reconstituted powdermay be mixed with soft drinks (e.g. caffeine-free dietcola) or fruit juices to mask the tasteActidose-Aqua c Advance (Alliance)Oral suspension, activated charcoal 1.04 g/5 mL, netprice 50-g pack (240 mL) = £8.69Carbomix c (Beacon)Powder, activated charcoal, net price 25-g pack =£8.50, 50-g pack = £11.90Charcodote c (TEVA UK)Oral suspension, activated charcoal 1 g/5 mL, netprice 50-g pack = £11.88Specific drugsAlcoholAcute intoxication with alcohol (ethanol) is common inadults but also occurs in children. The features includeataxia, dysarthria, nystagmus, and drowsiness, whichmay progress to coma, with hypotension and acidosis.Aspiration of vomit is a special hazard and hypoglycaemiamay occur in children and some adults. Patientsare managed supportively, with particular attention tomaintaining a clear airway and measures to reduce therisk of aspiration of gastric contents. The blood glucoseis measured and glucose given if indicated.The National Poisons Information Service (Tel:0844 892 0111) will provide specialist advice on allaspects of poisoning day and nightAnalgesics (non-opioid)Aspirin The main features of salicylate poisoning arehyperventilation, tinnitus, deafness, vasodilatation, andsweating. Coma is uncommon but indicates very severepoisoning. The associated acid-base disturbances arecomplex.Treatment must be in hospital, where plasma salicylate,pH, and electrolytes (particularly potassium) can bemeasured; absorption of aspirin may be slow and theplasma-salicylate concentration may continue to rise forseveral hours, requiring repeated measurement.Plasma-salicylate concentration may not correlatewith clinical severity in children, and clinical and biochemicalassessment is necessary. Generally, the clinicalseverity of poisoning is less below a plasma-salicylateconcentration of 500 mg/litre (3.6 mmol/litre) unlessthere is evidence of metabolic acidosis. Activated charcoalshould be given within 1 hour of ingesting morethan 125 mg/kg aspirin. Fluid losses should be replacedand intravenous sodium bicarbonate may be given(ensuring plasma-potassium concentration is maintainedwithin the reference range) to enhance urinarysalicylate excretion (optimum urinary pH 7.5–8.5); treatmentshould be given in a high dependency unit.Plasma-potassium concentration should be correctedbefore giving sodium bicarbonate as hypokalaemiamay complicate alkalinisation of the urine.Haemodialysis is the treatment of choice for severesalicylate poisoning and should be considered whenthe plasma-salicylate concentration exceeds 700 mg/litre (5.1 mmol/litre) or in the presence of severe metabolicacidosis, convulsions, renal failure, pulmonaryoedema or persistently high plasma-salicylate concentrationsunresponsive to urinary alkalinisation.NSAIDs Mefenamic acid has important consequencesin overdosage because it can cause convulsions, which ifprolonged or recurrent, require treatment with intravenouslorazepam or diazepam.Overdosage with ibuprofen may cause nausea, vomiting,epigastric pain, and tinnitus, but more serioustoxicity is very uncommon. Activated charcoal followedby symptomatic measures are indicated if more than100 mg/kg has been ingested within the preceding hour.ParacetamolIn cases of intravenous paracetamol poisoningcontact the National Poisons Information Servicefor advice on risk assessment and management.Single or repeated doses totalling as little as 150 mg/kgof paracetamol ingested within 24 hours may causesevere hepatocellular necrosis and, much less frequently,renal tubular necrosis. To avoid underestimatingthe potentially toxic paracetamol dose ingested byobese children who weigh more than 110 kg, use a bodyweightof 110 kg (rather than their actual body-weight)when calculating the total dose of paracetamol ingested(in mg/kg). Children at high-risk of liver damage, includingthose taking enzyme-inducing drugs or who aremalnourished (see below), may develop liver toxicitywith as little as 75 mg/kg of paracetamol taken within24 hours. Nausea and vomiting, the only early featuresof poisoning, usually settle within 24 hours. Persistencebeyond this time, often associated with the onset of rightsubcostal pain and tenderness, usually indicates developmentof hepatic necrosis. Liver damage is maximal 3–4 days after ingestion and may lead to encephalopathy,haemorrhage, hypoglycaemia, cerebral oedema, anddeath.Therefore, despite a lack of significant early symptoms,children who have taken an overdose of paracetamolshould be transferred to hospital urgently.Administration of activated charcoal should be consideredif paracetamol in excess of 150 mg/kg (or in excessof 75 mg/kg for those considered to be at high-risk, seebelow) is thought to have been ingested within theprevious hour.Acetylcysteine protects the liver if infused up to, andpossibly beyond, 24 hours of ingesting paracetamol. It ismost effective if given within 8 hours of ingestion, afterwhich effectiveness declines. In children who present 8–36 hours after a potentially toxic ingestion, acetylcysteinetreatment should commence immediately even ifplasma-paracetamol concentrations are not yet available.If more than 24 hours have elapsed advice shouldbe sought from the National Poisons Information Service.Giving acetylcysteine by mouth [unlicensed route]

BNFC 2011–2012 Emergency treatment of poisoning 27Emergency treatment of poisoningPatients whose plasma-paracetamol concentrations are on or above the normal treatment line should be treatedwith acetylcysteine by intravenous infusion (or, if acetylcysteine cannot be used, with methionine by mouth,provided the overdose has been taken within 10–12 hours and the patient is not vomiting).Children at high-risk of liver damage include those:. taking liver enzyme-inducing drugs (e.g. carbamazepine, phenobarbital, phenytoin, primidone, rifampicin,rifabutin, efavirenz, nevirapine, alcohol, St John’s wort);. who are malnourished (e.g. in anorexia or bulimia, cystic fibrosis, hepatitis C, in underweight childrenwith failure to thrive, in alcoholism, or those who are HIV-positive);. who have a febrile illness;. who have not eaten for a few days.These children should be treated if their plasma-paracetamol concentration is on or above the high-risktreatment line.The prognostic accuracy after 15 hours is uncertain but a plasma-paracetamol concentration on or above therelevant treatment line should be regarded as carrying a serious risk of liver damage.Graph reproduced courtesy of University of Wales College of Medicine Therapeutics and Toxicology Centreis an alternative if intravenous access is not possible—contact the National Poisons Information Service foradvice. In remote areas, methionine by mouth is analternative only if acetylcysteine cannot be givenpromptly. Once the child reaches hospital the need tocontinue treatment with the antidote will be assessedfrom the plasma-paracetamol concentration (related tothe time from ingestion).Children at risk of liver damage and therefore requiringtreatment can be identified from a single measurementof the plasma-paracetamol concentration, related to thetime from ingestion, provided this time interval is notless than 4 hours; earlier samples may be misleading.The concentration is plotted on a paracetamol treatmentgraph, with a reference line (‘normal treatmentline’) joining plots of 200 mg/litre (1.32 mmol/litre) at

28 Emergency treatment of poisoning BNFC 2011–2012Emergency treatment of poisoning4 hours and 6.25 mg/litre (0.04 mmol/litre) at 24 hours(see p. 27). Those whose plasma-paracetamol concentrationis on or above the normal treatment line aretreated with acetylcysteine by intravenous infusion (or,if acetylcysteine is not available, with methionine bymouth, provided the overdose has been taken within10–12 hours and the child is not vomiting).Children at high-risk of liver damage include those:. taking liver enzyme-inducing drugs (e.g. carbamazepine,phenobarbital, phenytoin, primidone, rifampicin,rifabutin, efavirenz, nevirapine, alcohol, StJohn’s wort);. who are malnourished (e.g. in anorexia or bulimia,cystic fibrosis, hepatitis C, in underweight childrenwith ‘failure to thrive’, in alcoholism, or those whoare HIV-positive);. who have a febrile illness;. who have not eaten for a few days.These children may develop toxicity at lower plasmaparacetamolconcentrations and should be treated if theconcentration is on or above the high-risk treatment line(which joins plots that are at 50% of the plasma-paracetamolconcentrations of the normal treatment line).The prognostic accuracy of plasma-paracetamol concentrationtaken after 15 hours is uncertain, but aconcentration on or above the relevant treatment lineshould be regarded as carrying a serious risk of liverdamage.The plasma-paracetamol concentration may be difficultto interpret when paracetamol has been ingested overseveral hours (staggered overdose). If there is doubtabout timing or the need for treatment then the childshould be treated with acetylcysteine.The National Poisons Information Service (Tel:0844 892 0111) will provide specialist advice on allaspects of poisoning day and nightACETYLCYSTEINECautions asthma (see Side-effects below, but do notdelay acetylcysteine treatment); acetylcysteine maymildly increase INR and prothrombin timeSide-effects hypersensitivity-like reactions managedby reducing infusion rate or suspending until reactionsettled (rash also managed by giving antihistamine;acute asthma managed by giving nebulised shortactingbeta 2 agonist)—contact the National PoisonsInformation Service if reaction severe; mild increasein INR and prothrombin timeIndication and doseParacetamol overdosage see notes above. By intravenous infusionNeonate initially 150 mg/kg in 3 mL/kg Glucose5% and given over 15 minutes, followed by 50 mg/kg in 7 mL/kg Glucose 5% and given over 4 hours,then 100 mg/kg in 14 mL/kg Glucose 5% andgiven over 16 hoursChild 1 month–5 years (or body-weight under20 kg) initially 150 mg/kg in 3 mL/kg Glucose 5%and given over 15 minutes, followed by 50 mg/kgin 7 mL/kg Glucose 5% and given over 4 hours,then 100 mg/kg in 14 mL/kg Glucose 5% andgiven over 16 hoursChild 5–12 years (or body-weight over 20 kg)initially 150 mg/kg in 100 mL Glucose 5% andgiven over 15 minutes, followed by 50 mg/kg in250 mL Glucose 5% and given over 4 hours, then100 mg/kg in 500 mL Glucose 5% and given over16 hoursChild 12–18 years initially 150 mg/kg (max.16.5 g) in 200 mL Glucose 5% and given over 15minutes, followed by 50 mg/kg (max. 5.5 g) in500 mL Glucose 5% and given over 4 hours, then100 mg/kg (max.11 g) in 1 litre Glucose 5% andgiven over 16 hoursNote Glucose 5% is preferred infusion fluid; Sodium Chloride0.9% is an alternative if Glucose 5% unsuitableAcetylcysteine (Non-proprietary) AConcentrate for intravenous infusion, acetylcysteine200 mg/mL, net price 10-mL amp = £1.96Parvolex c (UCB Pharma) AConcentrate for intravenous infusion, acetylcysteine200 mg/mL, net price 10-mL amp = £2.25Electrolytes Na + 14 mmol/10-mL ampMETHIONINEHepatic impairment may precipitate comaSide-effects nausea, vomiting, drowsiness, irritabilityIndication and doseParacetamol overdosage see notes above. By mouthChild under 6 years 1 g every 4 hours for a total of4 dosesChild 6–18 years 2.5 g every 4 hours for a total of4 dosesMethionine (Pharma Nord)Tablets, f/c, methionine 500 mg, net price 20-tabpack = £9.95Analgesics (opioid)Opioids (narcotic analgesics) cause varying degrees ofcoma, respiratory depression, and pinpoint pupils. Thespecific antidote naloxone is indicated if there is comaor bradypnoea. Since naloxone has a shorter duration ofaction than many opioids, close monitoring andrepeated injections are necessary according to the respiratoryrate and depth of coma. When repeated administrationof naloxone is required, it can be given bycontinuous intravenous infusion instead and the rateof infusion adjusted according to vital signs. All childrenshould be observed for at least 6 hours after the lastdose of naloxone. The effects of some opioids, such asbuprenorphine, are only partially reversed by naloxone.Dextropropoxyphene and methadone have very longdurations of action; patients may need to be monitoredfor long periods following large overdoses.Naloxone reverses the opioid effects of dextropropoxyphene;the long duration of action of dextropropoxyphenecalls for prolonged monitoring and further dosesof naloxone may be required. Norpropoxyphene, ametabolite of dextropropoxyphene, also has cardiotoxiceffects which may require treatment with sodiumbicarbonate, or magnesium sulphate, or both; arrhythmiasmay occur for up to 12 hours.

BNFC 2011–2012 Emergency treatment of poisoning 29NALOXONE HYDROCHLORIDECautions physical dependence on opioids; cardiacirritability; naloxone is short-acting, see notes abovePregnancy section 15.1.7Breast-feeding section 15.1.7Indication and doseSafe PracticeDoses used in acute opioid overdosage may not beappropriate for the management of opioid-inducedrespiratory depression and sedation in those receivingpalliative care and in chronic opioid use; see alsosection 15.1.7 for management of postoperative respiratorydepressionOverdosage with opioids. By intravenous injectionNeonate 10 micrograms/kg; if no response, givesubsequent dose of 100 micrograms/kg (thenreview diagnosis); further doses may be required ifrespiratory function deterioratesChild 1 month–12 years 10 micrograms/kg; if noresponse, give subsequent dose of 100 micrograms/kg(then review diagnosis); further dosesmay be required if respiratory function deterioratesChild 12–18 years 0.4–2 mg; if no responserepeat at intervals of 2–3 minutes to a max. of10 mg (then review diagnosis); further doses maybe required if respiratory function deteriorates. By subcutaneous or intramuscular injectionAs intravenous injection but only if intravenousroute not feasible (onset of action slower). By continuous intravenous infusion using aninfusion pumpNeonate rate adjusted according to response(initially, rate may be set at 60% of the initialresuscitative intravenous injection dose per hour)Child 1 month–18 years rate adjusted accordingto response (initially, rate may be set at 60% of theinitial resuscitative intravenous injection dose perhour)Note The initial resuscitative intravenous injection doseis that which maintained satisfactory ventilation for atleast 15 minutesReversal of postoperative respiratory depression,reversal of respiratory and CNS depressionin neonate following maternal opioid useduring labour section 15.1.7Administration for continuous intravenous infusion,dilute to a concentration of up to 200 micrograms/mLwith Glucose 5% or Sodium Chloride 0.9%disposable syringe = £12.96, 5-mL disposable syringe= £12.68AntidepressantsTricyclic and related antidepressantsTricyclicand related antidepressants cause dry mouth, coma ofvarying degree, hypotension, hypothermia, hyperreflexia,extensor plantar responses, convulsions, respiratoryfailure, cardiac conduction defects, and arrhythmias.Dilated pupils and urinary retention also occur. Metabolicacidosis may complicate severe poisoning; deliriumwith confusion, agitation, and visual and auditory hallucinations,are common during recovery.Assessment in hospital is strongly advised in case ofpoisoning by tricyclic and related antidepressants butsymptomatic treatment can be given before transfer.Supportive measures to ensure a clear airway andadequate ventilation during transfer are mandatory.Intravenous lorazepam or diazepam (preferably in emulsionform) may be required to treat convulsions. Activatedcharcoal given within 1 hour of the overdosereduces absorption of the drug. Although arrhythmiasare worrying, some will respond to correction of hypoxiaand acidosis. The use of anti-arrhythmic drugs is bestavoided, but intravenous infusion of sodium bicarbonatecan arrest arrhythmias or prevent them in those with anextended QRS duration. Diazepam given by mouth isusually adequate to sedate delirious children but largedoses may be required.Selective serotonin re-uptake inhibitors (SSRIs)Symptoms of poisoning by selective serotonin re-uptakeinhibitors include nausea, vomiting, agitation, tremor,nystagmus, drowsiness, and sinus tachycardia; convulsionsmay occur. Rarely, severe poisoning results inthe serotonin syndrome, with marked neuropsychiatriceffects, neuromuscular hyperactivity, and autonomicinstability; hyperthermia, rhabdomyolysis, renal failure,and coagulopathies may develop.Management of SSRI poisoning is supportive. Activatedcharcoal given within 1 hour of the overdose reducesabsorption of the drug. Convulsions can be treated withlorazepam, diazepam, or buccal midazolam [unlicenseduse] (see p. 25). Contact the National Poisons InformationService for the management of hyperthermia or theserotonin syndrome.AntimalarialsOverdosage with quinine, chloroquine, or hydroxychloroquineis extremely hazardous and difficult totreat. Urgent advice from the National Poisons InformationService is essential. Life-threatening featuresinclude arrhythmias (which can have a very rapidonset) and convulsions (which can be intractable).Emergency treatment of poisoningNaloxone (Non-proprietary) AInjection, naloxone hydrochloride 20 micrograms/mL, net price 2-mL amp = £5.50; 400 micrograms/mL, net price 1-mL amp = £4.10; 1 mg/mL, 2-mLprefilled syringe = £8.36Minijet c Naloxone (UCB Pharma) AInjection, naloxone hydrochloride 400 micrograms/mL, net price 1-mL disposable syringe = £20.40, 2-mLBeta-blockersTherapeutic overdosages with beta-blockers may causelightheadedness, dizziness, and possibly syncope as aresult of bradycardia and hypotension; heart failure maybe precipitated or exacerbated. These complications aremost likely in children with conduction system disordersor impaired myocardial function. Bradycardia is themost common arrhythmia caused by beta-blockers,

30 Emergency treatment of poisoning BNFC 2011–2012Emergency treatment of poisoningbut sotalol may induce ventricular tachyarrhythmias(sometimes of the torsade de pointes type). The effectsof massive overdosage can vary from one beta-blockerto another; propranolol overdosage in particular maycause coma and convulsions.Acute massive overdosage must be managed in hospitaland expert advice should be obtained. Maintenance of aclear airway and adequate ventilation is mandatory. Anintravenous injection of atropine is required to treatbradycardia (40 micrograms/kg, max. 3 mg). Cardiogenicshock unresponsive to atropine is probably besttreated with an intravenous injection of glucagon (50–150 micrograms/kg, max. 10 mg) [unlicensed indicationand dose] in glucose 5% (with precautions to protect theairway in case of vomiting) followed by an intravenousinfusion of 50 micrograms/kg/hour. If glucagon is notavailable, intravenous isoprenaline (available from ‘special-order’manufacturers or specialist importing companies,see p. 809) is an alternative. A cardiac pacemakercan be used to increase the heart rate.Calcium-channel blockersFeatures of calcium-channel blocker poisoning includenausea, vomiting, dizziness, agitation, confusion, andcoma in severe poisoning. Metabolic acidosis andhyperglycaemia may occur. Verapamil and diltiazemhave a profound cardiac depressant effect causing hypotensionand arrhythmias, including complete heartblock and asystole. The dihydropyridine calcium-channelblockers cause severe hypotension secondary toprofound peripheral vasodilatation.Activated charcoal should be considered if the childpresents within 1 hour of overdosage with a calciumchannelblocker; repeated doses of activated charcoalare considered if a modified-release preparation isinvolved (although activated charcoal may be effectivebeyond 1 hour with modified-release preparations). Inchildren with significant features of poisoning, calciumchloride or calcium gluconate (section 9.5.1.1) is givenby injection; atropine is given to correct symptomaticbradycardia. In severe cases, an insulin and glucoseinfusion may be required in the management of hypotensionand myocardial failure. For the management ofhypotension, the choice of inotropic sympathomimeticdepends on whether hypotension is secondary to vasodilatationor to myocardial depression—advice shouldbe sought from the National Poisons Information Service.Hypnotics and anxiolyticsBenzodiazepines Benzodiazepines taken alone causedrowsiness, ataxia, dysarthria, nystagmus, and occasionallyrespiratory depression, and coma. Theypotentiate the effects of other central nervous systemdepressants taken concomitantly. Activated charcoalcan be given within 1 hour of ingesting a significantquantity of benzodiazepine, provided the child is awakeand the airway is protected. Use of the benzodiazepineantagonist flumazenil [unlicensed indication] can behazardous, particularly in mixed overdoses involvingtricyclic antidepressants or in benzodiazepine-dependentpatients. Flumazenil may prevent the need forventilation, particularly in children with severe respiratorydisorders; it should be used on expert advice andnot as a diagnostic test in children with a reduced levelof consciousness.Iron saltsIron poisoning in childhood is usually accidental. Thesymptoms are nausea, vomiting, abdominal pain, diarrhoea,haematemesis, and rectal bleeding. Hypotensionand hepatocellular necrosis can occur later. Coma,shock and metabolic acidosis indicate severe poisoning.Advice should be sought from the National PoisonsInformation Service if a significant quantity of iron hasbeen ingested within the previous hour.Mortality is reduced by intensive and specific therapywith desferrioxamine, which chelates iron. The serumironconcentration is measured as an emergency andintravenous desferrioxamine given to chelate absorbediron in excess of the expected iron binding capacity. Insevere toxicity intravenous desferrioxamine should begiven immediately without waiting for the result of theserum-iron measurement.DESFERRIOXAMINE MESILATE(Deferoxamine Mesilate)Cautions section 9.1.3Renal impairment section 9.1.3Pregnancy section 9.1.3Breast-feeding section 9.1.3Side-effects section 9.1.3Licensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseIron poisoning. By continuous intravenous infusionNeonate up to 15 mg/kg/hour, reduced after 4–6hours; max. 80 mg/kg in 24 hours (in severe cases,higher doses on advice from the National PoisonsInformation Service)Child 1 month–18 years up to 15 mg/kg/hour,reduced after 4–6 hours; max. 80 mg/kg in 24hours (in severe cases, higher doses on advicefrom the National Poisons Information Service)Chronic iron overload section 9.1.3PreparationsSection 9.1.3LithiumLithium intoxication can occur as a complication oflong-term therapy and is caused by reduced excretionof the drug because of a variety of factors includingdehydration, deterioration of renal function, infections,and co-administration of diuretics or NSAIDs (or otherdrugs that interact). Acute deliberate overdoses mayalso occur with delayed onset of symptoms (12 hours ormore) due to slow entry of lithium into the tissues andcontinuing absorption from modified-release formulations.The early clinical features are non-specific and mayinclude apathy and restlessness which could be confusedwith mental changes due to the child’s depressive

BNFC 2011–2012 Emergency treatment of poisoning 31illness. Vomiting, diarrhoea, ataxia, weakness, dysarthria,muscle twitching, and tremor may follow. Severepoisoning is associated with convulsions, coma, renalfailure, electrolyte imbalance, dehydration, and hypotension.Therapeutic serum-lithium concentrations are withinthe range of 0.4–1 mmol/litre; concentrations in excessof 2 mmol/litre are usually associated with serioustoxicity and such cases may need treatment withhaemodialysis if neurological symptoms or renal failureare present. In acute overdosage, much higher serumlitiumconcentrations may be present without featuresof toxicity and all that is usually necessary is to takemeasures to increase urine output (e.g. by increasingfluid intake, but avoiding diuretics). Otherwise, treatmentis supportive with special regard to electrolytebalance, renal function, and control of convulsions.Whole-bowel irrigation should be considered for significantingestion, but advice should be sought from theNational Poisons Information Service, p. 24.The National Poisons Information Service (Tel:0844 892 0111) will provide specialist advice on allaspects of poisoning day and nightPhenothiazines and related drugsPhenothiazines cause less depression of consciousnessand respiration than other sedatives. Hypotension,hypothermia, sinus tachycardia, and arrhythmias maycomplicate poisoning. Dystonic reactions can occurwith therapeutic doses (particularly with prochlorperazineand trifluoperazine), and convulsions may occur insevere cases. Arrhythmias may respond to correction ofhypoxia, acidosis, and other biochemical abnormalities,but specialist advice should be sought if arrhythmiasresult from a prolonged QT interval; the use of someanti-arrhythmic drugs can worsen such arrhythmias.Dystonic reactions are rapidly abolished by injectionof drugs such as procyclidine (section 4.9.2) or diazepam(section 4.8.2, emulsion preferred).Atypical antipsychotic drugsFeatures of poisoning by atypical antipsychotic drugs(section 4.2.1) include drowsiness, convulsions, extrapyramidalsymptoms, hypotension, and ECG abnormalities(including prolongation of the QT interval). Managementis supportive. Activated charcoal can be givenwithin 1 hour of ingesting a significant quantity of anatypical antipsychotic drug.StimulantsAmfetamines Amfetamines cause wakefulness, excessiveactivity, paranoia, hallucinations, and hypertensionfollowed by exhaustion, convulsions, hyperthermia, andcoma. The early stages can be controlled by diazepamor lorazepam; advice should be sought from theNational Poisons Information Service (p. 24) on themanagement of hypertension. Later, tepid sponging,anticonvulsants, and artificial respiration may beneeded.Cocaine Cocaine stimulates the central nervous system,causing agitation, dilated pupils, tachycardia,hypertension, hallucinations, hyperthermia, hypertonia,and hyperreflexia; cardiac effects include chest pain,myocardial infarction, and arrhythmias.Initial treatment of cocaine poisoning involves intravenousadministration of diazepam to control agitationand cooling measures for hyperthermia (see p. 25);hypertension and cardiac effects require specific treatmentand expert advice should be sought.Ecstasy Ecstasy (methylenedioxymethamfetamine,MDMA) may cause severe reactions, even at dosesthat were previously tolerated. The most serious effectsare delirium, coma, convulsions, ventricular arrhythmias,hyperthermia, rhabdomyolysis, acute renal failure,acute hepatitis, disseminated intravascular coagulation,adult respiratory distress syndrome, hyperreflexia,hypotension and intracerebral haemorrhage; hyponatraemiahas also been associated with ecstasy use andsyndrome of inappropriate antidiuretic hormone secretion(SIADH) can occur.Treatment of methylenedioxymethamfetamine poisoningis supportive, with diazepam to control severeagitation or persistent convulsions and close monitoringincluding ECG. Self-induced water intoxication shouldbe considered in patients with ecstasy poisoning.‘Liquid ecstasy’ is a term used for sodium oxybate(gamma-hydroxybutyrate, GHB), which is a sedative.TheophyllineTheophylline and related drugs are often prescribed asmodified-release formulations and toxicity can thereforebe delayed. They cause vomiting (which may be severeand intractable), agitation, restlessness, dilated pupils,sinus tachycardia, and hyperglycaemia. More seriouseffects are haematemesis, convulsions, and supraventricularand ventricular arrhythmias. Severe hypokalaemiamay develop rapidly.Repeated doses of activated charcoal can be used toeliminate theophylline even if more than 1 hour haselapsed after ingestion and especially if a modifiedreleasepreparation has been taken (see also underActive Elimination Techniques). Ondansetron (section4.6) may be effective for severe vomiting that is resistantto other antiemetics. Hypokalaemia is corrected byintravenous infusion of potassium chloride (section9.2.2.1) in 0.9% sodium chloride and may be so severeas to require high doses under ECG monitoring. Convulsionsshould be controlled by intravenous administrationof lorazepam or diazepam (see Convulsions,p. 25). For the management of agitation associatedwith theophylline overdosage, seek specialist advice.Provided the child does not suffer from asthma, a shortactingbeta-blocker (section 2.4) can be administeredintravenously to reverse severe tachycardia, hypokalaemia,and hyperglycaemia.Other poisonsConsult either the National Poisons Information Serviceday and night or TOXBASE, see p. 24.Emergency treatment of poisoning

32 Emergency treatment of poisoning BNFC 2011–2012Emergency treatment of poisoningCyanidesOxygen should be administered to children with cyanidepoisoning. The choice of antidote depends on theseverity of poisoning, certainty of diagnosis, and thecause. Dicobalt edetate is the antidote of choice whenthere is a strong clinical suspicion of severe cyanidepoisoning. Dicobalt edetate itself is toxic, associatedwith anaphylactoid reactions, and is potentially fatal ifadministered in the absence of cyanide poisoning. Aregimen of sodium nitrite followed by sodium thiosulphateis an alternative if dicobalt edetate is not available.Hydroxocobalamin (Cyanokit c —no other preparationof hydroxocobalamin is suitable) can be considered foruse in victims of smoke inhalation who show signs ofsignificant cyanide poisoning.DICOBALT EDETATECautions owing to toxicity to be used only for definitecyanide poisoning when patient tending to lose, or haslost, consciousness; not to be used as a precautionarymeasureSide-effects hypotension, tachycardia, and vomiting;anaphylactoid reactions including facial and laryngealoedema and cardiac abnormalitiesIndication and doseSevere poisoning with cyanides. By intravenous injectionConsult the National Poisons Information Service1Dicobalt Edetate (Non-proprietary) AInjection, dicobalt edetate 15 mg/mL, net price 20-mL (300-mg) amp = £13.751. A restriction does not apply where administration is forsaving life in emergencyHYDROXOCOBALAMINSide-effects gastro-intestinal disturbances, transienthypertension, peripheral oedema, dyspnoea, throatdisorders, hot flush, dizziness, headache, restlessness,memory impairment, red coloration of urine, lymphocytopenia,eye disorders, pustular rashes, pruritus,reversible red coloration of skin and mucous membranesIndication and dosePoisoning with cyanides see notes above. By intravenous infusionChild body-weight 5 kg and over 70 mg/kg(max. 5 g) over 15 minutes; a second doseof 70 mg/kg (max. 5 g) can be given over15 minutes–2 hours depending on severity ofpoisoning and patient stabilityAdministration for intravenous infusion, reconstitute2.5-g vial with 100 mL Sodium Chloride 0.9%; gentlyinvert vial for at least 30 seconds to mix; do not shakeCyanokit c (Swedish Orphan) TAIntravenous infusion, powder for reconstitution,hydroxocobalamin, net price 2 2.5-g vials = £772.00Note Deep red colour of hydroxocobalamin may interferewith laboratory tests (see Side-effects, above)SODIUM NITRITESide-effects flushing and headache due to vasodilatationIndication and dosePoisoning with cyanides (used in conjunctionwith sodium thiosulphate)See under preparation1Sodium Nitrite AInjection, sodium nitrite 3% (30 mg/mL) in water forinjectionsDose. By intravenous injection over 5–20 minutesChild 1 month–18 years 4–10 mg/kg max. 300 mg(0.13–0.33 mL/kg, max. 10 mL, of 3% solution) followedby sodium thiosulphate injection 400 mg/kg, max. 12.5 g(0.8 mL/kg, max. 25 mL, of 50% solution) over 10 minutesAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 8091. A restriction does not apply where administration is forsaving life in emergencySODIUM THIOSULPHATEIndication and dosePoisoning with cyanides (used in conjunction withsodium nitrite)See above under Sodium Nitrite1Sodium Thiosulphate AInjection, sodium thiosulphate 50% (500 mg/mL) inwater for injectionsAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 8091. A restriction does not apply where administration is forsaving life in emergencyEthylene glycol and methanolFomepizole (available from ‘special-order’ manufacturersor specialist importing companies, see p. 809) isthe treatment of choice for ethylene glycol and methanol(methyl alcohol) poisoning. If necessary, ethanol (bymouth or by intravenous infusion) can be used, but withcaution. Advice on the treatment of ethylene glycol andmethanol poisoning should be obtained from theNational Poisons Information Service. It is importantto start antidote treatment promptly in cases of suspectedpoisoning with these agents.Heavy metalsHeavy metal antidotes include succimer (DMSA) [unlicensed],unithiol (DMPS) [unlicensed], sodium calciumedetate, and dimercaprol. Dimercaprol in the managementof heavy metal poisoning has been superseded byother chelating agents. In all cases of heavy metal poisoning,the advice of the National Poisons InformationService should be sought.SODIUM CALCIUM EDETATE(Sodium Calciumedetate)Renal impairment use with caution in mild impairment;avoid in moderate to severe impairment—contact the National Poisons Information Service foradvice

BNFC 2011–2012 Emergency treatment of poisoning 33Side-effects nausea, diarrhoea, abdominal pain, painat site of injection, thrombophlebitis if given toorapidly, renal damage particularly in overdosage;hypotension, lacrimation, myalgia, nasal congestion,sneezing, malaise, thirst, fever, chills, headache andzinc depletion also reportedLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseLead poisoning. By intravenous infusionChild 1 month–18 years 40 mg/kg twice daily forup to 5 days; if necessary a second course can begiven at least 7 days after the first course, and athird course can be given at least 7 days after thesecond courseAdministration for intravenous infusion, dilute to aconcentration of not more 30 mg/mL with Glucose5% or Sodium Chloride 0.9%; give over at least 1 hourLedclair c (Durbin) AInjection, sodium calcium edetate 200 mg/mL, netprice 5-mL amp = £7.29Noxious gasesCarbon monoxideCarbon monoxide poisoning isusually due to inhalation of smoke, car exhaust, orfumes caused by blocked flues or incomplete combustionof fuel gases in confined spaces.Immediate treatment of carbon monoxide poisoning isessential. The child should be moved to fresh air, theairway cleared, and high-flow oxygen 100% administeredas soon as available. Artificial respiration shouldbe given as necessary and continued until adequatespontaneous breathing starts, or stopped only afterpersistent and efficient treatment of cardiac arrest hasfailed. The child should be admitted to hospital becausecomplications may arise after a delay of hours or days.Cerebral oedema may occur in severe poisoning and istreated with an intravenous infusion of mannitol (section2.2.5). Referral for hyperbaric oxygen treatmentshould be discussed with the National Poisons InformationService if the patient is pregnant or in cases ofsevere poisoning such as if the child is or has beenunconscious, or has psychiatric or neurological featuresother than a headache or has myocardial ischaemia oran arrhythmia, or has a blood carboxyhaemoglobinconcentration of more than 20%.Sulphur dioxide, chlorine, phosgene, ammoniaAll of these gases can cause upper respiratory tract andconjunctival irritation. Pulmonary oedema, with severebreathlessness and cyanosis may develop suddenly upto 36 hours after exposure. Death may occur. Childrenare kept under observation and those who developpulmonary oedema are given oxygen. Assisted ventilationmay be necessary in the most serious cases.CS SprayCS spray, which is used for riot control, irritates the eyes(hence ‘tear gas’) and the respiratory tract; symptomsnormally settle spontaneously within 15 minutes. Ifsymptoms persist, the patient should be removed to awell-ventilated area, and the exposed skin washed withsoap and water after removal of contaminated clothing.Contact lenses should be removed and rigid oneswashed (soft ones should be discarded). Eye symptomsshould be treated by irrigating the eyes with physiologicalsaline (or water if saline is not available) andadvice sought from an ophthalmologist. Patients withfeatures of severe poisoning, particularly respiratorycomplications, should be admitted to hospital for symptomatictreatment.Nerve agentsTreatment of nerve agent poisoning is similar to organophosphorusinsecticide poisoning (see below), butadvice must be sought from the National Poisons InformationService. The risk of cross-contamination is significant;adequate decontamination and protectiveclothing for healthcare personnel are essential. In emergenciesinvolving the release of nerve agents, kits(‘NAAS pods’) containing pralidoxime can be obtainedthrough the Ambulance Service from the National BloodService (or the Welsh Blood Service in South Wales ordesignated hospital pharmacies in Northern Ireland andScotland—see TOXBASE for list of designated centres).The National Poisons Information Service (Tel:0844 892 0111) will provide specialist advice on allaspects of poisoning day and nightPesticidesOrganophosphorus insecticides Organophosphorusinsecticides are usually supplied as powders ordissolved in organic solvents. All are absorbed throughthe bronchi and intact skin as well as through the gutand inhibit cholinesterase activity, thereby prolongingand intensifying the effects of acetylcholine. Toxicitybetween different compounds varies considerably, andonset may be delayed after skin exposure.Anxiety, restlessness, dizziness, headache, miosis,nausea, hypersalivation, vomiting, abdominal colic,diarrhoea, bradycardia, and sweating are common featuresof organophosphorus poisoning. Muscle weaknessand fasciculation may develop and progress to generalisedflaccid paralysis, including the ocular and respiratorymuscles. Convulsions, coma, pulmonary oedemawith copious bronchial secretions, hypoxia, and arrhythmiasoccur in severe cases. Hyperglycaemia andglycosuria without ketonuria may also be present.Further absorption of the organophosphorus insecticideshould be prevented by moving the child to fresh air,removing soiled clothing, and washing contaminatedskin. In severe poisoning it is vital to ensure a clearairway, frequent removal of bronchial secretions, andadequate ventilation and oxygenation; gastric lavagemay be considered provided that the airway is protected.Atropine will reverse the muscarinic effects ofacetylcholine and is given by intravenous injection in adose of 20 micrograms/kg (max. 2 mg) as atropine sulphateevery 5 to 10 minutes (according to the severity ofpoisoning) until the skin becomes flushed and dry, thepupils dilate, and bradycardia is abolished.Pralidoxime chloride, a cholinesterase reactivator, isused as an adjunct to atropine in moderate or severepoisoning. It improves muscle tone within 30 minutes ofEmergency treatment of poisoning

34 Emergency treatment of poisoning BNFC 2011–2012Emergency treatment of poisoningadministration. Pralidoxime chloride is continued untilthe patient has not required atropine for 12 hours.Pralidoxime chloride can be obtained from designatedcentres, the names of which are held by the NationalPoisons Information Service (see p. 24).The National Poisons Information Service (Tel:0844 892 0111) will provide specialist advice on allaspects of poisoning day and nightPRALIDOXIME CHLORIDECautions myasthenia gravisContra-indications poisoning with carbamates ororganophosphorus compounds without anticholinesteraseactivityRenal impairment use with cautionSide-effects drowsiness, dizziness, disturbances ofvision, nausea, tachycardia, headache, hyperventilation,and muscular weaknessLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseAdjunct to atropine in the treatment of poisoningby organophosphorus insecticide ornerve agent. By intravenous infusion over 20 minutesChild under 18 years initially 30 mg/kg, followedby 8 mg/kg/hour; usual max. 12 g in 24 hoursNote The loading dose may be administered by intravenousinjection (diluted to a concentration of 50 mg/mL with water for injections) over at least 5 minutes ifpulmonary oedema is present or if it is not practical toadminister an intravenous infusion; pralidoxime chloridedoses may differ from those in product literature1Pralidoxime chloride AInjection, powder for reconstitution pralidoximechloride 1 g/vialAvailable as Protopam c (from designated centres for organophosphorusinsecticide poisoning or from the National BloodService (or Welsh Ambulance Services for Mid West and SouthEast Wales)—see TOXBASE for list of designated centres)1. A restriction does not apply where administration is forsaving life in emergencySnake bites and animal stingsSnake bites Envenoming from snake bite is uncommonin the UK. Many exotic snakes are kept, someillegally, but the only indigenous venomous snake is theadder (Vipera berus). The bite may cause local andsystemic effects. Local effects include pain, swelling,bruising, and tender enlargement of regional lymphnodes. Systemic effects include early anaphylacticsymptoms (transient hypotension with syncope, angioedema,urticaria, abdominal colic, diarrhoea, and vomiting),with later persistent or recurrent hypotension,ECG abnormalities, spontaneous systemic bleeding,coagulopathy, adult respiratory distress syndrome, andacute renal failure. Fatal envenoming is rare but thepotential for severe envenoming must not be underestimated.Early anaphylactic symptoms should be treated withadrenaline (epinephrine) (section 3.4.3). Indicationsfor antivenom treatment include systemic envenoming,especially hypotension (see above), ECG abnormalities,vomiting, haemostatic abnormalities, and marked localenvenoming such that after bites on the hand or foot,swelling extends beyond the wrist or ankle within 4hours of the bite. The contents of one vial (10 mL) ofEuropean viper venom antiserum (available fromMovianto) is given by intravenous injection over 10–15 minutes or by intravenous infusion over 30 minutesafter diluting in sodium chloride intravenous infusion0.9% (use 5 mL diluent/kg body-weight). The samedose should be used for adults and children. Thedose can be repeated after 1–2 hours if symptoms ofsystemic envenoming persist. However, for those childrenwho present with clinical features of severe envenoming(e.g. shock, ECG abnormalities, or local swellingthat has advanced from the foot to above the knee orfrom the hand to above the elbow within 2 hours of thebite), an initial dose of 2 vials (20 mL) of the antiserum isrecommended; if symptoms of systemic envenomingpersist contact the National Poisons Information Service.Adrenaline (epinephrine) injection must be immediatelyto hand for treatment of anaphylactic reactionsto the antivenom (for the management of anaphylaxissee section 3.4.3).Antivenom is available for bites by certain foreignsnakes and spiders, stings by scorpions and fish. Forinformation on identification, management, and forsupply in an emergency, telephone the National PoisonsInformation Service. Whenever possible the TOXBASEentry should be read, and relevant information collected,before telephoning the National Poisons InformationService (see p. 24).Insect stings Stings from ants, wasps, hornets, andbees cause local pain and swelling but seldom causesevere direct toxicity unless many stings are inflicted atthe same time. If the sting is in the mouth or on thetongue local swelling may threaten the upper airway.The stings from these insects are usually treated bycleaning the area with a topical antiseptic. Bee stingsshould be removed as quickly as possible. Anaphylacticreactions require immediate treatment with intramuscularadrenaline (epinephrine); self-administered (oradministered by a carer) intramuscular adrenaline (e.g.EpiPen c ) is the best first-aid treatment for children withsevere hypersensitivity. An inhaled bronchodilatorshould be used for asthmatic reactions. For themanagement of anaphylaxis, see section 3.4.3. A shortcourse of an oral antihistamine or a topical corticosteroidmay help to reduce inflammation and relieveitching. A vaccine containing extracts of bee and waspvenom can be used to reduce the risk of severeanaphylaxis and systemic reactions in children withsystemic hypersensitivity to bee or wasp stings (section3.4.2).Marine stings The severe pain of weeverfish (Trachinusvipera) and Portuguese man-o’-war stings can berelieved by immersing the stung area immediately inuncomfortably hot, but not scalding, water (not morethan 458 C). Children stung by jellyfish and Portugueseman-o’-war around the UK coast should be removedfrom the sea as soon as possible. Adherent tentaclesshould be lifted off carefully (wearing gloves or usingtweezers) or washed off with seawater. Alcoholic solutions,including suntan lotions, should not be appliedbecause they can cause further discharge of stinginghairs. Ice packs can be used to reduce pain.

BNFC 2011–2012 351 Gastro-intestinal system1.1 Dyspepsia and gastro-oesophagealreflux disease 351.1.1 Antacids and simeticone 361.1.2 Compound alginate preparations 381.2 Antispasmodics and other drugsaltering gut motility 391.3 Antisecretory drugs and mucosalprotectants 421.3.1 H 2 -receptor antagonists 431.3.2 Selective antimuscarinics 441.3.3 Chelates and complexes 441.3.4 Prostaglandin analogues 441.3.5 Proton pump inhibitors 451.4 Acute diarrhoea 461.4.1 Adsorbents and bulk-formingdrugs 471.4.2 Antimotility drugs 471.5 Chronic bowel disorders 481.5.1 Aminosalicylates 491.5.2 Corticosteroids 531.5.3 Drugs affecting the immuneresponse 541.5.4 Food allergy 561.6 Laxatives 571.6.1 Bulk-forming laxatives 571.6.2 Stimulant laxatives 591.6.3 Faecal softeners 611.6.4 Osmotic laxatives 611.6.5 Bowel cleansing preparations 641.6.6 Peripheral opioid-receptorantagonists 651.7 Local preparations for anal andrectal disorders 661.7.1 Soothing anal and rectal preparations661.7.2 Compound anal and rectal preparationswith corticosteroids 661.7.3 Rectal sclerosants 671.7.4 Management of anal fissures 671.8 Stoma and enteral feeding tubes 681.9 Drugs affecting intestinal secretions681.9.1 Drugs affecting biliary compositionand flow 681.9.2 Bile acid sequestrants 701.9.3 Aprotinin 701.9.4 Pancreatin 70This chapter includes advice on the drug managementof the following:Clostridium difficile infection, p. 49constipation, p. 57Crohn’s disease, p. 48food allergy, p. 56Helicobacter pylori infection, p. 42irritable bowel syndrome, p. 49malabsorption syndromes, p. 49NSAID-associated ulcers, p. 43ulcerative colitis, p. 481.1 Dyspepsia and gastrooesophagealrefluxdisease1.1.1 Antacids and simeticone1.1.2 Compound alginate preparationsDyspepsiaDyspepsia covers upper abdominal pain, fullness, earlysatiety, bloating, and nausea. It can occur with gastricand duodenal ulceration (section 1.3), gastro-oesophagealreflux disease, gastritis, and upper gastro-intestinalmotility disorders, but most commonly it is ofuncertain origin.Children with dyspepsia should be advised about lifestylechanges (see Gastro-oesophageal reflux disease,below). Some medications may cause dyspepsia—theseshould be stopped, if possible.A compound alginate preparation (section 1.1.2) mayprovide relief from dyspepsia; persistent dyspepsiarequires investigation. Treatment with a H 2-receptorantagonist (section 1.3.1) or a proton pump inhibitor(section 1.3.5) should be initiated only on the advice of ahospital specialist.Helicobacter pylori may be present in children withdyspepsia. H. pylori eradication therapy (section 1.3)should be considered for persistent dyspepsia if it isulcer-like. However, most children with functional(investigated, non-ulcer) dyspepsia do not benefit symptomaticallyfrom H. pylori eradication.Gastro-oesophageal reflux diseaseGastro-oesophageal reflux disease includes non-erosivegastro-oesophageal reflux and erosive oesophagitis.Uncomplicated gastro-oesophageal reflux is commonin infancy and most symptoms, such as intermittentvomiting or repeated, effortless regurgitation, resolve1 Gastro-intestinal system

36 1.1.1 Antacids and simeticone BNFC 2011–20121 Gastro-intestinal systemwithout treatment between 12 and 18 months of age.Older children with gastro-oesophageal reflux diseasemay have heartburn, acid regurgitation and dysphagia.Oesophageal inflammation (oesophagitis), ulceration orstricture formation may develop in early childhood;gastro-oesophageal reflux disease may also be associatedwith chronic respiratory disorders includingasthma.Parents and carers of neonates and infants should bereassured that most symptoms of uncomplicated gastrooesophagealreflux resolve without treatment. Anincrease in the frequency and a decrease in the volumeof feeds may reduce symptoms. A feed thickener or prethickenedformula feed (Appendix 2) can be used on theadvice of a dietician. If necessary, a suitable alginatecontainingpreparation (section 1.1.2) can be usedinstead of thickened feeds.Older children should be advised about life-stylechanges such as weight reduction if overweight, andthe avoidance of alcohol and smoking. An alginatecontainingantacid (section 1.1.2) can be used to relievesymptoms.Children who do not respond to these measures or whohave problems such as respiratory disorders or suspectedoesophagitis need to be referred to hospital.On the advice of a paediatrician, a histamine H 2 -receptor antagonist (section 1.3.1) can be used torelieve symptoms of gastro-oesophageal reflux disease,promote mucosal healing and permit reduction in antacidconsumption. A proton pump inhibitor (section1.3.5) can be used for the treatment of moderate, nonerosiveoesophagitis that is unresponsive to an H 2-receptor antagonist. Endoscopically confirmed erosive,ulcerative, or stricturing disease in children is usuallytreated with a proton pump inhibitor. Reassessment isnecessary if symptoms persist despite 4–6 weeks oftreatment; long-term use of an H 2 -receptor antagonistor proton pump inhibitor should not be undertakenwithout full assessment of the underlying condition.For endoscopically confirmed erosive, ulcerative, orstricturing disease, the proton pump inhibitor usuallyneeds to be maintained at the minimum effective dose.Motility stimulants (section 1.2), such as domperidoneor erythromycin may improve gastro-oesophagealsphincter contraction and accelerate gastric emptying.Evidence for the long-term efficacy of motilitystimulants in the management of gastro-oesophagealreflux in children is unconvincing.For advice on specialised formula feeds, see section9.4.2.Antacids (usually containing aluminium or magnesiumcompounds) can be used for short-term relief of intermittentsymptoms of ulcer dyspepsia and non-erosivegastro-oesophageal reflux (see section 1.1) in children;they are also used in functional (non-ulcer) dyspepsia,but the evidence of benefit is uncertain.Aluminium- and magnesium-containing antacids,being relatively insoluble in water, are long-acting ifretained in the stomach. Magnesium-containingantacids tend to be laxative whereas aluminium-containingantacids may be constipating; antacids containingboth magnesium and aluminium may reduce thesecolonic side-effects. Aluminium-containing antacidsshould not be used in children with renal impairment,or in neonates and infants because accumulation maylead to increased plasma-aluminium concentrations.Complexes such as hydrotalcite confer no specialadvantage.Calcium-containing antacids can induce rebound acidsecretion; with modest doses the clinical significance ofthis is doubtful, but prolonged high doses also causehypercalcaemia and alkalosis.Simeticone (activated dimeticone) is used to treatinfantile colic, but the evidence of benefit is uncertain.Simeticone is added to an antacid as an antifoamingagent to relieve flatulence; such preparations may alsobe useful for the relief of hiccup in palliative care (seePrescribing in Palliative Care, p. 19).Alginates act as mucosal protectants in gastro-oesophagealreflux disease (section 1.1.2). The amount ofadditional ingredient or antacid in individual preparationsvaries widely, as does their sodium content, so thatpreparations may not be freely interchangeable.Hepatic impairment In children with fluid retention,avoid antacids containing large amounts of sodium.Avoid antacids that cause constipation because thiscan precipitate coma. Avoid antacids containingmagnesium salts in hepatic coma if there is a risk ofrenal failure.Renal impairment In children with fluid retention,avoid antacids containing large amounts of sodium.There is a risk of accumulation and aluminium toxicitywith antacids containing aluminium salts. Absorption ofaluminium from aluminium salts is increased by citrates,which are contained in many effervescent preparations(such as effervescent analgesics). Antacids containingmagnesium salts should be avoided or used at a reduceddose because there is an increased risk of toxicity.Interactions Antacids should preferably not be takenat the same time as other drugs since they may impairabsorption. Antacids may also damage enteric coatingsdesigned to prevent dissolution in the stomach. See alsoAppendix 1 (antacids, calcium salts).Low Na +The words ‘low Na + ’ added after some preparationsindicate a sodium content of less than 1 mmol pertablet or 10-mL dose.1.1.1 Antacids and simeticoneAluminium- and magnesiumcontainingantacidsALUMINIUM HYDROXIDECautions see notes above; interactions: Appendix 1(antacids)Contra-indications hypophosphataemia; neonatesand infantsHepatic impairment see notes aboveRenal impairment see notes aboveSide-effects see notes above

BNFC 2011–2012 1.1.1 Antacids and simeticone 37Indication and doseDyspepsia for dose see preparationsHyperphosphataemia section 9.5.2.2Co-magaldroxCo-magaldrox is a mixture of aluminium hydroxide andmagnesium hydroxide; the proportions are expressed in theform x/y where x and y are the strengths in milligrams per unitdose of magnesium hydroxide and aluminium hydroxiderespectivelyMaalox c (Sanofi-Aventis)Suspension, sugar-free, co-magaldrox 195/220(magnesium hydroxide 195 mg, dried aluminiumhydroxide 220 mg/5 mL (low Na + )). Net price 500 mL= £2.79Dose. By mouthChild 14–18 years 10–20 mL 20–60 minutes after mealsand at bedtime, or when requiredMucogel c (Chemidex)Suspension, sugar-free, co-magaldrox 195/220(magnesium hydroxide 195 mg, dried aluminiumhydroxide 220 mg/5 mL (low Na + )). Net price 500 mL= £1.71Dose. By mouthChild 12–18 years 10–20 mL 3 times daily, 20–60 minutesafter meals and at bedtime, or when requiredMAGNESIUM TRISILICATECautions heart failure, hypertension; metabolic orrespiratory alkalosis, hypermagnesaemia; interactions:Appendix 1 (antacids)Contra-indications severe renal failure; hypophosphataemiaHepatic impairment see notes aboveRenal impairment see notes above; magnesium trisilicatemixture has a high sodium contentSide-effects see notes above; silica-based renalstones reported on long-term treatmentIndication and doseDyspepsia for dose see under preparationMagnesium Trisilicate Mixture, BP(Magnesium Trisilicate Oral Suspension)Oral suspension, 5% each of magnesium trisilicate,light magnesium carbonate, and sodium bicarbonatein a suitable vehicle with a peppermint flavour. Containsabout 6 mmol Na + /10 mLDose. By mouthChild 5–12 years 5–10 mL with water 3 times daily or asrequiredChild 12–18 years 10–20 mL with water 3 times daily oras requiredAluminium-magnesium complexesHYDROTALCITEAluminium magnesium carbonate hydroxidehydrateCautions see notes above; interactions: Appendix 1(antacids)Hepatic impairment see notes aboveRenal impairment see notes aboveSide-effects see notes aboveIndication and doseDyspepsia for dose see under preparationWith simeticoneAltacite Plus csee belowAntacid preparations containingsimeticoneAltacite Plus c (Peckforton)Suspension, sugar-free, co-simalcite 125/500 (simeticone125 mg, hydrotalcite 500 mg)/5 mL (low Na + ).Net price 500 mL = £2.79Dose. By mouthChild 8–12 years 5 mL 4 times daily (between meals andat bedtime) when requiredChild 12–18 years 10 mL 4 times daily (between mealsand at bedtime) when requiredAsilone c (Thornton & Ross)Suspension, sugar-free, dried aluminium hydroxide420 mg, simeticone 135 mg, light magnesium oxide70 mg/5 mL (low Na + ). Net price 500 mL = £1.95Dose. By mouthChild 12–18 years 5–10 mL after meals and at bedtimeor when required up to 4 times dailyMaalox Plus c (Sanofi-Aventis)Suspension, sugar-free, dried aluminium hydroxide220 mg, simeticone 25 mg, magnesium hydroxide195 mg/5 mL (low Na + ). Net price 500 mL = £2.79Dose. By mouthChild 2–5 years 5 mL 3 times dailyChild 5–12 years 5–10 mL 3–4 times dailyChild 12–18 years 5–10 mL 4 times daily (after mealsand at bedtime) or when requiredSimeticone aloneSIMETICONEActivated dimeticoneIndication and doseColic or wind pain for dose see under individualpreparations1 Gastro-intestinal system

38 1.1.2 Compound alginate preparations BNFC 2011–20121 Gastro-intestinal systemDentinox c (DDD) UColic drops (= emulsion), simeticone 21 mg/2.5-mLdose. Net price 100 mL = £1.73Dose. By mouthNeonate 2.5 mL with or after each feed (max. 6 doses in24 hours); may be added to bottle feedChild 1 month–2 years 2.5 mL with or after each feed(max. 6 doses in 24 hours); may be added to bottle feedNote The brand name Dentinox c is also used for otherpreparations including teething gelInfacol c (Forest) ULiquid, sugar-free, simeticone 40 mg/mL (low Na + ).Net price 50 mL = £2.26. Counselling, use of dropperDose. By mouthNeonate 0.5–1 mL before feedsChild 1 month–2 years 0.5–1 mL before feeds1.1.2 Compound alginatepreparationsAlginate taken in combination with an antacid increasesthe viscosity of stomach contents and can protect theoesophageal mucosa from acid reflux. Some alginatecontainingpreparations form a viscous gel (‘raft’) thatfloats on the surface of the stomach contents, therebyreducing symptoms of reflux. Alginate-containing preparationsare used in the management of mild symptomsof dyspepsia and gastro-oesophageal reflux disease(see section 1.1). Antacids may damage entericcoatings designed to prevent dissolution in the stomach.For interactions, see Appendix 1 (antacids, calciumsalts).Preparations containing aluminium should not be usedin children with renal impairment, or in neonates andinfants.Alginate raft-forming oral suspensionsThe following preparations contain sodium alginate,sodium bicarbonate, and calcium carbonate in a suitableflavoured vehicle, and conform to the specification forAlginate Raft-forming Oral Suspension, BP.Acidex c (Pinewood)Liquid, sugar-free, sodium alginate 250 mg, sodiumbicarbonate 133.5 mg, calcium carbonate 80 mg/5 mL. Contains about 3 mmol Na + /5 mL, net price500 mL (aniseed- or peppermint-flavour) = £2.30Dose. By mouthChild 6–12 years 5–10 mL after meals and at bedtimeChild 12–18 years 10–20 mL after meals and at bedtimePeptac c (IVAX)Suspension, sugar-free, sodium bicarbonate133.5 mg, sodium alginate 250 mg, calcium carbonate80 mg/5 mL. Contains 3.1 mmol Na + /5 mL. Net price500 mL (aniseed- or peppermint-flavoured) = £2.16DoseChild 6–12 years 5–10 mL after meals and at bedtimeChild 12–18 years 10–20 mL after meals and at bedtimeOther compound alginate preparationsGastrocote c (Actavis)Tablets, alginic acid 200 mg, dried aluminium hydroxide80 mg, magnesium trisilicate 40 mg, sodiumbicarbonate 70 mg. Contains about 1 mmol Na + /tablet. Net price 100-tab pack = £3.51Cautions diabetes mellitus (high sugar content)Dose. By mouthChild 6–18 years 1–2 tablets chewed 4 times daily (aftermeals and at bedtime)Liquid, sugar-free, peach-coloured, dried aluminiumhydroxide 80 mg, magnesium trisilicate 40 mg, sodiumalginate 220 mg, sodium bicarbonate 70 mg/5 mL. Contains 2.13 mmol Na + /5 mL. Net price500 mL = £2.67Dose. By mouthChild 6–12 years 5–10 mL 4 times daily (after meals andat bedtime)Child 12–18 years 5–15 mL 4 times daily (after mealsand at bedtime)Gaviscon c Advance (Reckitt Benckiser)Tablets, sugar-free, sodium alginate 500 mg, potassiumbicarbonate 100 mg. Contains 2.25 mmol Na + ,1 mmol K + /tablet. Net price 60–tab pack (peppermint-flavour)= £3.07Excipients include aspartame (section 9.4.1)Dose. By mouthChild 6–12 years 1 tablet to be chewed after meals andat bedtime (under medical advice only)Child 12–18 years 1–2 tablets to be chewed after mealsand at bedtimeSuspension, sugar-free, aniseed- or peppermint-flavour,sodium alginate 500 mg, potassium bicarbonate100 mg/5 mL. Contains 2.3 mmol Na + , 1 mmol K + /5 mL, net price 250 mL = £2.56, 500 mL = £5.12Dose. By mouthChild 2–12 years 2.5–5 mL after meals and at bedtime(under medical advice only)Child 12–18 years 5–10 mL after meals and at bedtimeGaviscon c Infant (Reckitt Benckiser)Oral powder, sugar-free, sodium alginate 225 mg,magnesium alginate 87.5 mg, with colloidal silica andmannitol/dose. Contains 0.92 mmol Na + /dose. Netprice 30 doses = £2.46Dose. By mouthNeonate body-weight under 4.5 kg 1 ‘dose’ mixed withfeeds (or water, for breast-fed infants) when required(max. 6 times in 24 hours)Neonate body-weight over 4.5 kg 2 ‘doses’ mixed withfeeds (or water, for breast-fed infants) when required(max. 6 times in 24 hours)

BNFC 2011–2012 1.2 Antispasmodics and other drugs altering gut motility 39Child 1 month–2 yearsBody-weight under 4.5 kg dose as for neonateBody–weight over 4.5 kg 2 ‘doses’ mixed with feeds (orwater, for breast-fed infants) when required (max. 6 timesin 24 hours)Note Not to be used in preterm neonates, or where excessivewater loss likely (e.g. fever, diarrhoea, vomiting, high roomtemperature), or if intestinal obstruction. Not to be used withother preparations containing thickening agentsSafe PracticeEach half of the dual sachet is identified as ‘onedose’. To avoid errors prescribe with directions interms of ‘dose’Topal c (Fabre)Tablets, alginic acid 200 mg, dried aluminium hydroxide30 mg, light magnesium carbonate 40 mg withlactose 220 mg, sucrose 880 mg, sodium bicarbonate40 mg (low Na + ). Net price 42-tab pack = £1.67Cautions diabetes mellitus (high sugar content)Dose. By mouthChild 12–18 years 1–3 tablets chewed 4 times daily(after meals and at bedtime)1.2 Antispasmodics andother drugs altering gutmotilityDrugs in this section include antimuscarinic compoundsand drugs believed to be direct relaxants of intestinalsmooth muscle. The smooth muscle relaxant propertiesof antimuscarinic and other antispasmodic drugs maybe useful in irritable bowel syndrome.The dopamine-receptor antagonist domperidone stimulatestransit in the gut.AntimuscarinicsAntimuscarinics (formerly termed ‘anticholinergics’)reduce intestinal motility. They are occasionally usedfor the management of irritable bowel syndrome but theevidence of their value has not been established andresponse varies. Other indications for antimuscarinicdrugs include asthma and airways disease (section3.1.2), motion sickness (section 4.6), urinary frequencyand enuresis (section 7.4.2), mydriasis and cycloplegia(section 11.5), premedication (section 15.1.3), palliativecare (p. 19), and as an antidote to organophosphoruspoisoning (p. 33).Antimuscarinics that are used for gastro-intestinalsmooth muscle spasm include the tertiary amine dicycloverinehydrochloride and the quaternary ammoniumcompounds propantheline bromide and hyoscinebutylbromide. The quaternary ammonium compoundsare less lipid soluble than atropine and so are less likelyto cross the blood-brain barrier; they are also less wellabsorbed from the gastro-intestinal tract.Dicycloverine hydrochloride may also have some directaction on smooth muscle. Hyoscine butylbromide isadvocated as a gastro-intestinal antispasmodic, but itis poorly absorbed; the injection may be useful in endoscopyand radiology.Cautions Antimuscarinics should be used with cautionin children (especially children with Down’s syndrome)due to increased risk of side-effects; they should also beused with caution in autonomic neuropathy, hypertension,conditions characterised by tachycardia(including hyperthyroidism, cardiac insufficiency, cardiacsurgery), pyrexia, and in children susceptible toangle-closure glaucoma. Antimuscarinics are not usedin children with gastro-oesophageal reflux disease,diarrhoea or ulcerative colitis. Interactions: Appendix1 (antimuscarinics).Contra-indications Antimuscarinics are contra-indicatedin myasthenia gravis (but may be used to decreasemuscarinic side-effects of anticholinesterases—section10.2.1), paralytic ileus, pyloric stenosis, and toxic megacolon.Side-effects Side-effects of antimuscarinics includeconstipation, transient bradycardia (followed by tachycardia,palpitation and arrhythmias), reduced bronchialsecretions, urinary urgency and retention, dilatation ofthe pupils with loss of accommodation, photophobia,dry mouth, flushing and dryness of the skin. Side-effectsthat occur occasionally include nausea, vomiting, andgiddiness; very rarely, angle closure glaucoma mayoccur.DICYCLOVERINE HYDROCHLORIDE(Dicyclomine hydrochloride)Cautions see notes aboveContra-indications see notes above; child under 6monthsPregnancy not known to be harmful; manufactureradvises use only if essentialBreast-feeding avoid—present in milk; apnoeareported in infantSide-effects see notes aboveIndication and doseSymptomatic relief of gastro-intestinal disorderscharacterised by smooth muscle spasm. By mouthChild 6 months–2 years 5–10 mg 3–4 times daily15 minutes before feedsChild 2–12 years 10 mg 3 times dailyChild 12–18 years 10–20 mg 3 times dailyMerbentyl c (Sanofi-Aventis) ATablets, dicycloverine hydrochloride 10 mg, net price100-tab pack = £4.84; 20 mg (Merbentyl 20 c ), 84-tabpack = £8.14Syrup, dicycloverine hydrochloride 10 mg/5 mL, netprice 120 mL = £1.77Note Dicycloverine hydrochloride can be sold to the publicprovided that max. single dose is 10 mg and max. daily dose is60 mgCompound preparationsKolanticon c (Peckforton)Gel, sugar-free, dicycloverine hydrochloride 2.5 mg,dried aluminium hydroxide 200 mg, light magnesiumoxide 100 mg, simeticone 20 mg/5 mL, net price200 mL = £2.21, 500 mL = £3.35DoseChild 12–18 years 10–20 mL every 4 hours whenrequired1 Gastro-intestinal system

40 1.2 Antispasmodics and other drugs altering gut motility BNFC 2011–20121 Gastro-intestinal systemHYOSCINE BUTYLBROMIDECautions see notes above; also intestinal and urinaryoutlet obstructionContra-indications see notes abovePregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding amount too small to be harmfulSide-effects see notes aboveLicensed use tablets not licensed for use in childrenunder 6 years; injection not licensed for use inchildren (age range not specified by manufacturer)Indication and doseSymptomatic relief of gastro-intestinal or genito-urinarydisorders characterised by smoothmuscle spasm. By mouthChild 6–12 years 10 mg 3 times dailyChild 12–18 years 20 mg 4 times dailyExcessive respiratory secretions and bowelcolic in palliative care (see also p. 20). By mouthChild 1 month–2 years 300–500 micrograms/kg(max. 5 mg) 3–4 times dailyChild 2–5 years 5 mg 3–4 times dailyChild 5–12 years 10 mg 3–4 times dailyChild 12–18 years 10–20 mg 3–4 times daily. By intramuscular or intravenous injectionChild 1 month–4 years 300–500 micrograms/kg(max. 5 mg) 3–4 times dailyChild 5–12 years 5–10 mg 3–4 times dailyChild 12–18 years 10–20 mg 3–4 times dailyAcute spasm, spasm in diagnostic procedures. By intramuscular or intravenous injectionChild 2–6 years 5 mg repeated after 30 minutes ifnecessary (may be repeated more frequently inendoscopy), max. 15 mg dailyChild 6–12 years 5–10 mg repeated after 30minutes if necessary (may be repeated more frequentlyin endoscopy), max. 30 mg dailyChild 12–18 years 20 mg repeated after 30 minutesif necessary (may be repeated more frequentlyin endoscopy), max. 80 mg dailyAdministration for intravenous injection, may bediluted with Glucose 5% or Sodium Chloride 0.9%;give over at least 1 minute.For administration by mouth, injection solution maybe used; content of ampoule may be stored in arefrigerator for up to 24 hours after openingBuscopan c (Boehringer Ingelheim) ATablets, coated, hyoscine butylbromide 10 mg, netprice 56-tab pack = £2.25Note Hyoscine butylbromide tablets can be sold to the publicfor medically confirmed irritable bowel syndrome, providedsingle dose does not exceed 20 mg, daily dose does notexceed 80 mg, and pack does not contain a total of more than240 mgInjection, hyoscine butylbromide 20 mg/mL. Netprice 1-mL amp = 22pPROPANTHELINE BROMIDECautions see notes aboveContra-indications see notes aboveHepatic impairment manufacturer advises cautionRenal impairment manufacturer advises cautionPregnancy manufacturer advises avoid unless essentialBreast-feeding may suppress lactationSide-effects see notes aboveLicensed use tablets not licensed for use in childrenunder 12 yearsIndication and doseSymptomatic relief of gastro-intestinal disorderscharacterised by smooth muscle spasm. By mouthChild 1 month–12 years 300 micrograms/kg(max. 15 mg) 3–4 times daily at least one hourbefore foodChild 12–18 years 15 mg 3 times daily at leastone hour before meals and 30 mg at night (max.120 mg daily)Pro-Banthine c (Archimedes) ATablets, pink, s/c, propantheline bromide 15 mg, netprice 112-tab pack = £14.40. Label: 23Extemporaneous formulations available seeExtemporaneous Preparations, p. 6Other antispasmodicsAlverine, mebeverine, and peppermint oil arebelieved to be direct relaxants of intestinal smoothmuscle and may relieve pain in irritable bowelsyndrome and primary dysmenorrhoea. They have noserious adverse effects; peppermint oil occasionallycauses heartburn.ALVERINE CITRATEContra-indications paralytic ileusPregnancy use with cautionBreast-feeding manufacturer advises avoid—limitedinformation availableSide-effects nausea; headache, dizziness; pruritus,rash; hepatitis also reportedIndication and doseAdjunct in gastro-intestinal disorders characterisedby smooth muscle spasm, dysmenorrhoea. By mouthChild 12–18 years 60–120 mg 1–3 times dailySpasmonal c (Norgine)Capsules, alverine citrate 60 mg (blue/grey), netprice 100-cap pack = £9.47; 120 mg (Spasmonal cForte, blue/grey), 60-cap pack = £10.94MEBEVERINE HYDROCHLORIDECautions avoid in acute porphyria (section 9.8.2)Contra-indications paralytic ileusPregnancy not known to be harmful—manufacturersadvise cautionSide-effects allergic reactions (including rash, urticaria,angioedema) reported

BNFC 2011–2012 1.2 Antispasmodics and other drugs altering gut motility 41Licensed use tablets and liquid not licensed for usein children under 10 years; granules not licensed foruse in children under 12 years; modified-releasecapsules not licensed for use in children under 18yearsIndication and doseAdjunct in gastro-intestinal disorders characterisedby smooth muscle spasm. By mouthChild 3–4 years 25 mg 3 times daily, preferably 20minutes before mealsChild 4–8 years 50 mg 3 times daily, preferably 20minutes before mealsChild 8–10 years 100 mg 3 times daily, preferably20 minutes before mealsChild 10–18 years 135–150 mg 3 times daily,preferably 20 minutes before mealsSide-effects heartburn, perianal irritation; rarely,allergic reactions (including rash, headache, bradycardia,muscle tremor, ataxia)Local irritation Capsules should not be broken or chewedbecause peppermint oil may irritate mouth or oesophagusIndication and doseRelief of abdominal colic and distension, particularlyin irritable bowel syndrome. By mouthChild 15–18 years 1–2 capsules, swallowedwhole with water, 3 times daily for up to 3 monthsif necessaryColpermin c (McNeil)Capsules, e/c, light blue/dark blue, blue band,peppermint oil 0.2 mL. Net price 100-cap pack =£12.05. Label: 5, 25Excipients include arachis (peanut) oilMebeverine Hydrochloride (Non-proprietary) ATablets, mebeverine hydrochloride 135 mg, net price100-tab pack = £4.21Oral suspension, mebeverine hydrochloride (asmebeverine embonate) 50 mg/5 mL, net price 300 mL= £137.00Colofac c (Abbott Healthcare) ATablets, s/c, mebeverine hydrochloride 135 mg, netprice 100-tab pack = £7.52Modified releaseColofac c MR (Abbott Healthcare) ACapsules, m/r, mebeverine hydrochloride 200 mg,net price 60-cap pack = £6.67. Label: 25DoseIrritable bowel syndrome. By mouthChild 12–18 years 1 capsule twice dailyCompound preparations1Fybogel c Mebeverine (Reckitt Benckiser) AGranules, buff, effervescent, ispaghula husk 3.5 g,mebeverine hydrochloride 135 mg/sachet, net price10 sachets = £2.50. Label: 13, 22, counselling, seebelowExcipients include aspartame (section 9.4.1)Electrolytes K + 2.5 mmol/sachetDoseIrritable bowel syndrome. By mouthChild 12–18 years 1 sachet in water, morning andevening 30 minutes before food; an additional sachetmay also be taken before the midday meal if necessaryCounselling Preparations that swell in contact with liquidshould always be carefully swallowed with water and shouldnot be taken immediately before going to bed1. 10-sachet pack can be sold to the public for use in childrenover 12 yearsPEPPERMINT OILCautionssensitivity to mentholPregnancy not known to be harmfulBreast-feeding significant levels of menthol in breastmilk unlikelyMotility stimulantsDomperidone and metoclopramide (section 4.6) aredopamine receptor antagonists which stimulate gastricemptying and small intestinal transit, and enhance thestrength of oesophageal sphincter contraction. Metoclopramideand occasionally domperidone can cause acutedystonic reactions—for further details of this and otherside-effects, see section 4.6.A low dose of erythromycin stimulates gastro-intestinalmotility and may be used on the advice of a paediatricgastroenterologist to promote tolerance of enteral feeds;erythromycin may be less effective as a prokinetic drugin preterm neonates than in older children.DOMPERIDONECautions see under Domperidone (section 4.6)Side-effects see under Domperidone (section 4.6);also QT-interval prolongation reportedLicensed use not licensed for use in gastro-intestinalstasis; not licensed for use in children for gastrooesophagealreflux diseaseIndication and doseGastro-oesophageal reflux disease (but efficacynot proven, see section 1.1), gastro-intestinalstasis. By mouthNeonate 100–300 micrograms/kg 4–6 times dailybefore feedsChild 1 month–12 years 200–400 micrograms/kg (max. 20 mg) 3–4 times daily before foodChild 12–18 years 10–20 mg, 3–4 times dailybefore foodNausea and vomiting section 4.6PreparationsSection 4.6ERYTHROMYCINCautions see section 5.1.5; interactions: Appendix 1(macrolides)Side-effects see section 5.1.51 Gastro-intestinal system

42 1.3 Antisecretory drugs and mucosal protectants BNFC 2011–20121 Gastro-intestinal systemLicensed use not licensed for use in gastro-intestinalstasisIndication and doseGastro-intestinal stasis. By mouthNeonate 3 mg/kg 4 times dailyChild 1 month–18 years 3 mg/kg 4 times daily. By intravenous infusionNeonate 3 mg/kg 4 times dailyChild 1 month–1 year 3 mg/kg 4 times dailyPreparationsSection 5.1.51.3 Antisecretory drugs andmucosal protectants1.3.1 H 2 -receptor antagonists1.3.2 Selective antimuscarinics1.3.3 Chelates and complexes1.3.4 Prostaglandin analogues1.3.5 Proton pump inhibitorsPeptic ulceration commonly involves the stomach, duodenum,and lower oesophagus; after gastric surgery itinvolves the gastro-enterostomy stoma.Healing can be promoted by general measures, stoppingsmoking and taking antacids and by antisecretory drugtreatment, but relapse is common when treatmentceases. Nearly all duodenal ulcers and most gastriculcers not associated with NSAIDs are caused byHelicobacter pylori.The management of H. pylori infection and of NSAIDassociatedulcers is discussed below.Helicobacter pylori infectionEradication of Helicobacter pylori reduces the recurrenceof gastric and duodenal ulcers and the risk ofrebleeding. The presence of H. pylori should be confirmedbefore starting eradication treatment. If possible,the antibacterial sensitivity of the organism should beestablished at the time of endoscopy and biopsy. Acidinhibition combined with antibacterial treatment ishighly effective in the eradication of H. pylori; reinfectionis rare. Antibiotic-associated colitis is an uncommonrisk.Treatment to eradicate H. pylori infection in childrenshould be initiated under specialist supervision. Oneweektriple-therapy regimens that comprise omeprazole,amoxicillin, and either clarithromycin or metronidazoleare recommended. Resistance to clarithromycinor to metronidazole is much more commonthan to amoxicillin and can develop during treatment.A regimen containing amoxicillin and clarithromycin istherefore recommended for initial therapy and one containingamoxicillin and metronidazole is recommendedfor eradication failure or for a child who has beentreated with a macrolide for other infections. There isusually no need to continue antisecretory treatment(with a proton pump inhibitor or H 2 -receptor antagonist);however, if the ulcer is large, or complicated byhaemorrhage or perforation then antisecretory treatmentis continued for a further 3 weeks. Lansoprazolemay be considered if omeprazole is unsuitable. Treatmentfailure usually indicates antibacterial resistance orpoor compliance.Two-week triple-therapy regimens offer the possibilityof higher eradication rates compared to one-week regimens,but adverse effects are common and poor complianceis likely to offset any possible gain.Two-week dual-therapy regimens using a proton pumpinhibitor and a single antibacterial produce low rates ofH. pylori eradication and are not recommended.For the role of H. pylori eradication therapy in childrenstarting or taking NSAIDs, see NSAID-associated ulcers,below.Recommended regimens for Helicobacter pylori eradicationEradication therapy Age range Oral dose(to be used in combination with omeprazole, section 1.3.5)Amoxicillin 1–6 years 250 mg twice daily (with clarithromycin)125 mg 3 times daily (with metronidazole)6–12 years 500 mg twice daily (with clarithromycin)250 mg 3 times daily (with metronidazole)12–18 years 1 g twice daily (with clarithromycin)500 mg 3 times daily (with metronidazole)Clarithromycin1–12 years 7.5 mg/kg (max. 500 mg) twice daily (with metronidazole oramoxicillin)12–18 years 500 mg twice daily (with metronidazole or amoxicillin)Metronidazole 1–6 years 100 mg twice daily (with clarithromycin)100 mg 3 times daily (with amoxicillin)6–12 years 200 mg twice daily (with clarithromycin)200 mg 3 times daily (with amoxicillin)12–18 years 400 mg twice daily (with clarithromycin)400 mg 3 times daily (with amoxicillin)

BNFC 2011–2012 1.3.1 H 2 -receptor antagonists 43Test for Helicobacter pylori13C-Urea breath test kits are available for confirming thepresence of gastro-duodenal infection with Helicobacterpylori. The test involves collection of breath samplesbefore and after ingestion of an oral solution of 13 C-urea;the samples are sent for analysis by an appropriatelaboratory. The test should not be performed within 4weeks of treatment with an antibacterial or within 2weeks of treatment with an antisecretory drug. A specific13 C-Urea breath test kit for children is available(Helicobacter Test INFAI for children of the age 3–11 c ). However the appropriateness of testing for H.pylori infection in children has not been established.Breath, saliva, faecal, and urine tests for H. pylori arefrequently unreliable in children; the most accuratemethod of diagnosis is endoscopy with biopsy.Helicobacter Test INFAI for children of the age 3–11 c (Infai) AOral powder, 13 C-urea 45 mg, net price 1 kit (including4 breath sample containers, straws) = £19.20 (spectrometricanalysis included)Helicobacter Test INFAI c (Infai) AOral powder, 13 C-urea 75 mg, net price 1 kit (including4 breath-sample containers, straws) = £19.20 (spectrometricanalysis included); 1 kit (including 2 breathbags) = £14.20 (spectroscopic analysis not included);50-test set = £855.00 (spectrometric analysisincluded)NSAID-associated ulcersGastro-intestinal bleeding and ulceration can occur withNSAID use (section 10.1.1). In adults, the risk of seriousupper gastro-intestinal side-effects varies between individualNSAIDs (see Gastro-intestinal side-effects,p. 501). Whenever possible, NSAIDs should be withdrawnif an ulcer occurs.Children at high risk of developing gastro-intestinalcomplications with a NSAID include those with a historyof peptic ulcer disease or serious upper gastrointestinalcomplication, those taking other medicinesthat increase the risk of upper gastro-intestinal sideeffects,or those with serious co-morbidity. In children atrisk of ulceration, a proton pump inhibitor (section 1.3.5)or an H 2 -receptor antagonist, such as ranitidine, may beconsidered for protection against gastric and duodenalulcers associated with non-selective NSAIDs.NSAID use and H. pylori infection are independent riskfactors for gastro-intestinal bleeding and ulceration. Inchildren already taking a NSAID, eradication of H.pylori is unlikely to reduce the risk of NSAID-inducedbleeding or ulceration. However, in children about tostart long-term NSAID treatment who are H. pyloripositive and have dyspepsia or a history of gastric orduodenal ulcer, eradication of H. pylori may reduce theoverall risk of ulceration.If the NSAID can be discontinued in a child who hasdeveloped an ulcer, a proton pump inhibitor usuallyproduces the most rapid healing; alternatively theulcer can be treated with an H 2 -receptor antagonist.If NSAID treatment needs to continue, the ulcer istreated with a proton pump inhibitor (section 1.3.5).1.3.1 H 2 -receptor antagonistsHistamine H 2 -receptor antagonists heal gastric andduodenal ulcers by reducing gastric acid output as aresult of histamine H 2 -receptor blockade; they are alsoused to relieve symptoms of dyspepsia and gastrooesophagealreflux disease (section 1.1). H 2 -receptorantagonists should not normally be used for Zollinger–Ellison syndrome because proton pump inhibitors (section1.3.5) are more effective.Maintenance treatment with low doses has largely beenreplaced in Helicobacter pylori positive children byeradication regimens (section 1.3).H 2 -receptor antagonist therapy can promote healing ofNSAID-associated ulcers (section 1.3).Treatment with a H 2 -receptor antagonist has not beenshown to be beneficial in haematemesis and melaena,but prophylactic use reduces the frequency of bleedingfrom gastroduodenal erosions in hepatic coma, andpossibly in other conditions requiring intensive care.Treatment also reduces the risk of acid aspiration inobstetric patients at delivery (Mendelson’s syndrome).H 2-receptor antagonists are also used to reduce thedegradation of pancreatic enzyme supplements (section1.9.4) in children with cystic fibrosis.Side-effects Side-effects of H 2 -receptor antagonistsinclude diarrhoea, headache, and dizziness. Rash(including erythema multiforme and toxic epidermalnecrolysis) occurs less frequently. Other side-effectsreported rarely or very rarely include hepatitis, cholestaticjaundice, bradycardia, psychiatric reactions(including confusion, depression, and hallucinations)particularly in the very ill, blood disorders (includingleucopenia, thrombocytopenia, and pancytopenia),arthralgia, and myalgia. There are isolated reports ofgynaecomastia and impotence.RANITIDINECautions acute porphyria; interactions: Appendix 1(histamine H 2 -antagonists)Renal impairment use half normal dose if estimatedglomerular filtration rate less than 50 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid unless essential,but not known to be harmfulBreast-feeding significant amount present in milk,but not known to be harmfulSide-effects see notes above; also less commonlyblurred vision; also reported pancreatitis, involuntarymovement disorders, interstitial nephritis, alopeciaLicensed use oral preparations not licensed for usein children under 3 years; injection not licensed foruse in children under 6 monthsIndication and doseReflux oesophagitis, benign gastric and duodenalulceration, prophylaxis of stress ulceration,other conditions where gastric acidreduction is beneficial (see notes above and section1.9.4). By mouthNeonate 2 mg/kg 3 times daily but absorptionunreliable; max. 3 mg/kg 3 times daily1 Gastro-intestinal system

44 1.3.3 Chelates and complexes BNFC 2011–20121 Gastro-intestinal systemChild 1–6 months 1 mg/kg 3 times daily; max.3 mg/kg 3 times dailyChild 6 months–3 years 2–4 mg/kg twice dailyChild 3–12 years 2–4 mg/kg (max. 150 mg) twicedaily; increased up to 5 mg/kg (max. 300 mg)twice daily in severe gastro-oesophageal refluxdiseaseChild 12–18 years 150 mg twice daily or 300 mgat night; increased if necessary, to 300 mg twicedaily or 150 mg 4 times daily for up to 12 weeks inmoderate to severe gastro-oesophageal refluxdiseaseNote In fat malabsorption syndrome, give 1–2 hoursbefore food to enhance effects of pancreatic enzymereplacement. By slow intravenous injectionNeonate 0.5–1 mg/kg every 6–8 hoursChild 1 month–18 years 1 mg/kg (max. 50 mg)every 6–8 hours (may be given as an intermittentinfusion at a rate of 25 mg/hour)Administration For slow intravenous injection diluteto a concentration of 2.5 mg/mL with Glucose 5% orSodium Chloride 0.9%; give over at least 3 minutesRanitidine (Non-proprietary) ATablets, ranitidine (as hydrochloride) 150 mg, netprice 60-tab pack = £1.97; 300 mg, 30-tab pack =£2.17Brands include Ranitic cEffervescent tablets, ranitidine (as hydrochloride)150 mg, net price 60-tab pack = £18.04; 300 mg, 30-tab pack = £17.03. Label: 13Excipients may include sodium (check with supplier)Oral solution, ranitidine (as hydrochloride) 75 mg/5 mL, 100 mL = £7.44, 300 mL = £19.61Excipients may include alcohol (check with supplier)Note Ranitidine can be sold to the public for children over 16years (provided packs do not contain more than 2 weeks’supply) for the short-term symptomatic relief of heartburn,dyspepsia, and hyperacidity, and for the prevention of thesesymptoms when associated with consumption of food or drink(max. single dose 75 mg, max. daily dose 300 mg)Injection, ranitidine (as hydrochloride) 25 mg/mL,net price 2-mL amp = 57pZantac c (GSK) ATablets, f/c, ranitidine (as hydrochloride) 150 mg, netprice 60-tab pack = £1.30; 300 mg, 30-tab pack =£1.30Syrup, sugar-free, ranitidine (as hydrochloride)75 mg/5 mL. Net price 300 mL = £20.76Excipients include alcohol 8%Injection, ranitidine (as hydrochloride) 25 mg/mL.Net price 2-mL amp = 57p1.3.2 Selective antimuscarinicsClassification not used in BNF for Children.1.3.3 Chelates and complexesSucralfate is a complex of aluminium hydroxide andsulphated sucrose that appears to act by protecting themucosa from acid-pepsin attack; it has minimal antacidproperties. Sucralfate can be used to prevent stressulceration in children receiving intensive care. It shouldbe used with caution in this situation (important:reports of bezoar formation, see Bezoar Formationbelow).SUCRALFATECautions administration of sucralfate and enteralfeeds should be separated by 1 hour; interactions:Appendix 1 (sucralfate)Bezoar formation Following reports of bezoar formationassociated with sucralfate, caution is advised in seriously illpatients, especially those receiving concomitant enteralfeeds or those with predisposing conditions such as delayedgastric emptyingRenal impairment use with caution; aluminium isabsorbed and may accumulatePregnancy no evidence of harm; absorption fromgastro-intestinal tract negligibleBreast-feeding amount probably too small to beharmfulSide-effects constipation; less frequently diarrhoea,nausea, indigestion, flatulence, gastric discomfort,back pain, dizziness, headache, drowsiness, bezoarformation (see above), dry mouth, and rashLicensed use not licensed for use in children under15 years; tablets not licensed for prophylaxis ofstress ulcerationIndication and doseProphylaxis of stress ulceration in child underintensive care. By mouthChild 1 month–2 years 250 mg 4–6 times dailyChild 2–12 years 500 mg 4–6 times dailyChild 12–15 years 1 g 4–6 times dailyChild 15–18 years 1 g 6 times daily; max. 8 gdailyBenign gastric and duodenal ulceration. By mouthChild 1 month–2 years 250 mg 4–6 times dailyChild 2–12 years 500 mg 4–6 times dailyChild 12–15 years 1 g 4–6 times dailyChild 15–18 years 2 g twice daily (on rising and atbedtime) or 1 g 4 times daily (1 hour before mealsand at bedtime) taken for 4–6 weeks, or in resistantcases up to 12 weeks; max. 8 g dailyAdministration for administration by mouth, sucralfateshould be given 1 hour before meals, see alsoCautions, above; oral suspension blocks fine-borefeeding tubes; crushed tablets may be dispersed inwater.Antepsin c (Chugai) ATablets, scored, sucralfate 1 g, net price 50-tab pack =£5.77. Label: 5Suspension, sucralfate, 1 g/5 mL, net price 250 mL(aniseed- and caramel-flavoured) = £5.77. Label: 51.3.4 Prostaglandin analoguesClassification not used in BNF for Children.

BNFC 2011–2012 1.3.5 Proton pump inhibitors 451.3.5 Proton pump inhibitorsProton pump inhibitors inhibit gastric acid secretion byblocking the hydrogen-potassium adenosine triphosphataseenzyme system (the ‘proton pump’) of the gastricparietal cell. Omeprazole is an effective short-termtreatment for gastric and duodenal ulcers; it is alsoused in combination with antibacterials for the eradicationof Helicobacter pylori (see p. 42 for specific regimens).An initial short course of omeprazole is thetreatment of choice in gastro-oesophageal reflux diseasewith severe symptoms; children with endoscopicallyconfirmed erosive, ulcerative, or stricturing oesophagitisusually need to be maintained on omeprazole.Omeprazole is also used for the prevention and treatmentof NSAID-associated ulcers (see p. 43). In childrenwho need to continue NSAID treatment after an ulcerhas healed, the dose of omeprazole should not normallybe reduced because asymptomatic ulcer deteriorationmay occur.Omeprazole is effective in the treatment of theZollinger-Ellison syndrome (including cases resistantto other treatment). It is also used to reduce the degradationof pancreatic enzyme supplements (section 1.9.4)in children with cystic fibrosis.Lansoprazole is not licensed for use in children, butmay be considered when the available formulations ofomeprazole are unsuitable.Esomeprazole can be used for the management ofgastro-oesophageal reflux disease when the availableformulations of omeprazole and lansoprazole are unsuitable.Side-effects Side-effects of the proton pump inhibitorsinclude gastro-intestinal disturbances (includingnausea, vomiting, abdominal pain, flatulence, diarrhoea,constipation), and headache. Less frequent side-effectsinclude dry mouth, peripheral oedema, dizziness, sleepdisturbances, fatigue, paraesthesia, arthralgia, myalgia,rash, and pruritus. Other side-effects reported rarely orvery rarely include taste disturbance, stomatitis, hepatitis,jaundice, hypersensitivity reactions (includinganaphylaxis, bronchospasm), fever, depression, hallucinations,confusion, gynaecomastia, interstitial nephritis,hyponatraemia, blood disorders (including leucopenia,leucocytosis, pancytopenia, thrombocytopenia), visualdisturbances, sweating, photosensitivity, alopecia, Stevens-Johnsonsyndrome, and toxic epidermal necrolysis.By decreasing gastric acidity, proton pump inhibitorsmay increase the risk of gastro-intestinal infections(including Clostridium difficile infection).ESOMEPRAZOLECautions interactions: Appendix 1 (proton pumpinhibitors)Hepatic impairment child 1–12 years max. 10 mgdaily in severe impairment; child 12–18 years max.20 mg daily in severe impairmentRenal impairment manufacturer advises caution insevere renal insufficiencyPregnancy manufacturer advises caution—no informationavailableBreast-feeding manufacturer advises avoid—noinformation availableSide-effects see notes aboveLicensed use tablets not licensed for use in children1–12 yearsIndication and doseGastro-oesophageal reflux disease (in the presenceof erosive reflux oesophagitis). By mouthChild 1–12 yearsBody-weight 10–20 kg 10 mg once daily for 8weeksBody-weight over 20 kg 10–20 mg once daily for8 weeksChild 12–18 years 40 mg once daily for 4 weeks,continued for further 4 weeks if not fully healed orsymptoms persist; maintenance 20 mg dailySymptomatic treatment of gastro-oesophagealreflux disease (in the absence of oesophagitis). By mouthChild 1–12 years, body-weight over 10 kg10 mg once daily for up to 8 weeksChild 12–18 years 20 mg once daily for up to 4weeksNexium c (AstraZeneca) ATablets, f/c, esomeprazole (as magnesium trihydrate)20 mg (light pink), net price 28-tab pack = £18.50;40 mg (pink), 28-tab pack = £25.19. Counselling,administrationAdministration Swallow whole or disperse in water; do not chewor crush tabletsGranules, yellow, e/c, esomeprazole (as magnesiumtrihydrate) 10 mg/sachet, net price 28-sachet pack =£25.19. Label: 25, counselling, administrationAdministration Disperse the contents of each sachet in approx.15 mL water. Stir and leave to thicken for a few minutes; stir againbefore administration and use within 30 minutes; rinse containerwith 15 mL water to obtain full dose; can be administered throughnasogastric or gastric tubeLANSOPRAZOLECautions interactions: Appendix 1 (proton pumpinhibitors)Hepatic impairment use half normal dose in moderateto severe liver diseasePregnancy manufacturer advises avoidBreast-feeding avoid unless essential—present inmilk in animal studiesSide-effects see notes above; also glossitis, pancreatitis,anorexia, restlessness, tremor, impotence,petechiae, and purpura; very rarely colitis, raisedserum cholesterol or triglyceridesLicensed use not licensed for use in childrenIndication and doseGastro-oesophageal reflux disease, acidrelateddyspepsia, treatment of duodenal andbenign gastric ulcer including those complicatingNSAID therapy, fat malabsorptiondespite pancreatic enzyme replacement therapyin cystic fibrosis. By mouthChild body-weight under 30 kg 0.5–1 mg/kg(max. 15 mg) once daily in the morningChild body-weight over 30 kg 15–30 mg oncedaily in the morning1 Gastro-intestinal system

46 1.4 Acute diarrhoea BNFC 2011–20121 Gastro-intestinal systemAdministration for administration by a nasogastrictube or an oral syringe, Zoton FasTab c can bedispersed in a small amount of waterZoton c (Wyeth) AFasTab c (= orodispersible tablet), lansoprazole15 mg, net price 28-tab pack = £2.99; 30 mg, 28-tabpack = £5.50. Label: 5, 22, counselling, administrationExcipients include aspartame (section 9.4.1)Counselling Tablets should be placed on the tongue,allowed to disperse and swallowed, or may be swallowedwhole with a glass of water.OMEPRAZOLECautions interactions: Appendix 1 (proton pumpinhibitors)Hepatic impairment no more than 700 micrograms/kg (max. 20 mg) once dailyPregnancy not known to be harmfulBreast-feeding present in milk but not known to beharmfulSide-effects see notes above; also agitation andimpotenceLicensed use capsules and tablets not licensed foruse in children except for severe ulcerating refluxoesophagitis in children over 1 year; injection notlicensed for use in children under 12 yearsIndication and doseGastro-oesophageal reflux disease, acidrelateddyspepsia, treatment of duodenal andbenign gastric ulcers including those complicatingNSAID therapy, prophylaxis of acidaspiration, Zollinger-Ellison syndrome, fatmalabsorption despite pancreatic enzymereplacement therapy in cystic fibrosis. By mouthNeonate 700 micrograms/kg once daily, increasedif necessary after 7–14 days to 1.4 mg/kg; someneonates may require up to 2.8 mg/kg once dailyChild 1 month–2 years 700 micrograms/kg oncedaily, increased if necessary to 3 mg/kg (max.20 mg) once dailyChild body-weight 10–20 kg 10 mg once dailyincreased if necessary to 20 mg once daily (insevere ulcerating reflux oesophagitis, max. 12weeks at higher dose)Child body-weight over 20 kg 20 mg once dailyincreased if necessary to 40 mg once daily (insevere ulcerating reflux oesophagitis, max. 12weeks at higher dose). By intravenous injection over 5 minutes or byintravenous infusionChild 1 month–12 years initially 500 micrograms/kg(max. 20 mg) once daily, increased to2 mg/kg (max. 40 mg) once daily if necessaryChild 12–18 years 40 mg once dailyHelicobacter pylori eradication (in combinationwith antibacterials see p. 42). By mouthChild 1–12 years 1–2 mg/kg (max. 40 mg) oncedailyChild 12–18 years 40 mg once dailyAdministration for administration by mouth, swallowwhole, or disperse Losec MUPS c tablets in water, ormix capsule contents or Losec MUPS c tablets withfruit juice or yoghurt. Preparations consisting of ane/c tablet within a capsule should not be opened.For administration through an enteral feeding tube,use Losec MUPS c or the contents of a capsulecontaining omeprazole dispersed in a large volume ofwater, or in 10 mL Sodium Bicarbonate 8.4% (1 mmolNa + /mL) (allow to stand for 10 minutes beforeadministration).For intermittent intravenous infusion, dilute reconstitutedsolution to a concentration of 400 micrograms/mL with Glucose 5% or Sodium Chloride 0.9%; giveover 20–30 minutesOmeprazole (Non-proprietary) ACapsules, enclosing e/c granules, omeprazole 10 mg,net price 28-cap pack = £1.81; 20 mg, 28-cap pack =£1.92; 40 mg, 7-cap pack = £1.95, 28-cap pack =£21.65. Counselling, administrationNote Some preparations consist of an e/c tablet within acapsuleBrands include Mepradec cDental prescribing on NHS Gastro-resistant omeprazolecapsules may be prescribedTablets, e/c, omeprazole 10 mg, net price 28-tab pack= £5.84; 20 mg, 28-tab pack = £5.71; 40 mg, 7-tab pack= £5.15. Label: 25Intravenous infusion, powder for reconstitution,omeprazole (as sodium salt), net price 40-mg vial =£5.18Losec c (AstraZeneca) AMUPS c (multiple-unit pellet system = dispersibletablets), f/c, omeprazole 10 mg (light pink), net price28-tab pack = £7.75; 20 mg (pink), 28-tab pack =£11.60; 40 mg (red-brown), 7-tab pack = £5.80.Counselling, administrationCapsules, enclosing e/c granules, omeprazole 10 mg(pink), net price 28-cap pack = £7.75; 20 mg (pink/brown), 28-cap pack = £11.60; 40 mg (brown), 7-cappack = £5.80. Counselling, administrationIntravenous infusion, powder for reconstitution,omeprazole (as sodium salt), net price 40-mg vial =£5.41Injection, powder for reconstitution, omeprazole (assodium salt), net price 40-mg vial (with solvent) =£5.411.4 Acute diarrhoea1.4.1 Adsorbents and bulk-forming drugs1.4.2 Antimotility drugsThe priority in acute diarrhoea, as in gastro-enteritis, isthe prevention or reversal of fluid and electrolyte depletion—thisis particularly important in infants. For detailsof oral rehydration preparations, see section 9.2.1.2.Severe dehydration requires immediate admission tohospital and urgent replacement of fluid and electrolytes.Antimotility drugs (section 1.4.2) relieve symptoms ofdiarrhoea. They are used in the management of uncomplicatedacute diarrhoea in adults, but are not recom-

BNFC 2011–2012 1.4.1 Adsorbents and bulk-forming drugs 47mended for use in children under 12 years. Fluid andelectrolyte replacement (section 9.2.1.2) are of primeimportance in the treatment of acute diarrhoea.Antispasmodics (section 1.2) are occasionally of valuein treating abdominal cramp associated with diarrhoeabut they should not be used for primary treatment.Antispasmodics and antiemetics should be avoided inyoung children with gastro-enteritis since they are rarelyeffective and have troublesome side-effects.Antibacterial drugs are generally unnecessary in simplegastro-enteritis because the complaint usually resolvesquickly without such treatment, and infective diarrhoeasin the UK often have a viral cause. Systemic bacterialinfection does, however, need appropriate systemictreatment; for drugs used in campylobacter enteritis,shigellosis, and salmonellosis, see p. 244Colestyramine (section 1.9.2) binds unabsorbed bilesalts and provides symptomatic relief of diarrhoea followingileal disease or resection.1.4.1 Adsorbents and bulkformingdrugsAdsorbents such as kaolin are not recommended foracute diarrhoeas. Bulk-forming drugs, such as ispaghula,methylcellulose, and sterculia (section 1.6.1)are rarely effective in controlling faecal consistency inileostomy and colostomy.1.4.2 Antimotility drugsAntimotility drugs have a role in the management ofuncomplicated acute diarrhoea in adults but not inchildren under 12 years; see also section 1.4. However,in the case of dehydration, fluid and electrolyte replacement(section 9.2.1.2) are of primary importance.For comments on their role in chronic bowel disorderssee section 1.5. Antimotility drugs are also used inchildren with stoma (section 1.8).CODEINE PHOSPHATECautions see section 4.7.2; tolerance and dependencemay occur with prolonged use; interactions: Appendix1 (opioid analgesics)Contra-indications see section 4.7.2; also conditionswhere inhibition of peristalsis should be avoided,where abdominal distension develops, or in acutediarrhoeal conditions such as acute ulcerative colitisor antibiotic-associated colitisHepatic impairment section 4.7.2Renal impairment section 4.7.2Pregnancy section 4.7.2Breast-feeding section 4.7.2Side-effects section 4.7.2Indication and doseDiarrhoea (but see notes above). By mouthChild 12–18 years 30 mg (range 15–60 mg) 3–4times dailyPain section 4.7.2PreparationsSection 4.7.2CO-PHENOTROPEA mixture of diphenoxylate hydrochloride and atropinesulphate in the mass proportions 100 parts to 1part respectivelyCautions section 4.7.2; also young children are particularlysusceptible to overdosage and symptoms maybe delayed and observation is needed for at least 48hours after ingestion; presence of subclinical doses ofatropine may give rise to atropine side-effects insusceptible individuals or in overdosage (section 1.2);interactions: Appendix 1 (antimuscarinics, opioidanalgesics)Contra-indications section 4.7.2 and also see underAntimuscarinics (section 1.2)Hepatic impairment section 4.7.2; also avoid injaundiceRenal impairment section 4.7.2Pregnancy section 4.7.2Breast-feeding may be present in milkSide-effects section 4.7.2 and also see under Antimuscarinics(section 1.2); also abdominal pain, anorexia,feverLicensed use not licensed for use in children under 4yearsIndication and doseSee preparationsAdministration for administration by mouth tabletsmay be crushedCo-phenotrope (Non-proprietary) ATablets, co-phenotrope 2.5/0.025 (diphenoxylatehydrochloride 2.5 mg, atropine sulphate 25 micrograms),net price 100 = £8.95Brands include Lomotil cDoseControl of faecal consistency after colostomy orileostomy, adjunct to rehydration in acute diarrhoea(but see notes above). By mouthChild 2–4 years half tablet 3 times dailyChild 4–9 years 1 tablet 3 times dailyChild 9–12 years 1 tablet 4 times dailyChild 12–16 years 2 tablets 3 times dailyChild 16–18 years initially 4 tablets then 2 tablets 4times dailyNote Co-phenotrope 2.5/0.025 can be sold to the public forchildren over 16 years (provided packs do not contain morethan 20 tablets) as an adjunct to rehydration in acute diarrhoea(max. daily dose 10 tablets)LOPERAMIDE HYDROCHLORIDECautions see notes above; interactions: Appendix 1(loperamide)Contra-indications conditions where inhibition ofperistalsis should be avoided, where abdominal distensiondevelops, or in conditions such as activeulcerative colitis or antibiotic-associated colitisHepatic impairment risk of accumulation—manufactureradvises cautionPregnancy manufacturer advises avoid—no informationavailableBreast-feeding amount probably too small to beharmful1 Gastro-intestinal system

48 1.5 Chronic bowel disorders BNFC 2011–20121 Gastro-intestinal systemSide-effects abdominal cramps, dizziness, drowsiness,and skin reactions including urticaria; paralyticileus and abdominal bloating also reportedLicensed use capsules not licensed for use in childrenunder 8 years; syrup not licensed for use inchildren under 4 years; not licensed for use inchildren for chronic diarrhoeaIndication and doseChronic diarrhoea. By mouthChild 1 month–1 year 100–200 micrograms/kgtwice daily, 30 minutes before feeds; up to 2 mg/kgdaily in divided doses occasionally requiredChild 1–12 years 100–200 micrograms/kg (max.2 mg) 3–4 times daily; up to 1.25 mg/kg daily individed doses may be required (max. 16 mg daily)Child 12–18 years 2–4 mg 2–4 times daily (max.16 mg daily)Acute diarrhoea (but see notes above). By mouthChild 4–8 years 1 mg 3–4 times daily for up to 3days onlyChild 8–12 years 2 mg 4 times daily for up to 5daysChild 12–18 years initially 4 mg, then 2 mg aftereach loose stool for up to 5 days (usual dose 6–8 mg daily; max. 16 mg daily)Loperamide (Non-proprietary) ACapsules, loperamide hydrochloride 2 mg, net price30-cap pack = £1.07Tablets, loperamide hydrochloride 2 mg, net price 30-tab pack = £2.15Brands include Norimode cNote Loperamide can be sold to the public, for use in childrenover 12 years, provided it is licensed and labelled for thetreatment of acute diarrhoeaImodium c (Janssen) ACapsules, green/grey, loperamide hydrochloride2 mg. Net price 30-cap pack = £1.09Syrup, sugar-free, red, loperamide hydrochloride1 mg/5 mL. Net price 100 mL = £1.17Compound preparationsImodium c Plus (McNeil)Caplets (= tablets), loperamide hydrochloride 2 mg,simeticone 125 mg, net price 6-tab pack = £2.27, 12-tab pack = £3.58DoseAcute diarrhoea with abdominal colicChild 12–18 years initially 1 caplet, then 1 caplet aftereach loose stool; max. 4 caplets daily for up to 2 days1.5 Chronic bowel disordersIndividual symptoms of chronic bowel disorders needspecific treatment including dietary manipulation aswell as drug treatment and the maintenance of a liberalfluid intake.Inflammatory bowel diseaseChronic inflammatory bowel diseases include ulcerativecolitis and Crohn’s disease. The treatment of inflammatorybowel disease in children should be initiated andsupervised by a paediatric gastroenterologist. Effectivemanagement requires drug therapy, attention to nutrition,and in severe or chronic active disease, surgery.Aminosalicylates (balsalazide, mesalazine, olsalazine,and sulfasalazine), corticosteroids (hydrocortisone,budesonide, and prednisolone), and drugs that affectthe immune response are used in the treatment ofinflammatory bowel disease.Treatment of acute ulcerative colitis and Crohn’sdisease Acute mild to moderate disease affecting therectum (proctitis) or the recto-sigmoid (distal colitis) istreated initially with local application of an aminosalicylate(section 1.5.1); alternatively a local corticosteroid(section 1.5.2) can be used but it is less effective. Foampreparations and suppositories are useful for childrenwho have difficulty retaining liquid enemas.Diffuse inflammatory bowel disease or disease that doesnot respond to local therapy requires oral treatment.Mild disease affecting the proximal colon can be treatedwith an oral aminosalicylate alone; a combination of alocal and an oral aminosalicylate can be used in proctitisor distal colitis. Refractory or moderate inflammatorybowel disease usually requires adjunctive use of an oralcorticosteroid such as prednisolone (section 1.5.2) for4–8 weeks. Modified-release budesonide is used forchildren with Crohn’s disease affecting the ileum andthe ascending colon; it causes fewer systemic sideeffectsthan oral prednisolone, but may be less effective.As an alternative to an oral corticosteroid, enteralnutrition (Appendix 2) may be used for 6–8 weeks inchildren with active Crohn’s disease.Severe inflammatory bowel disease or disease that isnot responding to an oral corticosteroid requires hospitaladmission and treatment with an intravenouscorticosteroid such as hydrocortisone (p. 375) ormethylprednisolone (p. 376); other therapy mayinclude intravenous fluid and electrolyte replacement,and possibly parenteral nutrition. Children with ulcerativecolitis that fails to respond adequately to thesemeasures may benefit from a short course of ciclosporin.Children with unresponsive or chronically activeCrohn’s disease may benefit from azathioprine,mercaptopurine, or once-weekly methotrexate; thesedrugs have a slow onset of action.Infliximab (section 1.5.3) is used in specialist centresfor children with severe active Crohn’s disease whosecondition has not responded adequately to treatmentwith a corticosteroid and a conventional drug thataffects the immune response, or who are intolerant ofthem. Infliximab has also been used for the treatment ofsevere, refractory ulcerative colitis. There are concernsabout the long-term safety of infliximab in children;hepatosplenic T-cell lymphoma has been reported.Crohn’s disease of the mouth or of the perineum is morecommon in children than in adults and it is difficult totreat; elimination diets and the use of a topical corticosteroid(section 13.4) may be beneficial, but a systemiccorticosteroid (section 6.3.2) and occasionally azathioprinemay be required in severe cases.

BNFC 2011–2012 1.5.1 Aminosalicylates 49NICE guidanceInfliximab for Crohn’s disease (May 2010)In children over 6 years of age, infliximab is recommendedfor the treatment of severe active Crohn’sdisease that has not responded to conventionaltherapy (including corticosteroids, other drugsaffecting the immune response, and primary nutritiontherapy) or when conventional therapy cannotbe used because of intolerance or contra-indications.Infliximab should be given as a planned course oftreatment for 12 months or until treatment failure,whichever is shorter. Treatment should be continuedbeyond 12 months only if there is evidence of activedisease—in these cases the need for treatmentshould be reviewed at least annually. If the diseaserelapses after stopping treatment, infliximab can berestarted [but see Hypersensitivity Reactions underInfliximab, p. 55].NICE guidanceInfliximab for subacute manifestations ofulcerative colitis (April 2008)Infliximab is not recommended for the treatment ofsubacute manifestations of moderate to severeactive ulcerative colitis that would normally be managedin an outpatient setting.Maintenance of remission of acute ulcerativecolitis and Crohn’s disease Children should beadvised not to smoke because smoking increases therisk of relapse in Crohn’s disease. Smoking cessation(section 4.10.2) should be encouraged when necessary.Aminosalicylates are efficacious in the maintenance ofremission of ulcerative colitis, but there is no evidenceof efficacy in the maintenance of remission of Crohn’sdisease. Corticosteroids are not suitable for maintenancetreatment because of their side-effects. In resistantor frequently relapsing cases either azathioprine(section 1.5.3) or mercaptopurine (section 1.5.3) maybe helpful. Methotrexate (section 1.5.3) is used inCrohn’s disease when azathioprine or mercaptopurineare ineffective or not tolerated. Infliximab (p. 55) canbe used for maintenance therapy in Crohn’s disease orulcerative colitis in children who respond to the initialinduction course of this drug. There are concerns aboutthe long-term safety of infliximab in children.Fistulating Crohn’s disease Treatment may not benecessary for simple, asymptomatic perianal fistulas.Metronidazole (section 5.1.11) or ciprofloxacin (section5.1.12) may be beneficial for the treatment offistulating Crohn’s disease [both unlicensed for thisindication]. Metronidazole by mouth is used at a doseof 7.5 mg/kg 3 times daily, usually for 1 month; it shouldnot be used for longer than 3 months because of concernsabout peripheral neuropathy. Ciprofloxacin bymouth is given at a dose of 5 mg/kg twice daily. Otherantibacterials should be given if specifically indicated(e.g. sepsis associated with fistulas and perianal disease)and for managing bacterial overgrowth in the smallbowel. Fistulas may also require surgical explorationand local drainage.Either azathioprine or mercaptopurine is used as asecond-line treatment for fistulating Crohn’s disease andcontinued for maintenance. Infliximab is used for fistulatingCrohn’s disease refractory to conventionaltreatments; maintenance therapy with infliximab shouldbe considered for patients who respond to the initialinduction course.Adjunctive treatment of inflammatory bowel diseaseDue attention should be paid to diet; high-fibre orlow-residue diets should be used as appropriate.Antimotility drugs such as codeine phosphate and loperamide,and antispasmodic drugs may precipitate paralyticileus and megacolon in active ulcerative colitis;treatment of the inflammation is more logical. Laxativesmay be required in proctitis. Diarrhoea resulting fromthe loss of bile-salt absorption (e.g. in terminal ilealdisease or bowel resection) may improve with colestyramine(section 1.9.2), which binds bile salts.Irritable bowel syndromeIrritable bowel syndrome can present with pain, constipation,or diarrhoea. Some children have importantpsychological aggravating factors which respond toreassurance. The fibre intake of children with irritablebowel syndrome should be reviewed. If an increase indietary fibre is required, soluble fibre (e.g. oats, ispaghulahusk, or sterculia) is recommended; insolublefibre (e.g. bran) should be avoided. A laxative (section1.6) can be used to treat constipation. An osmoticlaxative, such as a macrogol, is preferred; lactulosemay cause bloating. Loperamide (section 1.4.2) mayrelieve diarrhoea and antispasmodic drugs (section 1.2)may relieve pain. Opioids with a central action, such ascodeine, are better avoided because of the risk of dependence.Clostridium difficile infectionClostridium difficile infection is caused by colonisationof the colon with Clostridium difficile and production oftoxin. It often follows antibiotic therapy and is usually ofacute onset, but may become chronic. It is a particularhazard of ampicillin, amoxicillin, co-amoxiclav, secondandthird-generation cephalosporins, clindamycin, andquinolones, but few antibacterials are free of this sideeffect.Oral metronidazole (section 5.1.11) or oralvancomycin (section 5.1.7) are used as specific treatment;vancomycin may be preferred for very sickpatients. Metronidazole can be given by intravenousinfusion if oral treatment is inappropriate.Malabsorption syndromesIndividual conditions need specific management andalso general nutritional consideration. Coeliac disease(gluten enteropathy) usually needs a gluten-free diet(Appendix 2) and pancreatic insufficiency needs pancreatinsupplements (section 1.9.4).For further information on foods for special diets(ACBS), see Appendix 2.1.5.1 AminosalicylatesSulfasalazine is a combination of 5-aminosalicylic acid(‘5-ASA’) and sulfapyridine; sulfapyridine acts only as acarrier to the colonic site of action but still causes sideeffects.In the newer aminosalicylates, mesalazine (5-aminosalicylic acid), balsalazide (a prodrug of 5-amino-1 Gastro-intestinal system

50 1.5.1 Aminosalicylates BNFC 2011–20121 Gastro-intestinal systemsalicylic acid) and olsalazine (a dimer of 5-aminosalicylicacid which cleaves in the lower bowel), the sulfonamide-relatedside-effects of sulfasalazine are avoided,but 5-aminosalicylic acid alone can still cause sideeffectsincluding blood disorders (see recommendationbelow) and lupus-like syndrome also seen with sulfasalazine.Cautions Renal function should be monitored beforestarting an oral aminosalicylate, at 3 months of treatment,and then annually during treatment (more frequentlyin renal impairment). Blood disorders can occurwith aminosalicylates (see recommendation below).Blood disordersChildren receiving aminosalicylates and their carersshould be advised to report any unexplained bleeding,bruising, purpura, sore throat, fever or malaisethat occurs during treatment. A blood count shouldbe performed and the drug stopped immediately ifthere is suspicion of a blood dyscrasia.Contra-indications Aminosalicylates should beavoided in salicylate hypersensitivity.Side-effects Side-effects of the aminosalicylatesinclude diarrhoea, nausea, vomiting, abdominal pain,exacerbation of symptoms of colitis, headache, hypersensitivityreactions (including rash and urticaria); sideeffectsthat occur rarely include acute pancreatitis,hepatitis, myocarditis, pericarditis, lung disorders(including eosinophilia and fibrosing alveolitis), peripheralneuropathy, blood disorders (including agranulocytosis,aplastic anaemia, leucopenia, methaemoglobinaemia,neutropenia, and thrombocytopenia—see alsorecommendation above), renal dysfunction (interstitialnephritis, nephrotic syndrome), myalgia, arthralgia, skinreactions (including lupus erythematosus-likesyndrome, Stevens-Johnson syndrome), alopecia.BALSALAZIDE SODIUMCautions see notes above; also history of asthma;interactions: Appendix 1 (aminosalicylates)Blood disorders see recommendation aboveContra-indications see notes aboveHepatic impairment avoid in severe impairmentRenal impairment manufacturer advises avoid inmoderate to severe impairmentPregnancy manufacturer advises avoidBreast-feeding monitor infant for diarrhoeaSide-effects see notes above; also cholelithiasisLicensed use not licensed for use in children under18 yearsIndication and doseTreatment of mild to moderate ulcerative colitisand maintenance of remission. By mouthChild 12–18 years acute attack, 2.25 g 3 timesdaily until remission occurs or for up to max. 12weeks; maintenance, 1.5 g twice daily, adjustedaccording to response (max. 3 g twice daily)Colazide c (Almirall) ACapsules, beige, balsalazide sodium 750 mg, net price130-cap pack = £30.42. Label: 21, 25, counselling,blood disorder symptoms (see recommendationabove)MESALAZINECautions see notes above; interactions: Appendix 1(aminosalicylates)Blood disorders see recommendation aboveContra-indications see notes above; blood clottingabnormalitiesHepatic impairment avoid in severe impairmentRenal impairment use with caution; avoid if estimatedglomerular filtration rate less than 20 mL/minute/1.73 m 2Pregnancy negligible quantity crosses placentaBreast-feeding diarrhoea reported but negligibleamounts detected in breast milk; monitor infant fordiarrhoeaSide-effects see notes aboveLicensed use Asacol c (all preparations) and Salofalkc enema not licensed for use in children under18 years; Salofalk c suppositories, Pentasa c tabletsand suppositories not licensed for use in childrenunder 15 years; Pentasa c granules not licensed foruse in children under 6 years; Salofalk c rectal foamno dose recommendations for children (age rangenot specified by manufacturer)Indication and doseTreatment of mild to moderate ulcerative colitisand maintenance of remission for dose see underpreparations belowNote The delivery characteristics of oral mesalazinepreparations may vary; these preparations should not beconsidered interchangeableAsacol c (Warner Chilcott) AFoam enema, mesalazine 1 g/metered application,net price 14-application canister with disposableapplicators and plastic bags = £26.72. Counselling,blood disorder symptoms (see recommendationabove)Excipients include disodium edetate, hydroxybenzoates (parabens),polysorbate 20, sodium metabisulphiteDoseAcute attack affecting the rectosigmoid region. By rectumChild 12–18 years 1 metered application (mesalazine1 g) into the rectum daily for 4–6 weeksAcute attack affecting the descending colon. By rectumChild 12–18 years 2 metered applications (mesalazine2 g) once daily for 4–6 weeksSuppositories, mesalazine 250 mg, net price 20-suppospack = £4.82; 500 mg, 10-suppos pack = £4.82.Counselling, blood disorder symptoms (see recommendationabove)DoseTreatment and maintenance of remission of ulcerativecolitis affecting the rectosigmoid region. By rectumChild 12–18 years 250–500 mg 3 times daily, with lastdose at bedtime

BNFC 2011–2012 1.5.1 Aminosalicylates 51Asacol c MR (Warner Chilcott) ATablets, red, e/c, mesalazine 400 mg, net price 90-tabpack = £29.41, 120-tab pack = £39.21. Label: 5, 25,counselling, blood disorder symptoms (see recommendationabove)DoseAcute attack. By mouthChild 12–18 years 800 mg 3 times dailyMaintenance of remission of ulcerative colitis andCrohn’s ileo-colitis. By mouthChild 12–18 years 400–800 mg 2–3 times dailyNote Preparations that lower stool pH (e.g. lactulose) mayprevent release of mesalazineIpocol c (Sandoz) ATablets, e/c, mesalazine 400 mg, net price 120-tabpack = £41.62. Label: 5, 25, counselling, blood disordersymptoms (see recommendation above)DoseAcute attack. By mouthChild 12–18 years 800 mg 3 times dailyMaintenance of remission. By mouthChild 12–18 years 400–800 mg 3 times dailyMesren MR c (IVAX) ATablets, red-brown, e/c, mesalazine 400 mg, net price90-tab pack = £19.50, 120-tab pack = £26.00. Label: 5,25, counselling, blood disorder symptoms (seerecommendation above)DoseAcute attack. By mouthChild 12–18 years 800 mg 3 times dailyMaintenance of remission of ulcerative colitis andCrohn’s ileo-colitis. By mouthChild 12–18 years 400–800 mg 3 times dailyPentasa c (Ferring) ATablets, m/r, scored, mesalazine 500 mg (grey), netprice 100-tab pack = £24.21. Counselling, administration(see dose), blood disorder symptoms (seerecommendation above)DoseAcute attack. By mouthChild 5–15 years 15–20 mg/kg (max. 1 g) 3 times dailyChild 15–18 years 1–2 g twice daily; total daily dosemay alternatively be given in 3 divided dosesMaintenance of remission. By mouthChild 5–15 years 10 mg/kg (max. 500 mg) 2–3 timesdailyChild 15–18 years 2 g once dailyAdministration tablets may be halved, quartered, or dispersedin water, but should not be chewedGranules, m/r, pale grey-brown, mesalazine 1 g/sachet, net price 50-sachet pack = £28.82;2 g/sachet, 60-sachet pack = £72.05. Counselling,administration (see dose), blood disorder symptoms(see recommendation above)DoseAcute attack. By mouthChild 5–12 years 15–20 mg/kg (max. 1 g) 3 times dailyChild 12–18 years 1–2 g twice daily; total daily dosemay alternatively be given in 3–4 divided dosesMaintenance of remission. By mouthChild 5–12 years 10 mg/kg (max. 500 mg) 2–3 timesdailyChild 12–18 years 2 g once dailyAdministration contents of one sachet should be weighedand divided immediately before use; discard any remaininggranules. Granules should be placed on tongue and washeddown with water or orange juice without chewingRetention enema, mesalazine 1 g in 100-mL pack, netprice 7 enemas = £17.73. Counselling, blood disordersymptoms (see recommendation above)DoseAcute attack affecting the rectosigmoid region. By rectumChild 12–18 years 1 g at bedtimeSuppositories, mesalazine 1 g, net price 28-suppospack = £40.01. Counselling, blood disorder symptoms(see recommendation above)DoseAcute attack, ulcerative proctitis. By rectumChild 12–18 years 1 g daily for 2–4 weeksMaintenance, ulcerative proctitis. By rectumChild 12–18 years 1 g dailySalofalk c (Dr Falk) ATablets, e/c, yellow, mesalazine 250 mg, net price100-tab pack = £16.19; 500 mg, 100-tab pack =£32.38. Label: 5, 25, counselling, blood disordersymptoms (see recommendation above)DoseAcute attack. By mouthChild 6–18 years and body-weight under 40 kg 10–20 mg/kg 3 times dailyChild 6–18 years and body-weight over 40 kg 0.5–1 g3 times dailyMaintenance of remission. By mouthChild 6–18 years and body-weight under 40 kg 5–10 mg/kg 3 times daily; total daily dose may alternativelybe given in 2 divided dosesChild 6–18 years and body-weight over 40 kg 500 mg3 times dailyGranules, m/r, grey, e/c, vanilla-flavoured, mesalazine500 mg/sachet, net price 100-sachet pack =£28.74; 1 g/sachet, 50-sachet pack = £28.74; 1.5 g/sachet, 60-sachet pack = £48.85. Counselling,administration (see dose), blood disorder symptoms(see recommendation above)Excipients include aspartame (section 9.4.1)DoseAcute attack. By mouthChild 6–18 years and body-weight under 40 kg 10–20 mg/kg 3 times daily1 Gastro-intestinal system

52 1.5.1 Aminosalicylates BNFC 2011–20121 Gastro-intestinal systemChild 6–18 years and body-weight over 40 kg 1.5–3 gonce daily (preferably in the morning) or 0.5–1 g 3 timesdailyMaintenance of remission. By mouthChild 6–18 years and body-weight under 40 kg 5–10 mg/kg 3 times daily; total daily dose may alternativelybe given in 2 divided dosesChild 6–18 years and body-weight over 40 kg 500 mg3 times dailyAdministration Granules should be placed on tongue andwashed down with water without chewingNote Preparations that lower stool pH (e.g. lactulose) mayprevent release of mesalazineSuppositories, mesalazine 500 mg. Net price 30-suppos pack = £14.81. Counselling, blood disordersymptoms (see recommendation above)DoseAcute attack. By rectumChild 12–18 years 0.5–1 g 2–3 times daily adjustedaccording to responseEnema, mesalazine 2 g in 59-mL pack. Net price 7enemas = £29.92. Counselling, blood disorder symptoms(see recommendation above)DoseAcute attack or maintenance. By rectumChild 12–18 years 2 g once daily at bedtimeRectal foam, mesalazine 1 g/metered application, netprice 14-application canister with disposable applicatorsand plastic bags = £30.17. Counselling, blooddisorder symptoms (see recommendation above)Excipients include cetostearyl alcohol, disodium edetate, polysorbate60, propylene glycol, sodium metabisulphiteDoseMild ulcerative colitis affecting sigmoid colon andrectum. By rectumChild 12–18 years 2 metered applications (mesalazine2 g) into the rectum at bedtime or in 2 divided dosesOLSALAZINE SODIUMCautions see notes above; interactions: Appendix 1(aminosalicylates)Blood disorders see recommendation aboveContra-indications see notes aboveRenal impairment use with caution; manufactureradvises avoid in significant impairmentPregnancy manufacturer advises avoid unless potentialbenefit outweighs riskBreast-feeding monitor infant for diarrhoeaSide-effects see notes above; watery diarrhoea common;also reported, tachycardia, palpitation, pyrexia,blurred vision, and photosensitivityLicensed use not licensed for use in children under12 yearsIndication and doseTreatment of acute attack of mild ulcerativecolitis. By mouthChild 2–18 years 500 mg twice daily after foodincreased if necessary over 1 week to max. 1 g 3times dailyMaintenance of remission of mild ulcerativecolitis. By mouthChild 2–18 years 250–500 mg twice daily afterfoodAdministration Capsules can be opened and contentssprinkled on foodDipentum c (UCB Pharma) ACapsules, brown, olsalazine sodium 250 mg. Netprice 112-cap pack = £19.77. Label: 21, counselling,blood disorder symptoms (see recommendationabove)Tablets, yellow, scored, olsalazine sodium 500 mg.Net price 60-tab pack = £21.18. Label: 21, counselling,blood disorder symptoms (see recommendationabove)SULFASALAZINE(Sulphasalazine)Cautions see notes above; also history of allergy orasthma; G6PD deficiency (section 9.1.5); slow acetylatorstatus; risk of haematological and hepatic toxicity(differential white cell, red cell, and plateletcounts initially and at monthly intervals for first 3months; liver function tests at monthly intervals forfirst 3 months); maintain adequate fluid intake; uppergastro-intestinal side-effects common with doses over4 g daily; acute porphyria (section 9.8.2); interactions:Appendix 1 (aminosalicylates)Blood disorders see recommendation aboveContra-indications see notes above; also sulfonamidehypersensitivity; child under 2 years of ageHepatic impairment use with cautionRenal impairment risk of toxicity, including crystalluria,in moderate impairment—ensure high fluidintake; avoid in severe impairmentPregnancy theoretical risk of neonatal haemolysis inthird trimester; adequate folate supplements shouldbe given to motherBreast-feeding small amount in milk (1 report ofbloody diarrhoea); theoretical risk of neonatal haemolysisespecially in G6PD-deficient infantsSide-effects see notes above; also cough, insomnia,dizziness, fever, blood disorders (including Heinzbody anaemia, megaloblastic anaemia), proteinuria,tinnitus, stomatitis, taste disturbances, and pruritus;less commonly dyspnoea, depression, convulsions,vasculitis, and alopecia; also reported loss of appetite,hypersensitivity reactions (including exfoliativedermatitis, epidermal necrolysis, photosensitivity,anaphylaxis, serum sickness), ataxia, hallucinations,aseptic meningitis, oligospermia, crystalluria, disturbancesof smell, and parotitis; yellow-orange discolorationof skin, urine, and other body fluids; some softcontact lenses may be stainedIndication and doseTreatment of acute attack of mild to moderateand severe ulcerative colitis, active Crohn’sdisease. By mouthChild 2–12 years 10–15 mg/kg (max. 1 g) 4–6times daily until remission occurs; increased tomax. 60 mg/kg daily in divided doses, if necessaryChild 12–18 years 1–2 g 4 times daily untilremission occurs

BNFC 2011–2012 1.5.2 Corticosteroids 53Maintenance of remission of mild to moderateand severe ulcerative colitis. By mouthChild 2–12 years 5–7.5 mg/kg (max. 500 mg) 4times dailyChild 12–18 years 500 mg 4 times dailyTreatment of mild to moderate or severe ulcerativecolitis and maintenance of remission,active Crohn’s disease. By rectum as suppositoriesChild 5–8 years 500 mg twice dailyChild 8–12 years 500 mg in the morning and 1 gat nightChild 12–18 years 0.5–1 g twice dailyJuvenile idiopathic arthritis section 10.1.3Sulfasalazine (Non-proprietary) ATablets, sulfasalazine 500 mg, net price 112 = £6.74.Label: 14, counselling, blood disorder symptoms (seerecommendation above), contact lenses may bestainedTablets, e/c, sulfasalazine 500 mg. Net price 112-tabpack = £14.46. Label: 5, 14, 25, counselling, blooddisorder symptoms (see recommendation above),contact lenses may be stainedBrands include Sulazine EC cSuspension, sulfasalazine 250 mg/5 mL, net price500 mL = £29.50. Label: 14, counselling, blood disordersymptoms (see recommendation above), contactlenses may be stainedExcipients may include alcoholSalazopyrin c (Pharmacia) ATablets, yellow, scored, sulfasalazine 500 mg. Netprice 112-tab pack = £6.97. Label: 14, counselling,blood disorder symptoms (see recommendationabove), contact lenses may be stainedEN-Tabs c (= tablets e/c), yellow, f/c, sulfasalazine500 mg. Net price 112-tab pack = £8.43. Label: 5, 14,25, counselling, blood disorder symptoms (seerecommendation above), contact lenses may bestainedSuppositories, yellow, sulfasalazine 500 mg. Netprice 10 = £3.30. Label: 14, counselling, blood disordersymptoms (see recommendation above), contactlenses may be stained1.5.2 CorticosteroidsFor the role of corticosteroids in acute ulcerative colitisand Crohn’s disease, see Inflammatory Bowel Disease,p. 48.BUDESONIDECautions section 6.3.2; interactions: Appendix 1(corticosteroids)Contra-indications section 6.3.2Hepatic impairment section 6.3.2Pregnancy section 6.3.2Breast-feeding section 6.3.2Side-effects section 6.3.2Licensed use not licensed for use in childrenIndication and doseSee preparationsAdministration Capsules can be opened and thecontents mixed with apple or orange juiceBudenofalk c (Dr Falk) ACapsules, pink, enclosing e/c granules, budesonide3 mg, net price 100-cap pack = £75.05. Label: 5, 10,steroid card, 22, 25DoseMild to moderate Crohn’s disease affecting ileum orascending colon, chronic diarrhoea due to collagenouscolitis. By mouthChild 12–18 years 3 mg 3 times daily for up to 8 weeks;reduce dose for the last 2 weeks of treatment. See alsosection 6.3.2Entocort c (AstraZeneca) ACR Capsules, grey/pink, enclosing e/c, m/r granules,budesonide 3 mg, net price 100-cap pack = £99.00.Label: 5, 10, steroid card, 22, 25Note Dispense in original container (contains desiccant)DoseMild to moderate Crohn’s disease affecting the ileumor ascending colon. By mouthChild 12–18 years 9 mg once daily in the morningbefore breakfast for up to 8 weeks; reduce dose for thelast 2–4 weeks of treatment. See also section 6.3.2Enema, budesonide 2 mg/100 mL when dispersibletablet reconstituted in isotonic saline vehicle, netprice pack of 7 dispersible tablets and bottles ofvehicle = £33.00DoseUlcerative colitis involving rectal and recto-sigmoiddisease. By rectumChild 12–18 years 1 enema at bedtime for 4 weeksHYDROCORTISONECautions section 6.3.2; systemic absorption mayoccur; prolonged use should be avoidedContra-indications intestinal obstruction, bowel perforation,recent intestinal anastomoses, extensive fistulas;untreated infectionSide-effects section 6.3.2; also local irritationIndication and doseInflammatory bowel disease. By intravenous administrationSee p. 375. By rectumSee preparationsColifoam c (Meda) AFoam in aerosol pack, hydrocortisone acetate 10%,net price 14-application cannister with applicator =£9.28Excipients include cetyl alcohol, hydroxybenzoates (parabens), propyleneglycolDoseUlcerative colitis, proctitis, proctosigmoiditis. By rectumChild 2–18 years initially 1 metered application (125 mghydrocortisone acetate) inserted into the rectum once ortwice daily for 2–3 weeks, then once on alternate days1 Gastro-intestinal system

54 1.5.3 Drugs affecting the immune response BNFC 2011–20121 Gastro-intestinal systemPREDNISOLONECautions section 6.3.2; systemic absorption mayoccur; prolonged use should be avoidedContra-indications section 6.3.2; intestinal obstruction,bowel perforation, recent intestinal anastomoses,extensive fistulas; untreated infectionHepatic impairment section 6.3.2Renal impairment section 6.3.2Pregnancy section 6.3.2Breast-feeding section 6.3.2Side-effects section 6.3.2Licensed use Predfoam c , Predsol c retentionenema not licensed for use in children (age rangenot specified by manufacturer)Indication and doseUlcerative colitis, Crohn’s disease see also underpreparations, below. By mouthChild 2–18 years 2 mg/kg (max. 60 mg) oncedaily until remission occurs, followed by reducingdoses. By rectumSee under preparationsOther indications section 6.3.2Oral preparationsSection 6.3.2Rectal preparationsPredenema c (Chemidex) ARetention enema, prednisolone 20 mg (as sodiummetasulphobenzoate) in 100-mL single-dose disposablepack. Net price 1 (standard tube) = 71p, 1 (longtube) = £1.21DoseUlcerative colitis. By rectumChild 12–18 years initially 20 mg at bedtime for 2–4weeks, continued if good responsePredfoam c (Forest) AFoam in aerosol pack, prednisolone 20 mg (as metasulphobenzoatesodium)/metered application, netprice 14-application cannister with disposable applicators= £6.32Excipients include cetostearyl alcohol, disodium edetate, polysorbate20, sorbic acidDoseProctitis and distal ulcerative colitis. By rectumChild 12–18 years 1 metered application (20 mg prednisolone)inserted into the rectum once or twice daily for2 weeks, continued for further 2 weeks if good responsePredsol c (UCB Pharma) ASuppositories, prednisolone 5 mg (as sodium phosphate).Net price 10 = £1.35DoseProctitis and rectal complications of Crohn’s disease. By rectumChild 2–18 years 5 mg inserted night and morning aftera bowel movement1.5.3 Drugs affecting theimmune responseAzathioprine, mercaptopurine, or once weeklymethotrexate are used to induce remission in unresponsiveor chronically active Crohn’s disease. Azathioprineor mercaptopurine may also be helpful for retainingremission in frequently relapsing inflammatorybowel disease; once weekly methotrexate is used inCrohn’s disease when azathioprine or mercaptopurineare ineffective or not tolerated. Response to azathioprineor mercaptopurine may not become apparent forseveral months. Folic acid (section 9.1.2) should begiven to reduce the possibility of methotrexate toxicity.Folic acid can be given at a dose of 5 mg weekly;alternative regimens may be used in some settings.Ciclosporin (cyclosporin) is a potent immunosuppressantand is markedly nephrotoxic. In children withsevere ulcerative colitis unresponsive to other treatment,ciclosporin may reduce the need for urgent colorectalsurgery.AZATHIOPRINECautions section 8.2.1; interactions: Appendix 1(azathioprine)Contra-indications section 8.2.1Hepatic impairment section 8.2.1Renal impairment section 8.2.1Pregnancy section 8.2.1Breast-feeding section 8.2.1Side-effects section 8.2.1Licensed use not licensed for use in ulcerative colitisor Crohn’s diseaseIndication and doseSevere ulcerative colitis and Crohn’s disease. By mouthChild 2–18 years initially 2 mg/kg once daily,then increased if necessary up to 2.5 mg/kg oncedailyTransplantation rejection section 8.2.1Rheumatic diseases section 10.1.3PreparationsSection 8.2.1CICLOSPORINCautions section 8.2.2; interactions: Appendix 1(ciclosporin)Hepatic impairment section 8.2.2Renal impairment section 8.2.2Pregnancy section 8.2.2Breast-feeding section 8.2.2Side-effects section 8.2.2Licensed use not licensed for use in ulcerative colitis

BNFC 2011–2012 1.5.3 Drugs affecting the immune response 55Indication and doseRefractory ulcerative colitis. By mouthChild 2–18 years initially 2 mg/kg twice daily,dose adjusted according to blood-ciclosporinconcentration and response; max. 5 mg/kg twicedailyImportant For advice on counselling and conversionbetween preparations, see section 8.2.2. By intravenous infusionChild 3–18 years initially 0.5–1 mg/kg twicedaily, dose adjusted according to blood-ciclosporinconcentration and responseNephrotic syndrome section 8.2.2Transplantation rejection and auto-immuneconditions section 8.2.2Atopic dermatitis and psoriasis section 13.5.3Administration for intermittent intravenous infusion,dilute to a concentration of 0.5–2.5 mg/mL withGlucose 5% or Sodium Chloride 0.9% and give over2–6 hours; not to be used with PVC equipment;observe patient for signs of anaphylaxis for at least 30minutes after starting infusion and at frequent intervalsthereafterPreparationsSection 8.2.2MERCAPTOPURINE(6-Mercaptopurine)Cautions section 8.1.3; see also Azathioprine, section8.2.1Contra-indications section 8.1.3Hepatic impairment section 8.1.3Renal impairment section 8.1.3Pregnancy section 8.1.3Breast-feeding section 8.1.3Side-effects section 8.1.3Licensed use not licensed for use in severe ulcerativecolitis and Crohn’s disease; for other indications,see section 8.1.3Indication and doseSevere ulcerative colitis and Crohn’s disease. By mouthChild 2–18 years 1–1.5 mg/kg once daily (initialmax. 50 mg; may be increased to 75 mg once daily)Acute leukaemias section 8.1.3PreparationsSection 8.1.3METHOTREXATECautions section 10.1.3Contra-indications section 10.1.3Hepatic impairment section 10.1.3Renal impairment section 8.1.3Pregnancy section 8.1.3Breast-feeding section 8.1.3Side-effects section 10.1.3Licensed use not licensed for use in children fornon-malignant conditionsIndication and doseSevere acute Crohn’s disease. By subcutaneous or intramuscular injectionChild 7–18 years 15 mg/m 2 (max. 25 mg) onceweeklyMaintenance of remission of severe Crohn’sdisease. By mouth or by subcutaneous or intramuscularinjectionChild 7–18 years 15 mg/m 2 (max. 25 mg) onceweekly; dose reduced according to response tolowest effective doseSafe PracticeNote that the above dose is a weekly dose. To avoiderror with low-dose methotrexate, it is recommendedthat:. the child or their carer is carefully advised of the dose andfrequency and the reason for taking methotrexate and anyother prescribed medicine (e.g. folic acid);. only one strength of methotrexate tablet (usually 2.5 mg) isprescribed and dispensed;. the prescription and the dispensing label clearly show thedose and frequency of methotrexate administration;. the child or their carer is warned to report immediately theonset of any feature of blood disorders (e.g. sore throat,bruising, and mouth ulcers), liver toxicity (e.g. nausea,vomiting, abdominal discomfort, and dark urine), and respiratoryeffects (e.g. shortness of breath).Malignant disease section 8.1.3Rheumatic disease section 10.1.3Psoriasis section 13.5.3PreparationsSection 10.1.3Cytokine modulatorsInfliximab is a monoclonal antibody which inhibits thepro-inflammatory cytokine, tumour necrosis factoralpha. It should be administered under specialist supervisionwhere adequate resuscitation facilities are availableand is used in the treatment of severe refractory orfistulating Crohn’s disease in children. Infliximab shouldbe used only when treatment with other immunomodulatingdrugs has failed or is not tolerated and for childrenin whom surgery is inappropriate.INFLIXIMABCautions monitor for infections before, during, and for6 months after treatment (see also Tuberculosisbelow); predisposition to infection; chronic hepatitisB—monitor for active infection; heart failure (discontinueif symptoms develop or worsen; avoid inmoderate or severe heart failure); demyelinating CNSdisorders (risk of exacerbation); history of malignancy(consider discontinuing treatment if malignancy1 Gastro-intestinal system

56 1.5.4 Food allergy BNFC 2011–20121 Gastro-intestinal systemdevelops); history of prolonged immunosuppressantor PUVA treatment in patients with psoriasis; interactions:Appendix 1 (infliximab)Tuberculosis Children should be evaluated for tuberculosisbefore treatment. Active tuberculosis should be treated withstandard treatment (section 5.1.9) for at least 2 monthsbefore starting infliximab. Children who have previouslyreceived adequate treatment for tuberculosis can startinfliximab but should be monitored every 3 months forpossible recurrence. In those without active tuberculosis butwho were previously not treated adequately, chemoprophylaxisshould ideally be completed before starting infliximab.In children at high risk of tuberculosis who cannot beassessed by tuberculin skin test, chemoprophylaxis can begiven concurrently with infliximab. Children and their carersshould be advised to seek medical attention if symptomssuggestive of tuberculosis (e.g. persistent cough, weight loss,and fever) developHypersensitivity reactions Hypersensitivity reactions(including fever, chest pain, hypotension, hypertension,dyspnoea, pruritus, urticaria, serum sickness-like reactions,angioedema, anaphylaxis) reported during or within 1–2hours after infusion (risk greatest during first or secondinfusion or in children who discontinue other immunosuppressants).All children should be observed carefully for1–2 hours after infusion and resuscitation equipment shouldbe available for immediate use. Prophylactic antipyretics,antihistamines, or hydrocortisone may be administered.Readministration not recommended after infliximab-freeinterval of more than 16 weeks—risk of delayed hypersensitivityreactions. Children and carers should be advisedto keep Alert card with them at all times and seek medicaladvice if symptoms of delayed hypersensitivity developContra-indications severe infections (see also undercautions)Pregnancy use only if essential; manufacturer advisesadequate contraception during and for at least 6months after last doseBreast-feeding amount probably too small to beharmfulSide-effects see under Cytokine Modulators (section10.1.3) and Cautions above; also diarrhoea, dyspepsia;flushing, chest pain; dyspnoea; dizziness,fatigue; sinusitis; rash, increased sweating, dry skin;less commonly constipation, gastro-oesophagealreflux, cholecystitis, palpitation, arrhythmia, hypertension,hypotension, vasospasm, cyanosis, bradycardia,syncope, oedema, thrombophlebitis, epistaxis,pleurisy, confusion, agitation, nervousness, amnesia,sleep disturbances, vaginitis, demyelinating disorders,antibody formation, pyelonephritis, myalgia, arthralgia,eye disorders, abnormal skin pigmentation,ecchymosis, cheilitis, and alopecia; rarely hepatitis,intestinal stenosis, intestinal perforation, gastrointestinalhaemorrhage, pancreatitis, lymphoma(including hepatosplenic T-cell lymphoma), circulatoryfailure, meningitis, and seizure; very rarely pericardialeffusion, and skin reactions (including Stevens-Johnsonsyndrome and toxic epidermalnecrolysis); also reported interstitial lung disease,transverse myelitis, neuropathy, paraesthesia, newonset or worsening psoriasisLicensed use not licensed for fistulating Crohn’sdisease in childrenIndication and doseSevere active Crohn’s disease. By intravenous infusionChild 6–18 years initially 5 mg/kg, then 5 mg/kg2 weeks and 6 weeks after initial dose, then 5 mg/kg every 8 weeks; interval between maintenancedoses adjusted according to response; discontinueif no response within 10 weeks of initial doseFistulating Crohn’s disease. By intravenous infusionChild 6–18 years initially 5 mg/kg, then 5 mg/kg2 weeks and 6 weeks after initial dose, then ifcondition has responded, consult literature forguidance on further dosesAdministration for intravenous infusion reconstituteeach 100-mg vial of powder with 10 mL Water forInjections; to dissolve, gently swirl vial without shaking;allow to stand for 5 minutes; dilute required dosewith Sodium Chloride 0.9% to a final volume of250 mL and give through a low protein-binding filter(1.2 micron or less) over at least 2 hours; start infusionwithin 3 hours of reconstitutionRemicade c (Schering-Plough) AIntravenous infusion, powder for reconstitution,infliximab, net price 100-mg vial = £419.62. Label: 10,alert card, counselling, tuberculosis and hypersensitivityreactions1.5.4 Food allergyAllergy with classical symptoms of vomiting, colic anddiarrhoea caused by specific foods such as cow’s milkshould be managed by strict avoidance. The conditionshould be distinguished from symptoms of occasionalfood intolerance in children with irritable bowelsyndrome. Sodium cromoglicate (sodium cromoglycate)may be helpful as an adjunct to dietary avoidance.SODIUM CROMOGLICATE(Sodium cromoglycate)Pregnancy not known to be harmfulBreast-feeding unlikely to be present in milkSide-effects occasional nausea, rashes, and joint painIndication and doseFood allergy (in conjunction with dietaryrestriction). By mouthChild 2–14 years 100 mg 4 times daily beforemeals, dose may be increased after 2–3 weeks to amax. 40 mg/kg daily and then reduced accordingto responseChild 14–18 years 200 mg 4 times daily beforemeals, dose may be increased after 2–3 weeks tomax. 40 mg/kg daily and then reduced accordingto responseAsthma section 3.3.1Allergic conjunctivitis section 11.4.2Allergic rhinitis section 12.2.1Administration capsules may be swallowed whole orthe contents dissolved in hot water and diluted withcold water before takingNalcrom c (Sanofi-Aventis) ACapsules, sodium cromoglicate 100 mg. Net price100-cap pack = £59.75. Label: 22, counselling,administration

BNFC 2011–2012 1.6 Laxatives 571.6 Laxatives1.6.1 Bulk-forming laxatives1.6.2 Stimulant laxatives1.6.3 Faecal softeners1.6.4 Osmotic laxatives1.6.5 Bowel cleansing preparations1.6.6 Peripheral opioid-receptorantagonistsBefore prescribing laxatives it is important to be surethat the child is constipated and that the constipation isnot secondary to an underlying undiagnosed complaint.Laxatives should be prescribed by a healthcare professionalexperienced in the management of constipationin children. Delays of greater than 3 days between stoolsmay increase the likelihood of pain on passing hardstools leading to anal fissure, anal spasm and eventuallyto a learned response to avoid defaecation.In infants, increased intake of fluids, particularly fruitjuice containing sorbitol (e.g. prune, pear, or apple), maybe sufficient to soften the stool. In infants under 1 yearof age with mild constipation, lactulose (section 1.6.4)can be used to soften the stool; either an oral preparationcontaining macrogols or, rarely, glycerol suppositoriescan be used to clear faecal impaction. The infantshould be referred to a hospital paediatric specialist ifthese measures fail.The diet of children over 1 year of age should bereviewed to ensure that it includes an adequate intakeof fibre and fluid. An osmotic laxative containingmacrogols (section 1.6.4) can also be used, particularlyin children with chronic constipation; lactulose is analternative in children who cannot tolerate a macrogol.If there is an inadequate response to the osmotic laxative,a stimulant laxative (section 1.6.2) can be added.Treatment of faecal impaction may initially increasesymptoms of soiling and abdominal pain. In childrenover 1 year of age with faecal impaction, an oral preparationcontaining macrogols (section 1.6.4) is used toclear faecal mass and to establish and maintain softwell-formed stools. If disimpaction does not occur after2 weeks, a stimulant laxative (section 1.6.2) can beadded. If the impacted mass is not expelled followingtreatment with macrogols and a stimulant laxative, asodium citrate enema can be administered. Althoughrectal administration of laxatives may be effective, thisroute is frequently distressing for the child and may leadto persistence of withholding. A phosphate enema maybe administered under specialist supervision if disimpactiondoes not occur after a sodium citrate enema; abowel cleansing preparation (section 1.6.5) is an alternative.Manual evacuation under anaesthetic may benecessary if disimpaction does not occur after oral andrectal treatment, or if the child is afraid.Long-term regular use of laxatives is essential to maintainwell-formed stools and prevent recurrence in childrenwith chronic constipation or a history of faecalimpaction; intermittent use may provoke relapses. Inchildren with chronic constipation, laxatives should becontinued for several weeks after a regular pattern ofbowel movements or toilet training is established. Thedose of laxatives should then be tapered gradually, overa period of months, according to response. Some childrenmay require laxative therapy for several years.For children with chronic constipation, it may benecessary to exceed the licensed doses of somelaxatives. Parents and carers of children should beadvised to adjust the dose of laxative in order toestablish a regular pattern of bowel movements inwhich stools are soft, well-formed, and passed withoutdiscomfort.Laxatives should be administered at a time thatproduces an effect that is likely to fit in with thechild’s toilet routine.For the role of laxatives in the treatment of irritablebowel syndrome, see p. 49. For the prevention of opioidinducedconstipation in palliative care, see p. 18.Pregnancy If dietary and lifestyle changes fail tocontrol constipation in pregnancy, moderate doses ofpoorly absorbed laxatives may be used. A bulk-forminglaxative should be tried first. An osmotic laxative, suchas lactulose, can also be used. Bisacodyl or senna maybe suitable, if a stimulant effect is necessary.Laxatives are also of value in drug-induced constipation(see Prescribing in Palliative Care, p. 18), in distal intestinalobstruction syndrome in children with cystic fibrosis,for the expulsion of parasites after anthelmintictreatment, and to clear the alimentary tract beforesurgery and radiological procedures (section 1.6.5).The laxatives that follow have been divided into 5main groups (sections 1.6.1–1.6.5). This simple classificationdisguises the fact that some laxatives havea complex action.1.6.1 Bulk-forming laxativesBulk-forming laxatives are of value if the diet is deficientin fibre. They relieve constipation by increasing faecalmass which stimulates peristalsis; children and theircarers should be advised that the full effect may takesome days to develop.During treatment with bulk-forming laxatives, adequatefluid intake must be maintained to avoid intestinalobstruction. Proprietary preparations containing a bulkingagent such as ispaghula husk are often difficult toadminister to children.Bulk-forming laxatives may be used in the managementof children with haemorrhoids, anal fissure, and irritablebowel syndrome.ISPAGHULA HUSKCautions adequate fluid intake should be maintainedto avoid intestinal obstructionContra-indications difficulty in swallowing, intestinalobstruction, colonic atony, faecal impactionSide-effects flatulence and abdominal distension(especially during the first few days of treatment),gastro-intestinal obstruction or impaction; hypersensitivityreportedLicensed use Isogel c licensed for use in children(age range not specified by manufacturer)1 Gastro-intestinal system

58 1.6.1 Bulk-forming laxatives BNFC 2011–20121 Gastro-intestinal systemIndication and doseSee under preparationsCounselling Preparations that swell in contact with liquidshould always be carefully swallowed with water and shouldnot be taken immediately before going to bedFibrelief c (Manx)Granules, sugar- and gluten-free, ispaghula husk3.5 g/sachet (natural or orange flavour), net price 10sachets = £1.23, 30 sachets = £2.07. Label: 13, counselling,see aboveExcipients include aspartame (section 9.4.1)DoseConstipation. By mouthChild 12–18 years 1–6 sachets daily in water in 1–3divided doses, preferably after mealsFybogel c (Reckitt Benckiser)Granules, buff, effervescent, sugar- and gluten-free,ispaghula husk 3.5 g/sachet (low Na + ), net price 30sachets (plain, lemon, or orange flavour) = £1.84.Label: 13, counselling, see aboveExcipients include aspartame 16 mg/sachet (see section 9.4.1)DoseConstipation. By mouthChild 6–12 years ½–1 level 5-mL spoonful in watertwice daily, preferably after mealsChild 12–18 years 1 sachet (or 2 level 5-mL spoonfuls)in water twice daily, preferably after mealsIsogel c (Potters)Granules, brown, sugar- and gluten-free, ispaghulahusk 90%. Net price 200 g = £2.67. Label: 13, counselling,see aboveDoseConstipation. By mouthChild 6–12 years 1 level 5-mL spoonful in water once ortwice daily, preferably at mealtimesChild 12–18 years 2 level 5-mL spoonfuls in water onceor twice daily, preferably at mealtimesNote May be difficult to obtainIspagel Orange c (LPC)Granules, beige, effervescent, sugar- and gluten-free,ispaghula husk 3.5 g/sachet, net price 30 sachets =£2.10. Label: 13, counselling, see aboveExcipients include aspartame (section 9.4.1)DoseConstipation. By mouthChild 6–12 years ½–1 level 5-mL spoonful in watertwice daily, preferably after mealsChild 12–18 years 1 sachet (or 2 level 5-mL spoonfuls)in water 1–3 times daily, preferably after mealsRegulan c (Procter & Gamble)Powder, beige, sugar- and gluten-free, ispaghula husk3.4 g/5.85-g sachet (orange or lemon/lime flavour).Net price 30 sachets = £2.44. Label: 13, counselling,see aboveExcipients include aspartame (section 9.4.1)DoseConstipation. By mouthChild 6–12 years ½–1 level 5-mL spoonful in water 1–3times daily, preferably after mealsChild 12–18 years 1 sachet in 150 mL water 1–3 timesdaily, preferably after mealsMETHYLCELLULOSECautions see under Ispaghula HuskContra-indications see under Ispaghula Husk; alsoinfective bowel diseaseSide-effects see under Ispaghula HuskLicensed use no age limit specified by manufacturerIndication and doseSee under preparation belowCounselling Preparations that swell in contact with liquidshould always be carefully swallowed with water and shouldnot be taken immediately before going to bedCelevac c (Amdipharm)Tablets, pink, scored, methylcellulose ‘450’ 500 mg,net price 112-tab pack = £3.22. Counselling, see aboveand doseDoseConstipation, diarrhoea (see notes above). By mouthChild 7–12 years 2 tablets twice dailyChild 12–18 years 3–6 tablets twice dailyAdministration In constipation the dose should be takenwith at least 300 mL liquid. In diarrhoea, ileostomy, andcolostomy control, avoid liquid intake for 30 minutes beforeand after doseExtemporaneous formulations available seeExtemporaneous Preparations, p. 6STERCULIACautions see under Ispaghula HuskContra-indications see under Ispaghula HuskSide-effects see under Ispaghula HuskIndication and doseConstipation for dose see under preparationCounselling Preparations that swell in contact with liquidshould always be carefully swallowed with water and shouldnot be taken immediately before going to bedNormacol c (Norgine)Granules, coated, gluten-free, sterculia 62%. Netprice 500 g = £5.94; 60 7-g sachets = £4.99.Label: 25, 27, counselling, see aboveDose. By mouthChild 6–12 years ½–1 heaped 5-mL spoonful or thecontents of ½–1 sachet, washed down without chewingwith plenty of liquid once or twice daily after mealsChild 12–18 years 1–2 heaped 5-mL spoonfuls or thecontents of 1–2 sachets, washed down without chewingwith plenty of liquid once or twice daily after mealsAdministration May be mixed with soft food (e.g. yoghurt)before swallowing, followed by plenty of liquid.Normacol Plus c (Norgine)Granules, brown, coated, gluten-free, sterculia 62%,frangula (standardised) 8%. Net price 500 g = £6.34;60 7 g sachets = £5.34. Label: 25, 27, Counselling,see aboveDose. By mouthChild 6–12 years ½-1 heaped 5-mL spoonful or thecontents of ½-1 sachet, washed down without chewingwith plenty of liquid, once or twice daily after mealsChild 12–18 years 1–2 heaped 5-mL spoonfuls or thecontents of 1–2 sachets, washed down without chewingwith plenty of liquid, once or twice daily after meals

BNFC 2011–2012 1.6.2 Stimulant laxatives 591.6.2 Stimulant laxativesStimulant laxatives include bisacodyl, sodium picosulfate,and members of the anthraquinone group, sennaand dantron. The indications for dantron are limited(see below) by its potential carcinogenicity (based onrodent carcinogenicity studies) and evidence of genotoxicity.Powerful stimulants such as cascara (an anthraquinone)and castor oil are obsolete. Docusate sodiumprobably acts both as a stimulant and as a softeningagent.Stimulant laxatives increase intestinal motility and oftencause abdominal cramp; they should be avoided inintestinal obstruction. Stools should be softened byincreasing dietary fibre and liquid or with an osmoticlaxative (section 1.6.4) before giving a stimulant laxative.In chronic constipation, especially where withholdingof stool occurs, additional doses of a stimulantlaxative may be required. Long-term use of stimulantlaxatives is sometimes necessary (see section 1.6), butexcessive use can cause diarrhoea and related effectssuch as hypokalaemia.Glycerol suppositories act as a lubricant and as a rectalstimulant by virtue of the mildly irritant action of glycerol.BISACODYLCautions prolonged use (risk of electrolyte imbalance)Contra-indications intestinal obstruction, acuteabdominal conditions, acute inflammatory boweldisease, severe dehydrationPregnancy see Pregnancy, p. 57Side-effects see notes above; nausea and vomiting;colitis also reported; suppositories local irritationIndication and doseConstipation (tablets act in 10–12 hours; suppositoriesact in 20–60 minutes). By mouthChild 4–18 years 5–20 mg once daily, adjustedaccording to response. By rectum (suppositories)Child 2–18 years 5–10 mg once daily, adjustedaccording to responseBowel clearance before radiological proceduresand surgery. By mouth and by rectumChild 4–10 years by mouth, 5 mg at bedtime for 2days before procedure and, if necessary, by rectum,5 mg suppository 1 hour before procedureChild 10–18 years by mouth, 10 mg at bedtimefor 2 days before procedure and, if necessary, byrectum, 10 mg suppository 1 hour before procedureBisacodyl (Non-proprietary)Tablets, e/c, bisacodyl 5 mg, net price 100 = £3.27.Label: 5, 25Suppositories, bisacodyl 10 mg, net price 12 = £1.11Paediatric suppositories, bisacodyl 5 mg, net price 5= 94pNote The brand name Dulcolax c D (Boehringer Ingelheim)is used for bisacodyl tablets, net price 10-tab pack =74p; suppositories (10 mg), 10 = £1.57; paediatric suppositories(5 mg), 5 = 94pThe brand names Dulcolax c Pico Liquid and Dulcolax cPico Perles are used for sodium picosulfate preparationsDANTRON(Danthron)Cautions avoid prolonged contact with skin (as inincontinent patients or infants wearing nappies)—riskof irritation and excoriation; rodent studies indicatepotential carcinogenic riskContra-indications see Bisacodyl abovePregnancy manufacturers of co-danthramer and codanthrusateadvise avoid—no information availableBreast-feeding manufacturers of co-danthramer andco-danthrusate advise avoid—limited informationavailableSide-effects see notes above; also urine may becoloured redIndication and doseConstipation in terminally ill children for dosesee under preparationsWith poloxamer ‘188’ (as co-danthramer)Note Co-danthramer suspension 5 mL = one co-danthramercapsule, but strong co-danthramer suspension 5 mL = twostrong co-danthramer capsulesCo-danthramer (Non-proprietary) ACapsules, co-danthramer 25/200 (dantron 25 mg,poloxamer ‘188’ 200 mg). Net price 60-cap pack =£12.86. Label: 14, (urine red)Dose. By mouthChild 6–12 years 1 capsule at night (restricted indications,see notes above)Child 12–18 years 1–2 capsules at night (restrictedindications, see notes above)Strong capsules, co-danthramer 37.5/500 (dantron37.5 mg, poloxamer ‘188’ 500 mg). Net price 60-cappack = £15.55. Label: 14, (urine red)Dose. By mouthChild 12–18 years 1–2 capsules at night (restrictedindications, see notes above)Suspension, co-danthramer 25/200 in 5 mL (dantron25 mg, poloxamer ‘188’ 200 mg/5 mL). Net price300 mL = £11.27, 1 litre = £37.57. Label: 14, (urinered)Brands include Codalax c D, Danlax cDose. By mouthChild 2–12 years 2.5–5 mL at night (restricted indications,see notes above)Child 12–18 years 5–10 mL at night (restricted indications,see notes above)Strong suspension, co-danthramer 75/1000 in 5 mL(dantron 75 mg, poloxamer ‘188’ 1 g/5 mL). Net price300 mL = £30.13. Label: 14, (urine red)Brands include Codalax Forte c DDose. By mouthChild 12–18 years 5 mL at night (restricted indications,see notes above)1 Gastro-intestinal system

60 1.6.2 Stimulant laxatives BNFC 2011–20121 Gastro-intestinal systemWith docusate sodium (as co-danthrusate)Co-danthrusate (Non-proprietary) ACapsules, co-danthrusate 50/60 (dantron 50 mg,docusate sodium 60 mg). Net price 63-cap pack =£15.87. Label: 14, (urine red)Brands include Normax c DDose. By mouthChild 6–12 years 1 capsule at night (restricted indications,see notes above)Child 12–18 years 1–3 capsules at night (restrictedindications, see notes above)Suspension, yellow, co-danthrusate 50/60 (dantron50 mg, docusate sodium 60 mg/5 mL). Net price200 mL = £8.75. Label: 14, (urine red)Brands include Normax cDose. By mouthChild 6–12 years 5 mL at night (restricted indications,see notes above)Child 12–18 years 5–15 mL at night (restricted indications,see notes above)DOCUSATE SODIUM(Dioctyl sodium sulphosuccinate)Cautions see notes above; do not give with liquidparaffinContra-indications see notes above; also for rectalpreparations, haemorrhoids or anal fissurePregnancy not known to be harmful—manufactureradvises cautionBreast-feeding present in milk following oral administration—manufactureradvises caution; rectaladministration not known to be harmfulSide-effects see notes above; also rashLicensed use adult oral solution and capsules notlicensed for use in children under 12 yearsIndication and doseConstipation. By mouthChild 6 months–2 years 12.5 mg 3 times daily,adjusted according to response (use paediatric oralsolution)Child 2–12 years 12.5–25 mg 3 times daily,adjusted according to response (use paediatric oralsolution)Child 12–18 years up to 500 mg daily in divideddoses, adjusted according to responseNote Oral preparations act within 1–2 days; response torectal administration usually occurs within 20 minutesAdjunct in abdominal radiological procedures. By mouthChild 12–18 years 400 mg with barium mealAdministration for administration by mouth, solutionmay be mixed with milk or squashDioctyl c (UCB Pharma)Capsules, yellow/white, docusate sodium 100 mg,net price 30-cap pack = £1.92, 100-cap pack = £6.40Docusol c (Typharm)Adult oral solution, sugar-free, docusate sodium50 mg/5 mL, net price 300 mL = £5.49Paediatric oral solution, sugar-free, docusate sodium12.5 mg/5 mL, net price 300 mL = £5.29Rectal preparationsNorgalax Micro-enema c (Norgine)Enema, docusate sodium 120 mg in 10-g single-dosedisposable packs. Net price 10-g unit = 57pDose. By rectumChild 12–18 years 1 enema as a single doseGLYCEROL(Glycerin)Indication and doseConstipation. By rectumChild 1 month–1 year 1-g suppository as requiredChild 1–12 years 2-g suppository as requiredChild 12–18 years 4-g suppository as requiredGlycerol Suppositories, BP(Glycerin Suppositories)Suppositories, gelatin 140 mg, glycerol 700 mg, purifiedwater to 1 g, net price 12 = £1.27 (1 g), £1.29 (2 g),£1.48 (4 g)Administration Moisten with water before insertionSENNACautions see notes aboveContra-indications see notes abovePregnancy see Pregnancy, p. 57Breast-feeding not known to be harmfulSide-effects see notes aboveLicensed use tablets not licensed for use in childrenunder 6 years; syrup not licensed for use in childrenunder 2 yearsIndication and doseConstipation for dose see under preparationsNote Onset of action 8–12 hours; initial dose should belowSenna (Non-proprietary)Tablets, total sennosides (calculated as sennoside B)7.5 mg. Net price 60 = £1.47Brands include Senokot c DDose. By mouthChild 2–4 years ½–2 tablets once daily, adjustedaccording to responseChild 4–6 years ½–4 tablets once daily, adjustedaccording to responseChild 6–18 years 1–4 tablets once daily, adjustedaccording to responseManevac c (HFA Healthcare)Granules, coated, senna fruit 12.4%, ispaghula 54.2%,net price 400 g = £7.45. Label: 25, counselling,administrationExcipients include sucrose 800 mg per level 5-mL spoonful of granulesDose. By mouthChild 12–18 years 1–2 level 5-mL spoonfuls at nightwith at least 150 mL water, fruit juice, milk, or warm drinkCounselling Preparations that swell in contact with liquidshould always be carefully swallowed with water or appropriatefluid and should not be taken immediately beforegoing to bed

BNFC 2011–2012 1.6.3 Faecal softeners 61Senokot c (Reckitt Benckiser)Tablets D, see aboveSyrup, sugar-free, brown, total sennosides (calculatedas sennoside B) 7.5 mg/5 mL. Net price 500 mL =£2.69Dose. By mouthChild 1 month–4 years 2.5–10 mL once daily, adjustedaccording to responseChild 4–18 years 2.5–20 mL once daily, adjustedaccording to responseSODIUM PICOSULFATE(Sodium picosulphate)Cautions see notes above; active inflammatory boweldisease (avoid if fulminant)Contra-indications see notes above; severe dehydrationPregnancy see Pregnancy, p. 57Breast-feeding not known to be present in milk butmanufacturer advises avoid unless potential benefitoutweighs riskSide-effects see notes aboveLicensed use elixir, licensed for use in children (agerange not specified by manufacturer); Perles c notlicensed for use in children under 4 yearsIndication and doseConstipation. By mouthChild 1 month–4 years 2.5–10 mg once daily,adjusted according to responseChild 4–18 years 2.5–20 mg once daily, adjustedaccording to responseNote onset of action 6–12 hoursBowel evacuation before abdominal radiologicaland endoscopic procedures on the colon,and surgery section 1.6.5Sodium Picosulfate (Non-proprietary)Elixir, sodium picosulfate 5 mg/5 mL, net price100 mL = £1.85Note The brand name Dulcolax c Pico Liquid (BoehringerIngelheim) is used for sodium picosulfate elixir 5 mg/5 mLDulcolax c Pico (Boehringer Ingelheim)Perles c (= capsules), sodium picosulfate 2.5 mg, netprice 20-cap pack = £1.93, 50-cap pack = £2.73Note The brand name Dulcolax c is also used for bisacodyltablets and suppositoriesBowel cleansing preparationsSection 1.6.51.6.3 Faecal softenersEnemas containing arachis oil (ground-nut oil, peanutoil) lubricate and soften impacted faeces and promote abowel movement.Bulk laxatives (section 1.6.1) and non-ionic surfactant‘wetting’ agents e.g. docusate sodium (section 1.6.2)also have softening properties. Such drugs are usefulfor oral administration in the management of analfissure; glycerol suppositories (section 1.6.2) are usefulfor rectal use.ARACHIS OILCautions intestinal obstruction; hypersensitivity tosoyaContra-indications inflammatory bowel disease,hypersensitivity to arachis oil or peanutsLicensed use licensed for use in children (age rangenot specified by manufacturerIndication and doseImpacted faeces. By rectumChild 3–7 years 45–65 mL as requiredChild 7–12 years 65–100 mL as requiredChild 12–18 years 100–130 mL as requiredAdministration warm enema in warm water beforeuseArachis Oil Enema (Non-proprietary)Enema, arachis (peanut) oil in 130-mL single-dosedisposable packs. Net price 130 mL = £7.981.6.4 Osmotic laxativesOsmotic laxatives increase the amount of water in thelarge bowel, either by drawing fluid from the body intothe bowel or by retaining the fluid they were administeredwith.Lactulose is a semi-synthetic disaccharide which is notabsorbed from the gastro-intestinal tract. It produces anosmotic diarrhoea of low faecal pH, and discourages theproliferation of ammonia-producing organisms. It istherefore useful in the treatment of hepatic encephalopathy.Macrogols are inert polymers of ethylene glycol whichsequester fluid in the bowel; giving fluid with macrogolsmay reduce the dehydrating effect sometimes seen withosmotic laxatives. Macrogols are an effective non-traumaticmeans of evacuation in children with faecalimpaction and can be used in the long-term managementof chronic constipation.Saline purgatives such as magnesium hydroxide arecommonly abused but are satisfactory for occasionaluse; adequate fluid intake should be maintained.Magnesium salts are useful where rapid bowel evacuationis required. Sodium salts should be avoided as theymay give rise to sodium and water retention in susceptibleindividuals. Phosphate enemas are useful in bowelclearance before radiology, endoscopy, and surgery.Enemas containing phosphate or sodium citrate, andoral bowel cleansing preparations (section 1.6.5)should only be used on the advice of a specialist practitioner.LACTULOSECautions lactose intolerance; interactions: Appendix1 (lactulose)Contra-indications galactosaemia, intestinal obstructionPregnancy not known to be harmful; see alsoPregnancy, p. 57Side-effects nausea (can be reduced by administrationwith water, fruit juice or with meals), vomiting,flatulence, cramps, and abdominal discomfort1 Gastro-intestinal system

62 1.6.4 Osmotic laxatives BNFC 2011–20121 Gastro-intestinal systemLicensed use not licensed for use in children forhepatic encephalopathyIndication and doseConstipation (may take up to 48 hours to act). By mouthChild 1 month–1 year 2.5 mL twice daily,adjusted according to responseChild 1–5 years 2.5–10 mL twice daily, adjustedaccording to responseChild 5–18 years 5–20 mL twice daily, adjustedaccording to responseHepatic encephalopathy. By mouthChild 12–18 years 30–50 mL 3 times daily; adjustdose to produce 2–3 soft stools per dayLactulose (Non-proprietary)Solution, lactulose 3.1–3.7 g/5 mL with other ketoses.Net price 300-mL pack = £2.10, 500-mL pack = £2.59Brands include Duphalac c D, Lactugal c , Regulose cMACROGOLS(Polyethylene glycols)Cautions discontinue if symptoms of fluid andelectrolyte disturbance; see also preparations belowContra-indications intestinal perforation or obstruction,paralytic ileus, severe inflammatory conditionsof the intestinal tract (such as Crohn’s disease, ulcerativecolitis, and toxic megacolon); see also preparationsbelowPregnancy manufacturers advise use only if essential—noinformation availableBreast-feeding manufacturers advise use only ifessential—no information availableSide-effects abdominal distension and pain, nausea,flatulenceLicensed use Movicol c Paediatric Plain notlicensed for use in faecal impaction in childrenunder 5 years, or for chronic constipation in childrenunder 2 yearsIndication and doseSee under preparations belowMacrogol Oral Powder, Compound (Non-proprietary)Oral powder, macrogol ‘3350’ (polyethylene glycol‘3350’) 13.125 g, sodium bicarbonate 178.5 mg, sodiumchloride 350.7 mg, potassium chloride 46.6 mg/sachet, net price 20-sachet pack = £4.45, 30-sachetpack = £6.68. Label: 13Brands include Laxido c Orange, Molaxole cCautions patients with cardiovascular impairment should nottake more than 2 sachets in any 1 hourDoseChronic constipation. By mouthChild 12–18 years 1–3 sachets daily in divided dosesusually for up to 2 weeks; maintenance, 1–2 sachets dailyAdministration Mix contents of each sachet in half aglass (approx. 125 mL) of waterFaecal impaction. By mouthChild 12–18 years 4 sachets on first day, then increasedin steps of 2 sachets daily to max. 8 sachets daily; totaldaily dose to be drunk within a 6 hour periodAdministration Mix contents of 2 sachets in a glass(approx. 250 mL) of water. After reconstitution the solutionshould be kept in a refrigerator and discarded ifunused after 6 hoursMovicol c (Norgine)Oral powder, macrogol ‘3350’ (polyethylene glycol‘3350’) 13.125 g, sodium bicarbonate 178.5 mg, sodiumchloride 350.7 mg, potassium chloride 46.6 mg/sachet, net price 20-sachet pack (lime- and lemonflavoured)= £4.45, 30-sachet pack (lime- and lemonorchocolate- or plain- flavoured) = £6.68, 50-sachetpack (lime- and lemon- or plain- flavoured) = £11.13.Label: 13Note Amount of potassium chloride varies according toflavour of Movicol c as follows: plain-flavour (sugar-free) =50.2 mg/sachet; lime and lemon flavour = 46.6 mg/sachet;chocolate flavour = 31.7 mg/sachet. 1 sachet when reconstitutedwith 125 mL water provides K + 5.4 mmol/litreCautions patients with cardiovascular impairment should nottake more than 2 sachets in any 1 hourDoseChronic constipation. By mouthChild 12–18 years 1–3 sachets daily in divided dosesusually for up to 2 weeks; maintenance, 1–2 sachets dailyAdministration Mix contents of each sachet in half aglass (approx. 125 mL) of waterFaecal impaction. By mouthChild 12–18 years 4 sachets on first day, then increasedin steps of 2 sachets daily to max. 8 sachets daily; totaldaily dose to be drunk within a 6 hour periodAdministration Mix contents of 2 sachets in a glass(approx. 250 mL) of water. After reconstitution the solutionshould be kept in a refrigerator and discarded ifunused after 6 hoursMovicol c -Half (Norgine)Oral powder, sugar-free, macrogol ‘3350’ (polyethyleneglycol ‘3350’) 6.563 g, sodium bicarbonate89.3 mg, sodium chloride 175.4 mg, potassium chloride23.3 mg/sachet, net price 20-sachet pack (limeand lemon flavour) = £2.67, 30-sachet pack = £4.01.Label: 13Cautions patients with impaired cardiovascular function shouldnot take more than 4 sachets in any 1 hourDoseChronic constipation. By mouthChild 12–18 years 2–6 sachets daily in divided dosesusually for up to 2 weeks; maintenance, 2–4 sachets dailyAdministration Mix contents of each sachet in quarter ofa glass (approx. 60–65 mL) of waterFaecal impaction. By mouthChild 12–18 years 8 sachets on first day, then increasedin steps of 4 sachets daily to max. 16 sachets daily; totaldaily dose to be drunk within 6 hoursAdministration Mix contents of 4 sachets in a glass(approx. 250 mL) of water. After reconstitution the solutionshould be kept in a refrigerator and discarded ifunused after 6 hoursMovicol c Paediatric Plain (Norgine) AOral powder, sugar-free, macrogol ‘3350’ (polyethyleneglycol ‘3350’) 6.563 g, sodium bicarbonate

BNFC 2011–2012 1.6.4 Osmotic laxatives 6389.3 mg, sodium chloride 175.4 mg, potassium chloride25.1 mg/sachet, net price 30-sachet pack = £4.45.Label: 13Cautions with high doses, impaired gag reflex, reflux oesophagitis,impaired consciousnessContra-indications cardiovascular impairment, renal impairment–—noinformation availableDoseChronic constipation, prevention of faecal impaction. By mouthChild under 1 year ½–1 sachet dailyChild 1–6 years 1 sachet daily; adjust dose to produceregular soft stools (max. 4 sachets daily)Child 6–12 years 2 sachets daily; adjust dose to produceregular soft stools (max. 4 sachets daily)Administration Mix content of each sachet in quarter ofa glass (approx. 60–65 mL) of waterFaecal impaction. By mouthChild under 1 year ½–1 sachet dailyChild 1–5 years (treat until impaction resolves) 2sachets on first day, then 4 sachets daily for 2 days, then 6sachets daily for 2 days, then 8 sachets dailyChild 5–12 years (treat until impaction resolves) 4sachets on first day, then increased in steps of 2 sachetsdaily to max. 12 sachets dailyAdministration Mix each sachet in quarter of a glass(approx. 60–65 mL) of water; total daily dose to be takenover a 12-hour periodMAGNESIUM SALTSCautions see also notes above; interactions: Appendix1 (antacids)Contra-indications acute gastro-intestinal conditionsHepatic impairment avoid in hepatic coma if risk ofrenal failureRenal impairment avoid or reduce dose; increasedrisk of toxicitySide-effects colicIndication and doseConstipation see under preparations belowMagnesium hydroxideMagnesium Hydroxide Mixture, BPAqueous suspension containing about 8% hydratedmagnesium oxide. Do not store in cold placeDose. By mouthChild 3–12 years 5–10 mL with water at bedtime whenrequiredChild 12–18 years 30–45 mL with water at bedtimewhen requiredBowel cleansing preparationsSection 1.6.5PHOSPHATES (RECTAL)Cautions see also notes above; with enema, electrolytedisturbances, congestive heart failure, ascites,uncontrolled hypertension, maintain adequate hydrationContra-indications acute gastro-intestinal conditions(including gastro-intestinal obstruction, inflammatorybowel disease, and conditions associated withincreased colonic absorption)Renal impairment use enema with cautionSide-effects local irritation; with enema, electrolytedisturbancesIndication and doseConstipation, bowel evacuation before abdominalradiological procedures, endoscopy, andsurgeryFor dose see preparationsCarbalax c (Chemidex)Suppositories, sodium acid phosphate (anhydrous)1.3 g, sodium bicarbonate 1.08 g, net price 12 = £2.01Dose. By rectumChild 12–18 years 1 suppository, inserted 30 minutesbefore evacuation required; moisten with water beforeuseFleet c Ready-to-use Enema (Casen-Fleet)Enema, sodium acid phosphate 21.4 g, sodium phosphate9.4 g/118 mL, net price 133-mL pack (delivers118 mL dose) with standard tube = 57pDose. By rectumChild 3–7 years 40–60 mL once dailyChild 7–12 years 60–90 mL once dailyChild 12–18 years 90–118 mL once dailyPhosphates Enema BP Formula BEnema, sodium dihydrogen phosphate dihydrate12.8 g, disodium phosphate dodecahydrate 10.24 g,purified water, freshly boiled and cooled, to 128 mL.Net price 128 mL with standard tube = £2.98, withlong rectal tube = £3.98Dose. By rectumChild 3–7 years 45–65 mL once dailyChild 7–12 years 65–100 mL once dailyChild 12–18 years 100–128 mL once dailySODIUM CITRATE (RECTAL)Cautions see notes aboveContra-indications acute gastro-intestinal conditionsIndication and doseConstipation for dose see under preparationsMicolette Micro-enema c (Pinewood)Enema, sodium citrate 450 mg, sodium lauryl sulphoacetate45 mg, glycerol 625 mg, together withcitric acid, potassium sorbate, and sorbitol in a viscoussolution, in 5-mL single-dose disposable packswith nozzle. Net price 5 mL = 38pDose. By rectumChild 3–18 years 5–10 mL as a single doseMicralax Micro-enema c (UCB Pharma)Enema, sodium citrate 450 mg, sodium alkylsulphoacetate45 mg, sorbic acid 5 mg, together withglycerol and sorbitol in a viscous solution in 5-mLsingle-dose disposable packs with nozzle. Net price5 mL = 41pDose. By rectumChild 3–18 years 5 mL as a single dose1 Gastro-intestinal system

64 1.6.5 Bowel cleansing preparations BNFC 2011–20121 Gastro-intestinal systemRelaxit Micro-enema c (Crawford)Enema, sodium citrate 450 mg, sodium lauryl sulphate75 mg, sorbic acid 5 mg, together with glyceroland sorbitol in a viscous solution in 5-mL single-dosedisposable packs with nozzle. Net price 5 mL = 32pDose. By rectumChild 1 month–18 years 5 mL as a single dose (insertonly half nozzle length in child under 3 years)1.6.5 Bowel cleansingpreparationsBowel cleansing preparations are used before colonicsurgery, colonoscopy, or radiological examination toensure the bowel is free of solid contents. They arenot treatments for constipation.Cautions Bowel cleansing preparations should be usedwith caution in children, particularly in those with fluidand electrolyte disturbances. Renal function should bemeasured before starting treatment in patients at risk offluid and electrolyte disturbances. Hypovolaemiashould be corrected before administration of bowelcleansing preparations. Adequate hydration should bemaintained during treatment. Bowel cleansing preparationsshould be used with caution in colitis (avoid ifacute severe colitis), or in those who are debilitated.They should also be used with caution in patients withan impaired gag reflex or possibility of regurgitation oraspiration. Other oral drugs should not be taken onehour before or after administration of bowel cleansingpreparations because absorption may be impaired.Contra-indications Bowel cleansing preparations arecontra-indicated in patients with gastro-intestinalobstruction or perforation, gastric retention, acutesevere colitis, or toxic megacolon.Side-effects Side-effects of bowel cleansing preparationsinclude nausea, vomiting, abdominal pain (usuallytransient—reduced by taking more slowly), and abdominaldistention. Less frequent side-effects includeheadache, dizziness, dehydration, and electrolyte disturbances.MACROGOLSCautions see notes above; also heart failureContra-indications see notes above; also gastrointestinalulcerationPregnancy manufacturers advise use only if essential—noinformation availableBreast-feeding manufacturers advise use only ifessential—no information availableSide-effects see notes above; also anal discomfortLicensed use Klean-Prep c not licensed for use inchildrenIndication and doseSee preparationsKlean-Prep c (Norgine)Oral powder, sugar-free, macrogol ‘3350’ (polyethyleneglycol ‘3350’) 59 g, anhydrous sodium sulphate5.685 g, sodium bicarbonate 1.685 g, sodium chloride1.465 g, potassium chloride 743 mg/sachet, net price4 sachets = £8.23. Label: 10, patient informationleaflet, counsellingExcipients include aspartame (section 9.4.1)Electrolytes 1 sachet when reconstituted with 1 litre water provides Na +125 mmol, K + 10 mmol, Cl 35 mmol, HCO 320 mmolDoseBowel cleansing before radiological examination,colonoscopy, or surgery. By mouthChild 12–18 years a glass (approx. 250 mL) of reconstitutedsolution every 10–15 minutes, or by nasogastrictube 20–30 mL/minute, starting on the day before procedureuntil 4 litres have been consumed; alternatively,administration may be divided into two (2 litres ofreconstituted solution taken on the evening before procedureand 2 litres of reconstituted solution taken on themorning of procedure). Treatment can be stopped ifbowel motions become watery and clear. To facilitategastric emptying, domperidone (section 1.2) may begiven 30 minutes before startingDistal intestinal obstruction syndrome. By mouth, nasogastric or gastrostomy tubeChild 1–18 years 10 mL/kg/hour for 30 minutes, then20 mL/kg/hour for 30 minutes, then increase to 25 mL/kg/hour if tolerated; max. 100 mL/kg (or 4 litres) over 4hours; repeat 4-hour treatment if necessary.Administration 1 sachet should be reconstituted with 1 litreof water. Flavouring such as clear fruit cordials may be addedif required. Solid food should not be taken for at least 2 hoursbefore starting treatment. After reconstitution the solutionshould be kept in a refrigerator and discarded if unused after24 hours.MAGNESIUM CITRATEReconstitution of a sachet containing 11.57 g magnesium carbonateand 17.79 g anhydrous citric acid produces a solutioncontaining magnesium citrateCautions see notes aboveContra-indications see notes aboveHepatic impairment avoid in hepatic coma if risk ofrenal failureRenal impairment avoid if estimated glomerular filtrationrate less than 30 mL/minute/1.73 m 2 —risk ofhypermagnesaemiaPregnancy cautionBreast-feeding cautionSide-effects see notes aboveIndication and doseSee preparationsCitramag c (Sanochemia)Oral powder, sugar-free, effervescent, magnesiumcarbonate 11.57 g, anhydrous citric acid 17.79 g/sachet, net price 10-sachet pack (lemon and limeflavour) = £17.20. Label: 10, patient informationleaflet, 13, counselling, see belowElectrolytes Mg 2þ 118 mmol/sachetDoseBowel evacuation on day before radiological examination,colonoscopy, or surgery. By mouthChild 5–10 years on day before procedure, one-third ofa sachet at 8 a.m. and one-third of a sachet between 2and 4 p.m.

BNFC 2011–2012 1.6.5 Bowel cleansing preparations 65Child 10–18 years on day before procedure, ½–1 sachetat 8 a.m. and ½–1 sachet between 2 and 4 p.m.Counselling One sachet should be reconstituted with200 mL of hot water; the solution should be allowed to coolfor approx. 30 minutes before drinking. Low residue or fluidonly diet (e.g. water, fruit squash, lemonade, clear soup, blacktea or coffee) recommended before procedure (according tohospital advice) and copious intake of clear fluids recommendeduntil procedureSODIUM PICOSULFATE WITHMAGNESIUM CITRATECautions see notes above; also recent gastro-intestinalsurgery; cardiac disease (avoid in congestive cardiacfailure)Contra-indications see notes above; also gastrointestinalulceration; ascites; congestive cardiac failureHepatic impairment avoid in hepatic coma if risk ofrenal failureRenal impairment avoid if estimated glomerular filtrationrate less than 30 mL/minute/1.73 m 2 —risk ofhypermagnesaemiaPregnancy cautionBreast-feeding cautionSide-effects see notes above; also anal discomfort,sleep disturbances, fatigue, and rashIndication and doseSee preparationsPicolax c (Ferring)Oral powder, sugar-free, sodium picosulfate 10 mg/sachet, with magnesium citrate, net price 20-sachetpack = £33.90. Label: 10, patient information leaflet,13, counselling, see belowElectrolytes K + 5 mmol, Mg 2þ 87 mmol/sachetDoseBowel evacuation on day before radiological procedure,endoscopy, or surgery. By mouthChild 1–2 years ¼ sachet before 8 a.m. then ¼ sachet 6–8 hours laterChild 2–4 years ½ sachet before 8 a.m. then ½ sachet 6–8 hours laterChild 4–9 years 1 sachet before 8 a.m. then ½ sachet 6–8 hours laterChild 9–18 years 1 sachet before 8 a.m. then 1 sachet 6–8 hours laterNote Acts within 3 hours of first dose. Low residue dietrecommended on the day before procedure and copiousintake of water or other clear fluids recommended duringtreatmentCounselling One sachet should be reconstituted with150 mL (approx. half a glass) of cold water; children andcarers should be warned that heat is generated duringreconstitution and that the solution should be allowed to coolbefore drinkingAMIDOTRIZOATESDiatrizoatesCautions asthma or history of allergy, latent hyperthyroidism,dehydration and electrolyte disturbance(correct first); in children with oesophageal fistulae(aspiration may lead to pulmonary oedema); benignnodular goitre; enteritis; risk of anaphylactoid reactionsincreased by concomitant administration ofbeta-blockersContra-indications hypersensitivity to iodine, hyperthyroidismPregnancy manufacturer advises cautionSide-effects diarrhoea, nausea, vomiting; alsoreported, abdominal pain, intestinal perforation,bowel necrosis, oral mucosal blistering, hypersensitivityreactions, pyrexia, headache, dizziness, disturbancesin consciousness, hyperthyroidism, electrolytedisturbances, and skin reactions (including toxic epidermalnecrolysis)Licensed use not licensed for use in distal intestinalobstruction syndromeIndication and doseUncomplicated meconium ileus. By rectumNeonate 15–30 mL as a single doseDistal intestinal obstruction syndrome. By mouth or by rectumChild 1 month–2 years 15–30 mL as a single doseChild body-weight 15–25 kg 50 mL as a singledoseChild body-weight over 25 kg 100 mL as a singledoseAdministration Intravenous prehydration is essentialin neonates and infants. Fluid intake should beencouraged for 3 hours after administration. Bymouth, for child bodyweight under 25 kg, dilute Gastrografinc with 3 times its volume of water or fruitjuice; for child bodyweight over 25 kg, dilute Gastrografinc with twice its volume of water or fruit juice.By rectum, administration must be carried out slowlyunder radiological supervision to ensure required siteis reached. For child under 5 years, dilute Gastrografinc with 5 times its volume of water; for child over5 years dilute Gastrografin c with 4 times its volumeof water.Radiological investigations dose to be recommendedby radiologistGastrografin c (Bayer Schering)Solution, sodium amidotrizoate 100 mg, meglumineamidotrizoate 660 mg/mL, net price 100-mL bottle =£14.69Excipients include disodium edetate1 Gastro-intestinal systemAmidotrizoatesGastrografin c is an amidotrizoate radiological contrastmedium with high osmolality; it is used in thetreatment of meconium ileus in neonates and in themanagement of distal intestinal obstruction syndromein children with cystic fibrosis.1.6.6 Peripheral opioidreceptorantagonistsClassification not used in BNF for Children.

66 1.7 Local preparations for anal and rectal disorders BNFC 2011–20121 Gastro-intestinal system1.7 Local preparations foranal and rectal disorders1.7.1 Soothing anal and rectal preparations1.7.2 Compound anal and rectalpreparations with corticosteroids1.7.3 Rectal sclerosants1.7.4 Management of anal fissuresIn children with perianal soreness or pruritus ani, goodtoilet hygiene is essential; the use of alcohol-free ‘wetwipes’after each bowel motion, regular bathing and theavoidance of local irritants such as bath additives isrecommended. Excoriated skin is best treated with aprotective barrier emollient (section 13.2.2); in childrenover 1 month, hydrocortisone ointment or cream (section13.4) or a compound rectal preparation (section1.7.2) may be used for a short period of time, up to amaximum of 7 days.Pruritus ani caused by threadworm infection requirestreatment with an anthelmintic (section 5.5.1). Topicalapplication of white soft paraffin or other bland emollient(section 13.2.1) may reduce anal irritation causedby threadworms.Perianal erythema caused by streptococcal infectionshould be treated initially with an oral antibacterialsuch as phenoxymethylpenicillin (section 5.1.1.1) orerythromycin (section 5.1.5), while awaiting results ofculture and sensitivity testing.Perianal candidiasis (thrush) requires treatment with atopical antifungal preparation (section 13.10.2). Fortreatment of vulvovaginal candidiasis, see section 7.2.2.Proctitis associated with inflammatory bowel disease inchildren is treated with corticosteroids and aminosalicylates(section 1.5).For the management of anal fissures, see section 1.7.4.1.7.1 Soothing anal and rectalpreparationsHaemorrhoids in children are rare, but may occur ininfants with portal hypertension. Soothing rectal preparationscontaining mild astringents such as bismuthsubgallate, zinc oxide, and hammamelis may providesymptomatic relief, but proprietary preparations whichalso contain lubricants, vasoconstrictors, or mild antisepticsmay cause further perianal irritation.Local anaesthetics may be used to relieve pain inchildren with anal fissures or pruritus ani, but localanaesthetics are absorbed through the rectal mucosaand may cause sensitisation of the anal skin. Excessiveuse of local anaesthetics may result in systemic effects,see section 15.2. Preparations containing local anaestheticsshould be used for no longer than 2–3 days.Lidocaine ointment (section 15.2) may be appliedbefore defaecation to relieve pain associated with analfissure, but local anaesthetics can cause stinging initiallyand this may aggravate the child’s fear of pain.Other local anaesthetics such as tetracaine, cinchocaine(dibucaine), and pramocaine (pramoxine) may beincluded in rectal preparations, but these are moreirritant than lidocaine.Corticosteroids are often combined with local anaestheticsand soothing agents in topical preparations forhaemorrhoids and proctitis. Topical preparations containingcorticosteroids (section 1.7.2) should not be usedlong-term or if infection (such as herpes simplex) ispresent. For further information on the use of topicalcorticosteroids, see section 13.4.1.7.2 Compound anal and rectalpreparations withcorticosteroidsAnugesic-HC c (Pfizer) ACream, benzyl benzoate 1.2%, bismuth oxide 0.875%,hydrocortisone acetate 0.5%, Peru balsam 1.85%,pramocaine hydrochloride 1%, zinc oxide 12.35%. Netprice 30 g (with rectal nozzle) = £3.71DoseHaemorrhoids, pruritus ani. By rectumChild 12–18 years apply night and morning and after abowel movement; do not use for longer than 7 daysSuppositories, buff, benzyl benzoate 33 mg, bismuthoxide 24 mg, bismuth subgallate 59 mg, hydrocortisoneacetate 5 mg, Peru balsam 49 mg, pramocainehydrochloride 27 mg, zinc oxide 296 mg, net price 12= £2.69DoseHaemorrhoids, pruritus ani. By rectumChild 12–18 years insert 1 suppository night andmorning and after a bowel movement; do not use forlonger than 7 daysAnusol-HC c (McNeil) AOintment, benzyl benzoate 1.25%, bismuth oxide0.875%, bismuth subgallate 2.25%, hydrocortisoneacetate 0.25%, Peru balsam 1.875%, zinc oxide10.75%. Net price 30 g (with rectal nozzle) = £3.29DoseHaemorrhoids, pruritus ani. By rectumChild 12–18 years apply night and morning and after abowel movement; do not use for longer than 7 daysSuppositories, benzyl benzoate 33 mg, bismuth oxide24 mg, bismuth subgallate 59 mg, hydrocortisoneacetate 10 mg, Peru balsam 49 mg, zinc oxide 296 mg.Net price 12 = £2.31DoseHaemorrhoids, pruritus ani. By rectumChild 12–18 years insert 1 suppository night andmorning and after a bowel movement; do not use forlonger than 7 daysPerinal c (Dermal)Spray application, hydrocortisone 0.2%, lidocainehydrochloride 1%. Net price 30-mL pack = £6.11DoseHaemorrhoids, pruritus ani. By rectumChild 2–18 years spray once over the affected area upto 3 times daily; do not use for longer than 7 days withoutmedical advice (child under 14 years, on medical adviceonly)

BNFC 2011–2012 1.7.4 Management of anal fissures 67Proctofoam HC c (Meda) AFoam in aerosol pack, hydrocortisone acetate 1%,pramocaine hydrochloride 1%. Net price 21.2-g pack(approx. 40 applications) with applicator = £5.06DosePain and irritation associated with local, non-infectedanal or perianal conditions. By rectumChild 12–18 years 1 applicatorful (4–6 mg hydrocortisoneacetate, 4–6 mg pramocaine hydrochloride) byrectum 2–3 times daily and after a bowel movement(max. 4 times daily); do not use for longer than 7 daysProctosedyl c (Sanofi-Aventis) AOintment, cinchocaine (dibucaine) hydrochloride0.5%, hydrocortisone 0.5%, net price 30 g = £10.34(with cannula)DoseHaemorrhoids, pruritus ani. By rectumChild 1 month–18 years apply morning and night andafter a bowel movement, externally or by rectum; do notuse for longer than 7 daysSuppositories, cinchocaine (dibucaine) hydrochloride5 mg, hydrocortisone 5 mg, net price 12 =£4.66DoseHaemorrhoids, pruritus ani. By rectumChild 12–18 years insert 1 suppository night andmorning and after a bowel movement; do not use forlonger than 7 daysScheriproct c (Bayer Schering) AOintment, cinchocaine (dibucaine) hydrochloride0.5%, prednisolone hexanoate 0.19%, net price 30 g =£2.94DoseHaemorrhoids, pruritus ani. By rectumChild 1 month–18 years apply twice daily for 5–7 days(3–4 times daily on 1st day if necessary), then once dailyfor a few days after symptoms have clearedSuppositories, cinchocaine (dibucaine) hydrochloride1 mg, prednisolone hexanoate 1.3 mg, netprice 12 = £1.38DoseHaemorrhoids, pruritus ani. By rectumChild 12–18 years insert 1 suppository daily after abowel movement, for 5–7 days (in severe cases initially2–3 times daily)Ultraproct c (Meadow) AOintment, cinchocaine (dibucaine) hydrochloride0.5%, fluocortolone caproate 0.095%, fluocortolonepivalate 0.092%, net price 30 g (with rectal nozzle) =£4.57DoseHaemorrhoids, pruritus aniChild 1 month–18 years apply twice daily for 5–7 days(3–4 times daily on 1st day if necessary), then once dailyfor a few days after symptoms have clearedSuppositories, cinchocaine (dibucaine) hydrochloride1 mg, fluocortolone caproate 630 micrograms,fluocortolone pivalate 610 micrograms, netprice 12 = £2.15DoseHaemorrhoids, pruritus ani. By rectumChild 12–18 years insert 1 suppository daily after abowel movement, for 5–7 days (in severe cases initially2–3 times daily) then 1 suppository every other day for 1weekUniroid-HC c (Chemidex) AOintment, cinchocaine (dibucaine) hydrochloride0.5%, hydrocortisone 0.5%, net price 30 g (withapplicator) = £4.23DoseHaemorrhoids, pruritus ani. By rectumChild 1 month–18 years apply twice daily and after abowel movement, externally or by rectum; do not use forlonger than 7 days (child under 12 years, on medicaladvice only)Suppositories, cinchocaine (dibucaine) hydrochloride5 mg, hydrocortisone 5 mg, net price 12 =£1.91DoseHaemorrhoids, pruritus ani. By rectumChild 12–18 years insert 1 suppository twice daily andafter a bowel movement; do not use for longer than 7daysXyloproct c (AstraZeneca) AOintment (water-miscible), aluminium acetate 3.5%,hydrocortisone acetate 0.275%, lidocaine 5%, zincoxide 18%, net price 20 g (with applicator) = £2.26DoseHaemorrhoids, pruritus ani. By rectumChild 1 month–18 years apply several times daily;short-term use only1.7.3 Rectal sclerosantsClassification not used in BNF for Children.1.7.4 Management of analfissuresThe management of anal fissures includes stool softening(section 1.6) and the short-term use of a topicalpreparation containing a local anaesthetic (section1.7.1). If these measures are inadequate, children withchronic anal fissures should be referred for specialisttreatment in hospital. Topical glyceryl trinitrate, 0.05%or 0.1% ointment, may be used in children to relax theanal sphincter, relieve pain and aid healing of analfissures. Excessive application of topical nitrates causesside-effects such as headache, flushing, dizziness, andpostural hypotension.Before considering surgery, diltiazem 2% ointment maybe used in children with chronic anal fissures resistant totopical nitrates.1 Gastro-intestinal system

68 1.8 Stoma and enteral feeding tubes BNFC 2011–20121 Gastro-intestinal systemOintments containing glyceryl trinitrate in a range ofstrengths or diltiazem 2% are available as manufacturedspecials (see Special-order Manufacturers, p. 809).1.8 Stoma and enteralfeeding tubesStomaPrescribing for children with stoma calls for special care.The following is a brief account of some of the mainpoints to be borne in mind.When a solid-dose formulation such as a capsule or atablet is given the contents of the ostomy bag should bechecked for any remnants; response to treatment shouldbe carefully monitored because of the possibility ofincomplete absorption. Enteric-coated and modifiedreleasepreparations are unsuitable, particularly in childrenwith an ileostomy, as there may not be sufficientrelease of the active ingredient.Laxatives Enemas and washouts should be used inchildren with stoma only under specialist supervision;they should not be prescribed for those with an ileostomyas they may cause rapid and severe loss of waterand electrolytes.Children with colostomy may suffer from constipationand whenever possible it should be treated by increasingfluid intake or dietary fibre. If a laxative (section 1.6)is required, it should generally be used for short periodsonly.Antidiarrhoeals Loperamide, codeine phosphate,and co-phenotrope (section 1.4.2) are effective forcontrolling excessive stool losses. Bulk-forming drugs(section 1.6.1) may be tried but it is often difficult toadjust the dose appropriately.Antibacterials should not be given for an episode ofacute diarrhoea.Antacids The tendency to diarrhoea from magnesiumsalts or constipation from aluminium salts may beincreased in children with stoma.Diuretics Diuretics should be used with caution inchildren with an ileostomy because they may becomeexcessively dehydrated and potassium depletion mayeasily occur. It is usually advisable to use a potassiumsparingdiuretic (section 2.2.3).Digoxin Children with stoma are particularly susceptibleto hypokalaemia. This predisposes children ondigoxin to digoxin toxicity; potassium supplements (section9.2.1.1) or a potassium-sparing diuretic (section2.2.3) may be advisable.Analgesics Opioid analgesics (section 4.7.2) maycause troublesome constipation in children with colostomy.When a non-opioid analgesic is required paracetamolis usually suitable; anti-inflammatory analgesicsmay cause gastric irritation and bleeding.Iron preparations Iron supplements may cause loosestools and sore skin at the stoma site. If this is troublesomeand if iron is definitely indicated a parenteral ironpreparation (section 9.1.1.2) should be used. Modifiedreleaseiron preparations should be avoided.Care of stoma Children and carers are usually givenadvice about the use of cleansing agents, protectivecreams, lotions, deodorants, or sealants whilst in hospital,either by the surgeon or by a stoma-care nurse.Voluntary organisations offer help and support topatients with stoma.Enteral feeding tubesCare is required in choosing an appropriate formulationof a drug for administration through a nasogastricnarrow-bore feeding tube or through a percutaneousendoscopic gastrostomy (PEG) or jejunostomy tube.Liquid preparations (or soluble tablets) are preferred;injection solutions may also be suitable for administrationthrough an enteral tube.If a solid formulation of a medicine needs to be given, itshould be given as a suspension of particles fine enoughto pass through the tube. It is possible to crush manyimmediate-release tablets but enteric-coated or modified-releasepreparations should not be crushed.Enteral feeds may affect the absorption of drugs and it istherefore important to consider the timing of drugadministration in relation to feeds. If more than onedrug needs to be given, they should be given separatelyand the tube should be flushed with water after eachdrug has been given.Clearing blockages Carbonated (sugar-free) drinksmay be marginally more effective than water in unblockingfeeding tubes, but mildly acidic liquids (such aspineapple juice or cola-based drinks) can coagulateprotein in feeds, causing further blockage. If thesemeasures fail to clear the enteral feeding tube, an alkalinesolution containing pancreatic enzymes may beintroduced into the tube (followed after at least 5 minutesby water). Specific products designed to break upblockages caused by formula feeds are also available.1.9 Drugs affecting intestinalsecretions1.9.1 Drugs affecting biliary compositionand flow1.9.2 Bile acid sequestrants1.9.3 Aprotinin1.9.4 Pancreatin1.9.1 Drugs affecting biliarycomposition and flowBile acids (ursodeoxycholic and chenodeoxycholicacid) may be used as dietary supplements in childrenwith inborn errors of bile acid synthesis. Ursodeoxycholicacid is used to improve the flow of bile in childrenwith cholestatic conditions such as familial intrahepaticcholestasis, biliary atresia in infants, cystic-fibrosisrelatedliver disease, and cholestasis caused by totalparenteral nutrition or following liver transplantation.

BNFC 2011–2012 1.9.1 Drugs affecting biliary composition and flow 69Ursodeoxycholic acid may also relieve the severe itchingassociated with cholestasis.In sclerosing cholangitis, ursodeoxycholic acid is usedto lower liver enzyme and serum-bilirubin concentrations.Ursodeoxycholic acid is also used in the treatment ofintrahepatic cholestasis in pregnancy.Smith-Lemli-Opitz syndrome Chenodeoxycholicand ursodeoxycholic acid have been used with cholesterolin children with Smith-Lemli-Opitz syndrome.Chenodeoxycholic acid is also used in combinationwith cholic acid to treat bile acid synthesis defects butcholic acid is difficult to obtain. Chenodeoxycholic acidand cholesterol are available from ‘special-order’ manufacturersor specialist importing companies, see p. 809.URSODEOXYCHOLIC ACIDCautions interactions: Appendix 1 (bile acids)Contra-indications radio-opaque stones; non-functioninggall bladder (in patients with radiolucentgallstones)Hepatic impairment avoid in chronic liver disease(but used in primary biliary cirrhosis)Pregnancy no evidence of harm but manufactureradvises avoidBreast-feeding not known to be harmful but manufactureradvises avoidSide-effects rarely, diarrhoeaLicensed use not licensed for use in children forindications shown belowIndication and doseCholestasis. By mouthNeonate 5 mg/kg 3 times daily, adjust dose andfrequency according to response, max. 10 mg/kg 3times dailyChild 1 month–2 years 5 mg/kg 3 times daily,adjust dose and frequency according to response,max. 10 mg/kg 3 times dailyImprovement of hepatic metabolism of essentialfatty acids and bile flow, in children withcystic fibrosis. By mouthChild 1 month–18 years 10–15 mg/kg twicedaily; total daily dose may alternatively be given in3 divided dosesCholestasis associated with total parenteralnutrition. By mouthNeonate 10 mg/kg 3 times dailyChild 1 month–18 years 10 mg/kg 3 times dailySclerosing cholangitis. By mouthChild 1 month–18 years 5–10 mg/kg 2–3 timesdaily, adjusted according to response, max. 15 mg/kg 3 times dailyUrsodeoxycholic Acid (Non-proprietary) ATablets, ursodeoxycholic acid 150 mg, net price 60-tab pack = £20.48. Label: 21Capsules, ursodeoxycholic acid 250 mg, net price 60-cap pack = £38.86. Label: 21Destolit c (Norgine) ATablets, scored, ursodeoxycholic acid 150 mg, netprice 60-tab pack = £17.67. Label: 21Urdox c (Wockhardt) ATablets, f/c, ursodeoxycholic acid 300 mg, net price60-tab pack = £26.50. Label: 21Ursofalk c (Dr Falk) ACapsules, ursodeoxycholic acid 250 mg, net price 60-cap pack = £30.17, 100-cap pack = £31.88. Label: 21Suspension, sugar-free, ursodeoxycholic acid250 mg/5 mL, net price 250 mL = £26.98. Label: 21Ursogal c (Galen) ATablets, scored, ursodeoxycholic acid 150 mg, netprice 60-tab pack = £17.05. Label: 21Capsules, ursodeoxycholic acid 250 mg, net price 60-cap pack = £30.50. Label: 21Other preparations for bile synthesisdefectsCHENODEOXYCHOLIC ACIDCautions see under Ursodeoxycholic Acid; interactions:Appendix 1 (bile acids)Contra-indications see under Ursodeoxycholic AcidPregnancy avoid—fetotoxicity reported in animalstudiesSide-effects see under Ursodeoxycholic AcidLicensed use not licensedIndication and doseCerebrotendinous xanthomatosis. By mouthNeonate 5 mg/kg 3 times dailyChild 1 month–18 years 5 mg/kg 3 times dailyDefective synthesis of bile acid. By mouthNeonate initially 5 mg/kg 3 times daily, reduced to2.5 mg/kg 3 times dailyChild 1 month–18 years initially 5 mg/kg 3 timesdaily, reduced to 2.5 mg/kg 3 times dailySmith-Lemli-Opitz syndrome see notes above. By mouthNeonate 7 mg/kg once daily or in divided dosesChild 1 month–18 years 7 mg/kg once daily or individed dosesAdministration for administration by mouth, add thecontents of a 250-mg capsule to 25 mL of sodiumbicarbonate solution 8.4% (1 mmol/mL) to produce asuspension containing chenodeoxycholic acid 10 mg/mL; use immediately after preparation, discard anyremaining suspension1 Gastro-intestinal system

70 1.9.2 Bile acid sequestrants BNFC 2011–20121 Gastro-intestinal systemChenofalk (Non-proprietary) ACapsules, chenodeoxycholic acid 250 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809CHOLESTEROLCautions consult product literatureContra-indications consult product literatureLicensed use not licensedIndication and doseSmith-Lemli-Opitz syndrome. By mouthNeonate 5–10 mg/kg 3–4 times dailyChild 1 month–18 years 5–10 mg/kg 3–4 timesdaily (doses up to 15 mg/kg 4 times daily havebeen used)Administration cholesterol powder can be mixed witha vegetable oil before administrationCholesterol Powder (Non-proprietary)Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 8091.9.2 Bile acid sequestrantsColestyramine is an anion-exchange resin that formsan insoluble complex with bile acids in the gastro-intestinaltract; it is used to relieve diarrhoea associated withsurgical procedures such as ileal resection, or followingradiation therapy. Colestyramine is also used in thetreatment of familial hypercholesterolaemia (see section2.12), and to relieve pruritus in children with partialbiliary obstruction, (for treatment of pruritus, see section3.4.1). Colestyramine is not absorbed from thegastro-intestinal tract, but will interfere with the absorptionof a number of drugs, so timing of administration isimportant.COLESTYRAMINE(Cholestyramine)Cautions section 2.12Contra-indications section 2.12Pregnancy section 2.12Breast-feeding section 2.12Side-effects section 2.12Licensed use not licensed for use in children under 6yearsIndication and dosePruritus associated with partial biliaryobstruction and primary biliary cirrhosis,diarrhoea associated with Crohn’s disease,ileal resection, vagotomy, diabetic vagalneuropathy, and radiation. By mouthChild 1 month–1 year 1 g once daily in a suitableliquid, adjusted according to response; total dailydose may alternatively be given in 2–4 divideddoses (max. 9 g daily)Child 1–6 years 2 g once daily in a suitable liquid,adjusted according to response; total daily dosemay alternatively be given in 2–4 divided doses(max. 18 g daily)Child 6–12 years 4 g once daily in a suitableliquid, adjusted according to response; total dailydose may alternatively be given in 2–4 divideddoses (max. 24 g daily)Child 12–18 years 4–8 g once daily in a suitableliquid, adjusted according to response; total dailydose may alternatively be given in 2–4 divideddoses (max. 36 g daily)Counselling Other drugs should be taken at least 1 hourbefore or 4–6 hours after colestyramine to reduce possibleinterference with absorptionNote For treatment of diarrhoea induced by bile acidmalabsorption, if no response within 3 days an alternativetherapy should be initiatedHypercholesterolaemia section 2.12Administration The contents of one sachet should bemixed with at least 150 mL of water or other suitableliquid such as fruit juice, skimmed milk, thin soups, orpulpy fruits with a high moisture contentPreparationsSection 2.121.9.3 AprotininClassification not used in BNF for Children.1.9.4 PancreatinPancreatin, containing a mixture of protease, lipase andamylase in varying proportions, aids the digestion ofstarch, fat, and protein. Supplements of pancreatin aregiven by mouth to compensate for reduced or absentexocrine secretion in cystic fibrosis, and following pancreatectomy,total gastrectomy, or chronic pancreatitis.The dose of pancreatin is adjusted according to size,number, and consistency of stools, and the nutritionalstatus of the child; extra allowance will be needed ifsnacks are taken between meals. Daily dose should notexceed 10 000 lipase units per kg body-weight per day,(important: see advice on Higher-strength preparationsbelow).Pancreatin preparationsPreparationProteaseunitsAmylaseunitsLipaseunitsCreon c 10 000 capsule, e/c 600 8000 10 000granulesCreon c Micro e/c granules 200 3600 5000(per 100 mg)Nutrizym 10 c capsule, e/c 500 9000 10 000minitabletsPancrex c granules (per 300 4000 5000gram)Pancrex V c capsule, powder 430 9000 8000Pancrex V ‘125’ c capsule, 160 3300 2950powderPancrex V c e/c tablet 110 1700 1900Pancrex V c Forte e/c tablet 330 5000 5600Pancrex V c powder (pergram)1400 30 000 25 000

BNFC 2011–2012 1.9.4 Pancreatin 71Higher-strength pancreatin preparations PancreaseHL c and Nutrizym 22 c have been associated with thedevelopment of large bowel strictures (fibrosing colonopathy)in children with cystic fibrosis aged between 2and 13 years. The following is recommended:. Pancrease HL c , Nutrizym 22 c should not be usedin children under 16 years with cystic fibrosis;. the total dose of pancreatic enzyme supplementsused in patients with cystic fibrosis should notusually exceed 10 000 units of lipase per kg bodyweightdaily;. if a patient on any pancreatin preparation developsnew abdominal symptoms (or any change in existingabdominal symptoms) the patient should bereviewed to exclude the possibility of colonicdamage.Possible risk factors are gender (boys at greater risk thangirls), more severe cystic fibrosis, and concomitant useof laxatives. The peak age for developing fibrosingcolonopathy is between 2 and 8 years.Higher-strength pancreatin preparationsPreparationProteaseunitsCreon c 25 000 capsule,e/c pelletsCreon c 40 000 capsule,e/c granulesNutrizym 22 c capsule,e/c minitabletsPancrease HL c capsule,e/c minitabletsAmylaseunitsLipaseunits1000 18 000 25 0001600 25 000 40 0001100 19 800 22 0001250 22 500 25 000Pancreatin is inactivated by gastric acid therefore pancreatinpreparations are best taken with food (or immediatelybefore or after food). In children with cysticfibrosis with persistent fat malabsorption despite optimaluse of enzyme replacement, an H 2 -receptorantagonist (section 1.3.1), or a proton pump inhibitor(section 1.3.5) may improve fat digestion and absorption.Enteric-coated preparations are designed to delivera higher enzyme concentration in the duodenum (providedthe capsule contents are swallowed whole withoutchewing). If the capsules are opened the enteric-coatedgranules should be mixed with milk, slightly acidic softfood or liquid such as apple juice, and then swallowedimmediately without chewing. Any left-over food orliquid containing pancreatin should be discarded.Since pancreatin is also inactivated by heat, excessiveheat should be avoided if preparations are mixed withliquids or food.Pancreatin can irritate the perioral skin and buccalmucosa if retained in the mouth, and excessive dosescan cause perianal irritation. Hypersensitivity reactionsmay occur particularly if the powder is handled.PANCREATINCautions see notes above; hyperuricaemia andhyperuricosuria have been associated with very highdoses; interactions: Appendix 1 (pancreatin)Pregnancy not known to be harmfulSide-effects nausea, vomiting, abdominal discomfort;skin and mucosal irritation (see notes above)Indication and dosePancreatic insufficiency for dose see individualpreparations, belowCreon c 10 000 (Abbott Healthcare)Capsules, brown/clear, enclosing buff-coloured e/cgranules of pancreatin (pork), providing: protease600 units, lipase 10 000 units, amylase 8000 units, netprice 100-cap pack = £12.93. Counselling, see doseDose. By mouthChild 1 month–18 years initially 1–2 capsules with eachmeal either taken whole or contents mixed with fluid orsoft food (then swallowed immediately without chewing),see notes aboveCreon c Micro (Abbott Healthcare)Gastro-resistant granules, brown, pancreatin (pork),providing: protease 200 units, lipase 5000 units, amylase3600 units per 100 mg, net price 20 g = £31.50.Counselling, see doseDose. By mouthNeonate initially 100 mg before each feed; granules canbe mixed with a small amount of breast milk or formulafeed and administered immediately (manufacturerrecommends mixing with a small amount of apple juicebefore administration)Child 1 month–18 years initially 100 mg before eachfeed or meal; granules can be mixed with a small amountof milk or soft food and administered immediately(manufacturer recommends mixing with acidic liquid orpureed fruit before administration); see notes aboveNote 100 mg granules = one measured scoopful (scoopsupplied with product). Granules should not be chewedbefore swallowing.Nutrizym 10 c (Merck Serono)Capsules, red/yellow, enclosing e/c minitablets ofpancreatin (pork) providing minimum of: protease500 units, lipase 10 000 units, amylase 9000 units. Netprice 100 = £14.47. Counselling, see doseDose. By mouthChild 1 month–18 years 1–2 capsules with meals and 1capsule with snacks, swallowed whole or contents takenwith water or mixed with soft food (then swallowedimmediately without chewing, see notes above); higherdoses may be required according to responsePancrex c (Paines & Byrne)Granules, pancreatin (pork), providing minimum of:protease 300 units, lipase 5000 units, amylase4000 units/g. Net price 300 g = £20.39. Label: 25,counselling, see doseExcipients include lactose (7 g per 10 g dose)Dose. By mouthChild 2–18 years 5–10 g just before meals washed downor mixed with milk or waterPancrex V c (Paines & Byrne)Capsules, pancreatin (pork), providing minimum of:protease 430 units, lipase 8000 units, amylase9000 units, net price 300-cap pack = £15.80. Counselling,see doseDose. By mouthChild 1 month–1 year contents of 1–2 capsules mixedwith feeds1 Gastro-intestinal system

72 1.9.4 Pancreatin BNFC 2011–20121 Gastro-intestinal systemChild 1–18 years 2–6 capsules with meals, swallowedwhole or sprinkled on foodCapsules ‘125’, pancreatin (pork), providing minimumof: protease 160 units, lipase 2950 units, amylase3300 units, net price 300-cap pack = £9.72. Counselling,see doseDose. By mouthNeonate contents of 1–2 capsules in each feed (or mixwith feed and give by spoon)Tablets, e/c, pancreatin (pork), providing minimumof: protease 110 units, lipase 1900 units, amylase1700 units, net price 300-tab pack = £4.51. Label: 5,25, counselling, see doseDose. By mouthChild 2–18 years 5–15 tablets before mealsTablets forte, e/c, pancreatin (pork), providing minimumof: protease 330 units, lipase 5600 units, amylase5000 units, net price 300-tab pack = £13.74. Label: 5,25, counselling, see doseDose. By mouthChild 2–18 years 6–10 tablets before mealsPowder, pancreatin (pork), providing minimum of:protease 1400 units, lipase 25 000 units, amylase30 000 units/g, net price 300 g = £24.28. Counselling,see doseDose. By mouthNeonate 250–500 mg with each feedChild 1 month–18 years 0.5–2 g with meals, washeddown or mixed with milk or waterNutrizym 22 c (Merck Serono) ACapsules, red/yellow, enclosing e/c minitablets ofpancreatin (pork), providing minimum of: protease1100 units, lipase 22 000 units, amylase 19 800 units,net price 100-cap pack = £33.33. Counselling, seeabove and under doseDose. By mouthChild 15–18 years 1–2 capsules with meals and 1capsule with snacks, swallowed whole or contents takenwith water or mixed with soft food (then swallowedimmediately without chewing), see notes abovePancrease HL c (Janssen) ACapsules, enclosing light brown e/c minitablets ofpancreatin (pork), providing minimum of: protease1250 units, lipase 25 000 units, amylase 22 500 units.Net price 100 = £31.70. Counselling, see above andunder doseDose. By mouthChild 15–18 years 1–2 capsules during each meal and 1capsule with snacks swallowed whole or contents mixedwith slightly acidic liquid or soft food (then swallowedimmediately without chewing), see notes aboveHigher-strength preparationsSee warning aboveCounselling It is important to ensure adequate hydration at alltimes in children receiving higher-strength pancreatin preparations.Creon c 25 000 (Abbott Healthcare) ACapsules, orange/clear, enclosing brown-colourede/c pellets of pancreatin (pork), providing: protease(total) 1000 units, lipase 25 000 units, amylase18 000 units, net price 100-cap pack = £28.25. Counselling,see above and under doseDose. By mouthChild 2–18 years initially 1 capsule with meals eithertaken whole or contents mixed with fluid or soft food(then swallowed immediately without chewing), seenotes aboveCreon c 40 000 (Abbott Healthcare) ACapsules, brown/clear, enclosing brown-colourede/c granules of pancreatin (pork), providing: protease(total) 1600 units, lipase 40 000 units, amylase25 000 units, net price 100-cap pack = £60.00. Counselling,see above and under doseDose. By mouthChild 2–18 years initially 1–2 capsules with meals eithertaken whole or contents mixed with fluid or soft food(then swallowed immediately without chewing), seenotes above

BNFC 2011–2012 732 Cardiovascular system2.1 Positive inotropic drugs 732.1.1 Cardiac glycosides 732.1.2 Phosphodiesterase type-3 inhibitors752.2 Diuretics 762.2.1 Thiazides and related diuretics 762.2.2 Loop diuretics 782.2.3 Potassium-sparing diuretics andaldosterone antagonists 802.2.4 Potassium-sparing diuretics withother diuretics 812.2.5 Osmotic diuretics 812.2.6 Mercurial diuretics 822.2.7 Carbonic anhydrase inhibitors 822.2.8 Diuretics with potassium 822.3 Anti-arrhythmic drugs 822.3.1 Management of arrhythmias 822.3.2 Drugs for arrhythmias 832.4 Beta-adrenoceptor blockingdrugs 872.5 Hypertension 922.5.1 Vasodilator antihypertensivedrugs and pulmonary hypertension932.5.1.1 Vasodilator antihypertensives 932.5.1.2 Pulmonary hypertension 952.5.2 Centrally acting antihypertensivedrugs 982.5.3 Adrenergic neurone blockingdrugs 982.5.4 Alpha-adrenoceptor blockingdrugs 992.5.5 Drugs affecting the renin-angiotensinsystem 1002.5.5.1 Angiotensin-converting enzymeinhibitors 1002.5.5.2 Angiotensin-II receptor antagonists1032.6 Nitrates, calcium-channel blockers,and other antianginal drugs 1042.6.1 Nitrates 1042.6.2 Calcium-channel blockers 1052.6.3 Other antianginal drugs 1102.6.4 Peripheral vasodilators andrelated drugs 1102.7 Sympathomimetics 1102.7.1 Inotropic sympathomimetics 1102.7.2 Vasoconstrictor sympathomimetics1122.7.3 Cardiopulmonary resuscitation 1142.8 Anticoagulants and protamine 1142.8.1 Parenteral anticoagulants 1142.8.2 Oral anticoagulants 1182.8.3 Protamine sulphate 1202.9 Antiplatelet drugs 1202.10 Myocardial infarction and fibrinolysis1212.10.1 Management of myocardialinfarction 1212.10.2 Fibrinolytic drugs 1212.11 Antifibrinolytic drugs andhaemostatics 1232.12 Lipid-regulating drugs 1252.13 Local sclerosants 1302.14 Drugs affecting the ductusarteriosus 130This chapter also includes advice on the drug managementof the following:arrhythmias, p. 82heart failure, p. 76hypertension, p. 92pulmonary hypertension, p. 952.1 Positive inotropic drugs2.1.1 Cardiac glycosides2.1.2 Phosphodiesterase type-3 inhibitorsPositive inotropic drugs increase the force of contractionof the myocardium. Drugs which produce inotropiceffects include cardiac glycosides, phosphodiesteraseinhibitors, and some sympathomimetics (section 2.7.1).2.1.1 Cardiac glycosidesThe cardiac glycoside digoxin increases the force ofmyocardial contraction and reduces conductivity withinthe atrioventricular (AV) node.Digoxin is most useful in the treatment of supraventriculartachycardias, especially for controlling ventricular2 Cardiovascular system

74 2.1.1 Cardiac glycosides BNFC 2011–20122 Cardiovascular systemresponse in persistent atrial fibrillation (section 2.3.1).Digoxin has a limited role in children with chronic heartfailure; for reference to the role of digoxin in heartfailure, see section 2.2.For the management of atrial fibrillation, the maintenancedose of digoxin is determined on the basis of theventricular rate at rest, which should not be allowed tofall below an acceptable level for the child.Digoxin is now rarely used for rapid control of heart rate(see section 2.3.2), even with intravenous administration,response may take many hours; persistence oftachycardia is therefore not an indication for exceedingthe recommended dose. The intramuscular route is notrecommended.In children with heart failure who are in sinus rhythm, aloading dose may not be required.Unwanted effects depend both on the concentration ofdigoxin in the plasma and on the sensitivity of theconducting system or of the myocardium, which isoften increased in heart disease. It can sometimes bedifficult to distinguish between toxic effects and clinicaldeterioration because the symptoms of both are similar.The plasma-digoxin concentration alone cannot indicatetoxicity reliably, but the likelihood of toxicityincreases progressively through the range 1.5 to 3 micrograms/litrefor digoxin. Renal function is very importantin determining digoxin dosage.Hypokalaemia predisposes the child to digitalis toxicityand should be avoided; it is managed by giving a potassium-sparingdiuretic or, if necessary, potassium supplements.If toxicity occurs, digoxin should be withdrawn; seriousmanifestations require urgent specialist management.Digoxin-specific antibody fragments are available forreversal of life-threatening overdosage (see below).DIGOXINCautions sick sinus syndrome; thyroid disease;hypoxia; severe respiratory disease; avoid hypokalaemia,hypomagnesaemia, hypercalcaemia, andhypoxia (risk of digitalis toxicity); monitor serumelectrolytes and renal function; avoid rapid intravenousadministration (risk of hypertension andreduced coronary flow); interactions: Appendix 1(cardiac glycosides)Contra-indications intermittent complete heart block,second degree AV block; supraventricular arrhythmiasassociated with accessory conducting pathwayse.g. Wolff-Parkinson-White syndrome (although canbe used in infancy); ventricular tachycardia or fibrillation;hypertrophic cardiomyopathy (unless concomitantatrial fibrillation and heart failure—but usewith caution); myocarditis; constrictive pericarditis(unless to control atrial fibrillation or improve systolicdysfunction—but use with caution)Renal impairment use half normal dose if estimatedglomerular filtration rate is 10–50 mL/minute/1.73 m 2 and use a quarter normal dose if estimatedglomerular filtration rate is less than 10 mL/minute/1.73 m 2 ; monitor plasma-digoxin concentration; toxicityincreased by electrolyte disturbancesPregnancy may need dosage adjustmentBreast-feeding amount too small to be harmfulSide-effects see notes above; also nausea, vomiting,diarrhoea; arrhythmias, conduction disturbances;dizziness; blurred or yellow vision; rash, eosinophilia;less commonly depression; very rarely anorexia,intestinal ischaemia and necrosis, psychosis, apathy,confusion, headache, fatigue, weakness, gynaecomastiaon long-term use, and thrombocytopeniaPharmacokinetics For plasma-digoxin concentrationassay, blood should be taken at least 6 hoursafter a dose; plasma-digoxin concentration shouldbe maintained in the range 0.8–2 micrograms/litre(see also notes above)Licensed use heart failure, supraventricular arrhythmiasIndication and doseSupraventricular arrhythmias and chronic heartfailure (see also notes above) consult productliterature for details. By mouthNeonate under 1.5 kg initially 25 micrograms/kgin 3 divided doses for 24 hours then 4–6 micrograms/kgdaily in 1–2 divided dosesNeonate 1.5–2.5 kg initially 30 micrograms/kg in3 divided doses for 24 hours then 4–6 micrograms/kg daily in 1–2 divided dosesNeonate over 2.5 kg initially 45 micrograms/kg in3 divided doses for 24 hours then 10 micrograms/kg daily in 1–2 divided dosesChild 1 month–2 years initially 45 micrograms/kg in 3 divided doses for 24 hours then 10 micrograms/kgdaily in 1–2 divided dosesChild 2–5 years initially 35 micrograms/kg in 3divided doses for 24 hours then 10 micrograms/kgdaily in 1–2 divided dosesChild 5–10 years initially 25 micrograms/kg(max. 750 micrograms) in 3 divided doses for 24hours then 6 micrograms/kg daily (max.250 micrograms daily) in 1–2 divided dosesChild 10–18 years initially 0.75–1.5 mg in 3divided doses for 24 hours then 62.5–250 microgramsdaily in 1–2 divided doses (higher dosesmay be necessary). By intravenous infusion (but rarely necessary)Neonate under 1.5 kg initially 20 micrograms/kgin 3 divided doses for 24 hours then 4–6 micrograms/kgdaily in 1–2 divided dosesNeonate 1.5–2.5 kg initially 30 micrograms/kg in3 divided doses for 24 hours then 4–6 micrograms/kg daily in 1–2 divided dosesNeonate over 2.5 kg initially 35 micrograms/kg in3 divided doses for 24 hours then 10 micrograms/kg daily in 1–2 divided dosesChild 1 month–2 years initially 35 micrograms/kg in 3 divided doses for 24 hours then 10 micrograms/kgdaily in 1–2 divided dosesChild 2–5 years initially 35 micrograms/kg in 3divided doses for 24 hours then 10 micrograms/kgdaily in 1–2 divided dosesChild 5–10 years initially 25 micrograms/kg(max. 500 micrograms) in 3 divided doses for 24hours then 6 micrograms/kg daily (max.250 micrograms daily) in 1–2 divided doses

BNFC 2011–2012 2.1.2 Phosphodiesterase type-3 inhibitors 75Child 10–18 years initially 0.5–1 mg in 3 divideddoses for 24 hours then 62.5–250 micrograms dailyin 1–2 divided doses (higher doses may be necessary)Note The above doses may need to be reduced if digoxin (oranother cardiac glycoside) has been given in the preceding 2weeks. When switching from intravenous to oral route mayneed to increase dose by 20–30% to maintain the sameplasma-digoxin concentration. Plasma monitoring may berequired when changing formulation to take account ofvarying bioavailabilities. For plasma concentration monitoring,blood should ideally be taken at least 6 hours after a doseAdministration for intravenous infusion, dilute withSodium Chloride 0.9% or Glucose 5% to a max.concentration of 62.5 micrograms/mL; loading dosesshould be given over 30–60 minutes and maintenancedose over 10–20 minutes.For oral administration, oral solution must not bedilutedDigoxin (Non-proprietary) ATablets, digoxin 62.5 micrograms, net price 28-tabpack = £2.03; 125 micrograms, 28-tab pack = £1.12;250 micrograms, 28-tab pack = £1.13Injection, digoxin 250 micrograms/mL, net price 2-mL amp = 70pExcipients include alcohol, propylene glycol (see Excipients, p. 2)Paediatric injection, digoxin 100 micrograms/mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Lanoxin c (Aspen) ATablets, digoxin 125 micrograms, net price 500-tabpack = £8.09; 250 micrograms (scored), 500-tab pack= £8.09Injection, digoxin 250 micrograms/mL, net price 2-mL amp = 66pLanoxin-PG c (Aspen) ATablets, blue, digoxin 62.5 micrograms, net price 500-tab pack = £8.09Elixir, yellow, digoxin 50 micrograms/mL. Do notdilute, measure with pipette. Net price 60 mL = £5.35.Counselling, use of pipetteDigoxin-specific antibodyDigoxin-specific antibody fragments are indicated forthe treatment of known or strongly suspected digoxin ordigitoxin overdosage when measures beyond the withdrawalof the cardiac glycoside and correction of anyelectrolyte abnormalities are felt to be necessary (seealso notes above).Digibind c (GSK) AInjection, powder for preparation of infusion, digoxinspecificantibody fragments (F(ab)) 38 mg. Net priceper vial = £93.97 (hosp. and poisons centres only)DoseConsult product literature or Poisons Information Centre2.1.2 Phosphodiesterase type-3 inhibitorsEnoximone and milrinone are phosphodiesterase type-3 inhibitors that exert most of their effect on the myocardium.They possess positive inotropic and vasodilatoractivity and are useful in infants and children withlow cardiac output especially after cardiac surgery.Phosphodiesterase type-3 inhibitors should be limitedto short-term use because long-term oral administrationhas been associated with increased mortality in adultswith congestive heart failure.ENOXIMONECautions heart failure associated with hypertrophiccardiomyopathy, stenotic or obstructive valvular diseaseor other outlet obstruction; monitor blood pressure,heart rate, ECG, central venous pressure, fluidand electrolyte status, renal function, platelet count,hepatic enzymes; avoid extravasation; interactions:Appendix 1 (phosphodiesterase type-3 inhibitors)Hepatic impairment dose reduction may be requiredRenal impairment consider dose reductionPregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding manufacturer advises caution—noinformation availableSide-effects ectopic beats; less frequently ventriculartachycardia or supraventricular arrhythmias (morelikely in children with pre-existing arrhythmias);hypotension; also headache, insomnia, nausea andvomiting, diarrhoea; occasionally, chills, oliguria,fever, urinary retention; upper and lower limb painLicensed use not licensed for use in childrenIndication and doseCongestive heart failure, low cardiac outputfollowing cardiac surgery. By intravenous injection and continuous intravenousinfusionNeonate initial loading dose of 500 micrograms/kg by slow intravenous injection, followed by 5–20 micrograms/kg/minute by continuous intravenousinfusion over 24 hours adjusted accordingto response; max 24 mg/kg over 24 hoursChild 1 month–18 years initial loading dose of500 micrograms/kg by slow intravenous injection,followed by 5–20 micrograms/kg/minute by continuousintravenous infusion over 24 hoursadjusted according to response; max. 24 mg/kgover 24 hoursAdministration for intravenous administration, diluteto concentration of 2.5 mg/mL with Sodium Chloride0.9% or Water for Injections; the initial loading doseshould be given by slow intravenous injection over atleast 15 minutes. Use plastic apparatus—crystal formationif glass usedPerfan c (INCA-Pharm) AInjection, enoximone 5 mg/mL. For dilution beforeuse. Net price 20-mL amp = £15.02Excipients include alcohol, propylene glycol (see Excipients, p. 2)MILRINONECautions see under Enoximone; also correct hypokalaemia;monitor renal function; interactions:Appendix 1 (phosphodiesterase type-3 inhibitors)Renal impairment use half to three-quarters normaldose and monitor response if estimated glomerularfiltration rate less than 50 mL/minute/1.73 m 2Pregnancy manufacturer advises use only if potentialbenefit outweighs risk2 Cardiovascular system

76 2.2 Diuretics BNFC 2011–20122 Cardiovascular systemBreast-feeding manufacturer advises caution—noinformation availableSide-effects ectopic beats, ventricular tachycardia,supraventricular arrhythmias (more likely in childrenwith pre-existing arrhythmias), hypotension; headache;less commonly ventricular fibrillation, chestpain, tremor, hypokalaemia, thrombocytopenia; veryrarely bronchospasm, anaphylaxis, and rashLicensed use not licensed for use in children under18 yearsIndication and doseCongestive heart failure, low cardiac outputfollowing cardiac surgery, shock. By intravenous infusionNeonate initially 50–75 micrograms/kg over 30–60 minutes (reduce or omit initial dose if at risk ofhypotension) then 30–45 micrograms/kg/hour bycontinuous intravenous infusion for 2–3 days(usually for 12 hours after cardiac surgery)Child 1 month–18 years initially 50–75 micrograms/kgover 30–60 minutes (reduce or omitinitial dose if at risk of hypotension) then 30–45 micrograms/kg/hour by continuous intravenousinfusion for 2–3 days (usually for 12 hoursafter cardiac surgery)Administration for intravenous infusion dilute withGlucose 5% or Sodium Chloride 0.9% or SodiumChloride and Glucose intravenous infusion to a concentrationof 200 micrograms/mL (higher concentrationsof 400 micrograms/mL have been used); loadingdose may be given undiluted if fluid-restrictedPrimacor c (Sanofi-Aventis) AInjection, milrinone (as lactate) 1 mg/mL, net price10-mL amp = £16.612.2 DiureticsDiuretics are used for a variety of conditions in childrenincluding pulmonary oedema (caused by conditionssuch as respiratory distress syndrome and bronchopulmonarydysplasia), congestive heart failure, and hypertension.Hypertension in children is often resistant totherapy and may require the use of several drugs incombination (see section 2.5). Maintenance of fluid andelectrolyte balance can be difficult in children on diuretics,particularly neonates whose renal function may beimmature.Loop diuretics (section 2.2.2) are used for pulmonaryoedema, congestive heart failure, and in renal disease.Thiazides (section 2.2.1) are used less commonly thanloop diuretics but are often used in combination withloop diuretics or spironolactone in the management ofpulmonary oedema and, in lower doses, for hypertensionassociated with cardiac disease.Aminophylline infusion has been used with intravenousfurosemide to relieve fluid overload in criticallyill children.Heart failure Heart failure is less common in childrenthan in adults; it can occur as a result of congenital heartdisease (e.g. septal defects), dilated cardiomyopathy,myocarditis, or cardiac surgery. Drug treatment ofheart failure due to left ventricular systolic dysfunctionis covered below; optimal management of heart failurewith preserved left ventricular function has not beenestablished.Acute heart failure can occur after cardiac surgery oras a complication in severe acute infections with orwithout myocarditis. Therapy consists of volume loading,vasodilator or inotropic drugs.Chronic heart failure is initially treated with a loopdiuretic (section 2.2.2), usually furosemide supplementedwith spironolactone, amiloride, or potassium.If diuresis with furosemide is insufficient, the addition ofmetolazone or a thiazide diuretic (section 2.2.1) canbe considered. With metolazone, the resulting diuresiscan be profound and care is needed to avoid potentiallydangerous electrolyte disturbance.If diuretics are insufficient an ACE inhibitor, titrated tothe maximum tolerated dose, can be used. ACE inhibitors(section 2.5.5.1) are used for the treatment of allgrades of heart failure in adults and can also be usefulfor children with heart failure. Addition of digoxin(section 2.1.1) can be considered in children who remainsymptomatic despite treatment with a diuretic and anACE inhibitor.Some beta-blockers improve outcome in adults withheart failure, but data on beta-blockers in children arelimited. Carvedilol (section 2.4) has vasodilatory propertiesand therefore (like ACE inhibitors) also lowersafterload.In children receiving specialist cardiology care, thephosphodiesterase type-3 inhibitor enoximone is sometimesused by mouth for its inotropic and vasodilatoreffects. Spironolactone (section 2.2.3) is usually used asa potassium-sparing drug with a loop diuretic; in adultslow doses of spironolactone are effective in the treatmentof heart failure. Careful monitoring of serumpotassium is necessary if spironolactone is used incombination with an ACE inhibitor.Potassium loss Hypokalaemia can occur with boththiazide and loop diuretics. The risk of hypokalaemiadepends on the duration of action as well as the potencyand is thus greater with thiazides than with an equipotentdose of a loop diuretic.Hypokalaemia is particularly dangerous in childrenbeing treated with cardiac glycosides. In hepatic failurehypokalaemia caused by diuretics can precipitateencephalopathy.The use of potassium-sparing diuretics (section 2.2.3)avoids the need to take potassium supplements.2.2.1 Thiazides and relateddiureticsThiazides and related compounds are moderatelypotent diuretics; they inhibit sodium reabsorption atthe beginning of the distal convoluted tubule. They areusually administered early in the day so that the diuresisdoes not interfere with sleep.In the management of hypertension a low dose of athiazide produces a maximal or near-maximal bloodpressure lowering effect, with very little biochemicaldisturbance. Higher doses cause more marked changesin plasma potassium, sodium, uric acid, glucose, andlipids, with little advantage in blood pressure control.For reference to the use of thiazides in chronic heartfailure see section 2.2.

BNFC 2011–2012 2.2.1 Thiazides and related diuretics 77Bendroflumethiazide is licensed for use in children;chlorothiazide is also used.Chlortalidone, a thiazide-related compound, has alonger duration of action than the thiazides and maybe given on alternate days in younger children.Metolazone is particularly effective when combinedwith a loop diuretic (even in renal failure) and is mosteffective when given 30–60 minutes before furosemide;profound diuresis can occur and the child should thereforebe monitored carefully.Cautions See also section 2.2. Thiazides and relateddiuretics can exacerbate diabetes, gout, and systemiclupus erythematosus. Electrolytes should be monitoredparticularly with high doses, long-term use, or in renalimpairment. Thiazides and related diuretics should alsobe used with caution in nephrotic syndrome, hyperaldosteronism,and malnourishment; interactions: Appendix1 (diuretics).Contra-indications Thiazides and related diureticsshould be avoided in refractory hypokalaemia, hyponatraemia,and hypercalcaemia, symptomatic hyperuricaemia,and Addison’s disease.Hepatic impairment Thiazides and related diureticsshould be used with caution in mild to moderate impairmentand avoided in severe impairment. Hypokalaemiamay precipitate coma, although hypokalaemia can beprevented by using a potassium-sparing diuretic.Renal impairment Thiazides and related diureticsshould be used with caution because they can furtherreduce renal function. They are ineffective if estimatedglomerular filtration rate is less than 30 mL/minute/1.73 m 2 and should be avoided; metolazone remainseffective but with a risk of excessive diuresis.Pregnancy Thiazides and related diuretics should notbe used to treat gestational hypertension. They maycause neonatal thrombocytopenia, bone marrow suppression,jaundice, electrolyte disturbances, and hypoglycaemia;placental perfusion may also be reduced.Stimulation of labour, uterine inertia, and meconiumstaining have also been reported.Breast-feeding The amount of bendroflumethiazide,chlorothiazide, chlortalidone, and metolazone present inmilk is too small to be harmful; large doses may suppresslactation.Side-effects Side-effects of thiazides and related diureticsinclude mild gastro-intestinal disturbances, posturalhypotension, altered plasma-lipid concentrations,metabolic and electrolyte disturbances including hypokalaemia(see also notes above), hyponatraemia, hypomagnesaemia,hypercalcaemia, hyperglycaemia, hypochloraemicalkalosis, and hyperuricaemia, and gout.Less common side-effects include blood disordersincluding agranulocytosis, leucopenia and thrombocytopenia,and impotence. Pancreatitis, intrahepatic cholestasis,cardiac arrhythmias, headache, dizziness, paraesthesia,visual disturbances, and hypersensitivityreactions (including pneumonitis, pulmonary oedema,photosensitivity, and severe skin reactions) have alsobeen reported.BENDROFLUMETHIAZIDE(Bendrofluazide)Cautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseOedema in heart failure, renal disease, andhepatic disease; pulmonary oedema; hypertension. By mouthChild 1 month–2 years 50–100 micrograms/kgdaily adjusted according to responseChild 2–12 years initially 50–400 micrograms/kg(max. 10 mg) daily then 50–100 micrograms/kgdaily adjusted according to response (max. 10 mgdaily)Child 12–18 years initially 5–10 mg daily or onalternate days (2.5 mg daily in hypertension) as asingle morning dose, adjusted according toresponse (max. 10 mg daily)Bendroflumethiazide (Non-proprietary) ATablets, bendroflumethiazide 2.5 mg, net price 28-tabpack = 79p; 5 mg, 28-tab pack = 86pBrands include Aprinox c , Neo-NaClex cExtemporaneous formulations available seeExtemporaneous Preparations, p. 6CHLOROTHIAZIDECautions see notes above; also neonate (theoreticalrisk of kernicterus if very jaundiced)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveLicensed use not licensedIndication and doseHeart failure, hypertension, ascites. By mouthNeonate 10–20 mg/kg twice dailyChild 1–6 months 10–20 mg/kg twice dailyChild 6 months–12 years 10 mg/kg twice daily(max. 1 g daily)Child 12–18 years 0.25–1 g once daily or 125–500 mg twice dailyChronic hypoglycaemia section 6.1.4Diabetes insipidus section 6.5.2PreparationsChlorothiazide oral suspension 250 mg/5 mL is availablefrom ‘special-order’ manufacturers or specialistimporting companies, see p. 8092 Cardiovascular system

78 2.2.2 Loop diuretics BNFC 2011–20122 Cardiovascular systemCHLORTALIDONE(Chlorthalidone)Cautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also rarely jaundiceIndication and doseHypertension. By mouthChild 5–12 years 0.5–1 mg/kg in the morningevery 48 hours; max. 1.7 mg/kg every 48 hoursChild 12–18 years 25 mg daily in the morning,increased to 50 mg daily if necessary (but see notesabove)Stable heart failure. By mouthChild 5–12 years 0.5–1 mg/kg in the morningevery 48 hours; max. 1.7 mg/kg every 48 hoursChild 12–18 years 25–50 mg daily in the morning,increased if necessary to 100–200 mg daily(reduce to lowest effective dose for maintenance)Ascites, oedema in nephrotic syndrome. By mouthChild 5–12 years 0.5–1 mg/kg in the morningevery 48 hours; max. 1.7 mg/kg every 48 hoursChild 12–18 years up to 50 mg dailyHygroton c (Alliance) ATablets, yellow, scored, chlortalidone 50 mg, net price28-tab pack = £1.64METOLAZONECautions see notes above; also acute porphyria (section9.8.2)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also chills, chest painLicensed use not licensed for use in childrenIndication and doseOedema resistant to loop diuretics in heartfailure, renal disease, and hepatic disease;pulmonary oedema; adjunct to loop diuretics toinduce diuresis. By mouthChild 1 month–12 years 100–200 micrograms/kg once or twice dailyChild 12–18 years 5–10 mg once daily in themorning, increased to 5–10 mg twice daily inresistant oedemaAdministration tablets may be crushed and mixedwith water immediately before useMetenix 5 c (Sanofi-Aventis) ATablets, blue, metolazone 5 mg, net price 100-tabpack = £18.20Extemporaneous formulations available seeExtemporaneous Preparations, p. 62.2.2 Loop diureticsLoop diuretics inhibit reabsorption of sodium, potassium,and chloride from the ascending limb of the loopof Henlé in the renal tubule and are powerful diuretics.Furosemide and bumetanide are similar in activity;they produce dose-related diuresis. Furosemide isused extensively in children. It can be used for pulmonaryoedema (e.g. in respiratory distress syndrome andbronchopulmonary dysplasia), congestive heart failure,and in renal disease.Cautions Hypovolaemia and hypotension should becorrected before initiation of treatment with loop diuretics;electrolytes should be monitored during treatment(see also Potassium Loss, section 2.2). Loop diureticsshould be used with caution in comatose and precomatosestates associated with liver cirrhosis. Loop diureticscan exacerbate diabetes (but hyperglycaemia less likelythan with thiazides) and gout; they can also cause acuteurinary retention in children with obstruction of urinaryoutflow, therefore adequate urinary output should beestablished before initiating treatment.Contra-indications Loop diuretics should be avoidedin severe hypokalaemia, severe hyponatraemia, anuria,and in renal failure due to nephrotoxic or hepatotoxicdrugs.Hepatic impairment Hypokalaemia induced by loopdiuretics may precipitate hepatic encephalopathy andcoma—potassium-sparing diuretics can be used to preventthis.Renal impairment High doses of loop diuretics mayoccasionally be needed; high doses or rapid intravenousadministration can cause tinnitus and deafness; highdoses of bumetanide can also cause musculoskeletalpain.Pregnancy Furosemide and bumetanide should not beused to treat gestational hypertension because of thematernal hypovolaemia associated with this condition.Side-effects Side-effects of loop diuretics include mildgastro-intestinal disturbances, pancreatitis, hepaticencephalopathy, postural hypotension, temporaryincrease in serum-cholesterol and triglyceride concentration,hyperglycaemia (less common than with thiazides),acute urinary retention, electrolyte disturbances(including hyponatraemia, hypokalaemia (see section2.2), increased calcium excretion (nephrocalcinosisand nephrolithiasis reported with long-term use of furosemidein preterm infants), hypochloraemia, and hypomagnesaemia),metabolic alkalosis, blood disorders(including bone marrow depression, thrombocytopenia,and leucopenia), hyperuricaemia, visual disturbances,tinnitus and deafness (usually with high doses and rapidintravenous administration, and in renal impairment),rash, and photosensitivity.

BNFC 2011–2012 2.2.2 Loop diuretics 79BUMETANIDECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding no information available; may inhibitlactationSide-effects see notes above; also gynaecomastia,breast pain, musculoskeletal pain (associated withhigh doses in renal failure)Licensed use not licensed for use in children under12 yearsIndication and doseOedema in heart failure, renal disease, andhepatic disease; pulmonary oedema. By mouthChild 1 month–12 years 15–50 micrograms/kg1–4 times daily (max. single dose 2 mg); do notexceed 5 mg dailyChild 12–18 years 1 mg in the morning, repeatedafter 6–8 hours if necessary; severe cases up to5 mg daily. By intravenous injectionChild 12–18 years 1–2 mg, repeated after 20minutes if necessary. By intravenous infusion over 30–60 minutesChild 1 month–12 years 25–50 micrograms/kgChild 12–18 years 1–5 mgAdministration for intravenous infusion, dilute withGlucose 5% or Sodium Chloride 0.9%; concentrationsabove 25 micrograms/mL may cause precipitationBumetanide (Non-proprietary) ATablets, bumetanide 1 mg, net price 28-tab pack =£1.12; 5 mg, 28-tab pack = £4.33Oral liquid, bumetanide 1 mg/5 mL, net price 150 mL= £128.00Injection, bumetanide 500 micrograms/mL, net price4-mL amp = £1.79Burinex c (LEO) ATablets, scored, bumetanide 1 mg, net price 28-tabpack = £1.52; 5 mg, 28-tab pack = £9.67Extemporaneous formulations available seeExtemporaneous Preparations, p. 6FUROSEMIDE(Frusemide)Cautions see notes above; also hypoproteinaemia mayreduce effect and increase risk of side-effects; hepatorenalsyndrome; risk of ototoxicity may be reducedby giving high oral doses in 2 or more divided doses;effect may be prolonged in neonates; some liquidpreparations contain alcohol, caution especially inneonates; interactions: Appendix 1 (diuretics)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes above; also lower rate ofinfusion may be necessaryPregnancy see notes aboveBreast-feeding amount too small to be harmful; mayinhibit lactationSide-effects see notes above; also intrahepaticcholestasis and goutIndication and doseOedema in heart failure, renal disease, andhepatic disease; pulmonary oedema. By mouthNeonate 0.5–2 mg/kg every 12–24 hours (every24 hours if postmenstrual age under 31 weeks)Child 1 month–12 years 0.5–2 mg/kg 2–3 timesdaily (every 24 hours if postmenstrual age under31 weeks); higher doses may be required in resistantoedema; max. 12 mg/kg daily, not to exceed80 mg dailyChild 12–18 years 20–40 mg daily, increased inresistant oedema to 80–120 mg daily. By slow intravenous injectionNeonate 0.5–1 mg/kg every 12–24 hours (every24 hours if postmenstrual age under 31 weeks)Child 1 month–12 years 0.5–1 mg/kg repeatedevery 8 hours as necessary; max. 2 mg/kg (max.40 mg) every 8 hoursChild 12–18 years 20–40 mg repeated every 8hours as necessary; higher doses may be requiredin resistant cases. By continuous intravenous infusionChild 1 month–18 years 0.1–2 mg/kg/hour (followingcardiac surgery, initially 100 micrograms/kg/hour, doubled every 2 hours until urine outputexceeds 1 mL/kg/hour)Oliguria. By mouthChild 12–18 years initially 250 mg daily; ifnecessary, dose increased in steps of 250 mg givenevery 4–6 hours; max. single dose 2 g (rarely used). By intravenous infusionChild 1 month–12 years 2–5 mg/kg up to 4 timesdaily (max. 1 g daily)Child 12–18 years initially 250 mg over 1 hour(rate not exceeding 4 mg/minute), increase to500 mg over 2 hours if satisfactory urine output notobtained, then give a further 1 g over 4 hours if nosatisfactory response within subsequent hour, if noresponse obtained dialysis probably required;effective dose (up to 1 g) can be repeated every 24hoursAdministration for administration by mouth, tabletscan be crushed and mixed with water or injectionsolution diluted and given by mouth.For intravenous injection, give over 5–10 minutes at ausual rate of 100 micrograms/kg/minute (notexceeding 500 micrograms/kg/minute), max. 4 mg/minute.For intravenous infusion, dilute with Sodium Chloride0.9% to a concentration of 1–2 mg/mL; glucosesolutions unsuitable (infusion pH must be above 5.5)2 Cardiovascular system

BNFC 2011–2012 2.2.4 Potassium-sparing diuretics with other diuretics 81Indication and doseOedema in heart failure and in ascites,nephrotic syndrome, reduction of hypokalaemiainduced by diuretics or amphotericin. By mouthNeonate 1–2 mg/kg daily in 1–2 divided doses; upto 7 mg/kg daily in resistant ascitesChild 1 month–12 years 1–3 mg/kg daily in 1–2divided doses; up to 9 mg/kg daily in resistantascitesChild 12–18 years 50–100 mg daily in 1–2divided doses; up to 9 mg/kg daily (max. 400 mgdaily) in resistant ascitesSpironolactone (Non-proprietary) ATablets, spironolactone 25 mg, net price 28 = £1.50;50 mg, 28 = £2.11; 100 mg, 28 = £2.46. Label: 21Oral suspensions, spironolactone 5 mg/5 mL,10 mg/5 mL, 25 mg/5 mL, 50 mg/5 mL, and 100 mg/5 mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Aldactone c (Pharmacia) ATablets, f/c, spironolactone 25 mg (buff), net price100-tab pack = £8.89; 50 mg (white), 100-tab pack =£17.78; 100 mg (buff), 28-tab pack = £9.96. Label: 21POTASSIUM CANRENOATECautions potential metabolic products carcinogenic inrodents; monitor electrolytes (discontinue if hyperkalaemia);hypotension; acute porphyria (section9.8.2); interactions: Appendix 1 (diuretics)Contra-indications hyperkalaemia; hyponatraemiaRenal impairment use with caution and monitorplasma-potassium concentration if estimated glomerularfiltration rate 30–60 mL/minute/1.73 m 2 ; avoidif estimated glomerular filtration rate less than 30 mL/minute/1.73 m 2Pregnancy crosses placenta; feminisation and undescendedtestes in male fetus in animal studies—manufactureradvises avoidBreast-feeding present in breast milk—manufactureradvises avoidSide-effects drowsiness, headache, ataxia; menstrualirregularities; hyperuricaemia; pain at injection site onrapid administration; less commonly thrombocytopenia,eosinophilia, and hyperkalaemia; rarely hepatotoxicity,agranulocytosis, osteomalacia, hoarsenessand deepening of voice, hypersensitivity reactions(including urticaria and erythema), and alopecia; alsogastro-intestinal disturbances, hypotension, transientconfusion with high doses, hyponatraemia, hypochloraemicacidosis, mastalgia, gynaecomastia, andhirsutismLicensed use not licensed for use in the UKIndication and doseShort-term diuresis for oedema in heart failureand in ascites. By intravenous injection over at least 3 minutesor intravenous infusionNeonate 1–2 mg/kg twice dailyChild 1 month–12 years 1–2 mg/kg twice dailyChild 12–18 years 1–2 mg/kg (max. 200 mg)twice dailyNote To convert to equivalent oral spironolactone dose,multiply potassium canrenoate dose by 0.7Administration consult product literaturePreparationsPotassium canrenoate injection is available from ‘special-order’manufacturers or specialist importing companies,see p. 8092.2.4 Potassium-sparingdiuretics with otherdiureticsAlthough it is preferable to prescribe diuretics separatelyin children, the use of fixed combinations maybe justified in older children if compliance is a problem.The most commonly used preparations are listed below(but they may not be licensed for use in children—consult product literature), for other preparations seethe BNF. For interactions, see Appendix 1 (diuretics).Amiloride with thiazidesCo-amilozide (Non-proprietary) ATablets, co-amilozide 2.5/25 (amiloride hydrochloride2.5 mg, hydrochlorothiazide 25 mg), net price28-tab pack = £3.73Brands include Moduret 25 cAmiloride with loop diureticsCo-amilofruse (Non-proprietary) ATablets, co-amilofruse 2.5/20 (amiloride hydrochloride2.5 mg, furosemide 20 mg). Net price 28-tabpack = £1.18, 56-tab pack = £1.83Brands include Frumil LS cTablets, co-amilofruse 5/40 (amiloride hydrochloride5 mg, furosemide 40 mg). Net price 28-tab pack =£1.17, 56-tab pack = £1.42Brands include Frumil cTablets, co-amilofruse 10/80 (amiloride hydrochloride10 mg, furosemide 80 mg), net price 28-tabpack = £11.512.2.5 Osmotic diureticsMannitol is used to treat cerebral oedema, raised intraocularpressure, peripheral oedema, and ascites.MANNITOLCautions extravasation causes inflammation andthrombophlebitis; monitor fluid and electrolyte balance,serum osmolality, and pulmonary and renalfunction; assess cardiac function before and duringtreatment; interactions: Appendix 1 (mannitol)Contra-indications severe heart failure; severe pulmonaryoedema; intracranial bleeding (except duringcraniotomy); anuria; severe dehydrationRenal impairment use with caution in severe impairmentPregnancy manufacturer advises avoid unless essential—noinformation available2 Cardiovascular system

82 2.2.7 Carbonic anhydrase inhibitors BNFC 2011–20122 Cardiovascular systemBreast-feeding manufacturer advises avoid unlessessential—no information availableSide-effects less commonly hypotension, thrombophlebitis,fluid and electrolyte imbalance; rarely drymouth, thirst, nausea, vomiting, oedema, raisedintracranial pressure, arrhythmia, hypertension,pulmonary oedema, chest pain, headache, convulsions,dizziness, chills, fever, urinary retention,focal osmotic nephrosis, dehydration, cramp, blurredvision, rhinitis, skin necrosis, and hypersensitivityreactions (including urticaria and anaphylaxis); veryrarely congestive heart failure and acute renal failureLicensed use not licensed for use in children under12 yearsIndication and doseCerebral oedema, raised intra-ocular pressure. By intravenous infusion over 30–60 minutesChild 1 month–12 years 0.25–1.5 g/kg repeatedif necessary 1–2 times after 4–8 hoursChild 12–18 years 0.25–2 g/kg repeated ifnecessary 1–2 times after 4–8 hoursPeripheral oedema and ascites. By intravenous infusion over 2–6 hoursChild 1 month–18 years 1–2 g/kgAdministration examine infusion for crystals; if crystalspresent, dissolve by warming infusion fluid (allowto cool to body temperature before administration);for mannitol 20%, an in-line filter is recommended(15-micron filters have been used)Mannitol (Baxter) AIntravenous infusion, mannitol 10%, net price 500-mL Viaflex c bag = £2.26, 500-mL Viaflo c bag =£2.15; 20%, 250-mL Viaflex c bag = £3.27, 250-mLViaflo c bag = £3.27, 500-mL Viaflex c bag = £3.29,500-mL Viaflo c bag = £3.122.2.6 Mercurial diureticsClassification not used in BNF for Children.2.2.7 Carbonic anhydraseinhibitorsThe carbonic anhydrase inhibitor acetazolamide is aweak diuretic although it is little used for its diureticeffect. Acetazolamide and eye drops of dorzolamide andbrinzolamide inhibit the formation of aqueous humourand are used in glaucoma (section 11.6). In children,acetazolamide is also used in the treatment of epilepsy(section 4.8.1), and raised intracranial pressure (section11.6).2.2.8 Diuretics with potassiumDiuretics and potassium supplements should be prescribedseparately for children.2.3 Anti-arrhythmic drugs2.3.1 Management of arrhythmias2.3.2 Drugs for arrhythmias2.3.1 Management ofarrhythmiasManagement of an arrhythmia requires precise diagnosisof the type of arrhythmia; electrocardiography andreferral to a paediatric cardiologist is essential; underlyingcauses such as heart failure require appropriatetreatment.Arrhythmias may be broadly divided into bradycardias,supraventricular tachycardias, and ventricular arrhythmias.Bradycardia Adrenaline (epinephrine) is useful in thetreatment of symptomatic bradycardia in an infant orchild.Supraventricular tachycardiasIn supraventricular tachycardia adenosine is given byrapid intravenous injection. If adenosine is ineffective,intravenous amiodarone, flecainide, or a beta-blocker(such as esmolol, see section 2.4) can be tried; verapamilcan also be considered in children over 1 year.Atenolol, sotalol (section 2.4), and flecainide are usedfor the prophylaxis of paroxysmal supraventriculartachycardias.The use of d.c. shock and vagal stimulation also have arole in the treatment of supraventricular tachycardia.Syndromes associated with accessory conductingpathways Amiodarone, flecainide, or a betablockeris used to prevent recurrence of supraventriculartachycardia in infants and young children with thesesyndromes (e.g. Wolff-Parkinson-White syndrome).Atrial flutter In atrial flutter without structural heartdefects, sinus rhythm is restored with d.c. shock orcardiac pacing; drug treatment is usually not necessary.Amiodarone is used in atrial flutter when structuralheart defects are present or after heart surgery. Sotalol(section 2.4) may also be considered.Atrial fibrillation Atrial fibrillation is very rare inchildren. To restore sinus rhythm d.c. shock is used;beta-blockers, alone or together with digoxin, may beuseful for ventricular rate control.Ectopic tachycardia Intravenous amiodarone is usedin conjunction with body cooling and synchronisedpacing in postoperative junctional ectopic tachycardia.Oral amiodarone or flecainide are used in congenitaljunctional ectopic tachycardia.Amiodarone, flecainide, or a beta-blocker are used inatrial ectopic tachycardia; amiodarone is preferred inthose with poor ventricular function.

BNFC 2011–2012 2.3.2 Drugs for arrhythmias 83Ventricular tachycardia and ventricularfibrillationPulseless ventricular tachycardia or ventricular fibrillationrequire resuscitation, see Paediatric Advanced LifeSupport algorithm (inside back cover). Amiodarone isused in resuscitation for pulseless ventricular tachycardiaor ventricular fibrillation unresponsive to d.c.shock; lidocaine can be used as an alternative only ifamiodarone is not available.Amiodarone is also used in a haemodynamically stablechild when drug treatment is required; lidocaine can beused as an alternative only if amiodarone is not available.Torsade de pointes Torsade de pointes is a form ofventricular tachycardia associated with long QTsyndrome, which may be congenital or drug induced.Episodes may be self-limiting, but are frequently recurrentand can cause impairment or loss of consciousness.If not controlled, the arrhythmia can progress to ventricularfibrillation and sometimes death. Intravenousmagnesium sulphate (section 9.5.1.3) can be used totreat torsade de pointes (dose recommendations vary—consult local guidelines). Anti-arrhythmics can furtherprolong the QT interval, thus worsening the condition.2.3.2 Drugs for arrhythmiasAnti-arrhythmic drugs can be classified clinically asthose acting on supraventricular arrhythmias (adenosine,digoxin, and verapamil), those acting on bothsupraventricular and ventricular arrhythmias (amiodarone,beta-blockers, flecainide, and procainamide),and those acting on ventricular arrhythmias (lidocaine).For the treatment of bradycardia, see section 2.3.1.Anti-arrhythmic drugs can also be classified accordingto their effects on the electrical behaviour of myocardialcells during activity (the Vaughan Williams classification)although this classification is of less clinical significance:Class I: membrane stabilising drugs (e.g. lidocaine,flecainide)Class II: beta-blockersClass III: amiodarone; sotalol (also Class II)Class IV: calcium-channel blockers (includes verapamilbut not dihydropyridines)Cautions The negative inotropic effects of anti-arrhythmicdrugs tend to be additive. Therefore special careshould be taken if two or more are used, especially ifmyocardial function is impaired. Most drugs that areeffective in countering arrhythmias can also provokethem in some circumstances; moreover, hypokalaemiaenhances the arrhythmogenic (pro-arrhythmic) effect ofmany drugs.Adenosine is the treatment of choice for terminatingsupraventricular tachycardias, including those associatedwith accessory conducting pathways (e.g. Wolff-Parkinson-White syndrome). It is also used in the diagnosisof supraventricular arrhythmias. It is not negativelyinotropic and does not cause significant hypotension;it can be used safely in children with impairedcardiac function or postoperative arrhythmias. Theinjection should be administered by rapid intravenousinjection into a central or large peripheral vein.Amiodarone is useful in the management of bothsupraventricular and ventricular tachyarrhythmias. Itcan be given by intravenous infusion and by mouth,and causes little or no myocardial depression. Unlikeoral amiodarone, intravenous amiodarone acts relativelyrapidly. Intravenous amiodarone is also used incardiopulmonary resuscitation for ventricular fibrillationor pulseless ventricular tachycardia unresponsiveto d.c. shock (see algorithm, inside back cover).Amiodarone has a very long half-life (extending toseveral weeks) and only needs to be given once daily(but high doses may cause nausea unless divided). Manyweeks or months may be required to achieve steadystateplasma-amiodarone concentration; this is particularlyimportant when drug interactions are likely (seealso Appendix 1).Most patients taking amiodarone develop cornealmicrodeposits (reversible on withdrawal of treatment);these rarely interfere with vision, but drivers may bedazzled by headlights at night. However, if vision isimpaired or if optic neuritis or optic neuropathy occur,amiodarone must be stopped to prevent blindness andexpert advice sought. Because of the possibility ofphototoxic reactions, children and carers should beadvised to shield the child’s skin from light duringtreatment and for several months after discontinuingamiodarone; a wide-spectrum sunscreen (section13.8.1) should be used to protect against both longwaveultraviolet and visible light.Amiodarone contains iodine and can cause disorders ofthyroid function; both hypothyroidism and hyperthyroidismcan occur. Clinical assessment alone is unreliable,and laboratory tests should be performed beforetreatment and every 6 months. Thyroxine (T4) may beraised in the absence of hyperthyroidism; therefore triiodothyronine(T3), T4, and thyroid-stimulating hormone(thyrotrophin, TSH) should all be measured. Araised T3 and T4 with a very low or undetectable TSHconcentration suggests the development of thyrotoxicosis.The thyrotoxicosis may be very refractory, andamiodarone should usually be withdrawn at least temporarilyto help achieve control; treatment with carbimazolemay be required. Hypothyroidism can be treatedwith replacement therapy without withdrawing amiodaroneif it is essential; careful supervision is required.Pneumonitis should always be suspected if new orprogressive shortness of breath or cough develops in apatient taking amiodarone. Fresh neurological symptomsshould raise the possibility of peripheral neuropathy.Amiodarone is also associated with hepatotoxicity(see under amiodarone, below).Beta-blockers act as anti-arrhythmic drugs principallyby attenuating the effects of the sympathetic system onautomaticity and conductivity within the heart, fordetails see section 2.4. For special reference to the roleof sotalol in ventricular arrhythmias, see section 2.4.Oral administration of digoxin (section 2.1.1) slows theventricular rate in atrial fibrillation and in atrial flutter.However, intravenous infusion of digoxin is rarely effectivefor rapid control of ventricular rate.Flecainide is useful for the treatment of resistant reentrysupraventricular tachycardia, ventricular tachycardia,ventricular ectopic beats, arrhythmias associatedwith accessory conducting pathways (e.g. Wolff-Parkinson-Whitesyndrome), and paroxysmal atrial fibrillation.Flecainide crosses the placenta and can be used tocontrol fetal supraventricular arrhythmias.2 Cardiovascular system

84 2.3.2 Drugs for arrhythmias BNFC 2011–20122 Cardiovascular systemLidocaine can be used in cardiopulmonary resuscitationin children with ventricular fibrillation or pulselessventricular tachycardia unresponsive to d.c. shock,but only if amiodarone is not available. Doses may needto be reduced in children with persistently poor cardiacoutput and hepatic or renal failure (see under lidocaine,below).Verapamil (section 2.6.2) can cause severe haemodynamiccompromise (refractory hypotension and cardiacarrest) when used for the acute treatment of arrhythmiasin neonates and infants; it is contra-indicated inchildren under 1 year. It is also contra-indicated in thosewith congestive heart failure, syndromes associatedwith accessory conducting pathways (e.g. Wolff-Parkinson-Whitesyndrome) and in most receiving concomitantbeta-blockers. It can be useful in older children withsupraventricular tachycardia.ADENOSINECautions monitor ECG and have resuscitation facilitiesavailable; atrial fibrillation or flutter with accessorypathway (conduction down anomalous pathwaymay increase); first degree AV block; bundle branchblock; left main coronary artery stenosis; uncorrectedhypovolaemia; stenotic valvular heart disease; left toright shunt; pericarditis; pericardial effusion; autonomicdysfunction; stenotic carotid artery diseasewith cerebrovascular insufficiency; recent myocardialinfarction; heart failure; heart transplant (see dose);interactions: Appendix 1 (adenosine)Contra-indications second- or third-degree AV blockand sick sinus syndrome (unless pacemaker fitted);long QT syndrome; severe hypotension; decompensatedheart failure; asthmaPregnancy large doses may produce fetal toxicity;manufacturer advises use only if essentialBreast-feeding no information available—unlikely tobe present in milk owing to short half-lifeSide-effects nausea; arrhythmia (discontinue if asystoleor severe bradycardia occur), sinus pause, AVblock, flushing, angina (discontinue), dizziness; dyspnoea;headache; less commonly metallic taste, palpitation,hyperventilation, weakness, blurred vision,sweating; very rarely transient worsening of intracranialhypertension, bronchospasm, injection-site reactions;also reported vomiting, syncope, hypotension(discontinue if severe), cardiac arrest, respiratoryfailure (discontinue), and convulsionsLicensed use not licensed for use in childrenIndication and doseArrhythmias (see also section 2.3.1), diagnosisof arrhythmias. By rapid intravenous injectionNeonates 150 micrograms/kg; if necessary repeatinjection every 1–2 minutes increasing dose by 50–100 micrograms/kg until tachycardia terminatedor max. single dose of 300 micrograms/kg givenChild 1 month–1 year 150 micrograms/kg; ifnecessary repeat injection every 1–2 minutesincreasing the dose by 50–100 micrograms/kguntil tachycardia terminated or max. single dose of500 micrograms/kg givenChild 1–12 years 100 micrograms/kg; ifnecessary repeat injection every 1–2 minutesincreasing dose by 50–100 micrograms/kg untiltachycardia terminated or max. single dose of500 micrograms/kg (max. 12 mg) givenChild 12–18 years initially 3 mg; if necessaryfollowed by 6 mg after 1–2 minutes, and then by12 mg after a further 1–2 minutesNote In some children over 12 years 3-mg dose ineffective(e.g. if a small peripheral vein is used for administration)and higher initial dose sometimes used; however,those with heart transplant are very sensitive tothe effects of adenosine, and should not receive higherinitial doses. In children receiving dipyridamole reducedose to a quarter of usual dose of adenosineAdministration by rapid intravenous injection over 2seconds into central or large peripheral vein followedby rapid Sodium Chloride 0.9% flush; Injection solutionmay be diluted with Sodium Chloride 0.9% ifrequiredAdenocor c (Sanofi-Aventis) AInjection, adenosine 3 mg/mL in physiological saline,net price 2-mL vial = £4.45 (hosp. only)Note Intravenous infusion of adenosine (Adenoscan c ,Sanofi-Aventis) may be used in conjunction with radionuclidemyocardial perfusion imaging in patients who cannotexercise adequately or for whom exercise is inappropriate—consult product literatureAMIODARONE HYDROCHLORIDECautions liver-function and thyroid-function testsrequired before treatment and then every 6 months(see notes above for tests of thyroid function); hypokalaemia(measure serum-potassium concentrationbefore treatment); pulmonary function tests and chestx-ray required before treatment; heart failure; severebradycardia and conduction disturbances in excessivedosage; intravenous use may cause moderate andtransient fall in blood pressure (circulatory collapseprecipitated by rapid administration or overdosage) orsevere hepato-cellular toxicity (monitor transaminasesclosely); ECG monitoring and resuscitationfacilities must be available during intravenous use;acute porphyria (section 9.8.2); avoid benzyl alcoholcontaining injections in neonates (see Excipients,p. 2); interactions: Appendix 1 (amiodarone)Contra-indications except in cardiac arrest: sinusbradycardia, sino-atrial heart block; unless pacemakerfitted avoid in severe conduction disturbances orsinus node disease; thyroid dysfunction; iodine sensitivity;avoid intravenous use in severe respiratoryfailure, circulatory collapse, or severe arterial hypotension;avoid bolus injection in congestive heartfailure or cardiomyopathy; avoid rapid loading aftercardiac surgeryPregnancy possible risk of neonatal goitre; use only ifno alternativeBreast-feeding avoid; significant amount present inmilk—risk of neonatal hypothyroidism from release ofiodineSide-effects nausea, vomiting, taste disturbances,raised serum transaminases (may require dosereduction or withdrawal if accompanied by acute liverdisorders), jaundice; bradycardia (see Cautions);pulmonary toxicity (including pneumonitis and fibrosis);tremor, sleep disorders; hypothyroidism, hyperthyroidism;reversible corneal microdeposits (sometimeswith night glare); phototoxicity, persistent slategreyskin discoloration (see also notes above); lesscommonly onset or worsening of arrhythmia, conductiondisturbances (see Cautions), peripheral

BNFC 2011–2012 2.3.2 Drugs for arrhythmias 85neuropathy and myopathy (usually reversible onwithdrawal); very rarely chronic liver disease includingcirrhosis, sinus arrest, bronchospasm (in patientswith severe respiratory failure), ataxia, benign intracranialhypertension, headache, vertigo, epididymoorchitis,impotence, haemolytic or aplastic anaemia,thrombocytopenia, rash (including exfoliativedermatitis), hypersensitivity including vasculitis, alopecia,impaired vision due to optic neuritis or opticneuropathy (including blindness), anaphylaxis onrapid injection, also hypotension, respiratory distresssyndrome, sweating, and hot flushesLicensed use not licensed for use in children under 3yearsIndication and doseSupraventricular and ventricular arrhythmiassee notes above (initiated in hospital or under specialistsupervision). By mouthNeonate initially 5–10 mg/kg twice daily for 7–10days, then reduced to maintenance dose of 5–10 mg/kg once dailyChild 1 month–12 years initially 5–10 mg/kg(max. 200 mg) twice daily for 7–10 days, thenreduced to maintenance dose of 5–10 mg/kg oncedaily (max. 200 mg daily)Child 12–18 years 200 mg 3 times daily for 1week then 200 mg twice daily for 1 week thenusually 200 mg daily adjusted according toresponse. By intravenous infusionNeonate initially 5 mg/kg over 30 minutes then5 mg/kg over 30 minutes every 12–24 hoursChild 1 month–18 years initially 5–10 mg/kgover 20 minutes–2 hours then by continuousinfusion 300 micrograms/kg/hour, increasedaccording to response to max. 1.5 mg/kg/hour; donot exceed 1.2 g in 24 hoursVentricular fibrillation or pulseless ventriculartachycardia refractory to defibrillation (see alsosection 2.3.1). By intravenous injectionNeonate 5 mg/kg over at least 3 minutesChild 1 month–18 years 5 mg/kg (max. 300 mg)over at least 3 minutesAdministration intravenous administration via centralvenous catheter recommended if repeated or continuousinfusion required, as infusion via peripheral veinsmay cause pain and inflammation.For intravenous infusion, dilute to a concentration ofnot less than 600 micrograms/mL with Glucose 5%;incompatible with Sodium Chloride infusion; avoidequipment containing the plasticizer di-2-ethylhexphthalate(DEHP).For administration by mouth, tablets may be crushedand dispersed in water; injection solution should notbe given orally (irritant)Amiodarone (Non-proprietary) ATablets, amiodarone hydrochloride 100 mg, net price28-tab pack = £1.75; 200 mg, 28-tab pack = £2.22.Label: 11Injection, amiodarone hydrochloride 30 mg/mL, netprice 10-mL prefilled syringe = £19.60Excipients may include benzyl alcohol (avoid in neonates unless nosafer alternative available, see Excipients, p. 2)Sterile concentrate, amiodarone hydrochloride50 mg/mL, net price 3-mL amp = £1.33, 6-mL amp =£2.86. For dilution and use as an infusionExcipients may include benzyl alcohol (avoid in neonates unless nosafer alternative available, see Excipients, p. 2)Extemporaneous formulations available seeExtemporaneous Preparations, p. 6Cordarone X c (Sanofi-Aventis) ATablets, scored, amiodarone hydrochloride 100 mg,net price 28-tab pack = £4.28; 200 mg, 28-tab pack =£6.99. Label: 11Sterile concentrate, amiodarone hydrochloride50 mg/mL, net price 3-mL amp = £1.33. For dilutionand use as an infusionExcipients include benzyl alcohol (avoid in neonates unless no saferalternative available, see Excipients, p. 2)FLECAINIDE ACETATECautions children with pacemakers (especially thosewho may be pacemaker dependent because stimulationthreshold may rise appreciably); atrial fibrillationfollowing heart surgery; monitor ECG and have resuscitationfacilities available during intravenous use;interactions: Appendix 1 (flecainide)Contra-indications heart failure; abnormal leftventricular function; long-standing atrial fibrillationwhere conversion to sinus rhythm not attempted;haemodynamically significant valvular heart disease;avoid in sinus node dysfunction, atrial conductiondefects, second-degree or greater AV block, bundlebranch block or distal block unless pacing rescueavailableHepatic impairment avoid or reduce dose in severeimpairment; monitor plasma concentration (seepharmacokinetics below)Renal impairment reduce dose by 25–50% if estimatedglomerular filtration rate less than 35 mL/minute/1.73 m 2 and monitor plasma-flecainide concentration(see pharmacokinetics below)Pregnancy used in pregnancy to treat maternal andfetal arrhythmias in specialist centres; toxicityreported in animal studies; infant hyperbilirubinaemiaalso reportedBreast-feeding significant amount present in milk butnot known to be harmfulSide-effects oedema, pro-arrhythmic effects; dyspnoea;dizziness, asthenia, fatigue, fever; visual disturbances;rarely pneumonitis, hallucinations,depression, confusion, amnesia, dyskinesia, convulsions,peripheral neuropathy; also reported gastrointestinaldisturbances, anorexia, hepatic dysfunction,flushing, syncope, drowsiness, tremor, vertigo, headache,anxiety, insomnia, ataxia, paraesthesia,hypoaesthesia, anaemia, leucopenia, thrombocytopenia,corneal deposits, tinnitus, increased antinuclearantibodies, hypersensitivity reactions (including rash,urticaria, and photosensitivity), increased sweatingPharmacokinetics plasma-flecainide concentrationfor optimal response 200–800 micrograms/litre;blood sample should be taken immediately beforenext dose2 Cardiovascular system

86 2.3.2 Drugs for arrhythmias BNFC 2011–20122 Cardiovascular systemLicensed use not licensed for use in children under12 yearsIndication and doseResistant re-entry supraventricular tachycardia,ventricular ectopic beats or ventriculartachycardia, arrhythmias associated withaccessory conduction pathways (e.g. Wolff-Parkinson-White syndrome), paroxysmal atrialfibrillation. By mouthNeonate 2 mg/kg 2–3 times daily adjustedaccording to response and plasma-flecainide concentrationChild 1 month–12 years 2 mg/kg 2–3 times dailyadjusted according to response and plasma-flecainideconcentration (max. 8 mg/kg/day or300 mg daily)Child 12–18 years initially 50–100 mg twicedaily; max. 300 mg daily (max. 400 mg daily forventricular arrhythmias in heavily built children). By slow intravenous injection or intravenousinfusionNeonate 1–2 mg/kg over 10–30 minutes; ifnecessary followed by continuous infusion at a rateof 100–250 micrograms/kg/hour until arrhythmiacontrolled; transfer to oral treatment as aboveChild 1 month–12 years 2 mg/kg over 10–30minutes; if necessary followed by continuousinfusion at a rate of 100–250 micrograms/kg/houruntil arrhythmia controlled (max. cumulative dose600 mg in 24 hours); transfer to oral treatment asaboveChild 12–18 years 2 mg/kg (max. 150 mg) over10–30 minutes; if necessary followed by continuousinfusion at a rate of 1.5 mg/kg/hour for 1 hour,then reduced to 100–250 micrograms/kg/houruntil arrhythmia controlled (max. cumulative dose600 mg in first 24 hours); transfer to oral treatmentas aboveAdministration for administration by mouth, milk,infant formula, and dairy products may reduceabsorption of flecainide—separate doses from feeds.Liquid has a local anaesthetic effect and should begiven at least 30 minutes before or after food. Do notstore liquid in refrigerator as precipitation occurs.For intravenous administration, give initial dose over30 minutes in children with sustained ventriculartachycardia or cardiac failure.Dilute injection using Glucose 5%; concentrations ofmore than 300 micrograms/mL are unstable inchloride-containing solutionsFlecainide (Non-proprietary) ATablets, flecainide acetate 50 mg, net price 60-tabpack = £6.04; 100 mg, 60-tab pack = £8.95Liquid, available from ‘special-order’ manufacturersor specialist importing companies, see p. 809Tambocor c (3M) ATablets, flecainide acetate 50 mg, net price 60-tabpack = £11.57; 100 mg (scored), 60-tab pack = £16.53Injection, flecainide acetate 10 mg/mL, net price 15-mL amp = £4.40Modified releaseTambocor c XL (Meda) ACapsules, m/r, grey/pink, flecainide acetate 200 mg,net price 30-cap pack = £14.77. Label: 25DoseSupraventricular arrhythmias. By mouthChild 12–18 years 200 mg once dailyNote Not to be used to control arrhythmias in acutesituations; children stabilised on 200 mg daily ofimmediate-release flecainide may be transferred toTambocor c XLLIDOCAINE HYDROCHLORIDE(Lignocaine hydrochloride)Cautions lower doses in congestive heart failure andfollowing cardiac surgery; monitor ECG; resuscitationfacilities should be available; interactions: Appendix1 (lidocaine)Contra-indications sino-atrial disorders, all grades ofatrioventricular block, severe myocardial depression;acute porphyria (section 9.8.2)Hepatic impairment caution—increased risk of sideeffectsRenal impairment possible accumulation of lidocaineand active metabolite; caution in severe impairmentPregnancy crosses the placenta but not known to beharmful in animal studies—use if benefit outweighsriskBreast-feeding present in milk but amount too smallto be harmfulSide-effects dizziness, paraesthesia, or drowsiness(particularly if injection too rapid); other CNS effectsinclude confusion, respiratory depression and convulsions;hypotension and bradycardia (may lead tocardiac arrest); rarely hypersensitivity reactionsincluding anaphylaxisLicensed use not licensed for use in children under 1yearIndication and doseVentricular arrhythmias, pulseless ventriculartachycardia or ventricular fibrillation. By intravenous or intraosseous injection, andintravenous infusionNeonate 0.5–1 mg/kg by injection followed byinfusion of 0.6–3 mg/kg/hour; if infusion notimmediately available following initial injection,injection of 0.5–1 mg/kg may be repeated atintervals of not less than 5 minutes (to max. totaldose 3 mg/kg) until infusion can be initiatedChild 1 month–12 years 0.5–1 mg/kg by injectionfollowed by infusion of 0.6–3 mg/kg/hour; ifinfusion not immediately available following initialinjection, injection of 0.5–1 mg/kg may berepeated at intervals of not less than 5 minutes (tomax. total dose 3 mg/kg) until infusion can beinitiatedChild 12–18 years 50–100 mg by injection followedby infusion of 120 mg over 30 minutes then240 mg over 2 hours then 60 mg/hour; reducedose further if infusion continued beyond 24 hours;if infusion not immediately available followinginitial injection, injection of 50–100 mg may berepeated at intervals of not less than 5 minutes (tomax. 300 mg in 1 hour) until infusion can beinitiated

BNFC 2011–2012 2.4 Beta-adrenoceptor blocking drugs 87Neonatal seizures (section 4.8.1). By intravenous infusionNeonate initially 2 mg/kg over 10 minutes, followedby 6 mg/kg/hour for 6 hours; reduce doseover the following 24 hours (4 mg/kg/hour for 12hours, then 2 mg/kg/hour for 12 hours)Note Preterm neonates may require lower dosesEye section 11.7Local anaesthesia section 15.2Administration for intravenous infusion, dilute withGlucose 5% or Sodium Chloride 0.9%Lidocaine (Non-proprietary) AInjection 1%, lidocaine hydrochloride 10 mg/mL, netprice 2-mL amp = 21p; 5-mL amp = 26p; 10-mL amp= 39p; 20-mL amp = 78pInjection 2%, lidocaine hydrochloride 20 mg/mL, netprice 2-mL amp = 32p; 5-mL amp = 31p; 10-mL amp= 60p; 20-mL amp = 80pInfusion, lidocaine hydrochloride 0.1% (1 mg/mL)and 0.2% (2 mg/mL) in glucose intravenous infusion5%. 500-mL containersMinijet c Lidocaine (UCB Pharma) AInjection, lidocaine hydrochloride 1% (10 mg/mL),net price 10-mL disposable syringe = £8.48; 2%(20 mg/mL), 5-mL disposable syringe = £8.182.4 Beta-adrenoceptorblocking drugsBeta-adrenoceptor blocking drugs (beta-blockers) blockthe beta-adrenoceptors in the heart, peripheral vasculature,bronchi, pancreas, and liver.Many beta-blockers are available but experience inchildren is limited to the use of only a few.Differences between beta-blockers may affect choice.The water-soluble beta-blockers, atenolol and sotalol,are less likely to enter the brain and may therefore causeless sleep disturbance and nightmares. Water-solublebeta-blockers are excreted by the kidneys and dosagereduction is often necessary in renal impairment.Some beta-blockers, such as atenolol, have an intrinsicallylonger duration of action and need to be given onlyonce daily. Carvedilol and labetalol are beta-blockerswhich have, in addition, an arteriolar vasodilating actionand thus lower peripheral resistance. Although carvediloland labetalol possess both alpha- and beta-blockingproperties, these drugs have no important advantagesover other beta-blockers in the treatment of hypertension.Beta-blockers slow the heart and can depress the myocardium;they are contra-indicated in children withsecond- or third-degree heart block. Sotalol may prolongthe QT interval, and it occasionally causes lifethreateningventricular arrhythmias (important: particularcare is required to avoid hypokalaemia in childrentaking sotalol).Beta-blockers can precipitate asthma and should usuallybe avoided in children with a history of asthma orbronchospasm. If there is no alternative, a child withwell-controlled asthma can be treated for a co-existingcondition (e.g. arrhythmia) with a cardioselective betablocker,which should be initiated with caution at a lowdose by a specialist and the child monitored closely foradverse effects. Atenolol and metoprolol have less effecton the beta 2 (bronchial) receptors and are, therefore,relatively cardioselective, but they are not cardiospecific;they have a lesser effect on airways resistance butare not free of this side-effect.Beta-blockers are also associated with fatigue, coldnessof the extremities, and sleep disturbances with nightmares(may be less common with the water-solublebeta-blockers, see above).Beta-blockers can affect carbohydrate metabolism causinghypoglycaemia or hyperglycaemia in children withor without diabetes; they can also interfere with metabolicand autonomic responses to hypoglycaemia therebymasking symptoms such as tachycardia. However, betablockersare not contra-indicated in diabetes, althoughthe cardioselective beta-blockers (e.g. atenolol andmetoprolol) may be preferred. Beta-blockers should beavoided altogether in those with frequent episodes ofhypoglycaemia.Pregnancy Beta-blockers may cause intra-uterinegrowth restriction, neonatal hypoglycaemia, and bradycardia;the risk is greater in severe hypertension. Theuse of labetalol in maternal hypertension is not knownto be harmful, except possibly in the first trimester.Information on the safety of carvedilol duringpregnancy is lacking. If beta-blockers are used close todelivery, infants should be monitored for signs of betablockade(and alpha-blockade with labetalol or carvedilol).For the treatment of hypertension in pregnancy,see section 2.5.Breast-feeding Infants should be monitored as thereis a risk of possible toxicity due to beta-blockade (andalpha-blockade with labetalol or carvedilol), but theamount of most beta-blockers present in milk is toosmall to affect infants. Atenolol and sotalol are presentin milk in greater amounts than other beta-blockers. Themanufacturer of esmolol advises avoidance if breastfeeding.Hypertension Beta-blockers are effective for reducingblood pressure (section 2.5), but their mode of action isnot understood; they reduce cardiac output, alter baroceptorreflex sensitivity, and block peripheral adrenoceptors.Some beta-blockers depress plasma renin secretion.It is possible that a central effect may also partlyexplain their mode of action. Blood pressure can usuallybe controlled with relatively few side-effects. In generalthe dose of beta-blocker does not have to be high.Labetalol may be given intravenously for hypertensiveemergencies in children (section 2.5); however, care isneeded to avoid dangerous hypotension or beta-blockade,particularly in neonates. Esmolol is also usedintravenously for the treatment of hypertension particularlyin the peri-operative period.Beta-blockers can be used to control the pulse rate inchildren with phaeochromocytoma (section 2.5.4).However, they should never be used alone as betablockadewithout concurrent alpha-blockade may leadto a hypertensive crisis; phenoxybenzamine shouldalways be used together with the beta-blocker.2 Cardiovascular system

88 2.4 Beta-adrenoceptor blocking drugs BNFC 2011–20122 Cardiovascular systemArrhythmias In arrhythmias (section 2.3), beta-blockersact principally by attenuating the effects of thesympathetic system on automaticity and conductivitywithin the heart. They can be used alone or in conjunctionwith digoxin to control the ventricular rate in atrialfibrillation. Beta-blockers are also useful in the managementof supraventricular tachycardias and ventriculartachycardias particularly to prevent recurrence of thetachycardia.Esmolol is a relatively cardioselective beta-blocker witha very short duration of action, used intravenously forthe short-term treatment of supraventricular arrhythmiasand sinus tachycardia, particularly in the perioperativeperiod.Sotalol is a non-cardioselective beta-blocker with additionalclass III anti-arrhythmic activity. Atenolol andsotalol suppress ventricular ectopic beats and non-sustainedventricular tachycardia (section 2.3.1). However,the pro-arrhythmic effects of sotalol, particularly inchildren with sick sinus syndrome, may prolong theQT interval and induce torsade de pointes.Heart failure Beta-blockers may produce benefit inheart failure by blocking sympathetic activity and theaddition of a beta-blocker such as carvedilol to othertreatment for heart failure may be beneficial. Treatmentshould be initiated by those experienced in the managementof heart failure (see section 2.2 for details on heartfailure).Thyrotoxicosis Beta-blockers are used in the managementof thyrotoxicosis including neonatal thyrotoxicosis;propranolol can reverse clinical symptoms within4 days. Beta-blockers are also used for the pre-operativepreparation for thyroidectomy; the thyroid gland isrendered less vascular, thus facilitating surgery (section6.2.2).Other uses In tetralogy of Fallot, esmolol or propranololmay be given intravenously in the initial managementof cyanotic spells; propranolol is given by mouthfor preventing cyanotic spells. If a severe cyanotic spellin a child with congenital heart disease persists despiteoptimal use of 100% oxygen, propranolol is given byintravenous infusion (for dose, see below). If cyanosis isstill present after 10 minutes, sodium bicarbonate intravenousinfusion is given in a dose of 1 mmol/kg tocorrect acidosis (or dose calculated according to arterialblood gas results); sodium bicarbonate 4.2% intravenousinfusion is appropriate for a child under 1 yearand sodium bicarbonate 8.4% intravenous infusion inchildren over 1 year. If blood-glucose concentration isless than 3 mmol/litre, glucose 10% intravenous infusionis given in a dose of 2 mL/kg (glucose 200 mg/kg)over 10 minutes, followed by morphine in a dose of100 micrograms/kg by intravenous or intramuscularinjection.Beta-blockers are also used in the prophylaxis ofmigraine (section 4.7.4.2). Betaxolol, carteolol,levobunolol, and timolol are used topically in glaucoma(section 11.6).PROPRANOLOL HYDROCHLORIDECautions see notes above; also avoid abrupt withdrawal;first-degree AV block; portal hypertension(risk of deterioration in liver function); diabetes (seealso notes above); history of obstructive airways disease(introduce cautiously and monitor lung function—seealso notes above); myasthenia gravis;symptoms of thyrotoxicosis may be masked (see alsonotes above); psoriasis; history of hypersensitivity—may increase sensitivity to allergens and result inmore serious hypersensitivity response, also mayreduce response to adrenaline (epinephrine); interactions:Appendix 1 (beta-blockers), important:verapamil interaction, see also p. 109Contra-indications asthma (but see notes above),uncontrolled heart failure, marked bradycardia,hypotension, sick sinus syndrome, second- or thirddegreeAV block, cardiogenic shock, metabolic acidosis,severe peripheral arterial disease; phaeochromocytoma(apart from specific use with alphablockers,see also notes above)Bronchospasm Beta-blockers, including those considered tobe cardioselective, should usually be avoided in children witha history of asthma or bronchospasm. However, where thereis no alternative a cardioselective beta-blocker can be givenwith caution under specialist supervisionHepatic impairment reduce oral doseRenal impairment manufacturer advises caution—dose reduction may be requiredPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also gastro-intestinaldisturbances; bradycardia, heart failure, hypotension,conduction disorders, peripheral vasoconstriction(including exacerbation of intermittent claudicationand Raynaud’s phenomenon); bronchospasm (seeabove), dyspnoea; headache, fatigue, sleep disturbances,paraesthesia, dizziness, psychoses; sexualdysfunction; purpura, thrombocytopenia; visual disturbances;exacerbation of psoriasis, alopecia; rarelyrashes and dry eyes (reversible on withdrawal);overdosage: see Emergency Treatment of Poisoning,p. 29Licensed use not licensed for treatment of hypertensionin children under 12 yearsIndication and doseArrhythmias. By mouthNeonate 250–500 micrograms/kg 3 times daily,adjusted according to responseChild 1 month–18 years 250–500 micrograms/kg 3–4 times daily, adjusted according to response;max. 1 mg/kg 4 times daily, total daily dose not toexceed 160 mg daily. By slow intravenous injection, with ECG monitoringNeonate 20–50 micrograms/kg repeated ifnecessary every 6–8 hoursChild 1 month–18 years 25–50 micrograms/kgrepeated every 6–8 hours if necessaryHypertension. By mouthNeonate initially 250 micrograms/kg 3 times daily,increased if necessary to max. 2 mg/kg 3 timesdailyChild 1 month–12 years 0.25–1 mg/kg 3 timesdaily, increased at weekly intervals to max. 5 mg/kg daily

BNFC 2011–2012 2.4 Beta-adrenoceptor blocking drugs 89Child 12–18 years initially 80 mg twice daily;increased at weekly intervals as required; maintenance160–320 mg daily; slow-release preparationsmay be used for once daily administrationTetralogy of Fallot. By mouthNeonate 0.25–1 mg/kg 2–3 times daily, max.2 mg/kg 3 times dailyChild 1 month–12 years 0.25–1 mg/kg 3–4 timesdaily, max. 5 mg/kg daily. By slow intravenous injection with ECG monitoringNeonate initially 15–20 micrograms/kg (max.100 micrograms/kg), repeated every 12 hours ifnecessaryChild 1 month–12 years initially 15–20 micrograms/kg(max. 100 micrograms/kg), repeatedevery 6–8 hours if necessary; higher doses rarelynecessaryMigraine prophylaxis. By mouthChild 2–12 years initially 200–500 micrograms/kg twice daily; usual dose 10–20 mg twice daily;max. 2 mg/kg twice dailyChild 12–18 years initially 20–40 mg twice daily;usual dose 40–80 mg twice daily; max. 2 mg/kg(max. 120 mg) twice dailyAdministration for slow intravenous injection, giveover at least 3–5 minutes; rate of administrationshould not exceed 1 mg/minute. May be diluted withSodium Chloride 0.9% or Glucose 5%. Incompatiblewith bicarbonate.Note Excessive bradycardia can be countered with intravenousinjection of atropine sulphate; for overdosage seeEmergency Treatment of Poisoning, p. 29Propranolol (Non-proprietary) ATablets, propranolol hydrochloride 10 mg, net price28-tab pack = 92p; 40 mg, 28-tab pack = 93p; 80 mg,56-tab pack = £1.54; 160 mg, 56-tab pack = £4.02.Label: 8Brands include Angilol cOral solution, propranolol hydrochloride 5 mg/5 mL,net price 150 mL = £12.50; 10 mg/5 mL, 150 mL =£16.45; 50 mg/5 mL, 150 mL = £19.98. Label: 8Brands include Syprol cInderal c (AstraZeneca) AInjection, propranolol hydrochloride 1 mg/mL, netprice 1-mL amp = 21pModified releaseNote Modified-release preparations for once daily administration;use in older children onlyHalf-Inderal LA c (AstraZeneca) ACapsules, m/r, lavender/pink, propranolol hydrochloride80 mg. Net price 28-cap pack = £5.40.Label: 8, 25Note Modified-release capsules containing propranololhydrochloride 80 mg also available; brands include BedranolSR c , Half Beta Prograne cInderal-LA (AstraZeneca) ACapsules, m/r, lavender/pink, propranolol hydrochloride160 mg. Net price 28-cap pack = £1.91.Label: 8, 25Note Modified-release capsules containing propranololhydrochloride 160 mg also available; brands includeBedranol SR c , Beta-Prograne c , Slo-Pro cATENOLOLCautions see under Propranolol HydrochlorideContra-indications see under Propranolol HydrochlorideRenal impairment initially use 50% of usual dose ifestimated glomerular filtration rate 10–35 mL/minute/1.73m 2 ; initially use 30–50% of usual dose ifestimated glomerular filtration rate less than 10 mL/minute/1.73 m 2Pregnancy see notes aboveBreast-feeding see notes aboveSide-effects see under Propranolol HydrochlorideLicensed use not licensed for use in children under12 yearsIndication and doseHypertension. By mouthNeonate 0.5–2 mg/kg once daily; may be given in2 divided dosesChild 1 month–12 years 0.5–2 mg/kg once daily(doses higher than 50 mg daily rarely necessary);may be given in 2 divided dosesChild 12–18 years 25–50 mg once daily (higherdoses rarely necessary); may be given in 2 divideddosesArrhythmias. By mouthNeonate 0.5–2 mg/kg once daily; may be given in2 divided dosesChild 1 month–12 years 0.5–2 mg/kg once daily(max. 100 mg daily); may be given in 2 divideddosesChild 12–18 years 50–100 mg once daily; may begiven in 2 divided dosesAtenolol (Non-proprietary) ATablets, atenolol 25 mg, net price 28-tab pack = 83p;50 mg, 28-tab pack = 86p; 100 mg, 28-tab pack = 91p.Label: 8Tenormin c (AstraZeneca) A‘25’ tablets, f/c, atenolol 25 mg, net price 28-tab pack= £1.16. Label: 8LS tablets, orange, f/c, scored, atenolol 50 mg, netprice 28-tab pack = £2.04. Label: 8Tablets, orange, f/c, scored, atenolol 100 mg, netprice 28-tab pack = £3.46. Label: 8Syrup, sugar-free, atenolol 25 mg/5 mL, net price300 mL = £8.55. Label: 8CARVEDILOLCautions see under Propranolol Hydrochloride;monitor renal function during dose titration in childrenwith heart failure who also have low blood2 Cardiovascular system

90 2.4 Beta-adrenoceptor blocking drugs BNFC 2011–20122 Cardiovascular systempressure, renal impairment, ischaemic heart disease,or diffuse vascular diseaseContra-indications see under Propranolol Hydrochloride;acute or decompensated heart failurerequiring intravenous inotropesHepatic impairment avoidPregnancy see notes aboveBreast-feeding see notes aboveSide-effects postural hypotension, dizziness, headache,fatigue, gastro-intestinal disturbances, bradycardia;occasionally diminished peripheral circulation,peripheral oedema and painful extremities, drymouth, dry eyes, eye irritation or disturbed vision,impotence, disturbances of micturition, influenza-likesymptoms; rarely angina, AV block, exacerbation ofintermittent claudication or Raynaud’s phenomenon;allergic skin reactions, exacerbation of psoriasis, nasalstuffiness, wheezing, depressed mood, sleep disturbances,paraesthesia, heart failure, changes in liverenzymes, thrombocytopenia, leucopenia alsoreportedLicensed use not licensed for use in children under18 yearsIndication and doseAdjunct in heart failure (limited informationavailable). By mouthChild 2–18 years initially 50 micrograms/kg(max. 3.125 mg) twice daily, double dose at intervalsof at least 2 weeks up to 350 micrograms/kg(max. 25 mg) twice dailyCarvedilol (Non-proprietary) ATablets, carvedilol 3.125 mg, net price 28-tab pack =£1.10; 6.25 mg, 28-tab pack = £1.25; 12.5 mg, 28-tabpack = £1.37; 25 mg, 28-tab pack = £1.84. Label: 8Eucardic c (Roche) ATablets, scored, carvedilol 3.125 mg (pink), net price28-tab pack = £7.13; 6.25 mg (yellow), 28-tab pack =£7.92; 12.5 mg (peach), 28-tab pack = £8.81; 25 mg,28-tab pack = £11.00. Label: 8ESMOLOL HYDROCHLORIDECautions see under Propranolol HydrochlorideContra-indications see under Propranolol HydrochlorideRenal impairment manufacturer advises cautionPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see under Propranolol Hydrochloride;infusion causes venous irritation and thrombophlebitisLicensed use not licensed for use in childrenIndication and doseArrhythmias, hypertensive emergencies (seealso notes above and section 2.5). By intravenous administrationChild 1 month–18 years initially by intravenousinjection over 1 minute 500 micrograms/kg thenby intravenous infusion 50 micrograms/kg/minutefor 4 minutes (rate reduced if low blood pressureor low heart rate); if inadequate response,repeat loading dose and increase maintenanceinfusion by 50 micrograms/kg/minute increments;repeat until effective or max. infusion of200 micrograms/kg/minute reached; doses over300 micrograms/kg/minute not recommendedTetralogy of Fallot. By intravenous administrationNeonate initially by intravenous injection over 1–2minutes 600 micrograms/kg then if necessary byintravenous infusion 300–900 micrograms/kg/minuteAdministration give through a central venous catheter;incompatible with bicarbonateBrevibloc c (Baxter) AInjection, esmolol hydrochloride 10 mg/mL, net price10-mL vial = £7.79, 250-mL infusion bag = £89.69LABETALOL HYDROCHLORIDECautions see under Propranolol Hydrochloride; interfereswith laboratory tests for catecholamines; liverdamage (see below)Liver damage Severe hepatocellular damage reported afterboth short-term and long-term treatment. Appropriatelaboratory testing needed at first symptom of liver dysfunctionand if laboratory evidence of damage (or if jaundice)labetalol should be stopped and not restartedContra-indications see under Propranolol HydrochlorideRenal impairment dose reduction may be requiredPregnancy see notes aboveBreast-feeding see notes aboveSide-effects postural hypotension (avoid uprightposition during and for 3 hours after intravenousadministration), tiredness, weakness, headache,rashes, scalp tingling, difficulty in micturition, epigastricpain, nausea, vomiting; liver damage (seeabove); rarely lichenoid rashLicensed use not licensed for use in childrenIndication and doseHypertensive emergencies see also section 2.5. By intravenous infusionNeonate 500 micrograms/kg/hour adjusted atintervals of at least 15 minutes according toresponse; max. 4 mg/kg/hourChild 1 month–12 years initially 0.5–1 mg/kg/hour adjusted at intervals of at least 15 minutesaccording to response; max. 3 mg/kg/hourChild 12–18 years 30–120 mg/hour adjusted atintervals of at least 15 minutes according toresponseNote Consult local guidelines. In hypertensiveencephalopathy reduce blood pressure to normotensivelevel over 24–48 hours (more rapid reduction may lead tocerebral infarction, blindness, and death). If child fitting,reduce blood pressure rapidly, but not to normal levelsHypertension. By mouthChild 1 month–12 years 1–2 mg/kg 3–4 times adayChild 12–18 years initially 50–100 mg twice dailyincreased if required at intervals of 3–14 days tousual dose of 200–400 mg twice daily (3–4 divideddoses if higher); max. 2.4 g daily

BNFC 2011–2012 2.4 Beta-adrenoceptor blocking drugs 91. By intravenous injectionChild 1 month–12 years 250–500 micrograms/kg as a single dose; max. 20 mgChild 12–18 years 50 mg over at least 1 minute,repeated after 5 minutes if necessary; max. totaldose 200 mgNote Excessive bradycardia can be countered with intravenousinjection of atropine sulphate; for overdosage seep. 29Administration for intravenous infusion, dilute to aconcentration of 1 mg/mL in Glucose 5% or SodiumChloride and Glucose 5%; if fluid restricted may begiven undiluted, preferably through a central venouscatheter.For administration by mouth, injection may be givenorally with squash or juiceLabetalol Hydrochloride (Non-proprietary) ATablets, f/c, labetalol hydrochloride 100 mg, net price56 = £7.85; 200 mg, 56 = £11.49; 400 mg, 56 = £20.60.Label: 8, 21Trandate c (UCB Pharma) ATablets, all orange, f/c, labetalol hydrochloride 50 mg,net price 56-tab pack = £3.64; 100 mg, 56-tab pack =£4.01; 200 mg, 56-tab pack = £6.51; 400 mg, 56-tabpack = £9.05. Label: 8, 21Injection, labetalol hydrochloride 5 mg/mL, net price20-mL amp = £2.04Extemporaneous formulations available seeExtemporaneous Preparations, p. 6METOPROLOL TARTRATECautions see under Propranolol HydrochlorideContra-indications see under Propranolol HydrochlorideHepatic impairment reduce dose in severe impairmentPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see under Propranolol HydrochlorideLicensed use not licensed for use in childrenIndication and doseHypertension. By mouthChild 1 month–12 years initially 1 mg/kg twicedaily, increased if necessary to max. 8 mg/kg(max. 400 mg) daily in 2–4 divided dosesChild 12–18 years initially 50–100 mg dailyincreased if necessary to 200 mg daily in 1–2divided doses; max. 400 mg daily (but high dosesrarely necessary)Arrhythmias. By mouthChild 12–18 years usually 50 mg 2–3 times daily;up to 300 mg daily in divided doses if necessaryMetoprolol Tartrate (Non-proprietary) ATablets, metoprolol tartrate 50 mg, net price 28-tabpack = £1.31, 56-tab pack = £1.74; 100 mg, 28-tabpack = £1.59, 56-tab pack = £2.51. Label: 8Lopresor c (Recordati) ATablets, f/c, scored, metoprolol tartrate 50 mg (pink),net price 56-tab pack = £2.57; 100 mg (blue), 56-tabpack = £6.68. Label: 8Modified releaseLopresor SR c (Recordati) ATablets, m/r, yellow, f/c, metoprolol tartrate 200 mg,net price 28-tab pack = £9.80. Label: 8, 25DoseHypertension. By mouthChild 12–18 years 200 mg once dailyExtemporaneous formulations available seeExtemporaneous Preparations, p. 6SOTALOL HYDROCHLORIDECautions see under Propranolol Hydrochloride; correcthypokalaemia, hypomagnesaemia, or otherelectrolyte disturbances; severe or prolonged diarrhoea;reduce dose or discontinue if corrected QTinterval exceeds 550 msecContra-indications see under Propranolol Hydrochloride;congenital or acquired long QT syndrome;torsade de pointesRenal impairment halve normal dose if estimatedglomerular filtration rate 30–60 mL/minute/1.73 m 2 ;use one-quarter normal dose if estimated glomerularfiltration rate 10–30 mL/minute/1.73 m 2 ; avoid ifestimated glomerular filtration rate less than 10 mL/minute/1.73 m 2Pregnancy see notes aboveBreast-feeding see notes aboveSide-effects see under Propranolol Hydrochloride;arrhythmogenic (pro-arrhythmic) effect (torsade depointes—increased risk in females)Licensed use not licensed for use in children under12 yearsIndication and doseVentricular arrhythmias, life-threateningventricular tachyarrhythmia and supraventriculararrhythmias initiated under specialist supervisionand ECG monitoring and measurement ofcorrected QT interval. By mouthNeonate initially 1 mg/kg twice daily, increased asnecessary every 3–4 days to max. 4 mg/kg twicedailyAtrial flutter, ventricular arrhythmias, lifethreateningventricular tachyarrhythmia andsupraventricular arrhythmias initiated underspecialist supervision and ECG monitoring andmeasurement of corrected QT interval. By mouthChild 1 month–12 years initially 1 mg/kg twicedaily, increased as necessary every 2–3 days tomax. 4 mg/kg twice daily (max. 80 mg twice daily)Child 12–18 years initially 80 mg once daily or40 mg twice daily, increased gradually at intervalsof 2–3 days to usual dose 80–160 mg twice daily;higher doses of 480–640 mg daily for life-threateningventricular arrhythmias under specialistsupervision2 Cardiovascular system

92 2.5 Hypertension BNFC 2011–20122 Cardiovascular systemAdministration for administration by mouth, tabletsmay be crushed and dispersed in waterNote Excessive bradycardia can be countered with intravenousinjection of atropine sulphate; for overdosage seeEmergency Treatment of Poisoning, p. 29Sotalol (Non-proprietary) ATablets, sotalol hydrochloride 40 mg, net price 56-tabpack = £1.29; 80 mg, 56-tab pack = £1.91; 160 mg, 28-tab pack = £2.32. Label: 8Beta-Cardone c (UCB Pharma) ATablets, scored, sotalol hydrochloride 40 mg (green),net price 56-tab pack = £1.29; 80 mg (pink), 56-tabpack = £1.91; 200 mg, 28-tab pack = £2.40. Label: 8Sotacor c (Bristol-Myers Squibb) ATablets, scored, sotalol hydrochloride 80 mg, netprice 28-tab pack = £3.06. Label: 8Extemporaneous formulations available seeExtemporaneous Preparations, p. 62.5 Hypertension2.5.1 Vasodilator antihypertensive drugsand pulmonary hypertension2.5.2 Centrally acting antihypertensivedrugs2.5.3 Adrenergic neurone blocking drugs2.5.4 Alpha-adrenoceptor blocking drugs2.5.5 Drugs affecting the renin-angiotensinsystemHypertension in children and adolescents can have asubstantial effect on long-term health. Possible causesof hypertension (e.g. congenital heart disease, renaldisease and endocrine disorders) and the presence ofany complications (e.g. left ventricular hypertrophy)should be established. Treatment should take accountof contributory factors and any factors that increase therisk of cardiovascular complications.Serious hypertension is rare in neonates but it canpresent with signs of congestive heart failure; thecause is often renal and can follow embolic arterialdamage.Children (or their parents or carers) should be givenadvice on lifestyle changes to reduce blood pressure orcardiovascular risk; these include weight reduction (inobese children), reduction of dietary salt, reduction oftotal and saturated fat, increasing exercise, increasingfruit and vegetable intake, and not smoking.Indications for antihypertensive therapy in childreninclude symptomatic hypertension, secondary hypertension,hypertensive target-organ damage, diabetesmellitus, persistent hypertension despite lifestyle measures(see above), and pulmonary hypertension (section2.5.1.2). The effect of antihypertensive treatment ongrowth and development is not known; treatmentshould be started only if benefits are clear.Antihypertensive therapy should be initiated with asingle drug at the lowest recommended dose; the dosecan be increased until the target blood pressure isachieved. Once the highest recommended dose isreached, or sooner if the patient begins to experienceside-effects, a second drug may be added if bloodpressure is not controlled. If more than one drug isrequired, these should be given as separate products toallow dose adjustment of individual drugs, but fixeddosecombination products may be useful in adolescentsif compliance is a problem.Acceptable drug classes for use in children with hypertensioninclude ACE inhibitors (section 2.5.5.1), alphablockers(section 2.5.4), beta-blockers (section 2.4),calcium-channel blockers (section 2.6.2), and thiazidediuretics (section 2.2.1). There is limited information onthe use of angiotensin-II receptor antagonists (section2.5.5.2) in children. Diuretics and beta-blockers have along history of safety and efficacy in children. Thenewer classes of antihypertensive drugs, includingACE inhibitors and calcium-channel blockers havebeen shown to be safe and effective in short-termstudies in children. Refractory hypertension may requireadditional treatment with agents such as minoxidil(section 2.5.1.1) or clonidine (section 2.5.2).Other measures to reduce cardiovascular riskAspirin (section 2.9) may be used to reduce the riskof cardiovascular events; however, concerns about anincreased risk of bleeding and Reye’s syndrome need tobe considered.A statin can be of benefit in older children who have ahigh risk of cardiovascular disease and have hypercholesterolaemia(see section 2.12).Hypertension in diabetes Hypertension can occurin type 2 diabetes and treatment prevents both macrovascularand microvascular complications. ACE inhibitors(section 2.5.5.1) may be considered in childrenwith diabetes and microalbuminaemia or proteinuricrenal disease (see also section 6.1.5). Beta-blockersare best avoided in children with, or at a high risk ofdeveloping, diabetes, especially when combined with athiazide diuretic.Hypertension in renal disease ACE inhibitors maybe considered in children with micro-albuminuria orproteinuric renal disease (see also section 6.1.5). Highdoses of loop diuretics may be required. Specific cautionsapply to the use of ACE inhibitors in renal impairment,see section 2.5.5.1, but ACE inhibitors may beeffective. Dihydropyridine calcium-channel blockersmay be added.Hypertension in pregnancy High blood pressure inpregnancy may usually be due to pre-existing essentialhypertension or to pre-eclampsia. Methyldopa (BNFsection 2.5.2) is safe in pregnancy. Beta-blockers areeffective and safe in the third trimester. Modified-releasepreparations of nifedipine [unlicensed] are also used forhypertension in pregnancy. Intravenous administrationof labetalol (section 2.4) can be used to control hypertensivecrises; alternatively hydralazine (section2.5.1.1) can be given by the intravenous route.Hypertensive emergencies Hypertensive emergenciesin children may be accompanied by signs of hypertensiveencephalopathy, including seizures. Controlledreduction in blood pressure over 72–96 hours is essential;rapid reduction can reduce perfusion leading to

BNFC 2011–2012 2.5.1 Vasodilator antihypertensive drugs 93organ damage. Treatment should be initiated with intravenousdrugs; once blood pressure is controlled, oraltherapy can be started. It may be necessary to infusefluids particularly during the first 12 hours to expandplasma volume should the blood pressure drop toorapidly.Controlled reduction of blood pressure is achieved byintravenous administration of labetalol (section 2.4) orsodium nitroprusside (section 2.5.1.1). Esmolol (section2.4) is useful for short-term use and has a shortduration of action. Nicardipine (section 2.6.2) can beadministered as a continuous intravenous infusion but itis not licensed for this use. In less severe cases, nifedipinecapsules (section 2.6.2) can be used.In resistant cases, diazoxide (section 2.5.1.1) is givenintravenously, but it can cause sudden hypotension.Other antihypertensive drugs which can be given intravenouslyinclude hydralazine (section 2.5.1.1) and clonidine(section 2.5.2).Hypertension in acute nephritis occurs as a result ofsodium and water retention; it should be treated withsodium and fluid restriction, and with furosemide (section2.2.2); antihypertensive drugs may be added ifnecessary.For advice on short-term management of hypertensiveepisodes in phaeochromocytoma, see under Phaeochromocytoma,section 2.5.4.2.5.1 Vasodilatorantihypertensive drugsand pulmonaryhypertension2.5.1.1 Vasodilator antihypertensivesVasodilators have a potent hypotensive effect, especiallywhen used in combination with a beta-blockerand a thiazide. Important: for a warning on the hazardsof a very rapid fall in blood pressure, see HypertensiveEmergencies, p. 92.Sodium nitroprusside is given by intravenous infusionto control severe hypertensive crisis when parenteraltreatment is necessary. At low doses it reduces systemicvascular resistance and increases cardiac output; at highdoses it can produce profound systemic hypotension—continuous blood pressure monitoring is thereforeessential. Sodium nitroprusside may also be used tocontrol paradoxical hypertension after surgery forcoarctation of the aorta.Diazoxide has also been used by intravenous injectionin hypertensive emergencies; however it is not first-linetherapy.Hydralazine is given by mouth as an adjunct to otherantihypertensives for the treatment of resistant hypertensionbut is rarely used; when used alone it causestachycardia and fluid retention. The incidence of sideeffectsis lower if the dose is kept low, but systemic lupuserythematosus should be suspected if there is unexplainedweight loss, arthritis, or any other unexplainedill health.Minoxidil should be reserved for the treatment ofsevere hypertension resistant to other drugs. Vasodilatationis accompanied by increased cardiac output andtachycardia and children develop fluid retention. Forthis reason the addition of a beta-blocker and a diuretic(usually furosemide, in high dosage) are mandatory.Hypertrichosis is troublesome and renders this drugunsuitable for females.Prazosin and doxazosin (section 2.5.4) have alphablockingand vasodilator properties.DIAZOXIDECautions during prolonged use monitor white cell andplatelet count, and regularly assess growth, bone, andpsychological development; interactions: Appendix 1(diazoxide)Renal impairment dose reduction may be requiredPregnancy prolonged use may produce alopecia,hypertrichosis, and impaired glucose tolerance inneonate; inhibits uterine activity during labourBreast-feeding manufacturer advises avoid—noinformation availableSide-effects tachycardia, hypotension, hyperglycaemia,sodium and water retention; rarely cardiomegaly,hyperosmolar non-ketotic coma, leucopenia,thrombocytopenia, and hirsuitismLicensed use tablets not licensed for resistanthypertensionIndication and doseHypertensive emergencies initiated on specialistadvice. By intravenous injectionChild 1 month–18 years 1–3 mg/kg (max.150 mg) as a single dose, repeat dose after 5–15minutes until blood pressure controlled; max. 4doses in 24 hoursResistant hypertension. By mouthNeonate initially 1.7 mg/kg 3 times daily, adjustedaccording to response; usual max. 15 mg/kg dailyChild 1 month–18 years initially 1.7 mg/kg 3times daily, adjusted according to response; usualmax. 15 mg/kg dailyIntractable hypoglycaemia section 6.1.4Administration intravenous injection over 30 seconds.Do not diluteEudemine c (Goldshield) AUInjection, diazoxide 15 mg/mL, net price 20-mL amp= £30.00Tablets, see section 6.1.4Extemporaneous formulations available seeExtemporaneous Preparations, p. 6HYDRALAZINE HYDROCHLORIDECautions cerebrovascular disease; occasionally bloodpressure reduction too rapid even with low parenteraldoses; manufacturer advises test for antinuclear factorand for proteinuria every 6 months and check acetylatorstatus before increasing dose, but evidence ofclinical value unsatisfactory; interactions: Appendix1 (hydralazine)2 Cardiovascular system

94 2.5.1 Vasodilator antihypertensive drugs BNFC 2011–20122 Cardiovascular systemContra-indications idiopathic systemic lupus erythematosus,severe tachycardia, high output heart failure,myocardial insufficiency due to mechanical obstruction,cor pulmonale; acute porphyria (section 9.8.2)Hepatic impairment reduce doseRenal impairment reduce dose if estimated glomerularfiltration rate less than 30 mL/minute/1.73 m 2Pregnancy neonatal thrombocytopenia reported, butrisk should be balanced against risk of uncontrolledmaternal hypertension; manufacturer advises avoidbefore third trimesterBreast-feeding present in milk but not known to beharmful; monitor infantSide-effects tachycardia, palpitation, flushing, hypotension,fluid retention, gastro-intestinal disturbances;headache, dizziness; systemic lupus erythematosuslikesyndrome after long-term therapy (especially inslow acetylator individuals); rarely rashes, fever, peripheralneuritis, polyneuritis, paraesthesia, arthralgia,myalgia, increased lacrimation, nasal congestion,dyspnoea, agitation, anxiety, anorexia; blood disorders(including leucopenia, thrombocytopenia,haemolytic anaemia), abnormal liver function, jaundice,raised plasma creatinine, proteinuria and haematuriareportedLicensed use not licensed for use in childrenIndication and doseHypertension. By mouthNeonate 250–500 micrograms/kg every 8–12hours increased as necessary to max. 2–3 mg/kgevery 8 hoursChild 1 month–12 years 250–500 micrograms/kg every 8–12 hours increased as necessary tomax. 7.5 mg/kg daily (not exceeding 200 mg daily)Child 12–18 years 25 mg twice daily, increased tousual max. 50–100 mg twice daily. By slow intravenous injectionNeonate 100–500 micrograms/kg repeated every4–6 hours as necessary; max. 3 mg/kg dailyChild 1 month–12 years 100–500 micrograms/kg repeated every 4–6 hours as necessary; max.3 mg/kg daily (not exceeding 60 mg daily)Child 12–18 years 5–10 mg repeated every 4–6hours as necessary. By continuous intravenous infusion (preferredroute in cardiac patients)Neonate 12.5–50 micrograms/kg/hour; max.2 mg/kg dailyChild 1 month–12 years 12.5–50 micrograms/kg/hour; max. 3 mg/kg dailyChild 12–18 years 3–9 mg/hour; max. 3 mg/kgdailyAdministration for intravenous injection, initiallyreconstitute 20 mg with 1 mL Water for Injections,then dilute to a concentration of 0.5–1 mg/mL withSodium Chloride 0.9% and administer over 5–20minutes.For continuous intravenous infusion, initially reconstitute20 mg with 1 mL Water for Injections, thendilute with Sodium Chloride 0.9%. Incompatible withGlucose intravenous infusion.For administration by mouth, diluted injection may begiven orallyHydralazine (Non-proprietary) ATablets, hydralazine hydrochloride 25 mg, net price56-tab pack = £9.32; 50 mg, 56-tab pack = £16.84Apresoline c (Amdipharm) ATablets, yellow, s/c, hydralazine hydrochloride 25 mg,net price 84-tab pack = £3.38Excipients include gluten, propylene glycol (see Excipients, p. 2)Injection, powder for reconstitution, hydralazinehydrochloride, net price 20-mg amp = £2.22Extemporaneous formulations available seeExtemporaneous Preparations, p. 6MINOXIDILCautions see notes above; acute porphyria (section9.8.2); interactions: Appendix 1 (vasodilator antihypertensives)Contra-indications phaeochromocytomaRenal impairment use with caution in significantimpairmentPregnancy avoid—possible toxicity including reducedplacental perfusion; neonatal hirsutism reportedBreast-feeding present in milk but not known to beharmfulSide-effects sodium and water retention; weight gain,peripheral oedema, tachycardia, hypertrichosis;reversible rise in creatinine and blood urea nitrogen;occasionally, gastro-intestinal disturbances, breasttenderness, rashesIndication and doseSevere hypertension. By mouthChild 1 month–12 years initially 200 micrograms/kgdaily in 1–2 divided doses, increased insteps of 100–200 micrograms/kg daily at intervalsof at least 3 days; max. 1 mg/kg dailyChild 12–18 years initially 5 mg daily in 1–2divided doses increased in steps of 5–10 mg atintervals of at least 3 days; max. 100 mg daily(seldom necessary to exceed 50 mg daily)Loniten c (Pharmacia) ATablets, scored, minoxidil 2.5 mg, net price 60-tabpack = £8.88; 5 mg, 60-tab pack = £15.83; 10 mg, 60-tab pack = £30.68Extemporaneous formulations available seeExtemporaneous Preparations, p. 6SODIUM NITROPRUSSIDECautions hypothyroidism, hyponatraemia, impairedcerebral circulation, hypothermia; monitor bloodpressure and blood-cyanide concentration, and iftreatment exceeds 3 days also blood-thiocyanateconcentration; avoid sudden withdrawal—terminateinfusion over 15–30 minutes; interactions: Appendix1 (nitroprusside)Contra-indications severe vitamin B 12 deficiency;Leber’s optic atrophy; compensatory hypertension

BNFC 2011–2012 2.5.1 Vasodilator antihypertensive drugs 95Hepatic impairment use with caution; avoid inhepatic failure—cyanide or thiocyanate metabolitesmay accumulateRenal impairment avoid prolonged use—cyanide orthiocyanate metabolites may accumulatePregnancy avoid prolonged use—potential for accumulationof cyanide in fetusBreast-feeding no information available; cautionadvised due to thiocyanate metaboliteSide-effects associated with over rapid reduction inblood pressure (reduce infusion rate): headache, dizziness,nausea, retching, abdominal pain, perspiration,palpitation, anxiety, retrosternal discomfort; occasionallyreduced platelet count, acute transient phlebitisCyanide Side-effects caused by excessive plasma concentrationof the cyanide metabolite include tachycardia,sweating, hyperventilation, arrhythmias, marked metabolicacidosis (discontinue and give antidote, see p. 32)Licensed use not licensed for use in the UKIndication and doseHypertensive emergencies. By continuous infusionNeonate 500 nanograms/kg/minute thenincreased in steps of 200 nanograms/kg/minute asnecessary to max. 8 micrograms/kg/minute (max.4 micrograms/kg/minute if used for longer than24 hours)Child 1 month–18 years 500 nanograms/kg/minute then increased in steps of 200 nanograms/kg/minute as necessary to max. 8 micrograms/kg/minute (max. 4 micrograms/kg/minute if usedfor longer than 24 hours)Administration for continuous intravenous infusion inGlucose 5%, infuse via infusion device to allow precisecontrol; protect infusion from light. For furtherdetails, consult product literatureSodium Nitroprusside (Non-proprietary) AIntravenous infusion, powder for reconstitution,sodium nitroprusside 10 mg/mL. For dilution and useas an infusion. Available from ‘special-order’ manufacturersor specialist importing companies, seep. 8092.5.1.2 Pulmonary hypertensionOnly pulmonary arterial hypertension is currently suitablefor drug treatment. Pulmonary arterial hypertensionincludes persistent pulmonary hypertension ofthe newborn, idiopathic pulmonary arterial hypertensionin children, and pulmonary hypertension relatedto congenital heart disease and cardiac surgery.Some types of pulmonary hypertension are treated withvasodilator antihypertensive therapy and oxygen. Diuretics(section 2.2) may also have a role in children withright-sided heart failure.Initial treatment of persistent pulmonary hypertensionof the newborn involves the administration of nitricoxide; epoprostenol can be used until nitric oxide isavailable. Oral sildenafil may be helpful in less severecases. Epoprostenol and sildenafil can cause profoundsystemic hypotension. In rare circumstances eithertolazoline or magnesium sulphate can be given byintravenous infusion when nitric oxide and epoprostenolhave failed.Treatment of idiopathic pulmonary arterial hypertensionis determined by acute vasodilator testing;drugs used for treatment include calcium-channelblockers (usually nifedipine, section 2.6.2), long-termintravenous epoprostenol, nebulised iloprost, bosentan,or sildenafil. Anticoagulation (usually with warfarin)may also be required to prevent secondarythrombosis.Inhaled nitric oxide is a potent and selective pulmonaryvasodilator. It acts on cyclic guanosine monophosphate(cGMP) resulting in smooth muscle relaxation.Inhaled nitric oxide is used in the treatment of persistentpulmonary hypertension of the newborn, and may alsobe useful in other forms of arterial pulmonary hypertension.Dependency can occur with high doses andprolonged use; to avoid rebound pulmonary hypertensionthe drug should be withdrawn gradually, oftenwith the aid of sildenafil.Excess nitric oxide can cause methaemoglobinaemia;therefore, methaemoglobin concentration should bemeasured regularly, particularly in neonates.Nitric oxide increases the risk of haemorrhage by inhibitingplatelet aggregation, but it does not usually causebleeding.Epoprostenol (prostacyclin) is a prostaglandin and apotent vasodilator. It is used in the treatment of persistentpulmonary hypertension of the newborn, idiopathicpulmonary arterial hypertension, and in the acute phasefollowing cardiac surgery. It is given by continuous 24-hour intravenous infusion.Epoprostenol is a powerful inhibitor of platelet aggregationand there is a possible risk of haemorrhage. It issometimes used as an antiplatelet in renal dialysis whenheparins are unsuitable or contra-indicated. It can alsocause serious systemic hypotension and, if withdrawnsuddenly, can cause pulmonary hypertensive crisis.Children on prolonged treatment can become tolerantto epoprostenol, and therefore require an increase indose.Iloprost is a synthetic analogue of epoprostenol and isefficacious when nebulised in adults with pulmonaryarterial hypertension, but experience in children is limited.It is more stable than epoprostenol and has alonger half-life.Bosentan is a dual endothelin receptor antagonist usedorally in the treatment of idiopathic pulmonary arterialhypertension. The concentration of endothelin, a potentvasoconstrictor, is raised in sustained pulmonary hypertension.Sildenafil, a vasodilator developed for the treatment oferectile dysfunction, is also used for pulmonary arterialhypertension. It is used either alone or as an adjunct toother drugs and has relatively few side-effects.Sildenafil is a selective phosphodiesterase type-5 inhibitor.Inhibition of this enzyme in the lungs enhances thevasodilatory effects of nitric oxide and promotes relaxationof vascular smooth muscle.Sildenafil has also been used in pulmonary hypertensionfor weaning children off inhaled nitric oxide followingcardiac surgery, and less successfully in idiopathic pulmonaryarterial hypertension.Tolazoline is now rarely used to correct pulmonaryartery vasospasm in pulmonary hypertension of thenewborn as better alternatives are available (see2 Cardiovascular system

96 2.5.1 Vasodilator antihypertensive drugs BNFC 2011–20122 Cardiovascular systemabove). Tolazoline is an alpha-blocker and producesboth pulmonary and systemic vasodilation.BOSENTANCautions not to be initiated if systemic systolic bloodpressure is below 85 mmHg; monitor liver functionbefore and at monthly intervals during treatment, and2 weeks after dose increase (reduce dose or suspendtreatment if liver enzymes raised significantly) — discontinueif symptoms of liver impairment (see Contra-indicationsbelow); monitor haemoglobin beforeand during treatment (monthly for first 4 months, then3-monthly thereafter), withdraw treatment gradually;interactions: Appendix 1 (bosentan)Contra-indications acute porphyria (section 9.8.2)Hepatic impairment avoid in moderate and severeimpairmentPregnancy avoid (teratogenic in animal studies);effective contraception required during and for atleast 3 months after administration (hormonalcontraception not considered effective); monthlypregnancy tests advisedBreast-feeding manufacturer advises avoid—noinformation availableSide-effects gastro-intestinal disturbances, drymouth, rectal haemorrhage, hepatic impairment (seeCautions, above); flushing, hypotension, palpitation,oedema, chest pain; dyspnoea; headache, dizziness,fatigue; back pain and pain in extremities; anaemia;hypersensitivity reactions (including rash, pruritus,and anaphylaxis)Licensed use not licensed for use in children under12 yearsIndication and doseIdiopathic pulmonary arterial hypertension. By mouthChild 3–18 years and body-weight 10–20 kginitially 31.25 mg once daily increased after 4weeks to 31.25 mg twice dailyChild 3–18 years and body-weight 20–40 kginitially 31.25 mg twice daily increased after 4weeks to 62.5 mg twice dailyChild 12–18 years and body-weight over 40 kginitially 62.5 mg twice daily increased after 4 weeksto 125 mg twice daily; max. 250 mg twice dailyAdministration tablets may be cut, or suspended inwater or non-acidic liquid. Suspension is stable atroom-temperature (max. 258C) for 24 hoursTracleer c (Actelion) TATablets, f/c, orange, bosentan (as monohydrate)62.5 mg, net price 56-tab pack = £1510.21; 125 mg,56-tab pack = £1510.21EPOPROSTENOLCautions anticoagulant monitoring required whengiven with anticoagulants; haemorrhagic diathesis;avoid abrupt withdrawal (see notes above); monitorblood pressure; concomitant use of drugs thatincrease risk of bleedingContra-indications severe left ventricular dysfunction;pulmonary veno-occlusive diseasePregnancy manufacturer advises caution—no informationavailableSide-effects see notes above; gastro-intestinal disturbances,hypotension, bradycardia, tachycardia, pallor,flushing, sweating with higher doses; headache; lassitude,anxiety, agitation; dry mouth, jaw pain, chestpain; also reported, hyperglycaemia and injection-sitereactionsLicensed use not licensed for use in childrenIndication and dosePersistent pulmonary hypertension of thenewborn. By continuous intravenous infusionNeonate initially 2 nanograms/kg/minuteadjusted according to response; usual max.20 nanograms/kg/minute (rarely up to 40 nanograms/kg/minute)Idiopathic pulmonary arterial hypertension. By continuous intravenous infusionChild 1 month–18 years initially 2 nanograms/kg/minute increased as necessary up to 40 nanograms/kg/minuteAdministration reconstitute using the glycine bufferdiluent provided to make a concentrate (pH 10.5);filter the concentrate using the filter provided. Theconcentrate can be administered via a central venouscatheter, alternatively it may be diluted further eitherwith the glycine buffer diluent or to a minimumconcentration of 1.43 micrograms/mL with SodiumChloride 0.9%. Solution stable for 12 hours at roomtemperature, although some units use for 24 hoursand allow for loss of potency; solution stable for 24hours if prepared in glycine buffer diluent only andadministered via an ambulatory cold pouch system(to maintain solution at 2–88C).Neonatal intensive care, prepare a filtered concentrateof 10 micrograms/mL using the 500-microgramvial. Neonate body-weight under 2 kg, using theconcentrate, dilute 150 micrograms/kg body-weightto a final volume of 50 mL with Sodium Chloride 0.9%;an intravenous infusion rate of 0.1 mL/hour providesa dose of 5 nanograms/kg/minute. Neonate bodyweightover 2 kg, using the concentrate, dilute60 micrograms/kg body-weight to a final volume of50 mL with Sodium Chloride 0.9%; an intravenousinfusion rate of 0.1 mL/hour provides a dose of2 nanograms/kg/minuteFlolan c (GSK) AInfusion, powder for reconstitution, epoprostenol (assodium salt), net price 500-microgram vial (withdiluent) = £62.05; 1.5-mg vial (T) (with diluent) =£125.00ILOPROSTCautions unstable pulmonary hypertension withadvanced right heart failure; hypotension (do notinitiate if systolic blood pressure below 85 mmHg);acute pulmonary infection; severe asthma; interactions:Appendix 1 (iloprost)Contra-indications decompensated cardiac failure(unless under medical supervision); severe coronaryheart disease; severe arrhythmias; congenital oracquired valvular defects of the myocardium; pulmonaryveno-occlusive disease; conditions whichincrease risk of haemorrhage

BNFC 2011–2012 2.5.1 Vasodilator antihypertensive drugs 97Hepatic impairment dose may need to be halved inliver cirrhosis—initially 2.5 micrograms at intervals ofat least 3 hours (max. 6 times daily), adjustedaccording to response (consult product literature)Pregnancy manufacturer advises avoid (toxicity inanimal studies); effective contraception must be usedduring treatmentBreast-feeding manufacturer advises avoid—noinformation availableSide-effects vasodilatation, hypotension, syncope,cough, headache, throat or jaw pain; nausea, vomiting,diarrhoea, chest pain, dyspnoea, bronchospasm,and wheezing also reportedLicensed use not licensed for use in children under18 yearsIndication and doseIdiopathic or familial pulmonary arterialhypertension. By inhalation of nebulised solutionChild 8–18 years initial dose 2.5 microgramsincreased to 5 micrograms for second dose, iftolerated maintain at 5 micrograms 6–9 times dailyaccording to response; reduce to 2.5 micrograms6–9 times daily if higher dose not toleratedRaynaud’s syndrome section 2.6.4.1Ventavis c (Bayer Schering) ANebuliser solution, iloprost (as trometamol)10 micrograms/mL, net price 30 1-mL (10 microgram)unit-dose vials = £400.19, 168 1-mL =£2241.08. For use with Prodose c D or Venta-Neb cD nebuliserMAGNESIUM SULPHATECautions see section 9.5.1.3Hepatic impairment see section 9.5.1.3Renal impairment see section 9.5.1.3Side-effects see section 9.5.1.3Indication and dosePersistent pulmonary hypertension of thenewborn. By intravenous infusionNeonate initially 200 mg/kg over 20–30 minutes;if response occurs, then by continuous intravenousinfusion of 20–75 mg/kg/hour (to maintainplasma-magnesium concentration between 3.5–5.5 mmol/litre), given for up to 5 daysSevere acute asthma section 3.1Torsade de pointes section 9.5.1.3Neonatal hypocalcaemia section 9.5.1.3Hypomagnesaemia section 9.5.1.3Administration for intravenous infusion, dilute to amax. concentration of 100 mg/mL (200 mg/mL iffluid restricted) with Glucose 5% or Sodium Chloride0.9%Magnesium Sulphate (Non-proprietary) AInjection, magnesium sulphate 50% (Mg 2þ approx.2 mmol/mL), net price 2-mL (1-g) amp= £2.39,5-mL (2.5-g) amp = £3.00, 10-mL (5-g) amp = 69p;prefilled 10-mL (5-g) syringe = £4.95SILDENAFILCautions hypotension (avoid if severe); intravascularvolume depletion; left ventricular outflow obstruction;autonomic dysfunction; avoid abrupt withdrawal;other cardiovascular disease; pulmonary veno-occlusivedisease; predisposition to priapism; anatomicaldeformation of the penis; bleeding disorders or activepeptic ulceration; ocular disorders; initiate cautiouslyif child also on epoprostenol, iloprost, bosentan ornitric oxide; interactions: Appendix 1 (sildenafil)Contra-indications recent history of stroke; history ofnon-arteritic anterior ischaemic optic neuropathy;hereditary degenerative retinal disorders; avoid concomitantuse of nitratesHepatic impairment reduce dose if not tolerated inmild to moderate impairment; manufacturer advisesavoid in severe impairmentRenal impairment reduce dose if not toleratedPregnancy manufacturer advises use only if potentialbenefit outweighs risk—no evidence of harm in animalstudiesBreast-feeding manufacturer advises avoid—noinformation availableSide-effects gastro-intestinal disturbances, drymouth; flushing, oedema; bronchitis, cough; headache,migraine, night sweats, paraesthesia, insomnia,anxiety, tremor, vertigo; fever, influenza-like symptoms;anaemia; back and limb pain, myalgia; visualdisturbances, retinal haemorrhage, photophobia,painful red eyes; nasal congestion, epistaxis; cellulitis,alopecia; less commonly gynaecomastia, priapism;also reported rash, retinal vascular occlusion, nonarteriticanterior ischaemic optic neuropathy (discontinueif sudden visual impairment occurs), andsudden hearing loss (advise patient to seek medicalhelp)Licensed use not licensed for use in children under18 yearsIndication and dosePulmonary hypertension after cardiac surgery,weaning from nitric oxide, idiopathic pulmonaryarterial hypertension, persistent pulmonaryhypertension of the newborn. By mouthNeonate initially 250–500 micrograms/kg every4–8 hours, adjusted according to response; max.2 mg/kg every 6 hours; start with lower dose andfrequency especially if used with other vasodilators(see Cautions above); withdraw graduallyChild 1 month–18 years initially 250–500 micrograms/kgevery 4–8 hours, adjusted according toresponse; max. 2 mg/kg every 6 hours; start withlower dose and frequency especially if used withother vasodilators (see Cautions above)Administration tablet may be dissolved in water orblackcurrant drink and given by mouth or through anasogastric tubeViagra c (Pfizer) ADTablets, all blue, f/c, sildenafil (as citrate), 25 mg, netprice 4-tab pack = £16.59, 8-tab pack = £33.19; 50 mg,4-tab pack = £21.27, 8-tab pack = £45.54; 100 mg, 4-tab pack = £23.50, 8-tab pack = £46.992 Cardiovascular system

98 2.5.2 Centrally acting antihypertensive drugs BNFC 2011–20122 Cardiovascular systemRevatio c (Pfizer) TATablets, f/c, sildenafil (as citrate), 20 mg, net price 90-tab pack = £373.50Extemporaneous formulations available seeExtemporaneous Preparations, p. 6TOLAZOLINECautions mitral stenosis; cardiotoxic accumulationmay occur with continuous infusion, particularly inrenal impairment—monitor blood pressure regularlyfor sustained systemic hypotension; interactions:Appendix 1 (alpha-blockers)Contra-indications peptic ulcer diseaseRenal impairment accumulates in renal impairment;risk of cardiotoxicity; lower doses may be necessarySide-effects nausea, vomiting, diarrhoea, epigastricpain; flushing, tachycardia, cardiac arrhythmias;headache, shivering, sweating; oliguria, metabolicalkalosis, haematuria, blood dyscrasias (includingthrombocytopenia); blotchy skin; at high doses severehypotension, marked hypertension, renal failure, andhaemorrhage reportedLicensed use not licensed for use in childrenIndication and doseCorrection of pulmonary vasospasm in neonates. By intravenous injection and continuous intravenousinfusion (maintenance)Neonate initially 1 mg/kg by intravenous injectionover 2–5 minutes, followed if necessary by continuousintravenous infusion of 200 micrograms/kg/hour with careful blood pressure monitoring;doses above 300 micrograms/kg/hour associatedwith cardiotoxicity and renal failure. By endotracheal administrationNeonate 200 micrograms/kgAdministration for continuous intravenous infusion,dilute with Glucose 5% or Sodium Chloride 0.9%.Prepare a fresh solution every 24 hours.For endotracheal administration, dilute with 0.5–1 mL of Sodium Chloride 0.9%Tolazoline (Non-proprietary)Injection, tolazoline 25 mg/mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 8092.5.2 Centrally actingantihypertensive drugsMethyldopa, a centrally acting antihypertensive, is oflittle value in the management of refractory sustainedhypertension in infants and children. On prolonged useit is associated with fluid retention (which may bealleviated by concomitant use of diuretics).Methyldopa is effective for the management of hypertensionin pregnancy (see BNF section 2.5.2).Clonidine is also a centrally acting antihypertensive buthas the disadvantage that sudden withdrawal may causea hypertensive crisis. Clonidine is also used underspecialist supervision for pain management, sedation,and opioid withdrawal, attention deficit hyperactivitydisorder, and Tourette syndrome.CLONIDINE HYDROCHLORIDE UCautions must be withdrawn gradually to avoidhypertensive crisis; mild to moderate bradyarrhythmia;constipation; polyneuropathy; Raynaud’ssyndrome or other occlusive peripheral vascular disease;history of depression; interactions: Appendix 1(clonidine)Skilled tasks Drowsiness may affect performance of skilledtasks (e.g. driving); effects of alcohol may be enhancedContra-indications severe bradyarrhythmia secondaryto second- or third-degree AV block or sick sinussyndromeRenal impairment use with cautionPregnancy may lower fetal heart rate, but risk shouldbe balanced against risk of uncontrolled maternalhypertension; avoid intravenous injectionBreast-feeding avoid—present in milkSide-effects constipation, nausea, dry mouth, vomiting,postural hypotension, dizziness, sleep disturbances,headache, malaise, drowsiness, depression,sexual dysfunction; less commonly bradycardia, Raynaud’ssyndrome, delusion, hallucination, paraesthesia,pruritus, rash, urticaria; rarely colonic pseudoobstruction,AV block, gynaecomastia, decreasedlacrimation, nasal dryness, alopecia; also reportedhepatitis, fluid retention, bradyarrhythmia, confusion,impaired visual accommodationLicensed use not licensed for use in childrenIndication and doseSevere hypertension. By mouthChild 2–18 years initially 0.5–1 microgram/kg 3times daily, increased gradually if necessary; max.25 micrograms/kg daily in divided doses (notexceeding 1.2 mg daily). By slow intravenous injectionChild 2–18 years 2–6 micrograms/kg (max.300 micrograms) as a single doseAdministration for intravenous injection, give over10–15 minutes; compatible with Sodium Chloride0.9% or Glucose 5%.For administration by mouth, tablets may be crushedand dissolved in waterCatapres c (Boehringer Ingelheim) AUTablets, scored, clonidine hydrochloride 100 micrograms,net price 100-tab pack = £5.32; 300 micrograms,100-tab pack = £12.39. Label: 3, 8Injection, clonidine hydrochloride 150 micrograms/mL, net price 1-mL amp = 28pExtemporaneous formulations available seeExtemporaneous Preparations, p. 62.5.3 Adrenergic neuroneblocking drugsAdrenergic neurone blocking drugs prevent the releaseof noradrenaline from postganglionic adrenergic neurones.These drugs do not control supine blood pressureand may cause postural hypotension. For this reason

BNFC 2011–2012 2.5.4 Alpha-adrenoceptor blocking drugs 99they have largely fallen from use in adults and are rarelyused in children.2.5.4 Alpha-adrenoceptorblocking drugsDoxazosin and prazosin have post-synaptic alphablockingand vasodilator properties and rarely causetachycardia. They can, however, reduce blood pressurerapidly after the first dose and should be introduced withcaution.Alpha-blockers can be used with other antihypertensivedrugs in the treatment of resistant hypertension.DOXAZOSINCautions care with initial dose (postural hypotension);pulmonary oedema due to aortic or mitral stenosis;cataract surgery (risk of intra-operative floppy irissyndrome); heart failure; interactions: Appendix 1(alpha-blockers)Driving May affect performance of skilled tasks e.g. drivingContra-indications history of postural hypotensionHepatic impairment use with caution; manufactureradvises avoid in severe impairment—no informationavailablePregnancy no evidence of teratogenicity; manufacturersadvise use only when potential benefit outweighsriskBreast-feeding accumulates in milk in animal studies—manufactureradvises avoidSide-effects gastro-intestinal disturbances; oedema,hypotension, postural hypotension, palpitation,tachycardia; dyspnoea, rhinitis, coughing; asthenia,fatigue, vertigo, dizziness, headache, paraesthesia,sleep disturbance, anxiety, depression; influenza-likesymptoms; back pain, myalgia; less commonly weightchanges; angina, myocardial infarction; hypoaesthesia,syncope, tremor, agitation, micturition disturbances,impotence, epistaxis, arthralgia, gout, tinnitus,hypersensitivity reactions (including pruritus,purpura, rash); very rarely cholestasis, hepatitis,jaundice, bradycardia, arrhythmias, bronchospasm,hot flushes, gynaecomastia, priapism, abnormal ejaculation,leucopenia, thrombocytopenia, blurredvision, and alopeciaLicensed use not licensed for use in childrenIndication and doseHypertension (see notes above). By mouthChild 6–12 years 500 micrograms once daily,increased at 1-week intervals to 2–4 mg dailyChild 12–18 years 1 mg daily, increased after 1–2weeks to 2 mg once daily, and thereafter to 4 mgonce daily if necessary; usual max. 4 mg daily(rarely up to 16 mg daily may be required)Dysfunctional voiding section 7.4.1Doxazosin (Non-proprietary) ATablets, doxazosin (as mesilate) 1 mg, net price 28-tab pack = 93p; 2 mg, 28-tab pack = 99p; 4 mg, 28-tabpack = £1.39. Counselling, initial dose, drivingBrands include Doxadura cCardura c (Pfizer) ATablets, doxazosin (as mesilate) 1 mg, net price 28-tabpack = £10.56; 2 mg, 28-tab pack = £14.08. Counselling,initial dose, drivingExtemporaneous formulations available seeExtemporaneous Preparations, p. 6Modified-releaseNote Children stabilised on immediate-release doxazosin canbe transferred to the equivalent dose of modified-release doxazosinDoxazosin (Non-proprietary) ATablets, m/r, doxazosin (as mesilate) 4 mg, net price28-tab pack = £6.33. Label: 25, counselling, initialdose, drivingBrands include Doxadura c XL, Raporsin c XL, Slocinx c XLCardura c XL (Pfizer) ATablets, m/r, doxazosin (as mesilate) 4 mg, net price28-tab pack = £5.70; 8 mg, 28-tab pack = £9.98.Label: 25, counselling, initial dose, drivingPRAZOSINCautions first dose may cause collapse due to hypotension(therefore should be taken on retiring to bed);cataract surgery (risk of intra-operative floppy irissyndrome); interactions: Appendix 1 (alpha-blockers)Driving May affect performance of skilled tasks e.g. drivingContra-indications not recommended for congestiveheart failure due to mechanical obstruction (e.g. aorticstenosis)Hepatic impairment start with low doses and adjustaccording to responseRenal impairment start with low doses in moderateto severe impairment; increase with cautionPregnancy no evidence of teratogenicity; manufactureradvises use only when potential benefit outweighsriskBreast-feeding present in milk; manufacturer advisesuse with cautionSide-effects gastro-intestinal disturbances; posturalhypotension, oedema, palpitation; dyspnoea, nasalcongestion; drowsiness, headache, depression, nervousness,vertigo; urinary frequency; weakness;blurred vision; less commonly tachycardia, insomnia,paraesthesia, sweating, impotence, arthralgia, eyedisorders, tinnitus, epistaxis, allergic reactionsincluding rash, pruritus, and urticaria; rarely pancreatitis,flushing, vasculitis, bradycardia, hallucinations,worsening of narcolepsy, gynaecomastia,priapism, urinary incontinence, and alopeciaLicensed use not licensed for use in children under12 yearsIndication and doseHypertension (see notes above). By mouthChild 1 month–12 years 10–15 micrograms/kg2–4 times daily (initial dose at bedtime) increasedgradually to max. 500 micrograms/kg daily individed doses (not exceeding 20 mg daily)Child 12–18 years 500 micrograms 2–3 timesdaily (initial dose at bedtime), increased after 3–7days to 1 mg 2–3 times daily for a further 3–7 days;further increased gradually if necessary to max.20 mg daily in divided doses2 Cardiovascular system

100 2.5.5 Drugs affecting the renin-angiotensin system BNFC 2011–20122 Cardiovascular systemCongestive heart failure (but rarely used, seesection 2.2). By mouthChild 1 month–12 years 5 micrograms/kg twicedaily (initial dose at bedtime), increased graduallyto max. 100 micrograms/kg daily in divided dosesChild 12–18 years 500 micrograms 2–4 timesdaily (initial dose at bedtime), increasing to 4 mgdaily in divided doses; maintenance 4–20 mg dailyin divided dosesAdministration for administration by mouth, tabletsmay be dispersed in waterPrazosin (Non-proprietary) ATablets, prazosin (as hydrochloride) 500 micrograms,net price 56-tab pack = £2.51; 1 mg, 56-tab pack =£3.23; 2 mg, 56-tab pack = £4.39; 5 mg, 56-tab pack =£8.75. Counselling, initial dose, drivingHypovase c (Pfizer) ATablets, prazosin (as hydrochloride) 500 micrograms,net price 60-tab pack = £2.69; 1 mg, scored, 60-tabpack = £3.46. Counselling, initial dose, drivingPhaeochromocytomaLong-term management of phaeochromocytomainvolves surgery. However, surgery should not takeplace until there is adequate blockade of both alphaandbeta-adrenoceptors. Alpha-blockers are used in theshort-term management of hypertensive episodes inphaeochromocytoma. Once alpha blockade is established,tachycardia can be controlled by the cautiousaddition of a beta-blocker (section 2.4); a cardioselectivebeta-blocker is preferred. There is no nationwide consensuson the optimal drug regimen or doses used forthe management of phaeochromocytoma.Phenoxybenzamine, a powerful alpha-blocker, is effectivein the management of phaeochromocytoma but ithas many side-effects.PHENOXYBENZAMINEHYDROCHLORIDECautions congestive heart failure; severe ischaemicheart disease (see also Contra-indications); cerebrovasculardisease (avoid if history of cerebrovascularaccident); monitor blood pressure regularly duringinfusion; carcinogenic in animals; avoid in acuteporphyria (section 9.8.2); avoid extravasation (irritantto tissues); avoid contact with skin (risk of contactsensitisation)Contra-indications history of cerebrovascular accident;avoid infusion in hypovolaemiaRenal impairment use with cautionPregnancy hypotension in newborn may occurBreast-feeding may be present in milkSide-effects postural hypotension with dizziness andmarked compensatory tachycardia, lassitude, nasalcongestion, miosis, inhibition of ejaculation; rarelygastro-intestinal disturbances; decreased sweatingand dry mouth after intravenous infusion; idiosyncraticprofound hypotension within few minutes ofstarting infusion; convulsions following rapid intravenousinfusion also reportedLicensed use not licensed for use in childrenIndication and doseHypertension in phaeochromocytoma. By mouthChild 1 month–18 years 0.5–1 mg/kg twice dailyadjusted according to response. By intravenous infusionChild 1 month–18 years 0.5–1 mg/kg dailyadjusted according to response; occasionally up to2 mg/kg daily may be required; do not repeat dosewithin 24 hoursAdministration for administration by mouth, capsulesmay be opened.For intravenous infusion, dilute with Sodium Chloride0.9% and give over at least 2 hours; max. 4 hoursbetween dilution and completion of infusionPhenoxybenzamine (Goldshield) AInjection concentrate, phenoxybenzamine hydrochloride50 mg/mL. To be diluted before use. Netprice 2-mL amp = £57.14 (hosp. only)Dibenyline c (Goldshield) ACapsules, red/white, phenoxybenzamine hydrochloride10 mg. Net price 30-cap pack = £10.842.5.5 Drugs affecting the reninangiotensinsystem2.5.5.1 Angiotensin-converting enzymeinhibitors2.5.5.2 Angiotensin-II receptor antagonists2.5.5.1 Angiotensin-converting enzymeinhibitorsAngiotensin-converting enzyme inhibitors (ACE inhibitors)inhibit the conversion of angiotensin I to angiotensinII. The main indications of ACE inhibitors inchildren are shown below. In infants and young children,captopril is often considered first.Initiation under specialist supervision Treatmentwith ACE inhibitors should be initiated under specialistsupervision and with careful clinical monitoring in children.Heart failure ACE inhibitors have a valuable role in allgrades of heart failure, usually combined with a loopdiuretic (section 2.2). Potassium supplements and potassium-sparingdiuretics should be discontinued beforeintroducing an ACE inhibitor because of the risk ofhyperkalaemia. In adults, a low dose of spironolactonemay be beneficial in severe heart failure and can be usedwith an ACE inhibitor provided serum potassium ismonitored carefully. Profound first-dose hypotensioncan occur when ACE inhibitors are introduced to childrenwith heart failure who are already taking a highdose of a loop diuretic (see Cautions below). Temporarywithdrawal of the loop diuretic reduces the risk, but cancause severe rebound pulmonary oedema.

BNFC 2011–2012 2.5.5 Drugs affecting the renin-angiotensin system 101Hypertension ACE inhibitors may be considered forhypertension when thiazides and beta-blockers are contra-indicated,not tolerated, or fail to control bloodpressure; they may be considered for hypertension inchildren with type 1 diabetes with nephropathy (see alsosection 6.1.5). ACE inhibitors can reduce blood pressurevery rapidly in some patients particularly in thosereceiving diuretic therapy (see Cautions, below); thefirst dose should preferably be given at bedtime.Diabetic nephropathy For comment on the role ofACE inhibitors in the management of diabetic nephropathy,see section 6.1.5.Renal effects Renal function and electrolytes shouldbe checked before starting ACE inhibitors (or increasingthe dose) and monitored during treatment (more frequentlyif features mentioned below are present).Hyperkalaemia and other side-effects of ACE inhibitorsare more common in children with impaired renal functionand the dose may need to be reduced (see RenalImpairment, below).Concomitant treatment with NSAIDs increases the riskof renal damage, and potassium-sparing diuretics (orpotassium-containing salt substitutes) increase the riskof hyperkalaemia.In children with severe bilateral renal artery stenosis (orsevere stenosis of the artery supplying a single functioningkidney), ACE inhibitors reduce or abolish glomerularfiltration and are likely to cause severe and progressiverenal failure. They are therefore contra-indicated inchildren known to have these forms of critical renovasculardisease.ACE inhibitor treatment is unlikely to have an adverseeffect on overall renal function in children with severeunilateral renal artery stenosis and a normal contralateralkidney, but glomerular filtration is likely to bereduced (or even abolished) in the affected kidney andthe long-term consequences are unknown.ACE inhibitors are therefore best avoided in those withknown or suspected renovascular disease, unless theblood pressure cannot be controlled by other drugs. Ifthey are used in these circumstances renal functionneeds to be monitored.ACE inhibitors should also be used with particularcaution in children who may have undiagnosed andclinically silent renovascular disease. ACE inhibitorsare useful for the management of hypertension andproteinuria in children with nephritis. They are thoughtto have a beneficial effect by reducing intra-glomerularhypertension and protecting the glomerular capillariesand membrane.Cautions ACE inhibitors need to be initiated with carein children receiving diuretics (important: see ConcomitantDiuretics, below); first doses can cause hypotensionespecially in children taking high doses of diuretics,on a low-sodium diet, on dialysis, dehydrated, orwith heart failure (see above). Discontinue if markedelevation of hepatic enzymes or jaundice (risk of hepaticnecrosis). Renal function should be monitored beforeand during treatment. For use in pre-existing renovasculardisease, see Renal Effects above. The risk ofagranulocytosis is possibly increased in collagen vasculardisease (blood counts recommended). ACE inhibitorsshould be used with care in children with severeor symptomatic aortic stenosis (risk of hypotension) andin hypertrophic cardiomyopathy. They should be usedwith care (or avoided) in those with a history of idiopathicor hereditary angioedema. Children with primaryaldosteronism and Afro-Caribbean children mayrespond less well to ACE inhibitors. Interactions:Appendix 1 (ACE inhibitors).Anaphylactoid reactions To prevent anaphylactoidreactions, ACE inhibitors should be avoided duringdialysis with high-flux polyacrylonitrile membranesand during low-density lipoprotein apheresis withdextran sulphate; they should also be withheld beforedesensitisation with wasp or bee venom.Concomitant diuretics ACE inhibitors can cause a veryrapid fall in blood pressure in volume-depleted children;treatment should therefore be initiated with very lowdoses. In some children the diuretic dose may need tobe reduced or the diuretic discontinued at least 24 hoursbeforehand (may not be possible in heart failure—risk ofpulmonary oedema). If high-dose diuretic therapy cannotbe stopped, close observation is recommended afteradministration of the first dose of ACE inhibitor, for atleast 2 hours or until the blood pressure has stabilised.Contra-indications ACE inhibitors are contra-indicatedin children with hypersensitivity to ACE inhibitors(including angioedema) and in bilateral renovasculardisease (see also above).Renal impairment See Renal Effects above; start withlow dose and adjust according to response.Pregnancy ACE inhibitors should be avoided inpregnancy unless essential—they may adversely affectfetal and neonatal blood pressure control and renalfunction; skull defects and oligohydramnios have alsobeen reported.Side-effects ACE inhibitors can cause profound hypotension(see Cautions), renal impairment (see RenalEffects above), and a persistent dry cough. They canalso cause angioedema (onset may be delayed; higherincidence reported in Afro-Caribbean patients), rash(which may be associated with pruritus and urticaria),pancreatitis, and upper respiratory-tract symptoms suchas sinusitis, rhinitis, and sore throat. Gastro-intestinaleffects reported with ACE inhibitors include nausea,vomiting, dyspepsia, diarrhoea, constipation, and abdominalpain. Altered liver function tests, cholestatic jaundice,hepatitis, fulminant hepatic necrosis, and hepaticfailure have been reported—discontinue if marked elevationof hepatic enzymes or jaundice. Hyperkalaemia,hypoglycaemia and blood disorders including thrombocytopenia,leucopenia, neutropenia, and haemolyticanaemia have also been reported. Other reportedside-effects include headache, dizziness, fatigue,malaise, taste disturbance, paraesthesia, bronchospasm,fever, serositis, vasculitis, myalgia, arthralgia, positiveantinuclear antibody, raised erythrocyte sedimentationrate, eosinophilia, leucocytosis, and photosensitivity.Neonates The neonatal response to treatment withACE inhibitors is very variable, and some neonatesdevelop profound hypotension with even small doses;a test-dose should be used initially and increased cautiously.Adverse effects such as apnoea, seizures, renalfailure, and severe unpredictable hypotension are verycommon in the first month of life and it is therefore2 Cardiovascular system

102 2.5.5 Drugs affecting the renin-angiotensin system BNFC 2011–20122 Cardiovascular systemrecommended that ACE inhibitors are avoided wheneverpossible, particularly in preterm neonates.CAPTOPRILCautions see notes above; acute porphyria (section9.8.2)Contra-indications see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding avoid in first few weeks after delivery,particularly in preterm infants—risk of profoundneonatal hypotension; can be used in older infant ifessential but monitor infant’s blood pressureSide-effects see notes above; tachycardia, serumsickness, weight loss, stomatitis, maculopapular rash,photosensitivity, flushing and acidosisLicensed use not licensed for use in children under18 yearsIndication and doseHypertension, heart failure, proteinuria innephritis (under specialist supervision). By mouthNeonate (caution, see neonatal informationabove) test dose, 10–50 micrograms/kg (10 micrograms/kgin neonate less than 37 weeks postmenstrualage), monitor blood pressure carefullyfor 1–2 hours; if tolerated give 10–50 micrograms/kg 2–3 times daily increased as necessary to max.2 mg/kg daily in divided doses (max. 300 micrograms/kgdaily in divided doses in neonate lessthan 37 weeks postmenstrual age)Child 1 month–12 years test dose, 100 micrograms/kg(max. 6.25 mg), monitor blood pressurecarefully for 1–2 hours; if tolerated give 100–300 micrograms/kg 2–3 times a day, increased asnecessary to max. 6 mg/kg daily in divided doses(max. 4 mg/kg daily in divided doses for child 1month–1 year)Child 12–18 years test dose, 100 micrograms/kgor 6.25 mg, monitor blood pressure carefully for 1–2 hours; if tolerated give 12.5–25 mg 2–3 times aday, increased as necessary to max. 150 mg dailyin divided dosesDiabetic nephropathy (under specialist supervision). By mouthChild 12–18 years test dose, 100 micrograms/kgor 6.25 mg, monitor blood pressure carefully for 1–2 hours; if tolerated, give 12.5–25 mg 2–3 times aday, increased as necessary to max. 150 mg dailyin divided dosesAdministration Administer under close supervision,see notes above. Give test dose whilst child supine.Tablets can be dispersed in waterCaptopril (Non-proprietary) ATablets, captopril 12.5 mg, net price 56-tab pack =£1.51; 25 mg, 56-tab pack = £1.56; 50 mg, 56-tab pack= £1.96Brands include Ecopace c , Kaplon cLiquid, various strengths available from ‘specialorder’manufacturers or specialist importing companies,see p. 809Capoten c (Squibb) ATablets, captopril 25 mg, net price 28-tab pack =£5.26; 50 mg (scored), 56-tab pack = £17.96Extemporaneous formulations available seeExtemporaneous Preparations, p. 6ENALAPRIL MALEATECautions see notes aboveContra-indications see notes aboveHepatic impairment monitor closelyRenal impairment see notes abovePregnancy see notes aboveBreast-feeding avoid in first few weeks after delivery,particularly in preterm infants—risk of profoundneonatal hypotension; can be used in older infant ifessential but monitor infant’s blood pressureSide-effects see notes above; also dyspnoea; depression,asthenia; blurred vision; less commonly drymouth, peptic ulcer, anorexia, ileus; arrhythmias,palpitation, flushing; confusion, nervousness, drowsiness,insomnia, vertigo; impotence; muscle cramps;tinnitus; alopecia, sweating; hyponatraemia; rarelystomatitis, glossitis, Raynaud’s syndrome, pulmonaryinfiltrates, allergic alveolitis, abnormal dreams,gynaecomastia, Stevens-Johnson syndrome, toxicepidermal necrolysis, exfoliative dermatitis, pemphigus;very rarely gastro-intestinal angioedemaLicensed use not licensed for use in children forcongestive heart failure, proteinuria in nephritis ordiabetic nephropathy; not licensed for use in childrenless than 20 kg for hypertensionIndication and doseHypertension, congestive heart failure, proteinuriain nephritis (under specialist supervision). By mouthNeonate (limited information) initially 10 micrograms/kgonce daily, monitor blood pressurecarefully for 1–2 hours, increased as necessary upto 500 micrograms/kg daily in 1–3 divided dosesChild 1 month–12 years initially 100 micrograms/kgonce daily, monitor blood pressurecarefully for 1–2 hours, increased as necessary upto max. 1 mg/kg daily in 1–2 divided dosesChild 12–18 years initially 2.5 mg once daily,monitor blood pressure carefully for 1–2 hours,usual maintenance dose 10–20 mg daily in 1–2divided doses; max. 40 mg daily in 1–2 divideddoses if body-weight over 50 kgDiabetic nephropathy (under specialist supervision). By mouthChild 12–18 years initially 2.5 mg once daily,monitor blood pressure carefully for 1–2 hours,usual maintenance dose 10–20 mg daily in 1–2divided doses; max. 40 mg daily in 1–2 divideddoses if body-weight over 50 kgAdministration tablets may be crushed and suspendedin water immediately before useEnalapril Maleate (Non-proprietary) ATablets, enalapril maleate 2.5 mg, net price 28-tabpack = £1.05; 5 mg, 28-tab pack = 96p; 10 mg, 28-tabpack = £1.05; 20 mg, 28-tab pack = £1.24Brands include Ednyt c

BNFC 2011–2012 2.5.5 Drugs affecting the renin-angiotensin system 103Liquid, various strengths available from ‘specialorder’manufacturers or specialist importing companies,see p. 809Innovace c (MSD) ATablets, enalapril maleate 2.5 mg, net price 28-tabpack = £5.35; 5 mg (scored), 28-tab pack = £7.51;10 mg (red), 28-tab pack = £10.53; 20 mg (peach), 28-tab pack = £12.51LISINOPRILCautions see notes aboveContra-indications see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding avoid—no information availableSide-effects see notes above; also less commonlytachycardia, palpitation, cerebrovascular accident,Raynaud’s syndrome, confusion, mood changes,vertigo, sleep disturbances, asthenia, impotence;rarely dry mouth, gynaecomastia, alopecia, psoriasis;very rarely allergic alveolitis, pulmonary infiltrates,profuse sweating, pemphigus, Stevens-Johnsonsyndrome, and toxic epidermal necrolysisLicensed use not licensed for use in childrenIndication and doseHypertension, proteinuria in nephritis (underspecialist supervision). By mouthChild 6–12 years initially 70 micrograms/kg(max. 5 mg) once daily, increased in intervals of 1–2 weeks to max. 600 micrograms/kg (or 40 mg)once dailyChild 12–18 years initially 5 mg once daily; usualmaintenance dose 10–20 mg once daily; max.80 mg once dailyDiabetic nephropathy (under specialist supervision). By mouthChild 12–18 years initially 5 mg once daily; usualmaintenance dose 10–20 mg once daily; max.80 mg once dailyHeart failure (adjunct) (under specialist supervision). By mouthChild 12–18 years initially 2.5 mg once daily;increased in steps no greater than 10 mg at intervalsof at least 2 weeks up to max. 35 mg oncedaily if toleratedLisinopril (Non-proprietary) ATablets, lisinopril (as dihydrate) 2.5 mg, net price 28-tab pack = 87p; 5 mg, 28-tab pack = 93p; 10 mg, 28-tab pack = £1.01; 20 mg, 28-tab pack = £1.19Liquid, various strengths available from ‘specialorder’manufacturers or specialist importing companies,see p. 809Zestril c (AstraZeneca) ATablets, lisinopril (as dihydrate) 2.5 mg, net price 28-tab pack = £1.78; 5 mg (pink), 28-tab pack = £1.31;10 mg (pink), 28-tab pack = £2.05; 20 mg (pink), 28-tab pack = £2.17Extemporaneous formulations available seeExtemporaneous Preparations, p. 62.5.5.2 Angiotensin-II receptorantagonistsLosartan and valsartan are specific angiotensin-IIreceptor antagonists with many properties similar tothose of the ACE inhibitors. However, unlike ACE inhibitors,they do not inhibit the breakdown of bradykininand other kinins, and thus are less likely to cause thepersistent dry cough which can complicate ACE inhibitortherapy. They are therefore a useful alternative forchildren who have to discontinue an ACE inhibitorbecause of persistent cough.Losartan or valsartan can be used as an alternative to anACE inhibitor in the management of hypertension.Cautions Angiotensin-II receptor antagonists shouldbe used with caution in renal artery stenosis (see alsoRenal Effects under ACE Inhibitors, section 2.5.5.1).Monitoring of plasma-potassium concentration isadvised, particularly in children with renal impairment.Angiotensin-II receptor antagonists should be used withcaution in aortic or mitral valve stenosis and in hypertrophiccardiomyopathy. They should be used withcaution in those with a history of angioedema. Childrenwith primary aldosteronism, and Afro-Caribbean children(particularly those with left ventricular hypertrophy),may not benefit from an angiotensin-II receptorantagonist. Interactions: Appendix 1 (angiotensin-IIreceptor antagonists).Pregnancy Angiotensin-II receptor antagonists shouldbe avoided in pregnancy, unless essential. They mayadversely affect fetal and neonatal blood pressure andrenal function; oligohydramnios and neonatal skulldefects have also been reported.Breast-feeding Information on the use of angiotensin-IIreceptor antagonists in breast-feeding patientsis limited, so they are not recommended in thesepatients. Alternative treatment options, with moreestablished safety information during breast-feeding,are available.Side-effects Side-effects of angiotensin-II receptorantagonists include symptomatic hypotension (includingdizziness), particularly in children with hyponatraemiaor intravascular volume depletion (e.g. thosetaking high-dose diuretics). Hyperkalaemia occurs occasionally;angioedema has also been reported (sometimeswith delayed onset).LOSARTAN POTASSIUMCautions see notes above; also severe heart failureHepatic impairment avoid—no information availableRenal impairment see notes above; also avoid ifestimated glomerular filtration rate less than 30 mL/minute/1.73m 2 —no information availablePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also malaise, anaemia;less commonly abdominal pain, constipation, diarr-2 Cardiovascular system

104 2.6 Nitrates and calcium-channel blockers BNFC 2011–20122 Cardiovascular systemhoea, nausea, vomiting, angina, palpitation, oedema,dyspnoea, cough, headache, sleep disorders, drowsiness,urticaria, pruritus, rash; rarely hepatitis, atrialfibrillation, cerebrovascular accident, and paraesthesia;also reported pancreatitis, depression, erectiledysfunction, thrombocytopenia, hyponatraemia,arthralgia, myalgia, rhabdomyolysis, tinnitus, photosensitivity,and vasculitis (including Henoch-Schönleinpurpura)Indication and doseHypertension (under specialist supervision). By mouthChild 6–18 yearsBody-weight 20–50 kg initially 700 micrograms/kg (max. 25 mg) once daily (lower dose in intravascularvolume depletion), adjusted according toresponse; max. 50 mg once dailyBody-weight 50 kg and over initially 50 mg oncedaily (initially 25 mg once daily in intravascularvolume depletion), adjusted according toresponse; max. 1.4 mg/kg (max. 100 mg) oncedailyLosartan Potassium (Non-proprietary)Tablets, losartan potassium 12.5 mg, net price 28-tabpack = £7.70; 25 mg, 28-tab pack = £2.64; 50 mg, 28-tab pack = £2.38; 100 mg, 28-tab pack = £2.84Cozaar c (MSD) TATablets, f/c, losartan potassium 12.5 mg (blue), netprice 28-tab pack = £8.09; 25 mg (white), 28-tab pack= £16.18; 50 mg (white, scored), 28-tab pack = £12.80;100 mg (white), 28-tab pack = £16.18Oral suspension, losartan potassium 12.5 mg/5 mLwhen reconstituted with solvent provided, net price200 mL (berry-citrus flavour) = £53.68VALSARTANCautions see notes aboveContra-indications biliary cirrhosis, cholestasisHepatic impairment max. 80 mg daily in mild tomoderate impairment; avoid in severe impairmentRenal impairment see notes above; also avoid ifestimated glomerular filtration rate less than 30 mL/minute/1.73m 2 —no information availablePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also less commonlyabdominal pain, nausea, diarrhoea, cough, malaise,headache; also reported anaemia, renal failure, neutropenia,thrombocytopenia, myalgia, vasculitis,serum sickness, rash, pruritusLicensed use capsules not licensed for use in childrenIndication and doseHypertension (under specialist supervision). By mouthChild 6–18 yearsBody-weight 18–35 kg initially 40 mg once daily,adjusted according to response; max. 80 mg dailyBody-weight 35–80 kg initially 80 mg once daily,adjusted according to response; max. 160 mg dailyBody-weight 80 kg and over initially 80 mg oncedaily, adjusted according to response; max. 320 mgdailyDiovan c (Novartis) TACapsules, valsartan 40 mg (grey), net price 28-cappack = £13.97; 80 mg (grey/pink), 28-cap pack =£13.97; 160 mg (grey/pink), 28-cap pack = £18.41Tablets, f/c, scored, valsartan 40 mg (yellow), netprice 7-tab pack = £3.49; 320 mg (dark grey-violet),28-tab pack = £20.232.6 Nitrates, calcium-channelblockers, and otherantianginal drugs2.6.1 Nitrates2.6.2 Calcium-channel blockers2.6.3 Other antianginal drugs2.6.4 Peripheral vasodilators and relateddrugsNitrates and calcium-channel blockers have a vasodilatingand, consequently, blood-pressure lowering effect.Vasodilators can act in heart failure by arteriolar dilatation,which reduces both peripheral vascular resistanceand left ventricular pressure during systole resulting inimproved cardiac output. They can also cause venousdilatation, which results in dilatation of capacitancevessels, increase of venous pooling, and diminution ofvenous return to the heart (decreasing left ventricularend-diastolic pressure).2.6.1 NitratesNitrates are potent coronary vasodilators, but theirprincipal benefit follows from a reduction in venousreturn which reduces left ventricular work. Unwantedeffects such as flushing, headache, and postural hypotensionmay limit therapy, especially if the child isunusually sensitive to the effects of nitrates or is hypovolaemic.For the use of glyceryl trinitrate in extravasation, seesection 10.3.Children receiving nitrates continuously throughout theday can develop tolerance (with reduced therapeuticeffects). Reduction of blood-nitrate concentrations tolow levels for 4 to 8 hours each day usually maintainseffectiveness in such patients.GLYCERYL TRINITRATECautions hypothyroidism; malnutrition; hypothermia;recent history of myocardial infarction; heart failuredue to obstruction; hypoxaemia or other ventilationand perfusion abnormalities; susceptibility to angleclosureglaucoma; metal-containing transdermal systemsshould be removed before magnetic resonanceimaging procedures, cardioversion, or diathermy;avoid abrupt withdrawal; monitor blood pressure andheart rate during infusion; tolerance (see notesabove); interactions: Appendix 1 (nitrates)

BNFC 2011–2012 2.6.2 Calcium-channel blockers 105Contra-indications hypersensitivity to nitrates; hypotensiveconditions and hypovolaemia; hypertrophiccardiomyopathy; aortic stenosis; cardiac tamponade;constrictive pericarditis; mitral stenosis; toxic pulmonaryoedema; head trauma; cerebral haemorrhage;cerebrovascular disease; marked anaemiaHepatic impairment caution in severe impairmentRenal impairment manufacturers advise use withcaution in severe impairmentPregnancy not known to be harmfulBreast-feeding no information available—manufacturersadvise use only if potential benefit outweighsriskSide-effects postural hypotension, tachycardia (butparadoxical bradycardia also reported); throbbingheadache, dizziness; less commonly nausea, vomiting,heartburn, flushing, syncope, temporary hypoxaemia,rash, application-site reactions with transdermalpatches; very rarely angle-closure glaucomaInjection Specific side-effects following injection (particularlyif given too rapidly) include severe hypotension, diaphoresis,apprehension, restlessness, muscle twitching, retrosternaldiscomfort, palpitation, abdominal pain; prolongedadministration has been associated with methaemoglobinaemiaLicensed use not licensed for use in childrenIndication and doseHypertension during and after cardiac surgery,heart failure after cardiac surgery, coronaryvasoconstriction in myocardial ischaemia,vasoconstriction in shock. By continuous intravenous infusionNeonate 0.2–0.5 micrograms/kg/minute, doseadjusted according to response; usual dose 1–3 micrograms/kg/minute; max. 10 micrograms/kg/minuteChild 1 month–18 years initially 0.2–0.5 micrograms/kg/minute,dose adjusted according toresponse, usual dose 1–3 micrograms/kg/minute;max. 10 micrograms/kg/minute (do not exceed200 micrograms/minute)Administration for continuous intravenous infusion,dilute to max. concentration of 400 micrograms/mL(but concentration of 1 mg/mL has been used via acentral venous catheter) with Glucose 5% or SodiumChloride 0.9%.Glass or polyethylene apparatus is preferable; loss ofpotency will occur if PVC is used.Neonatal intensive care, dilute 3 mg/kg body-weightto a final volume of 50 mL with infusion fluid; anintravenous infusion rate of 1 mL/hour provides adose of 1 microgram/kg/minuteGlyceryl Trinitrate (Non-proprietary) AInjection, glyceryl trinitrate 1 mg/mL. To be dilutedbefore use or given undiluted with syringe pump. Netprice 50-mL vial = £15.90Injection, glyceryl trinitrate 5 mg/mL. To be dilutedbefore use. Net price 5-mL amp = £6.49; 10-mL amp =£12.98Excipients may include ethanol, propylene glycolNitrocine c (UCB Pharma) AInjection, glyceryl trinitrate 1 mg/mL. To be dilutedbefore use or given undiluted with syringe pump. Netprice 10-mL amp = £5.88; 50-mL bottle = £13.77Excipients include propylene glycolNitronal c (Merck Serono) AInjection, glyceryl trinitrate 1 mg/mL. To be dilutedbefore use or given undiluted with syringe pump. Netprice 5-mL vial = £1.80; 50-mL vial = £14.762.6.2 Calcium-channel blockersCalcium-channel blockers (less correctly called ‘calcium-antagonists’)interfere with the inward displacementof calcium ions through the slow channels ofactive cell membranes. They influence the myocardialcells, the cells within the specialised conducting systemof the heart, and the cells of vascular smooth muscle.Thus, myocardial contractility may be reduced, theformation and propagation of electrical impulses withinthe heart may be depressed, and coronary or systemicvascular tone may be diminished.Calcium-channel blockers differ in their predilection forthe various possible sites of action and, therefore, theirtherapeutic effects are disparate, with much greatervariation than those of beta-blockers. There are importantdifferences between verapamil, diltiazem, and thedihydropyridine calcium-channel blockers (amlodipine,nicardipine, nifedipine, and nimodipine). Verapamil anddiltiazem should usually be avoided in heart failurebecause they may further depress cardiac function andcause clinically significant deterioration.Verapamil is used for the treatment of hypertension(section 2.5) and arrhythmias (section 2.3.2). However,it is no longer first-line treatment for arrhythmias inchildren because it has been associated with fatal collapseespecially in infants under 1 year; adenosine isnow recommended for first-line use.Verapamil is a highly negatively inotropic calcium channel-blockerand it reduces cardiac output, slows theheart rate, and may impair atrioventricular conduction.It may precipitate heart failure, exacerbate conductiondisorders, and cause hypotension at high doses andshould not be used with beta-blockers (see p. 109).Constipation is the most common side-effect.Nifedipine relaxes vascular smooth muscle and dilatescoronary and peripheral arteries. It has more influenceon vessels and less on the myocardium than does verapamil,and unlike verapamil has no anti-arrhythmic activity.It rarely precipitates heart failure because any negativeinotropic effect is offset by a reduction in leftventricular work. Short-acting formulations of nifedipineare not recommended for long-term management ofhypertension; their use may be associated with largevariations in blood pressure and reflex tachycardia.However, they may be used if a modified-release preparationdelivering the appropriate dose is not availableor if a child is unable to swallow (a liquid preparationmay be prepared using capsules). Nifedipine may alsobe used for the management of angina due to coronaryartery disease in Kawasaki disease or progeria and in themanagement of Raynaud’s syndrome.Nicardipine has similar effects to those of nifedipineand may produce less reduction of myocardial contractility;it is used to treat hypertensive crisis.Amlodipine also resembles nifedipine and nicardipinein its effects and does not reduce myocardial contractilityor produce clinical deterioration in heart failure. Ithas a longer duration of action and can be given oncedaily. Nifedipine and amlodipine are used for the treat-2 Cardiovascular system

106 2.6.2 Calcium-channel blockers BNFC 2011–20122 Cardiovascular systemment of hypertension. Side-effects associated with vasodilatationsuch as flushing and headache (which becomeless obtrusive after a few days), and ankle swelling(which may respond only partially to diuretics) arecommon.Nimodipine is related to nifedipine but the smoothmuscle relaxant effect preferentially acts on cerebralarteries. Its use is confined to prevention and treatmentof vascular spasm following aneurysmal subarachnoidhaemorrhage.Diltiazem is a peripheral vasodilator and also has milddepressor effects on the myocardium. It is used in thetreatment of Raynaud’s syndrome.Withdrawal There is some evidence that suddenwithdrawal of calcium-channel blockers may be associatedwith an exacerbation of myocardial ischaemia.AMLODIPINECautions acute porphyria (but see section 9.8.2);interactions: Appendix 1 (calcium-channel blockers)Contra-indications cardiogenic shock, significantaortic stenosisHepatic impairment may need dose reduction—halflifeprolongedPregnancy no information available—manufactureradvises avoid, but risk to fetus should be balancedagainst risk of uncontrolled maternal hypertensionBreast-feeding manufacturer advises avoid—noinformation availableSide-effects abdominal pain, nausea; palpitation,flushing, oedema; headache, dizziness, sleep disturbances,fatigue; less commonly gastro-intestinal disturbances,dry mouth, taste disturbances, hypotension,syncope, chest pain, dyspnoea, rhinitis, moodchanges, asthenia, tremor, paraesthesia, urinary disturbances,impotence, gynaecomastia, weightchanges, myalgia, muscle cramps, back pain, arthralgia,visual disturbances, tinnitus, pruritus, rashes(including isolated reports of erythema multiforme),sweating, alopecia, purpura, and skin discolouration;very rarely gastritis, pancreatitis, hepatitis, jaundice,cholestasis, gingival hyperplasia, myocardial infarction,arrhythmias, tachycardia, vasculitis, coughing,peripheral neuropathy, hyperglycaemia, thrombocytopenia,angioedema, and urticariaLicensed use not licensed for use in children under 6yearsIndication and doseHypertension. By mouthChild 1 month–12 years initially 100–200 micrograms/kgonce daily; if necessary increase atintervals of 1–2 weeks up to 400 micrograms/kgonce daily; max. 10 mg once dailyChild 12–18 years initially 5 mg once daily; ifnecessary increase at intervals of 1–2 weeks tomax. 10 mg once dailyAdministration tablets may be dispersed in waterNote Tablets from various suppliers may contain different salts(e.g. amlodipine besilate, amlodipine maleate, and amlodipinemesilate) but the strength is expressed in terms of amlodipine(base); tablets containing different salts are considered interchangeableAmlodipine (Non-proprietary) ATablets, amlodipine (as maleate or as mesilate) 5 mg,net price 28-tab pack = £1.05; 10 mg, 28-tab pack =£1.20Brands include Amlostin cIstin c (Pfizer) ATablets, amlodipine (as besilate) 5 mg, net price 28-tab pack = £11.08; 10 mg, 28-tab pack = £16.55Extemporaneous formulations available seeExtemporaneous Preparations, p. 6DILTIAZEM HYDROCHLORIDECautions heart failure or significantly impaired leftventricular function, bradycardia (avoid if severe), firstdegree AV block, or prolonged PR interval; interactions:Appendix 1 (calcium-channel blockers)Contra-indications severe bradycardia, significantaortic stenosis, cardiogenic shock, left ventricularfailure with pulmonary congestion, second- or thirddegreeAV block (unless pacemaker fitted), sick sinussyndrome; acute porphyria (section 9.8.2)Hepatic impairment reduce doseRenal impairment start with smaller dosePregnancy avoidBreast-feeding significant amount present in milk—no evidence of harm but avoid unless no safer alternativeSide-effects bradycardia, sino-atrial block, AV block,palpitation, dizziness, hypotension, malaise, asthenia,headache, hot flushes, gastro-intestinal disturbances,oedema (notably of ankles); rarely rashes (includingerythema multiforme and exfoliative dermatitis),photosensitivity; hepatitis, gynaecomastia, gumhyperplasia, extrapyramidal symptoms, depressionreportedLicensed use not licensed for use in childrenIndication and doseRaynaud’s syndrome. By mouthChild 12–18 years 30–60 mg 2–3 times dailyStandard formulationsNote These formulations are licensed as generics and there isno requirement for brand name dispensing. Although theirmeans of formulation has called for the strict designation‘modified-release’ their duration of action corresponds to thatof tablets requiring administration more frequentlyDiltiazem (Non-proprietary) ATablets, m/r (but see note above), diltiazem hydrochloride60 mg, net price 84-tab pack = £2.93.Label: 25Brands include Optil cTildiem c (Sanofi-Aventis) ATablets, m/r (but see note above), off-white, diltiazemhydrochloride 60 mg, net price 90-tab pack = £7.96.Label: 25NICARDIPINE HYDROCHLORIDECautions congestive heart failure or significantlyimpaired left ventricular function; avoid grapefruitjuice (may affect metabolism); interactions: Appendix1 (calcium-channel blockers)Contra-indications cardiogenic shock; significantaortic stenosis; acute porphyria (section 9.8.2)

BNFC 2011–2012 2.6.2 Calcium-channel blockers 107Hepatic impairment half-life prolonged in severeimpairment—may need dose reductionRenal impairment start with smaller dosePregnancy may inhibit labour; toxicity in animal studies;manufacturer advises avoid, but risk to fetusshould be balanced against risk of uncontrolledmaternal hypertensionBreast-feeding manufacturer advises avoid—noinformation availableSide-effects dizziness, headache, peripheral oedema,flushing, palpitation, nausea; also gastro-intestinaldisturbances, drowsiness, insomnia, tinnitus, hypotension,rashes, dyspnoea, paraesthesia, frequency ofmicturition; thrombocytopenia, depression andimpotence reportedLicensed use not licensed for use in childrenIndication and doseHypertensive crisis. By continuous intravenous infusionNeonate initially 500 nanograms/kg/minute,adjusted according to response; usual maintenanceof 1–4 micrograms/kg/minuteChild 1 month–18 years initially 500 nanograms/kg/minute, adjusted according to response; usualmaintenance of 1–4 micrograms/kg/minute (max.250 micrograms/minute)Administration for intravenous infusion, dilute to aconcentration of 100 micrograms/mL with Glucose5% or Sodium Chloride 0.9%; to minimise peripheralvenous irritation, change site of infusion every 12hoursCardene IV c AInjection, nicardipine 2.5 mg/mL (10-mL ampoule)Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809NIFEDIPINECautions see notes above; also poor cardiac reserve;heart failure or significantly impaired left ventricularfunction (heart failure deterioration observed); severehypotension; diabetes mellitus; avoid grapefruit juice(may affect metabolism); acute porphyria (but seesection 9.8.2); interactions: Appendix 1 (calciumchannelblockers)Contra-indications cardiogenic shock; significantaortic stenosisHepatic impairment dose reduction may be requiredin severe liver diseasePregnancy may inhibit labour; manufacturer advisesavoid before week 20, but risk to fetus should bebalanced against risk of uncontrolled maternalhypertension; use only if other treatment options arenot indicated or have failedBreast-feeding amount too small to be harmful butmanufacturer advises avoidSide-effects gastro-intestinal disturbance; hypotension,oedema, vasodilatation, palpitation; headache,dizziness, lethargy, asthenia; less commonlytachycardia, hypotension, syncope, chills, nasal congestion,dyspnoea, anxiety, sleep disturbance, vertigo,migraine, paraesthesia, tremor, polyuria, dysuria,nocturia, erectile dysfunction, epistaxis, myalgia, jointswelling, visual disturbance, sweating, and hypersensitivityreactions (including angioedema, jaundice,pruritus, urticaria, and rash); rarely anorexia, gumhyperplasia, mood disturbances, hyperglycaemia,male infertility, purpura, and photosensitivity reactions;also reported dysphagia, intestinal obstruction,intestinal ulcer, bezoar formation, gynaecomastia,agranulocytosis, and anaphylaxisLicensed use not licensed for use in childrenIndication and doseHypertensive crisis, acute angina in Kawasakidisease or progeria. By mouth (see Administration, below)Child 1 month–18 years 250–500 micrograms/kg (max. 20 mg) as a single doseHypertension, angina in Kawasaki disease orprogeria. By mouthChild 1 month–12 years 200–300 micrograms/kg 3 times daily; max. 3 mg/kg daily or 90 mg dailyChild 12–18 years 5–20 mg 3 times daily; max.90 mg dailyNote Dose frequency depends on preparation usedRaynaud’s syndrome. By mouthChild 2–18 years 2.5–10 mg 2–4 times daily; startwith low doses at night and increase gradually toavoid postural hypotensionNote Dose frequency depends on preparation usedPersistent hyperinsulinaemic hypoglycaemiasee also section 6.1.4. By mouthNeonate 100–200 micrograms/kg (max.600 micrograms/kg) 4 times dailyAdministration for rapid effect in hypertensive crisisor acute angina, bite capsules and swallow liquid oruse liquid preparation if 5-mg or 10-mg dose inappropriate;if liquid unavailable, extract contents ofcapsule via a syringe and use immediately—coversyringe with foil to protect contents from light; capsulecontents may be diluted with water if necessary.Modified-release tablets may be crushed—this mayalter the release profile; crushed tablets should beadministered within 30–60 seconds to avoid significantloss of potency of drugNifedipine (Non-proprietary) ACapsules, nifedipine 5 mg, net price 84-cap pack =£2.97; 10 mg, 84-cap pack = £4.00DoseGive 3 times dailyOral liquid, available from ‘special-order’ manufacturersor specialist importing companies, see p. 809Adalat c (Bayer Schering) ACapsules, orange, nifedipine 5 mg, net price 90-cappack = £5.73; 10 mg, 90-cap pack = £7.30Note Adalat liquid gel capsules contain 5 mg nifedipine in0.17 mL and 10 mg nifedipine in 0.34 mLDoseGive 3 times daily2 Cardiovascular system

108 2.6.2 Calcium-channel blockers BNFC 2011–20122 Cardiovascular systemModified releaseNote Different versions of modified-release preparations maynot have the same clinical effect. To avoid confusion betweenthese different formulations of nifedipine, prescribers shouldspecify the brand to be dispensed. Modified-release formulationsmay not be suitable for dose titration in hepatic diseaseAdalat c LA (Bayer Schering) ALA 20 tablets, m/r, f/c, pink, nifedipine 20 mg, netprice 28-tab pack = £4.97. Label: 25LA 30 tablets, m/r, f/c, pink, nifedipine 30 mg, netprice 28-tab pack = £6.85. Label: 25LA 60 tablets, m/r, f/c, pink, nifedipine 60 mg, netprice 28-tab pack = £9.03. Label: 25Counselling Tablet membrane may pass through gastrointestinaltract unchanged, but being porous has no effect onefficacyCautions dose form not appropriate for use in hepaticimpairment or where there is a history of oesophageal orgastro-intestinal obstruction, decreased lumen diameter ofthe gastro-intestinal tract, or inflammatory bowel disease(including Crohn’s disease)DoseGive once dailyAdalat c Retard (Bayer Schering) ARetard 10 tablets, m/r, f/c, grey-pink, nifedipine10 mg, net price 56-tab pack = £7.34. Label: 25Retard 20 tablets, m/r, f/c, grey-pink, nifedipine20 mg, net price 56-tab pack = £8.81. Label: 25DoseGive twice dailyAdipine c MR (Chiesi) ATablets, m/r, nifedipine 10 mg (pink), net price 56-tabpack = £3.73; 20 mg (pink), 56-tab pack = £5.21.Label: 25DoseGive twice dailyAdipine c XL (Chiesi) ATablets, m/r, red, nifedipine 30 mg, net price 28-tabpack = £4.70; 60 mg, 28-tab pack = £7.10. Label: 25DoseGive once dailyCoracten SR c (UCB Pharma) ACapsules, m/r, nifedipine 10 mg (grey/pink, enclosingyellow pellets), net price 60-cap pack = £3.90;20 mg (pink/brown, enclosing yellow pellets), 60-cappack = £5.41. Label: 25DoseGive twice dailyCoracten XL c (UCB Pharma) ACapsules, m/r, nifedipine 30 mg (brown), net price28-cap pack = £4.89; 60 mg (orange), 28-cap pack =£7.34. Label: 25DoseGive once dailyFortipine LA 40 c (Goldshield) ATablets, m/r, red, nifedipine 40 mg, net price 30-tabpack = £9.60. Label: 21, 25DoseGive 1–2 times dailyHypolar c Retard 20 (Sandoz) ATablets, m/r, red, f/c, nifedipine 20 mg, net price 56-tab pack = £5.75. Label: 25DoseGive twice dailyNifedipress c MR (Dexcel) ATablets, m/r, pink, nifedipine 10 mg, net price 56-tabpack = £9.23; 20 mg, 56-tab pack = £10.06. Label: 25DoseGive twice dailyNote Also available as Calchan c MRTensipine MR c (Genus) ATablets, m/r, pink-grey, nifedipine 10 mg, net price56-tab pack = £4.30; 20 mg, 56-tab pack = £5.49.Label: 21, 25DoseGive twice dailyValni XL c (Winthrop) ATablets, m/r, red, nifedipine 30 mg, net price 28-tabpack = £7.29; 60 mg, 28-tab pack = £9.13. Label: 25Cautions dose form not appropriate for use in hepaticimpairment, or where there is a history of oesophageal orgastro-intestinal obstruction, decreased lumen diameter ofthe gastro-intestinal tract, inflammatory bowel disease, orileostomy after proctocolectomyDoseGive once dailyNIMODIPINECautions cerebral oedema or severely raised intracranialpressure; hypotension; avoid concomitantadministration of nimodipine tablets and infusion,other calcium-channel blockers, or beta-blockers;concomitant nephrotoxic drugs; avoid grapefruit juice(may affect metabolism); interactions: Appendix 1(calcium-channel blockers, alcohol (infusion only))Contra-indications acute porphyria (section 9.8.2)Hepatic impairment elimination reduced in cirrhosis—monitorblood pressureRenal impairment manufacturer advises monitorrenal function closely with intravenous administrationPregnancy manufacturer advises use only if potentialbenefit outweighs risksBreast-feeding manufacturer advises avoid—presentin milkSide-effects hypotension, variation in heart-rate,flushing, headache, gastro-intestinal disorders,nausea, sweating and feeling of warmth; thrombocytopeniaand ileus reportedLicensed use not licensed for use in childrenIndication and doseTreatment of vasospasm following subarachnoidhaemorrhage under specialist advice only. By intravenous infusionChild 1 month–12 years initially 15 micrograms/kg/hour (max. 500 micrograms/hour) or initially7.5 micrograms/kg/hour if blood pressureunstable; increase after 2 hours to 30 micrograms/kg/hour (max. 2 mg/hour) if no severe decrease inblood pressure; continue for at least 5 days (max.14 days)Child 12–18 years initially 500 micrograms/hour(up to 1 mg/hour if body-weight over 70 kg and

BNFC 2011–2012 2.6.2 Calcium-channel blockers 109blood pressure stable), increase after 2 hours to 1–2 mg/hour if no severe fall in blood pressure;continue for at least 5 days (max. 14 days)Prevention of vasospasm following subarachnoidhaemorrhage. By mouthChild 1 month–18 years 0.9–1.2 mg/kg (max.60 mg) 6 times daily, starting within 4 days ofhaemorrhage and continued for 21 daysAdministration for continuous intravenous infusion,administer undiluted via a Y-piece on a centralvenous catheter connected to a running infusion ofGlucose 5%, or Sodium Chloride 0.9%; not to beadded to an infusion container; incompatible withpolyvinyl chloride giving sets or containers; protectinfusion from light.For administration by mouth, tablets may be crushedor halved but are light sensitive—administer immediatelyNimotop c (Bayer Schering) ATablets, yellow, f/c, nimodipine 30 mg, net price 100-tab pack = £33.60Intravenous infusion, nimodipine 200 micrograms/mL; also contains ethanol 20% and macrogol ‘400’17%. Net price 50-mL vial (with polyethylene infusioncatheter) = £11.46Note Polyethylene, polypropylene, or glass apparatus shouldbe used; PVC should be avoidedVERAPAMIL HYDROCHLORIDECautions first-degree AV block; patients taking betablockers(important: see below); avoid grapefruitjuice (may affect metabolism); interactions: Appendix1 (calcium-channel blockers)Verapamil and beta-blockers Verapamil injection shouldnot be given to patients recently treated with beta-blockersbecause of the risk of hypotension and asystole. The suggestionthat when verapamil injection has been given first, aninterval of 30 minutes before giving a beta-blocker is sufficienthas not been confirmed.It may also be hazardous to give verapamil and a betablockertogether by mouth (should only be contemplated ifmyocardial function well preserved).Contra-indications hypotension, bradycardia, second-and third-degree AV block, sick sinus syndrome,cardiogenic shock, sino-atrial block; history of heartfailure or significantly impaired left ventricular function,even if controlled by therapy; atrial flutter orfibrillation complicating syndromes associated withaccessory conducting pathways (e.g. Wolff-Parkinson-White syndrome); acute porphyria (section 9.8.2)Hepatic impairment oral dose may need to bereducedPregnancy may reduce uterine blood flow with fetalhypoxia; manufacturer advises avoid during first trimesterunless absolutely necessary; may inhibitlabourBreast-feeding amount too small to be harmfulSide-effects constipation; less commonly nausea,vomiting, flushing, headache, dizziness, fatigue, ankleoedema; rarely allergic reactions (erythema, pruritus,urticaria, angioedema, Stevens-Johnson syndrome);myalgia, arthralgia, paraesthesia, erythromelalgia;increased prolactin concentration; gynaecomastiaand gingival hyperplasia after long-term treatment;after intravenous administration or high doses, hypotension,heart failure, bradycardia, heart block, andasystole; hypersensitivity reactions involving reversiblyraised liver function testsLicensed use Modified release preparation notlicensed for use in childrenIndication and doseHypertension, prophylaxis of supraventriculararrhythmias under specialist advice only. By mouthChild 1–2 years 20 mg 2–3 times dailyChild 2–18 years 40–120 mg 2–3 times dailyTreatment of supraventricular arrhythmias. By intravenous injection over 2–3 minutes(with ECG and blood-pressure monitoring andunder specialist advice)Child 1–18 years 100–300 micrograms/kg (max.5 mg) as a single dose, repeated after 30 minutes ifnecessaryAdministration for intravenous injection, may bediluted with Glucose 5% or Sodium Chloride 0.9%;incompatible with solutions of pH greater than 6Verapamil (Non-proprietary) ATablets, coated, verapamil hydrochloride 40 mg, netprice 84-tab pack = £1.55; 80 mg, 84-tab pack = £1.91;120 mg, 28-tab pack = £1.54; 160 mg, 56-tab pack =£28.20Oral solution, verapamil hydrochloride 40 mg/5 mL,net price 150 mL = £36.90Brands include Zolvera cCordilox c (Dexcel) ATablets, yellow, f/c, verapamil hydrochloride 40 mg,net price 84-tab pack = £1.50; 80 mg, 84-tab pack =£2.05; 120 mg, 28-tab pack = £1.15; 160 mg, 56-tabpack = £2.80Injection, verapamil hydrochloride 2.5 mg/mL, netprice 2-mL amp = £1.11Securon c (Abbott) AInjection, verapamil hydrochloride 2.5 mg/mL, netprice 2-mL amp = £1.08Extemporaneous formulations available seeExtemporaneous Preparations, p. 6Modified releaseHalf Securon SR c (Abbott) ATablets, m/r, f/c, verapamil hydrochloride 120 mg,net price 28-tab pack = £7.71. Label: 25DoseGive once daily (doses above 240 mg daily, give 2–3times daily)Securon SR c (Abbott) ATablets, m/r, pale green, f/c, scored, verapamilhydrochloride 240 mg, net price 28-tab pack = £5.00.Label: 25DoseGive once daily (doses above 240 mg daily, give 2–3times daily)2 Cardiovascular system

110 2.6.4 Peripheral vasodilators and related drugs BNFC 2011–20122 Cardiovascular systemUniver c (Cephalon) ACapsules, m/r, verapamil hydrochloride 120 mg(yellow/dark blue), net price 28-cap pack = £4.86;180 mg (yellow), 56-cap pack = £11.38; 240 mg (yellow/darkblue), 28-cap pack = £7.67. Label: 25Excipients include propylene glycol (see Excipients, p. 2)DoseGive once dailyVerapress MR c (Dexcel) ATablets, m/r, pale green, f/c, verapamil hydrochloride240 mg, net price 28-tab pack = £6.04. Label: 25DoseGive 1–2 times dailyNote Also available as Cordilox c MRVertab c SR 240 (Chiesi) ATablets, m/r, pale green, f/c, scored, verapamilhydrochloride 240 mg, net price 28-tab pack = £5.45.Label: 25DoseGive 1–2 times daily2.6.3 Other antianginal drugsClassification not used in BNF for Children.2.6.4 Peripheral vasodilatorsand related drugsRaynaud’s syndrome consists of recurrent, long-lasting,and episodic vasospasm of the fingers and toes oftenassociated with exposure to cold. Management includesavoidance of exposure to cold and stopping smoking (ifappropriate). More severe symptoms may require vasodilatortreatment, which is most often successful inprimary Raynaud’s syndrome. Nifedipine and diltiazem(section 2.6.2) are useful for reducing the frequencyand severity of vasospastic attacks. In verysevere cases, where digital infarction is likely, intravenousinfusion of the prostacyclin analogue iloprostmay be helpful.Vasodilator therapy is not established as being effectivefor chilblains (section 13.13).ILOPROSTCautions see section 2.5.1.2Contra-indications see section 2.5.1.2Hepatic impairment dose may need to be halved inliver cirrhosisSide-effects see section 2.5.1.2Licensed use not licensed for use in childrenIndication and doseRaynaud’s syndrome see notes above. By intravenous infusionChild 12–18 years initially 30 nanograms/kg/hour, increased gradually to 60–120 nanograms/kg/hour given over 6 hours daily for 3–5 daysPulmonary hypertension section 2.5.1.2Administration for intravenous infusion, dilute to aconcentration of 200 nanograms/mL with Glucose5% or Sodium Chloride 0.9%; alternatively, may bediluted to a concentration of 2 micrograms/mL andgiven via syringe driverIloprost (Non-proprietary)Concentrate for infusion, iloprost (as trometamol)100 micrograms/mLFor dilution and use as an intravenous infusionNote available on a named patient basis from Bayer Scheringin 0.5 mL and 1 mL ampoules2.7 Sympathomimetics2.7.1 Inotropic sympathomimetics2.7.2 Vasoconstrictor sympathomimetics2.7.3 Cardiopulmonary resuscitationThe properties of sympathomimetics vary according towhether they act on alpha or on beta adrenergic receptors.Response to sympathomimetics can also varyconsiderably in children, particularly neonates. It isimportant to titrate the dose to the desired effect andto monitor the child closely.2.7.1 InotropicsympathomimeticsThe cardiac stimulants dobutamine and dopamine acton beta 1 receptors in cardiac muscle and increase contractilitywith little effect on rate.Dopamine has a variable, unpredictable, and dosedependent impact on vascular tone. Low dose infusion(2 micrograms/kg/minute) normally causes vasodilatation,but there is little evidence that this is clinicallybeneficial; moderate doses increase myocardial contractilityand cardiac output in older children, but in neonatesmoderate doses may cause a reduction in cardiacoutput. High doses cause vasoconstriction and increasevascular resistance, and should therefore be used withcaution following cardiac surgery, or where there is coexistingneonatal pulmonary hypertension.In neonates the response to inotropic sympathomimeticsvaries considerably, particularly in thoseborn prematurely; careful dose titration and monitoringare necessary.Isoprenaline injection is available from ‘special-order’manufacturers or specialist importing companies, seep. 809.Shock Shock is a medical emergency associated with ahigh mortality. The underlying causes of shock such ashaemorrhage, sepsis or myocardial insufficiency shouldbe corrected. Additional treatment is dependent on thetype of shock.Septic shock is associated with severe hypovolaemia(due to vasodilation and capillary leak) which should becorrected with crystalloids or colloids (section 9.2.2). Ifhypotension persists despite volume replacement,dopamine should be started. For shock refractory totreatment with dopamine, if cardiac output is high andperipheral vascular resistance is low (warm shock),noradrenaline (norepinephrine) (section 2.7.2) shouldbe added or if cardiac output is low and peripheral

BNFC 2011–2012 2.7.1 Inotropic sympathomimetics 111vascular resistance is high (cold shock), adrenaline(epinephrine) (section 2.7.2) should be added. Additionally,in cold shock, a vasodilator such as milrinone(section 2.1.2), glyceryl trinitrate (section 2.6.1), orsodium nitroprusside (on specialist advice only) (section2.5.1.1) can be used to reduce vascular resistance.If the shock is resistant to volume expansion and catecholamines,and there is suspected or proven adrenalinsufficiency, low dose hydrocortisone (section 6.3.2)can be used. ACTH-stimulated plasma-cortisol concentrationshould be measured; however, hydrocortisonecan be started without such information.Alternatively, if the child is resistant to catecholamines,and vascular resistance is low, vasopressin (section6.5.2) can be added.Neonatal septic shock can be complicated by the transitionfrom fetal to neonatal circulation. Treatment toreverse right ventricular failure, by decreasing pulmonaryartery pressures, is commonly needed in neonateswith fluid-refractory shock and persistent pulmonaryhypertension of the newborn (section 2.5.1.2).Rapid administration of fluid in neonates with patentductus arteriosus may cause left-to-right shunting andcongestive heart failure induced by ventricular overload.In cardiogenic shock, the aim is to improve cardiacoutput and to reduce the afterload on the heart. Ifcentral venous pressure is low, cautious volume expansionwith a colloid or crystalloid can be used. Aninotrope such as adrenaline (epinephrine) (section2.7.2) or dopamine should be given to increase cardiacoutput. Dobutamine is a peripheral vasodilator and isan alternative if hypotension is not significant.Milrinone (section 2.1.2) has both inotropic and vasodilatoryeffects and can be used when vascular resistanceis high. Alternatively, glyceryl trinitrate (2.6.1) orsodium nitroprusside (on specialist advice only) (section2.5.1.1) can be used to reduce vasoconstriction.Hypovolaemic shock should be treated with a crystalloidor colloid solution (or whole or reconstituted bloodif source of hypovolaemia is haemorrhage) and furthersteps to improve cardiac output and decrease vascularresistance can be taken, as in cardiogenic shock.The use of sympathomimetic inotropes and vasoconstrictorsshould preferably be confined to the intensivecare setting and undertaken with invasive haemodynamicmonitoring.For advice on the management of anaphylactic shock,see section 3.4.3.DOBUTAMINECautions arrhythmias, acute myocardial infarction,acute heart failure, severe hypotension, markedobstruction of cardiac ejection (such as idiopathichypertrophic subaortic stenosis); correct hypovolaemiabefore starting treatment; tolerance maydevelop with continuous infusions longer than 72hours; hyperthyroidism; interactions: Appendix 1(sympathomimetics)Contra-indications phaeochromocytomaPregnancy no evidence of harm in animal studies—manufacturers advise use only if benefit outweighsriskBreast-feeding manufacturers advise avoid—noinformation availableSide-effects nausea; hypotension, hypertension(marked increase in systolic blood pressure indicatesoverdose), arrhythmias, palpitation, chest pain; dyspnoea,bronchospasm; headache; fever; increasedurinary urgency; eosinophilia; rash, phlebitis; veryrarely myocardial infarction, hypokalaemia; alsoreported coronary artery spasm and thrombocytopeniaLicensed use strong sterile solution not licensed foruse in childrenIndication and doseInotropic support in low cardiac output states,after cardiac surgery, cardiomyopathies, shock. By continuous intravenous infusionNeonate initially 5 micrograms/kg/minute,adjusted according to response to 2–15 micrograms/kg/minute;max. 20 micrograms/kg/minuteChild 1 month–18 years initially 5 micrograms/kg/minute adjusted according to response to 2–20 micrograms/kg/minuteAdministration for continuous intravenous infusion,using infusion pump, dilute to a concentration of 0.5–1 mg/mL (max. 5 mg/mL if fluid restricted) withGlucose 5% or Sodium Chloride 0.9%; infuse higherconcentration solutions through central venouscatheter only. Incompatible with bicarbonate andother strong alkaline solutions.Neonatal intensive care, dilute 30 mg/kg body-weightto a final volume of 50 mL with infusion fluid; anintravenous infusion rate of 0.5 mL/hour provides adose of 5 micrograms/kg/minuteDobutamine (Non-proprietary) AInjection, dobutamine (as hydrochloride) 5 mg/mL.To be diluted before use or given undiluted withsyringe pump. Net price 50-mL vial = £7.50Excipients may include sulphitesConcentrate for intravenous infusion, dobutamine(as hydrochloride) 12.5 mg/mL. To be diluted beforeuse. Net price 20-mL amp = £5.20Excipients may include sulphitesDOPAMINE HYDROCHLORIDECautions correct hypovolaemia; hyperthyroidism;interactions: Appendix 1 (sympathomimetics)Contra-indications tachyarrhythmia, phaeochromocytomaPregnancy manufacturer advises use only if potentialbenefit outweighs riskSide-effects nausea, vomiting, chest pain, palpitation,tachycardia, vasoconstriction, hypotension, dyspnoea,headache; less commonly bradycardia, hypertension,gangrene, mydriasis; rarely fatal ventriculararrhythmiasLicensed use not licensed for use in children under12 yearsIndication and doseTo correct the haemodynamic imbalance due toacute hypotension, shock, cardiac failure,adjunct following cardiac surgery. By continuous intravenous infusionNeonate initially 3 micrograms/kg/minute,adjusted according to response (max. 20 micrograms/kg/minute)2 Cardiovascular system

112 2.7.2 Vasoconstrictor sympathomimetics BNFC 2011–20122 Cardiovascular systemChild 1 month–18 years initially 5 micrograms/kg/minute adjusted according to response (max.20 micrograms/kg/minute)Administration for continuous intravenous infusion,dilute to a max. concentration of 3.2 mg/mL withGlucose 5% or Sodium Chloride 0.9%. Infuse higherconcentrations through central venous catheter usinga syringe pump to avoid extravasation and fluidoverload. Incompatible with bicarbonate and otheralkaline solutions.Neonatal intensive care, dilute 30 mg/kg body-weightto a final volume of 50 mL with infusion fluid; anintravenous infusion rate of 0.3 mL/hour provides adose of 3 micrograms/kg/minuteDopamine (Non-proprietary) AConcentrate for intravenous infusion, dopaminehydrochloride 40 mg/mL, net price 5-mL amp = 90p;160 mg/mL, 5-mL amp = £3.40. To be diluted beforeuseIntravenous infusion, dopamine hydrochloride1.6 mg/mL in glucose 5% intravenous infusion, netprice 250-mL container (400 mg) = £11.69. Availablefrom ‘special-order’ manufacturers or specialistimporting companies, p. 8092.7.2 VasoconstrictorsympathomimeticsVasoconstrictor sympathomimetics raise blood pressuretransiently by acting on alpha-adrenergic receptorsto constrict peripheral vessels. They are sometimesused as an emergency method of elevating blood pressurewhere other measures have failed (see also section2.7.1).The danger of vasoconstrictors is that although theyraise blood pressure they also reduce perfusion of vitalorgans such as the kidney.Ephedrine is used to reverse hypotension caused byspinal and epidural anaesthesia.Metaraminol is used as a vasopressor during cardiopulmonarybypass.Phenylephrine causes peripheral vasoconstriction andincreases arterial pressure.Ephedrine, metaraminol and phenylephrine are rarelyneeded in children and should be used under specialistsupervision.Noradrenaline (norepinephrine) is reserved for childrenwith low systemic vascular resistance that is unresponsiveto fluid resuscitation following septic shock, spinalshock, and anaphylaxis.Adrenaline (epinephrine) is mainly used for its inotropicaction. Low doses (acting on beta receptors) causesystemic and pulmonary vasodilation, with someincrease in heart rate and stroke volume and also anincrease in contractility; high doses act predominantlyon alpha receptors causing intense systemic vasoconstriction.EPHEDRINE HYDROCHLORIDECautions hyperthyroidism, diabetes mellitus, hypertension,susceptibility to angle-closure glaucoma,interactions: Appendix 1 (sympathomimetics)Renal impairment use with cautionPregnancy increased fetal heart rate reported withparenteral ephedrineBreast-feeding irritability and disturbed sleepreportedSide-effects nausea, vomiting, anorexia; tachycardia(sometimes bradycardia), arrhythmias, anginal pain,vasoconstriction with hypertension, vasodilation withhypotension, dizziness and flushing; dyspnoea; headache,anxiety, restlessness, confusion, psychoses,insomnia, tremor; difficulty in micturition, urineretention; sweating, hypersalivation; changes inblood-glucose concentration; very rarely angle-closureglaucomaIndication and doseReversal of hypotension from epidural andspinal anaesthesia. By slow intravenous injection of a solutioncontaining ephedrine hydrochloride 3 mg/mLChild 1–12 years 500–750 micrograms/kg or 17–25 mg/m 2 every 3–4 minutes according toresponse; max. 30 mg during episodeChild 12–18 years 3–7.5 mg (max. 9 mg)repeated every 3–4 minutes according to response,max. 30 mg during episodeNasal congestion section 12.2.2Administration for slow intravenous injection, givevia central venous catheterEphedrine Hydrochloride (Non-proprietary) AInjection, ephedrine hydrochloride 3 mg/mL, netprice 10-mL amp = £3.25; 30 mg/mL, net price 1-mLamp = 41pMETARAMINOLCautions see under Noradrenaline; longer duration ofaction than noradrenaline (norepinephrine), seebelow; cirrhosis; interactions: Appendix 1(sympathomimetics)Hypertensive response Metaraminol has a longer durationof action than noradrenaline, and an excessive vasopressorresponse may cause a prolonged rise in blood pressureContra-indications see under NoradrenalinePregnancy may reduce placental prefusion—manufactureradvises use only if potential benefit outweighsriskBreast-feeding manufacturer advises caution—noinformation availableSide-effects see under Noradrenaline; tachycardia;fatal ventricular arrhythmia reported in Laennec’scirrhosisLicensed use not licensed for use in childrenIndication and doseAcute hypotension. By intravenous infusionChild 12–18 years 15–100 mg adjusted accordingto responseEmergency treatment of acute hypotension. By intravenous administrationChild 12–18 years initially by intravenous injection0.5–5 mg, then by intravenous infusion 15–100 mg adjusted according to response

BNFC 2011–2012 2.7.2 Vasoconstrictor sympathomimetics 113Administration for intravenous infusion, dilute to aconcentration of 30–200 micrograms/mL with Glucose5% or Sodium Chloride 0.9% and give through acentral venous catheterMetaraminol (Non-proprietary) AInjection, metaraminol 10 mg (as tartrate)/mL.Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809NORADRENALINE/NOREPINEPHRINECautions coronary, mesenteric, or peripheral vascularthrombosis; following myocardial infarction; Prinzmetal’svariant angina, hyperthyroidism, diabetesmellitus; hypoxia or hypercapnia; uncorrected hypovolaemia;extravasation at injection site may causenecrosis; susceptibility to angle-closure glaucomainteractions: Appendix 1 (sympathomimetics)Contra-indications hypertension (monitor bloodpressure and rate of flow frequently)Pregnancy avoid—may reduce placental perfusionSide-effects anorexia, nausea, vomiting, hypoxia,arrhythmias, peripheral ischaemia, palpitation,hypertension, bradycardia, tachycardia, dyspnoea,headache, insomnia, confusion, anxiety, psychosis,weakness, tremor, urinary retention, angle-closureglaucomaLicensed use not licensed for use in childrenIndication and doseAcute hypotension (septic shock) or shocksecondary to excessive vasodilation (asnoradrenaline). By continuous intravenous infusionNeonate 20–100 nanograms (base)/kg/minuteadjusted according to response; max. 1 microgram(base)/kg/minuteChild 1 month–18 years 20–100 nanograms(base)/kg/minute adjusted according toresponse; max. 1 microgram (base)/kg/minuteNote 500 micrograms of noradrenaline base is equivalentto 1 mg of acid tartrate. Dose expressed as the baseAdministration for continuous intravenous infusion,dilute to a max. concentration of noradrenaline (base)40 micrograms/mL (higher concentrations can beused if fluid-restricted) with Glucose 5% or SodiumChloride and Glucose. Infuse through central venouscatheter; discard if discoloured. Incompatible withbicarbonate or alkaline solutions.Neonatal intensive care, dilute 600 micrograms(base)/kg body-weight to a final volume of50 mL with infusion fluid; an intravenous infusion rateof 0.1 mL/hour provides a dose of 20 nanograms(base)/kg/minuteNoradrenaline/Norepinephrine (Non-proprietary) AInjection, noradrenaline base 1 mg/mL (equivalent tonoradrenaline acid tartrate 2 mg/mL). For dilutionbefore use. Net price 2-mL amp = £2.40, 4-mL amp =£4.40, 20-mL amp = £6.35Note For a period of time preparations on the UK marketmay be described as either noradrenaline base ornoradrenaline acid tartrate; doses above are expressed as thebasePHENYLEPHRINE HYDROCHLORIDECautions see under Noradrenaline; longer duration ofaction than noradrenaline (norepinephrine), seebelow; coronary diseaseHypertensive response Phenylephrine has a longer durationof action than noradrenaline, and an excessive vasopressorresponse may cause a prolonged rise in bloodpressureContra-indications see under Noradrenaline; severehyperthyroidismPregnancy avoid if possible; malformations reportedfollowing use in first trimester; fetal hypoxia andbradycardia reported in late pregnancy and labourSide-effects see under Noradrenaline; tachycardia orreflex bradycardiaLicensed use not licensed for use in children byintravenous infusion or injectionIndication and doseAcute hypotension. By subcutaneous or intramuscular injection(but intravenous injection preferred, see below)Child 1–12 years 100 micrograms/kg every 1–2hours as needed (max. 5 mg)Child 12–18 years 2–5 mg, followed if necessaryby further doses of 1–10 mg (max. initial dose5 mg). By slow intravenous injectionChild 1–12 years 5–20 micrograms/kg (max.500 micrograms) repeated as necessary after atleast 15 minutesChild 12–18 years 100–500 micrograms repeatedas necessary after at least 15 minutes. By intravenous infusionChild 1–16 years 100–500 nanograms/kg/minute,adjusted according to responseChild 16–18 years initially up to 180 micrograms/minutereduced to 30–60 micrograms/minute according to responseAdministration for intravenous injection, dilute to aconcentration of 1 mg/mL with Water for Injectionsand administer slowly.For intravenous infusion, dilute to a concentration of20 micrograms/mL with Glucose 5% or SodiumChloride 0.9% and administer as a continuous infusionvia a central venous catheter using a controlledinfusion devicePhenylephrine (Sovereign) AInjection, phenylephrine hydrochloride 10 mg/mL(1%), net price 1-mL amp = £5.50ADRENALINE/EPINEPHRINECautions ischaemic heart disease, severe angina,obstructive cardiomyopathy, hypertension, arrhythmias,cerebrovascular disease; occlusive vasculardisease, monitor blood pressure and ECG; cor pulmonale;organic brain damage, psychoneurosis;phaeochromocytoma; diabetes mellitus, hyperthyroidism;hypokalaemia, hypercalcaemia; susceptibilityto angle-closure glaucoma; interactions:Appendix 1 (sympathomimetics)Renal impairment manufacturers advise use withcaution in severe impairment2 Cardiovascular system

114 2.7.3 Cardiopulmonary resuscitation BNFC 2011–20122 Cardiovascular systemPregnancy may reduce placental perfusion and candelay second stage of labour; manufacturers adviseuse only if benefit outweighs riskBreast-feeding present in milk but unlikely to beharmful as poor oral bioavailabilitySide-effects nausea, vomiting, dry mouth, anorexia,hypersalivation; arrhythmias, palpitation, tachycardia,syncope, angina, hypertension (risk of cerebralhaemorrhage), cold extremities, pallor; dyspnoea,pulmonary oedema (on excessive dosage or extremesensitivity); anxiety, tremor, restlessness, headache,insomnia, confusion, weakness, dizziness, hallucinations,psychosis; hyperglycaemia; difficulty in micturition,urinary retention; metabolic acidosis; hypokalaemia;mydriasis, angle-closure glaucoma; tissuenecrosis at injection site and of extremities, liver andkidneys, sweatingIndication and doseAcute hypotension. By continuous intravenous infusionNeonate initially 100 nanograms/kg/minuteadjusted according to response; higher doses up to1.5 micrograms/kg/minute have been used inacute hypotensionChild 1 month–18 years initially 100 nanograms/kg/minute adjusted according to response; higherdoses up to 1.5 micrograms/kg/minute have beenused in acute hypotensionAnaphylaxis section 3.4.3Cardiopulmonary arrest section 2.7.3Administration for continuous intravenous infusion,dilute with Glucose 5% or Sodium Chloride 0.9% andgive through a central venous catheter. Incompatiblewith bicarbonate and alkaline solutions.Neonatal intensive care, dilute 3 mg/kg body-weightto a final volume of 50 mL with infusion fluid; anintravenous infusion rate of 0.1 mL/hour provides adose of 100 nanograms/kg/minuteNote These infusions are usually made up with adrenaline 1in 1000 (1 mg/mL) solution; this concentration of adrenalineis not licensed for intravenous administrationPreparationsSection 3.4.32.7.3 CardiopulmonaryresuscitationThe algorithms for cardiopulmonary resuscitation (seeinside back cover) reflect the recommendations of theResuscitation Council (UK); they cover paediatric basiclife support, paediatric advanced life support, and newbornlife support. The guidelines are available atwww.resus.org.uk.Paediatric advanced life support Cardiopulmonary(cardiac) arrest in children is rare and frequently representsthe terminal event of progressive shock or respiratoryfailure.During cardiopulmonary arrest in children withoutintravenous access, the intraosseous route is chosenbecause it provides rapid and effective response; ifcirculatory access cannot be gained, the endotrachealtube can be used. When the endotracheal route is usedten times the intravenous dose should be used; the drugshould be injected quickly down a narrow bore suctioncatheter beyond the tracheal end of the tube and thenflushed in with 1 or 2 mL of sodium chloride 0.9%. Theendotracheal route is useful for lipid-soluble drugs,including lidocaine, adrenaline, atropine, and naloxone.Drugs that are not lipid-soluble (e.g. sodium bicarbonateand calcium chloride) should not be administered bythis route because they will injure the airways.For the management of acute anaphylaxis see section3.4.3.2.8 Anticoagulants andprotamine2.8.1 Parenteral anticoagulants2.8.2 Oral anticoagulants2.8.3 Protamine sulphateAlthough thrombotic episodes are uncommon in childhood,anticoagulants may be required in children withcongenital heart disease; in children undergoing haemodialysis;for preventing thrombosis in children requiringchemotherapy and following surgery; and for systemicvenous thromboembolism secondary to inheritedthrombophilias, systemic lupus erythematosus, orindwelling central venous catheters.2.8.1 Parenteral anticoagulantsHeparinHeparin initiates anticoagulation rapidly but has a shortduration of action. It is now often referred to as beingstandard or unfractionated heparin to distinguish itfrom the low molecular weight heparins (see p. 116),which have a longer duration of action. For children athigh risk of bleeding, unfractionated heparin is moresuitable than low molecular weight heparin because itseffect can be terminated rapidly by stopping the infusion.Heparins are used in both the treatment and prophylaxisof thromboembolic disease, mainly to prevent furtherclotting rather than to lyse existing clots—surgery or athrombolytic drug may be necessary if a thrombusobstructs major vessels.Treatment For the initial treatment of thromboticepisodes unfractionated heparin is given as an intravenousloading dose, followed by continuous intravenousinfusion (using an infusion pump) or by intermittentsubcutaneous injection; the use of intermittentintravenous injection is no longer recommended. Alternatively,a low molecular weight heparin may be givenfor initial treatment. If an oral anticoagulant (usuallywarfarin, section 2.8.2) is also required, it may be startedat the same time as the heparin (the heparin needs to becontinued for at least 5 days and until the INR has beenin the therapeutic range for 2 consecutive days). Labora-

BNFC 2011–2012 2.8.1 Parenteral anticoagulants 115tory monitoring of coagulation activity, preferably on adaily basis, involves determination of the activatedpartial thromboplastin time (APTT) (for unfractionatedheparin only) or of the anti-Factor Xa concentration (forlow molecular weight heparins). Local guidelines onrecommended APTT for neonates and children shouldbe followed; monitoring of APTT should be discussedwith a specialist prior to treatment for thrombotic episodesin neonates.Prophylaxis Low-dose unfractionated heparin by subcutaneousinjection is used to prevent thrombotic episodesin ‘high-risk’ patients; laboratory monitoring ofAPTT or anti-Factor Xa concentration is also required inprophylactic regimens in children. Low molecularweight heparins, aspirin (section 2.9), and warfarin(section 2.8.2) can also be used for prophylaxis.Pregnancy Heparins are used for the management ofthromboembolic disease in pregnancy because they donot cross the placenta. Low molecular weight heparinsare preferred because they have a lower risk of osteoporosisand of heparin-induced thrombocytopenia. Lowmolecular weight heparins are eliminated more rapidlyin pregnancy, requiring alteration of the dosage regimenfor drugs such as dalteparin, enoxaparin, and tinzaparin.Treatment should be stopped at the onset of labour andadvice sought from a specialist on continuing therapyafter birth.Extracorporeal circuits Unfractionated heparin isalso used in the maintenance of extracorporeal circuitsin cardiopulmonary bypass and haemodialysis.Haemorrhage If haemorrhage occurs it is usuallysufficient to withdraw unfractionated or low molecularweight heparin, but if rapid reversal of the effects of theheparin is required, protamine sulphate (section 2.8.3) isa specific antidote (but only partially reverses the effectsof low molecular weight heparins).HEPARINCautions see notes above; concomitant use of drugsthat increase risk of bleeding; interactions: Appendix1 (heparin)Heparin-induced thrombocytopenia Clinically importantheparin-induced thrombocytopenia is immune-mediated anddoes not usually develop until after 5–10 days; it can becomplicated by thrombosis. Platelet counts should be measuredjust before treatment with unfractionated or lowmolecular weight heparin, and regular monitoring of plateletcounts is recommended if given for longer than 4 days. Signsof heparin-induced thrombocytopenia include a 50% reductionof platelet count, thrombosis, or skin allergy. If heparininducedthrombocytopenia is strongly suspected or confirmed,the heparin should be stopped and an alternativeanticoagulant, such as danaparoid, should be given. Ensureplatelet counts return to normal range in those who requirewarfarinHyperkalaemia Inhibition of aldosterone secretion byunfractionated or low molecular weight heparin can result inhyperkalaemia; patients with diabetes mellitus, chronic renalfailure, acidosis, raised plasma-potassium concentration, orthose taking potassium-sparing drugs seem to be moresusceptible. The risk appears to increase with duration oftherapy and plasma-potassium concentration should bemeasured in children at risk of hyperkalaemia before startingthe heparin and monitored regularly thereafter, particularly iftreatment is to be continued for longer than 7 daysContra-indications haemophilia and other haemorrhagicdisorders, thrombocytopenia (including historyof heparin-induced thrombocytopenia), recent cerebralhaemorrhage, severe hypertension; peptic ulcer;after major trauma or recent surgery to eye or nervoussystem; acute bacterial endocarditis; spinal orepidural anaesthesia with treatment doses of unfractionatedor low molecular weight heparin; hypersensitivityto unfractionated or low molecular weightheparinHepatic impairment risk of bleeding increased—reduce dose or avoid in severe impairment (includingoesophageal varices)Renal impairment risk of bleeding increased in severeimpairment—dose may need to be reducedPregnancy does not cross the placenta; maternalosteoporosis reported after prolonged use; multidosevials may contain benzyl alcohol—some manufacturersadvise avoid; see also notes aboveBreast-feeding not excreted in milk due to highmolecular weightSide-effects haemorrhage (see notes above), thrombocytopenia(see Cautions); rarely rebound hyperlipidaemiafollowing unfractionated heparin withdrawal,priapism, hyperkalaemia (see Cautions),osteoporosis (risk lower with low molecular weightheparins), alopecia on prolonged use, injection-sitereactions, skin necrosis, and hypersensitivity reactions(including urticaria, angioedema, and anaphylaxis)Licensed use some preparations licensed for use inchildrenIndication and doseMaintenance of neonatal umbilical arterialcatheter. By intravenous infusionNeonate 0.5 units/hourTreatment of thrombotic episodes. By intravenous administrationNeonate initially 75 units/kg (50 units/kg if under35 weeks postmenstrual age) by intravenousinjection, then by continuous intravenous infusion25 units/kg/hour, adjusted according to APTTChild 1 month–1 year initially 75 units/kg byintravenous injection, then by continuous intravenousinfusion 25 units/kg/hour, adjustedaccording to APTTChild 1–18 years initially 75 units/kg by intravenousinjection, then by continuous intravenousinfusion 20 units/kg/hour, adjusted according toAPTT. By subcutaneous injectionChild 1 month–18 years 250 units/kg twice daily,adjusted according to APTTProphylaxis of thrombotic episodes. By subcutaneous injectionChild 1 month–18 years 100 units/kg (max.5000 units) twice daily, adjusted according toAPTTPrevention of clotting in extracorporeal circuitsconsult product literatureMaintenance of cardiac shunts and criticalstents consult local protocol2 Cardiovascular system

116 2.8.1 Parenteral anticoagulants BNFC 2011–20122 Cardiovascular systemAdministration for continuous intravenous infusion,dilute with Glucose 5% or Sodium Chloride 0.9%.Maintenance of neonatal umbilical arterial catheter,dilute 50 units to a final volume of 50 mL with SodiumChloride 0.45% or use ready-made bag containing500 units in 500 mL Sodium Chloride 0.9%; infuse at0.5 mL/hour.Neonatal intensive care (treatment of thrombosis),dilute 1250 units/kg body-weight to a final volume of50 mL with infusion fluid; an intravenous infusion rateof 1 mL/hour provides a dose of 25 units/kg/hourHeparin Sodium (Non-proprietary) AInjection, heparin sodium 1000 units/mL, net price 1-mL amp = 99p, 5-mL amp = £2.50, 5-mL vial = £2.50,10-mL amp = £4.31, 20-mL amp = £7.09; 5000 units/mL, 1-mL amp = £1.94, 5-mL amp = £5.06, 5-mL vial= £5.64; 25 000 units/mL, 0.2-mL amp = £2.49, 1-mLamp = £5.13, 5-mL vial = £11.11Excipients may include benzyl alcohol (avoid in neonates, see Excipients,p. 2)Heparin Sodium (Baxter) AIntravenous Infusion, heparin sodium 1 unit/mL, insodium chloride intravenous infusion 0.9%, net price500–mL (500-unit) Viaflex c bag = £4.87Heparin Calcium (Non-proprietary) AInjection, heparin calcium 25 000 units/mL, net price0.2-mL amp = £2.61Low molecular weight heparinsDalteparin, enoxaparin, and tinzaparin are low molecularweight heparins used for treatment and prophylaxisof thrombotic episodes in children (see also Heparin,p. 114). Their duration of action is longer than thatof unfractionated heparin and in adults and older childrenonce-daily subcutaneous dosage is sometimespossible; however, younger children require relativelyhigher doses (possibly due to larger volume of distribution,altered heparin pharmacokinetics, or lower plasmaconcentrations of antithrombin) and twice daily dosageis sometimes necessary. Low molecular weight heparinsare convenient to use, especially in children with poorvenous access. Routine monitoring of anti-Factor Xaactivity is not usually required except in neonates;monitoring may also be necessary in severely ill childrenand those with renal or hepatic impairment.Haemorrhage See under Heparin.Hepatic impairment Reduce dose in severe impairment—riskof bleeding may be increased.Pregnancy Not known to be harmful, low molecularweight heparins do not cross the placenta; see alsoHeparin, p. 115.Breast-feeding Due to the relatively high molecularweight of these drugs and inactivation in the gastrointestinaltract, passage into breast-milk and absorptionby the nursing infant are likely to be negligible; howevermanufacturers advise avoid.DALTEPARIN SODIUMCautions see under Heparin and notes aboveContra-indications see under HeparinHepatic impairment see notes aboveRenal impairment risk of bleeding may beincreased—dose reduction and monitoring of anti-Factor Xa may be required; use of unfractionatedheparin may be preferablePregnancy see notes above; also multidose vial containsbenzyl alcohol—manufacturer advises avoidBreast-feeding see notes aboveSide-effects see under HeparinLicensed use not licensed for use in childrenIndication and doseTreatment of thrombotic episodes. By subcutaneous injectionNeonate 100 units/kg twice dailyChild 1 month–12 years 100 units/kg twice dailyChild 12–18 years 200 units/kg (max.18 000 units) once daily, if increased risk of bleedingreduced to 100 units/kg twice dailyTreatment of venous thromboembolism inpregnancy. By subcutaneous injectionChild 12–18 years early pregnancy body-weightunder 50 kg, 5000 units twice daily; body-weight50–70 kg, 6000 units twice daily; body-weight 70–90 kg, 8000 units twice daily; body-weight over90 kg, 10 000 units twice dailyProphylaxis of thrombotic episodes. By subcutaneous injectionNeonate 100 units/kg once dailyChild 1 month–12 years 100 units/kg once dailyChild 12–18 years 2500–5000 units once dailyFragmin c (Pharmacia) AInjection (single-dose syringe), dalteparin sodium12 500 units/mL, net price 2500-unit (0.2-mL) syringe= £1.86; 25 000 units/mL, 5000-unit (0.2-mL) syringe= £2.82, 7500-unit (0.3-mL) syringe = £4.23, 10 000-unit (0.4-mL) syringe = £5.65, 12 500-unit (0.5-mL)syringe = £7.06, 15 000-unit (0.6-mL) syringe = £8.47,18 000-unit (0.72-mL) syringe = £10.16Injection, dalteparin sodium 2500 units/mL (for subcutaneousor intravenous use), net price 4-mL(10 000-unit) amp = £5.12; 10 000-units/mL (for subcutaneousor intravenous use), 1-mL (10 000-unit)amp = £5.12; 25 000 units/mL (for subcutaneous useonly), 4-mL (100 000-unit) vial = £48.66Excipients include benzyl alcohol (in 100 000-unit/4 mL multidose vial)(avoid in neonates, see, p. 2)Injection (graduated syringe), dalteparin sodium10 000 units/mL, net price 1-mL (10 000-unit) syringe= £5.65ENOXAPARIN SODIUMCautions see under Heparin and notes aboveContra-indications see under HeparinHepatic impairment see notes aboveRenal impairment risk of bleeding may be increased;reduce dose if estimated glomerular filtration rate lessthan 30 mL/minute/1.73 m 2 ; monitoring of anti-FactorXa may be required; use of unfractionated heparinmay be preferablePregnancy see notes above

BNFC 2011–2012 2.8.1 Parenteral anticoagulants 117Breast-feeding see notes aboveSide-effects see under HeparinLicensed use not licensed for use in childrenIndication and doseTreatment of thrombotic episodes. By subcutaneous injectionNeonate 1.5–2 mg/kg twice dailyChild 1–2 months 1.5 mg/kg twice dailyChild 2 months–18 years 1 mg/kg twice dailyTreatment of venous thromboembolism inpregnancy. By subcutaneous injectionChild 12–18 years early pregnancy body-weightunder 50 kg, 40 mg (4000 units) twice daily; bodyweight50–70 kg, 60 mg (6000 units) twice daily;body-weight 70–90 kg, 80 mg (8000 units) twicedaily; body-weight over 90 kg, 100 mg(10 000 units) twice dailyProphylaxis of thrombotic episodes. By subcutaneous injectionNeonate 750 micrograms/kg twice dailyChild 1–2 months 750 micrograms/kg twice dailyChild 2 months–18 years 500 micrograms/kgtwice daily; max. 40 mg dailyClexane c (Sanofi-Aventis) AInjection, enoxaparin sodium 100 mg/mL, net price20-mg (0.2-mL, 2000-units) syringe = £3.03, 40-mg(0.4-mL, 4000-units) syringe = £4.04, 60-mg (0.6-mL,6000-units) syringe = £4.57, 80-mg (0.8-mL, 8000-units) syringe = £6.49, 100-mg (1-mL, 10 000-units)syringe = £8.04, 300-mg (3-mL, 30 000-units) vial(Clexane c Multi-Dose) = £21.33; 150 mg/mL(Clexane c Forte), 120-mg (0.8-mL, 12 000-units)syringe = £9.77, 150-mg (1-mL, 15 000-units) syringe= £11.10Excipients include benzyl alcohol (in 300 mg multidose vials) (avoid inneonates, see, p. 2)TINZAPARIN SODIUMCautions see under Heparin and notes aboveContra-indications see under HeparinHepatic impairment see notes aboveRenal impairment risk of bleeding may beincreased—dose reduction and monitoring of anti-Factor Xa may be required; unfractionated heparinmay be preferablePregnancy see notes above; also vials contain benzylalcohol—manufacturer advises avoidBreast-feeding see notes aboveSide-effects see under HeparinLicensed use not licensed for use in childrenIndication and doseTreatment of thrombotic episodes. By subcutaneous injectionChild 1–2 months 275 units/kg once dailyChild 2 months–1 year 250 units/kg once dailyChild 1–5 years 240 units/kg once dailyChild 5–10 years 200 units/kg once dailyChild 10–18 years 175 units/kg once dailyTreatment of venous thromboembolism inpregnancy. By subcutaneous injectionChild 12–18 years 175 units/kg once daily (basedon early pregnancy body-weight)Prophylaxis of thrombotic episodes. By subcutaneous injectionChild 1 month–18 years 50 units/kg once dailyInnohep c (LEO) AInjection, tinzaparin sodium 10 000 units/mL, netprice 2500-unit (0.25-mL) syringe = £1.98, 3500-unit(0.35-mL) syringe = £2.77, 4500-unit (0.45-mL)syringe = £3.56, 20 000-unit (2-mL) vial = £10.56Injection, tinzaparin sodium 20 000 units/mL, netprice 0.5-mL (10 000-unit) syringe = £8.46, 0.7-mL(14 000-unit) syringe = £11.85, 0.9-mL (18 000-unit)syringe = £15.23, 2-mL (40 000-unit) vial = £34.20Excipients include benzyl alcohol (in vials) (avoid in neonates, seeExcipients, p. 2), sulphites (in 20 000 units/mL vial and syringe)HeparinoidsDanaparoid is a heparinoid that has a role in childrenwho develop heparin-induced thrombocytopenia, providingthey have no evidence of cross-reactivity.DANAPAROID SODIUMCautions recent bleeding or risk of bleeding; concomitantuse of drugs that increase risk of bleeding;antibodies to heparins (risk of antibody-inducedthrombocytopenia)Contra-indications haemophilia and other haemorrhagicdisorders, thrombocytopenia (unless patienthas heparin-induced thrombocytopenia), recentcerebral haemorrhage, severe hypertension, activepeptic ulcer (unless this is the reason for operation),diabetic retinopathy, acute bacterial endocarditis,spinal or epidural anaesthesia with treatment doses ofdanaparoidHepatic impairment caution in moderate impairment(increased risk of bleeding); avoid in severe impairmentunless the child has heparin-induced thrombocytopeniaand no alternative availableRenal impairment use with caution in moderateimpairment; increased risk of bleeding (monitor anti-Factor Xa activity); avoid in severe impairment unlesschild has heparin-induced thrombocytopenia and noalternative availablePregnancy manufacturer advises avoid—limitedinformation available but not known to be harmfulBreast-feeding amount probably too small to beharmful but manufacturer advises avoidSide-effects haemorrhage; hypersensitivity reactions(including rash)Licensed use not licensed for use in childrenIndication and doseThromboembolic disease in children with historyof heparin-induced thrombocytopenia. By intravenous administrationNeonate initially 30 units/kg by intravenousinjection then by continuous intravenous infusion1.2–2 units/kg/hour adjusted according to coagulationactivity2 Cardiovascular system

118 2.8.2 Oral anticoagulants BNFC 2011–20122 Cardiovascular systemChild 1 month–16 years initially 30 units/kg(max. 1250 units if body-weight under 55 kg,2500 units if over 55 kg) by intravenous injectionthen by continuous intravenous infusion 1.2–2 units/kg/hour adjusted according to coagulationactivityChild 16–18 years initially 2500 units (1250 unitsif body-weight under 55 kg, 3750 units if over90 kg) by intravenous injection then by continuousintravenous infusion 400 units/hour for 2 hours,then 300 units/hour for 2 hours, then 200 units/hour for 5 days adjusted according to coagulationactivityAdministration for intravenous infusion, dilute withGlucose 5% or Sodium Chloride 0.9%Orgaran c (Organon) AInjection, danaparoid sodium 1250 units/mL, netprice 0.6-mL amp (750 units) = £26.68Heparin flushesThe use of heparin flushes should be kept to a minimum.For maintaining patency of peripheral venous catheters,sodium chloride 0.9% injection is as effective as heparinflushes. The role of heparin flushes in maintainingpatency of arterial and central venous catheters isunclear.Heparin Sodium (Non-proprietary) ASolution, heparin sodium 10 units/mL, net price 5-mL amp = £1.00; 100 units/mL, 2-mL amp = £1.05Excipients may include benzyl alcohol (avoid in neonates, see Excipients,p. 2)EpoprostenolEpoprostenol (prostacyclin) can be given to inhibitplatelet aggregation during renal dialysis when heparinsare unsuitable or contra-indicated. For its use in pulmonaryhypertension, see section 2.5.1.2. It is a potentvasodilator and therefore its side-effects include flushing,headache, and hypotension.2.8.2 Oral anticoagulantsOral anticoagulants antagonise the effects of vitamin Kand take at least 48 to 72 hours for the anticoagulanteffect to develop fully; if an immediate effect is required,unfractionated or low molecular weight heparin must begiven concomitantly.Uses Warfarin is the drug of choice for the treatment ofsystemic thromboembolism in children (not neonates)after initial heparinisation. It may also be used occasionallyfor the treatment of intravascular or intracardiacthrombi. Warfarin is used prophylactically in those withchronic atrial fibrillation, dilated cardiomyopathy, certainforms of reconstructive heart surgery, mechanicalprosthetic heart valves, and some forms of hereditarythrombophilia (e.g. homozygous protein C deficiency).Unfractionated or a low molecular weight heparin (section2.8.1) is usually preferred for the prophylaxis ofvenous thromboembolism in children undergoing surgery;alternatively warfarin can be continued in selectedchildren currently taking warfarin and who are at a highrisk of thromboembolism (seek expert advice).Dose The base-line prothrombin time should be determinedbut the initial dose should not be delayed whilstawaiting the result.An induction dose is usually given over 4 days (seeunder Warfarin Sodium below). The subsequent maintenancedose depends on the prothrombin time,reported as INR (international normalised ratio) andshould be taken at the same time each day. The followingindications and target INRs 1 for adults take intoaccount recommendations of the British Society forHaematology 2 ;. INR 2.5 for treatment of deep-vein thrombosis andpulmonary embolism (including those associatedwith antiphospholipid syndrome or for recurrencein patients no longer receiving warfarin), for atrialfibrillation, cardioversion (higher target values, suchas an INR of 3, can be used for up to 4 weeks beforethe procedure to avoid cancellations due to lowINR; anticoagulation should continue for at least 4weeks following the procedure), dilated cardiomyopathy,mural thrombus, symptomatic inheritedthrombophilia, coronary artery thrombosis (if anticoagulated),and paroxysmal nocturnal haemoglobinuria;. INR 3.5 for recurrent deep-vein thrombosis andpulmonary embolism (in patients currently receivingwarfarin with INR above 2);. For mechanical prosthetic heart valves, the recommendedtarget INR depends on the type and locationof the valve. Generally, a target INR of 3 isrecommended for mechanical aortic valves, and 3.5for mechanical mitral valves.Monitoring It is essential that the INR be determineddaily or on alternate days in early days of treatment,then at longer intervals (depending on response 3 ) thenup to every 12 weeks.Haemorrhage The main adverse effect of all oralanticoagulants is haemorrhage. Checking the INR andomitting doses when appropriate is essential; if theanticoagulant is stopped but not reversed, the INRshould be measured 2–3 days later to ensure that it isfalling. The following recommendations are based onthe result of the INR and whether there is major orminor bleeding; the recommendations apply to adultstaking warfarin:. Major bleeding—stop warfarin; give phytomenadione(vitamin K 1 ) 5–10 mg by slow intravenousinjection; give dried prothrombin complex (factorsII, VII, IX, and X—section 2.11) 30–50 units/kg (if1. An INR which is within 0.5 units of the target value isgenerally satisfactory; larger deviations require dosageadjustment. Target values (rather than ranges) are nowrecommended.2. Guidelines on Oral Anticoagulation (warfarin): thirdedition—2005 update. Br J Haematol 2005; 132: 277–285.3. Change in child’s clinical condition, particularly associatedwith liver disease, intercurrent illness, or drug administration,necessitates more frequent testing. See also interactions,Appendix 1 (warfarin). Major changes in diet(especially involving salads and vegetables) and in alcoholconsumption may also affect warfarin control.

BNFC 2011–2012 2.8.2 Oral anticoagulants 119dried prothrombin complex unavailable, fresh frozenplasma 15 mL/kg can be given but is lesseffective). INR > 8.0, no bleeding or minor bleeding—stopwarfarin and give phytomenadione (vitamin K 1 )2.5–5 mg by mouth using the intravenous preparationorally [unlicensed use], or 0.5–1 mg by slowintravenous injection (if complete reversal required5–10 mg by slow intravenous injection); repeat doseof phytomenadione if INR still too high after 24hours; restart warfarin when INR < 5.0. INR 5.0–8.0, no bleeding—stop warfarin; minorbleeding—stop warfarin and give phytomenadione(vitamin K 1 ) 1–2.5 mg by mouth using the intravenouspreparation orally [unlicensed use]; restartwarfarin when INR < 5.0. Unexpected bleeding at therapeutic levels—alwaysinvestigate possibility of underlying cause e.g.unsuspected renal or gastro-intestinal tract pathologyPregnancy Oral anticoagulants are teratogenic andshould not be given in the first trimester of pregnancy.Adolescents at risk of pregnancy should be warned ofthis danger since stopping warfarin before the sixthweek of gestation may largely avoid the risk of fetalabnormality. Oral anticoagulants cross the placenta withrisk of congenital malformations, and placental, fetal, orneonatal haemorrhage, especially during the last fewweeks of pregnancy and at delivery. Therefore, if at allpossible, oral anticoagulants should be avoided inpregnancy, especially in the first and third trimesters.Difficult decisions may have to be made, particularly inthose with prosthetic heart valves or with a history ofrecurrent venous thrombosis, pulmonary embolism, oratrial fibrillation.Babies of mothers taking warfarin at the time of deliveryneed to be offered immediate prophylaxis with at least100 micrograms/kg of intramuscular phytomenadione(vitamin K 1 ), see section 9.6.6.Dietary differences Infant formula is supplementedwith vitamin K, which makes formula-fed infants resistantto warfarin; they may therefore need higher doses.In contrast breast milk contains low concentrations ofvitamin K making breast-fed infants more sensitive towarfarin.Treatment booklets Anticoagulant treatment bookletsshould be issued to children or their carers, and areavailable for distribution to local healthcare professionalsfrom Health Authorities and from:3M Security Printing and Systems LimitedGorse StreetChaddertonOldham, OL9 9QHTel: 0845 610 1112nhsforms@spsl.uk.comThese booklets include advice for children or theircarers on anticoagulant treatment, an alert card to becarried by the patient at all times, and a section forrecording of INR results and dosage information. Electroniccopies are also available at www.npsa.nhs.uk/nrls/alerts-and-directives/alerts/anticoagulant.WARFARIN SODIUMCautions see notes above; also recent surgery; recentischaemic stroke; history of gastro-intestinal bleeding;peptic ulcer; concomitant use of drugs that increaserisk of bleeding; bacterial endocarditis (increased riskof bleeding; use only if warfarin otherwise indicated);avoid cranberry juice; interactions: Appendix 1(warfarin)Contra-indications haemorrhagic stroke; significantbleeding; avoid use within 48 hours postpartumHepatic impairment avoid in severe impairment,especially if prothrombin time already prolongedRenal impairment use with caution (avoid in severeimpairment)Pregnancy see notes aboveBreast-feeding not present in milk in significantamounts; no evidence of harm; see also notes aboveSide-effects haemorrhage—see notes above; alsonausea, vomiting, diarrhoea, jaundice, hepatic dysfunction,pancreatitis, pyrexia, alopecia, purpura,rash, ‘purple toes’, skin necrosis (increased risk inpatients with protein C or protein S deficiency)Licensed use not licensed for use in childrenIndication and doseTreatment and prophylaxis of thrombotic episodes. By mouthNeonate (under specialist advice) 200 micrograms/kgas a single dose on first day, reduced to100 micrograms/kg once daily for following 3 days(but if INR still below 1.4 use 200 micrograms/kgonce daily, or if INR above 3 use 50 micrograms/kg once daily, if INR above 3.5 omit dose); thenadjusted according to INR, usual maintenance100–300 micrograms/kg once daily (may need upto 400 micrograms/kg once daily especially ifbottle fed—see notes above)Child 1 month–18 years 200 micrograms/kg(max. 10 mg) as a single dose on first day, reducedto 100 micrograms/kg (max. 5 mg) once daily forfollowing 3 days (but if INR still below 1.4 use200 micrograms/kg (max. 10 mg) once daily, or ifINR above 3 use 50 micrograms/kg (max. 2.5 mg)once daily, or if INR above 3.5 omit dose); thenadjusted according to INR, usual maintenance100–300 micrograms/kg once daily (may need upto 400 micrograms/kg once daily especially ifbottle fed—see notes above)Note Induction dose may need to be altered according tocondition (e.g. abnormal liver function tests, cardiacfailure), concomitant interacting drugs, and if baselineINR above 1.3Warfarin (Non-proprietary) ATablets, warfarin sodium 500 micrograms (white), netprice 28-tab pack = £1.49; 1 mg (brown), 28-tab pack= 93p; 3 mg (blue), 28-tab pack = 95p; 5 mg (pink), 28-tab pack = £1.03. Label: 10, anticoagulant cardBrands include Marevan cOral suspension, warfarin sodium 5 mg/5 mL, netprice 150-mL = £90.00. Label: 10, anticoagulant cardExtemporaneous formulations available seeExtemporaneous Preparations, p. 62 Cardiovascular system

120 2.8.3 Protamine sulphate BNFC 2011–20122 Cardiovascular system2.8.3 Protamine sulphateProtamine sulphate is used to treat overdosage ofunfractionated or low molecular weight heparin. Thelong half-life of low molecular weight heparins shouldbe taken into consideration when determining the doseof protamine sulphate; the effects of low molecularweight heparins can persist for up to 24 hours afteradministration. Excessive doses of protamine sulphatecan have an anticoagulant effect.PROTAMINE SULPHATE(Protamine Sulfate)Cautions see above; also monitor activated partialthromboplastin time or other appropriate blood clottingparameters; if increased risk of allergic reaction toprotamine (includes previous treatment with protamineor protamine insulin, allergy to fish, and adolescentmales who are infertile)Side-effects nausea, vomiting, lassitude, flushing,hypotension, hypertension, bradycardia, dyspnoea,rebound bleeding, back pain; hypersensitivity reactions(including angioedema, anaphylaxis) and pulmonaryoedema reportedIndication and doseOverdosage with intravenous injection orintravenous infusion of unfractionated heparin. By intravenous injection (rate not exceeding5 mg/minute)Child 1 month–18 years to neutralise each100 units of unfractionated heparin, 1 mg if lessthan 30 minutes lapsed since overdose, 500–750 micrograms if 30–60 minutes lapsed, 375–500 micrograms if 60–120 minutes lapsed, 250–375 micrograms if over 120 minutes lapsed; max.50 mgOverdosage with subcutaneous injection ofunfractionated heparin. By intravenous injection and intravenous infusionChild 1 month–18 years 1 mg neutralises approx.100 units of unfractionated heparin; give 50–100%of the total dose by intravenous injection (rate notexceeding 5 mg/minute), then give any remainderof dose by intravenous infusion over 8–16 hours;max. total dose 50 mgOverdosage with subcutaneous injection of lowmolecular weight heparin. By intermittent intravenous injection (rate notexceeding 5 mg/minute) or by continuousintravenous infusionChild 1 month–18 years 1 mg neutralises approx.100 units low molecular weight heparin (consultproduct literature of low molecular weight heparinfor details); max. 50 mgAdministration may be diluted if necessary withSodium Chloride 0.9%Protamine Sulphate (Non-proprietary) AInjection, protamine sulphate 10 mg/mL, net price 5-mL amp = £1.43, 10-mL amp = £4.152.9 Antiplatelet drugsAntiplatelet drugs decrease platelet aggregation andinhibit thrombus formation in the arterial circulation,because in faster-flowing vessels, thrombi are composedmainly of platelets with little fibrin.Aspirin has limited use in children because it has beenassociated with Reye’s syndrome. Aspirin-containingpreparations should not be given to children and adolescentsunder 16 years, unless specifically indicated,such as for Kawasaki syndrome (see below), for prophylaxisof clot formation after cardiac surgery, or forprophylaxis of stroke in children at high risk.If aspirin causes dyspepsia, or if the child is at a high riskof gastro-intestinal bleeding, a proton pump inhibitor(section 1.3.5) or a H 2 -receptor antagonist (section1.3.1) can be added.Dipyridamole is also used as an antiplatelet drug toprevent clot formation after cardiac surgery and may beused with specialist advice for treatment of persistentcoronary artery aneurysms in Kawasaki syndrome.Kawasaki syndrome Initial treatment is with highdoseaspirin and a single dose of intravenous normalimmunoglobulin (p. 622); this combination has an additiveanti-inflammatory effect resulting in faster resolutionof fever and a decreased incidence of coronaryartery complications. After the acute phase, when thepatient is afebrile, aspirin is continued at a lower dose toprevent coronary artery abnormalities.ASPIRIN (antiplatelet)(Acetylsalicylic Acid)Cautions asthma; uncontrolled hypertension; previouspeptic ulceration (but manufacturers may adviseavoidance of low-dose aspirin in history of pepticulceration); concomitant use of drugs that increaserisk of bleeding; G6PD deficiency (section 9.1.5);interactions: Appendix 1 (aspirin)Contra-indications children under 16 years (risk ofReye’s syndrome) unless for indications below; activepeptic ulceration; haemophilia and other bleedingdisordersHypersensitivity Aspirin and other NSAIDs are contraindicatedin history of hypersensitivity to aspirin or anyother NSAID—which includes those in whom attacks ofasthma, angioedema, urticaria, or rhinitis have been precipitatedby aspirin or any other NSAIDHepatic impairment avoid in severe impairment—increased risk of gastro-intestinal bleedingRenal impairment use with caution (avoid in severeimpairment); sodium and water retention; deteriorationin renal function; increased risk of gastro-intestinalbleedingPregnancy use with caution during third trimester;impaired platelet function and risk of haemorrhage;delayed onset and increased duration of labour withincreased blood loss; avoid analgesic doses if possiblein last few weeks (low doses probably not harmful);with high doses, closure of fetal ductus arteriosus inutero and possibly persistent pulmonary hypertensionof newborn; kernicterus in jaundiced neonatesBreast-feeding avoid—possible risk of Reye’ssyndrome; regular use of high doses could impairplatelet function and produce hypoprothrombinaemiain infant if neonatal vitamin K stores low

BNFC 2011–2012 2.10 Myocardial infarction and fibrinolysis 121Side-effects bronchospasm; gastro-intestinalhaemorrhage (occasionally major), also otherhaemorrhage (e.g. subconjunctival)Licensed use Not licensed for use in children under16 yearsIndication and doseKawasaki syndrome. By mouthNeonate initially 8 mg/kg 4 times daily for 2 weeksor until afebrile, followed by 5 mg/kg once daily for6–8 weeks; if no evidence of coronary lesions after8 weeks, discontinue treatment or seek expertadviceChild 1 month–12 years initially 7.5–12.5 mg/kg4 times daily for 2 weeks or until afebrile, then 2–5 mg/kg once daily for 6–8 weeks; if no evidenceof coronary lesions after 8 weeks, discontinuetreatment or seek expert adviceAntiplatelet, prevention of thrombus formationafter cardiac surgery. By mouthNeonate 1–5 mg/kg once dailyChild 1 month–12 years 1–5 mg/kg (usual max.75 mg) once dailyChild 12–18 years 75 mg once dailyAspirin (Non-proprietary) ADispersible tablets, aspirin 75 mg, net price 28 =83p; 300 mg, 100-tab pack = £2.88 Label: 13, 21, 32Tablets, e/c, aspirin 75 mg, net price 28-tab pack =93p; 56-tab pack = £1.03; 300 mg, 100-tab pack =£5.29. Label: 5, 25, 32Brands include Micropirin cSuppositories, available from ‘special-order’ manufacturersor specialist importing companies, seep. 809Caprin c (Wockhardt) ATablets, e/c, pink, aspirin 75 mg, net price 28-tabpack = £1.51, 56-tab pack = £2.52. Label: 5, 25, 32Nu-Seals c Aspirin (Alliance) ATablets, e/c, aspirin 75 mg, net price 56-tab pack =£3.12; 300 mg, 100-tab pack = £4.15. Label: 5, 25, 32DIPYRIDAMOLECautions aortic stenosis, left ventricular outflowobstruction, heart failure; may exacerbate migraine;hypotension; myasthenia gravis (risk of exacerbation);concomitant use of drugs that increase risk of bleeding;coagulation disorders; interactions: Appendix 1(dipyridamole)Pregnancy not known to be harmfulBreast-feeding manufacturers advise use only ifessential—small amount present in milkSide-effects gastro-intestinal effects, dizziness, myalgia,throbbing headache, hypotension, hot flushes andtachycardia; hypersensitivity reactions such as rash,urticaria, severe bronchospasm and angioedema;increased bleeding during or after surgery; thrombocytopeniareportedLicensed use not licensed for use in childrenIndication and doseKawasaki syndrome. By mouthChild 1 month–12 years 1 mg/kg 3 times dailyPrevention of thrombus formation after cardiacsurgery. By mouthChild 1 month–12 years 2.5 mg/kg twice dailyChild 12–18 years 100–200 mg 3 times dailyAdministration injection solution can be given orallyDipyridamole (Non-proprietary) ATablets, coated, dipyridamole 25 mg, net price 84 =£3.11; 100 mg, 84 = £2.80. Label: 22Oral suspension, dipyridamole 50 mg/5 ml, net price150 mL = £40.63Persantin c (Boehringer Ingelheim) ATablets, s/c, dipyridamole, 100 mg, net price 84-tabpack = £4.16. Label: 22Injection, dipyridamole 5 mg/mL, net price 2-mLamp = 12p2.10 Myocardial infarction andfibrinolysis2.10.1 Management of myocardial infarction2.10.2 Fibrinolytic drugs2.10.1 Management ofmyocardial infarctionThis section is not included in BNF for Children.2.10.2 Fibrinolytic drugsFibrinolytic drugs act as thrombolytics by activatingplasminogen to form plasmin, which degrades fibrinand so breaks up thrombi.Alteplase, streptokinase, and urokinase are used inchildren to dissolve intravascular thrombi and unblockoccluded arteriovenous shunts, catheters, and indwellingcentral lines blocked with fibrin clots. Treatmentshould be started as soon as possible after a clot hasformed and discontinued once a pulse in the affectedlimb is detected, or the shunt or catheter unblocked.The safety and efficacy of treatment remains uncertain,especially in neonates. A fibrinolytic drug is probablyonly appropriate where arterial occlusion threatensischaemic damage; an anticoagulant may stop the clotgetting bigger. Alteplase is the preferred fibrinolytic inchildren and neonates; there is less risk of adverseeffects including allergic reactions.Cautions Thrombolytic drugs should be used withcaution if there is a risk of bleeding including thatfrom venepuncture or invasive procedures. They should2 Cardiovascular system

122 2.10.2 Fibrinolytic drugs BNFC 2011–20122 Cardiovascular systemalso be used with caution in external chest compression,pregnancy (see individual drugs), hypertension, otherconditions in which thrombolysis might give rise toembolic complications such as enlarged left atriumwith atrial fibrillation (risk of dissolution of clot andsubsequent embolisation), and recent or concurrentuse of drugs that increase the risk of bleeding.Contra-indications Thrombolytic drugs are contraindicatedin recent haemorrhage, trauma, or surgery(including dental extraction), coagulation defects, bleedingdiatheses, aortic dissection, aneurysm, coma, historyof cerebrovascular disease especially recent eventsor with any residual disability, recent symptoms ofpossible peptic ulceration, heavy vaginal bleeding,severe hypertension, active pulmonary disease withcavitation, acute pancreatitis, pericarditis, bacterialendocarditis, severe liver disease, and oesophageal varices;also in the case of streptokinase, previous allergicreactions to streptokinase.Prolonged persistence of antibodies to streptokinasecan reduce the effectiveness of subsequent treatment;therefore, streptokinase should not be used againbeyond 4 days of first administration. Streptokinaseshould also be avoided in children who have had streptococcalinfection in the last 12 months.Hepatic impairment Thrombolytic drugs should beavoided in severe hepatic impairment as there is anincreased risk of bleeding.Pregnancy Thrombolytic drugs can possibly lead topremature separation of the placenta in the first 18weeks of pregnancy. There is also a risk of maternalhaemorrhage throughout pregnancy and post-partum,and also a theoretical risk of fetal haemorrhage throughoutpregnancy.Side-effects Side-effects of thrombolytics are mainlybleeding, nausea, and vomiting. Reperfusion can causecerebral and pulmonary oedema. Hypotension can alsooccur and can usually be controlled by elevating thepatient’s legs, or by reducing the rate of infusion orstopping it temporarily. Back pain, fever, and convulsionshave been reported. Bleeding is usually limitedto the site of injection, but intracerebral haemorrhage orbleeding from other sites can occur. Serious bleedingcalls for discontinuation of the thrombolytic and mayrequire administration of coagulation factors and antifibrinolyticdrugs (e.g. tranexamic acid). Thrombolyticscan cause allergic reactions (including rash, flushing anduveitis) and anaphylaxis has been reported (for details ofmanagement see Allergic Emergencies, section 3.4.3).Guillain-Barré syndrome has been reported rarely afterstreptokinase treatment.ALTEPLASE(rt-PA, tissue-type plasminogen activator)Cautions see notes above; in children who have hadan acute stroke, monitor for intracranial haemorrhageand monitor blood pressureContra-indications see notes above; in children whohave had an acute stroke, convulsion accompanyingstroke, severe stroke, history of stroke in children withdiabetes, stroke in last 3 months, hypoglycaemia,hyperglycaemiaHepatic impairment see notes abovePregnancy see notes aboveSide-effects see notes above; also risk of cerebralbleeding increased in acute strokeLicensed use not licensed for use in childrenIndication and doseIntravascular thrombosis doses may vary—consultlocal guidelines. By intravenous infusionNeonate 100–500 micrograms/kg/hour for 3–6hours; use ultrasound assessment to monitor effectbefore considering a second course of treatmentChild 1 month–18 years 100–500 micrograms/kg/hour for 3–6 hours; max. 100 mg total dailydose; use ultrasound assessment to monitor effectbefore considering a second course of treatmentOccluded arteriovenous shunts, catheters, andindwelling central lines. By injection direct into catheter or central lineChild 1 month–18 years using 1 mg/mL solution,instill up to 2 mL according to dead-space ofcatheter or central line; aspirate lysate after 4hours; flush with Sodium Chloride 0.9%Administration for intravenous infusion, dissolve inWater for Injections to a concentration of 1 mg/mL or2 mg/mL and infuse intravenously; alternativelydilute further in Sodium Chloride 0.9% to a concentrationof not less than 200 micrograms/mL; not to bediluted in GlucoseActilyse c (Boehringer Ingelheim) AInjection, powder for reconstitution, alteplase 10 mg(5.8 million units)/vial, net price per vial (with diluent)= £120.00; 20 mg (11.6 million units)/vial (with diluentand transfer device) = £180.00; 50 mg (29 million -units)/vial (with diluent, transfer device, and infusionbag) = £300.00STREPTOKINASECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes abovePregnancy see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under18 yearsIndication and doseIntravascular thrombosis. By intravenous infusionChild 1 month–12 years initially 2500–4000 units/kg over 30 minutes, followed by continuousintravenous infusion of 500–1000 units/kg/hour for up to 3 days until reperfusion occursChild 12–18 years initially 250 000 units over 30minutes, followed by continuous intravenousinfusion of 100 000 units/hour for up to 3 daysuntil reperfusion occursAdministration reconstitute with Sodium Chloride0.9%, then dilute further with Glucose 5% or SodiumChloride 0.9% after reconstitution. Monitor fibrinogenconcentration closely; if fibrinogen concentration lessthan 1 g/litre, stop streptokinase infusion and startunfractionated heparin; restart streptokinase oncefibrinogen concentration reaches 1 g/litre

BNFC 2011–2012 2.11 Antifibrinolytic drugs and haemostatics 123Streptase c (CSL Behring) AInjection, powder for reconstitution, streptokinase,net price 250 000-unit vial = £15.91; 750 000-unit vial= £41.72; 1.5 million-unit vial = £83.44 (hosp. only)UROKINASECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes abovePregnancy see notes aboveSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseOccluded arteriovenous shunts, catheters, andindwelling central lines. By injection directly into catheter or central lineNeonate 5000–10 000 units in sodium chloride0.9% to fill catheter dead-space only; leave for 2–4hours then aspirate the lysate; flush with sodiumchloride 0.9%Child 1 month–18 years 5000–10 000 units insodium chloride 0.9% to fill catheter dead-spaceonly; leave for 2–4 hours then aspirate the lysate;flush with sodium chloride 0.9%Administration may be diluted, after reconstitution,with Sodium Chloride 0.9%Syner-KINASE c (Syner-Med) AInjection, powder for reconstitution, urokinase, netprice 10 000-unit vial = £35.95; 25 000-unit vial =£45.95; 100 000-unit vial = £112.95Note 50 000-unit vial and 250 000-unit vial also availablefrom ‘special-order’ manufacturers or specialist importingcompanies, see p. 8092.11 Antifibrinolytic drugs andhaemostaticsFibrin dissolution can be impaired by the administrationof tranexamic acid, which inhibits fibrinolysis. It can beused to prevent bleeding or treat bleeding associatedwith excessive fibrinolysis (e.g. in prostatectomy,bladder surgery, in dental extraction in children withhaemophilia, and in traumatic hyphaema) and in themanagement of menorrhagia, it may also be used inhereditary angioedema (section 3.4.3), epistaxis, andthrombolytic overdose. Tranexamic acid can also beused in cardiac surgery to reduce blood loss and toreduce the need for use of blood products.Desmopressin (section 6.5.2) is used in the managementof mild to moderate haemophilia and von Willebrands’disease. It is also used for testing fibrinolyticresponse.TRANEXAMIC ACIDCautions massive haematuria (avoid if risk of uretericobstruction); not for use in disseminated intravascularcoagulation; before initiating treatment for menorrhagia,exclude structural or histological causes orfibroids causing distortion of uterine cavity; irregularmenstrual bleeding (establish cause before initiatingtherapy); regular liver function tests in long-termtreatment of hereditary angioedemaContra-indications thromboembolic disease; historyof convulsionsRenal impairment reduce dose in mild to moderateimpairment; avoid in severe impairmentPregnancy no evidence of teratogenicity in animalstudies; manufacturer advises use only if potentialbenefit outweighs risk—crosses the placentaBreast-feeding small amount present in milk—antifibrinolyticeffect in infant unlikelySide-effects nausea, vomiting, diarrhoea (reducedose); rarely disturbances in colour vision (discontinue),thromboembolic events, convulsions, allergicskin reactions; dizziness and hypotension on rapidintravenous injectionLicensed use not licensed for reduction of bloodloss during cardiac surgeryIndication and doseInhibition of fibrinolysis, hereditary angioedema. By mouthChild 1 month–18 years 15–25 mg/kg (max.1.5 g) 2–3 times daily. By intravenous injection over at least 10 minutesChild 1 month–18 years 10 mg/kg (max. 1 g) 2–3times daily. By continuous intravenous infusionChild 1 month–18 years 45 mg/kg over 24 hoursPrevention of excessive bleeding after dentalprocedures (e.g. in haemophilia). By intravenous injection pre-operativelyChild 6–18 years 10 mg/kg (max. 1.5 g). By mouth pre-operativelyChild 6–18 years 15–25 mg/kg (max. 1.5 g). By mouth postoperativelyChild 6–18 years 15–25 mg/kg (max. 1.5 g) 2–3times daily for up to 8 days. Mouthwash 5% solution (specialist use only)Child 6–18 years rinse mouth with 5–10 mL 4times daily for 2 days; not to be swallowedNote Mouthwash available only as extemporaneouslyprepared preparation, see Extemporaneous Preparations,p. 6Menorrhagia. By mouthChild 12–18 years 1 g 3 times daily for up to 4days; max. 4 g daily (initiate when menstruationhas started)Reduction of blood loss during cardiac surgeryconsult local protocolAdministration for intravenous administration, dilutewith Glucose 5% or Sodium Chloride 0.9%Tranexamic acid (Non-proprietary) ATablets, tranexamic acid 500 mg, net price 60-tabpack = £5.272 Cardiovascular system

124 2.11 Antifibrinolytic drugs and haemostatics BNFC 2011–20122 Cardiovascular systemCyklokapron c (Meda) ATablets, f/c, scored, tranexamic acid 500 mg, netprice 60-tab pack = £14.30Cyklokapron c (Pfizer) AInjection, tranexamic acid 100 mg/mL, net price 5-mL amp = £1.55Blood productsThese products should be used on the advice of ahaematologist.DRIED PROTHROMBIN COMPLEX(Human Prothrombin Complex)Dried prothrombin complex is prepared from human plasma bya suitable fractionation technique, and contains factor IX,together with variable amounts of factors II, VII, and XCautions risk of thrombosis; disseminated intravascularcoagulation; history of myocardial infarction orcoronary heart disease; postoperative use; vaccinationagainst hepatitis A (p. 607) and hepatitis B(p. 608) may be requiredContra-indications angina; recent myocardial infarction(except in life-threatening haemorrhage followingoverdosage of oral anticoagulants, and before inductionof fibrinolytic therapy); history of heparininducedthrombocytopeniaHepatic impairment monitor closely (risk of thromboemboliccomplications)Side-effects thrombotic events (including disseminatedintravascular coagulation); rarely headache;very rarely pyrexia, antibody formation, hypersensitivityreactions (including anaphylaxis); nephroticsyndrome also reportedIndication and doseTreatment and peri-operative prophylaxis ofhaemorrhage in congenital deficiency of factorsII, VII, IX, or X if purified specific coagulationfactors not available, treatment and perioperativeprophylaxis of haemorrhage inacquired deficiency of factors II, VII, IX, or X(e.g. during warfarin treatment—see section2.8.2)Consult haematologistAvailable from CSL Behring (Beriplex c P/N), Octapharma(Octaplex c )FACTOR VIIa (RECOMBINANT)Eptacog alfa (activated)Cautions risk of thrombosis or disseminated intravascularcoagulationSide-effects very rarely nausea, thrombotic events(including myocardial infarction and cerebrovascularaccident), coagulation disorders, fever, pain, andallergic reactions including rashIndication and doseTreatment and prophylaxis of haemorrhage inhaemophilia A or B with inhibitors to factorsVIII or IX, acquired haemophilia, factor VIIdeficiency, or Glanzmann’s thrombastheniaConsult haematologistAvailable from Novo Nordisk (NovoSeven c T)FACTOR VIII FRACTION, DRIED(Human Coagulation Factor VIII, Dried)Dried factor VIII fraction is prepared from human plasma by asuitable fractionation technique; it may also contain varyingamounts of von Willebrand factorCautions monitor for development of factor VIII inhibitors;intravascular haemolysis after large or frequentlyrepeated doses in patients with blood groupsA, B, or AB—less likely with high potency concentrates;vaccination against hepatitis A (p. 607) andhepatitis B (p. 608) may be required (not necessarywith recombinant preparation)Side-effects gastro-intestinal disturbances, taste disturbances;flushing, palpitation; dyspnoea, coughing;headache, dizziness, paraesthesia, drowsiness; blurredvision; antibody formation; hypersensitivity reactionsincluding hypotension, angioedema, chills, fever,urticaria, and anaphylaxisIndication and doseTreatment and prophylaxis of haemorrhage incongenital factor VIII deficiency (haemophiliaA), acquired factor VIII deficiency, or von Willebrand’sdiseaseConsult haematologistAvailable from Biotest UK (Haemoctin c T), CSL Behring(Haemate c P), BPL (Optivate c ; 8Y c ), Grifols (Alphanate c ;Fanhdi c ), Octapharma (Octanate c ; Wilate c T);Haemoctin c , Optivate c , Fanhdi c , and Octanate c are notindicated for use in von Willebrand’s diseaseNote Preparation of recombinant human coagulation factorVIII (octocog alfa) available from CSL Behring (Helixate cNexGen), Baxter (Advate c ), Bayer Schering(Kogenate cBayer); preparation of recombinant human coagulationfactor VIII (moroctocog alfa) available from Wyeth (ReFactoAF c T); octocog alfa and moroctocog alfa are not indicatedfor use in von Willebrand’s diseaseFACTOR VIII INHIBITOR BYPASSINGFRACTIONPreparations with factor VIII inhibitor bypassing activity areprepared from human plasmaCautions vaccination against hepatitis A (p. 607) andhepatitis B (p. 608) may be requiredContra-indications disseminated intravascular coagulationSide-effects thrombosis, disseminated intravascularcoagulation, myocardial infarction; paraesthesia;pyrexia; hypersensitivity reactions including hypotension,flushing, urticaria, rash, and anaphylaxisIndication and doseTreatment and prophylaxis of haemorrhage incongenital factor VIII deficiency (haemophiliaA) and factor VIII inhibitors; treatment ofhaemorrhage in non-haemophiliac childrenwith acquired factor VIII inhibitorsConsult haematologistAvailable from Baxter (FEIBA c )FACTOR IX FRACTION, DRIEDDried factor IX fraction is prepared from human plasma by asuitable fractionation technique; it may also contain clottingfactors II, VII, and XCautions risk of thrombosis—principally with formerlow purity products; vaccination against hepatitis A(p. 607) and hepatitis B (p. 608) may be required (notnecessary with recombinant preparation)Contra-indications disseminated intravascular coagulation

BNFC 2011–2012 2.12 Lipid-regulating drugs 125Side-effects gastro-intestinal disturbances; headache,dizziness; allergic reactions including chills, feverIndication and doseTreatment and prophylaxis of haemorrhage incongenital factor IX deficiency (haemophilia B)Consult haematologistAvailable from CSL Behring (Mononine c ), BPL (Replenine c -VF, Dried Factor IX Fraction), Grifols (AlphaNine c )Note Preparation of recombinant coagulation factor IX(nonacog alfa) available from Wyeth (BeneFIX c )FACTOR XIII FRACTION, DRIED(Human Fibrin-stabilising Factor, Dried)Cautions vaccination against hepatitis A (p. 607) andhepatitis B (p. 608) may be requiredSide-effects rarely allergic reactions and feverIndication and doseCongenital factor XIII deficiencyConsult haematologistAvailable from CSL Behring (Fibrogammin c P)FRESH FROZEN PLASMAFresh frozen plasma is prepared from the supernatant liquidobtained by centrifugation of one donation of whole bloodCautions need for compatibility; vaccination againsthepatitis A (p. 607) and hepatitis B (p. 608) may berequiredContra-indications circulatory overload; avoid use asa volume expanderSide-effects allergic reactions including chills, fever,bronchospasm; acute respiratory distress syndromeIndication and doseReplacement of coagulation factors or otherplasma proteins where their concentration orfunctional activity is critically reducedConsult haematologistAvailable from Regional Blood Transfusion ServicesNote Children under 16 years should only receive virucidallyinactivated preparations of fresh frozen plasma, sourcedfrom ‘low prevalence BSE regions’ such as the USANote A preparation of solvent/detergent treated humanplasma (frozen) from pooled donors is available from Octapharma(Octaplas c )PROTEIN C CONCENTRATEProtein C is prepared from human plasmaCautions hypersensitivity to heparins; vaccinationagainst hepatitis A (p. 607) and hepatitis B (p. 608)may be requiredSide-effects very rarely fever, bleeding, dizziness, andhypersensitivity reactionsIndication and doseCongenital protein C deficiencyConsult haematologistAvailable from Baxter (Ceprotin c )2.12 Lipid-regulating drugsAtherosclerosis begins in childhood and raised serumcholesterolin children is associated with cardiovasculardisease in adulthood. Lowering the cholesterol, withouthindering growth and development in children andadolescents, should reduce the risk of cardiovasculardisease in later life.The risk factors for developing cardiovascular diseaseinclude raised serum cholesterol concentration,smoking, hypertension, impaired glucose tolerance,male sex, ethnicity, obesity, triglyceride concentration,chronic kidney disease, and a family history of cardiovasculardisease. Heterozygous familial hypercholesterolaemiais the most common cause of raisedserum cholesterol in children; homozygous familialhypercholesterolaemia is very rare and its specialisedmanagement is not covered in BNF for Children. Familialhypercholesterolaemia can lead to a greater risk ofearly coronary heart disease and should be managed bya specialist.Secondary causes of hypercholesterolaemia should beaddressed, these include obesity, diet, diabetes mellitus,hypothyroidism (see below), nephrotic syndrome,obstructive biliary disease, glycogen storage disease,and drugs such as corticosteroids.Management The aim of management of hypercholesterolaemiais to reduce the risk of atherosclerosiswhile ensuring adequate growth and development. Childrenwith hypercholesterolaemia (or their carers) shouldreceive advice on appropriate lifestyle changes such asimproved diet, increased exercise, weight reduction, andnot smoking; hypertension should also be managedappropriately (section 2.5). Drug therapy may also benecessary and is discussed below.Hypothyroidism Children with hypothyroidism shouldreceive adequate thyroid replacement therapy beforetheir requirement for lipid-regulating treatment isassessed because correction of hypothyroidism itselfmay resolve the lipid abnormality. Untreated hypothyroidismincreases the risk of myositis with lipidregulatingdrugs.Drug treatment in heterozygous familial hypercholesterolaemiaLifestyle modifications alone areunlikely to lower cholesterol concentration adequatelyin heterozygous familial hypercholesterolaemia anddrug treatment is often required. Lipid-regulatingdrugs should be considered by the age of 10 years.The decision to initiate drug treatment will depend onthe child’s age, the age of onset of coronary heartdisease within the family, and the presence of othercardiovascular risk factors. In children with a familyhistory of coronary heart disease in early adulthood,drug treatment before the age of 10 years, and acombination of lipid-regulating drugs may be necessary.Drug treatment in secondary hypercholesterolaemiaIf 6–12 months of dietary and other lifestyleinterventions has failed to lower cholesterol concentrationadequately, drug treatment may be indicated inchildren 10 years and older (rarely necessary in youngerchildren) who are at a high risk of developing cardiovasculardisease.Choice of drugs Experience in the use of lipidregulatingdrugs in children is limited and they shouldbe initiated on specialist advice.Statins are the drugs of first choice in children and aregenerally well tolerated; atorvastatin and simvastatinare the preferred statins. Other lipid-regulating drugscan be used if statins are ineffective or are not tolerated.2 Cardiovascular system

126 2.12 Lipid-regulating drugs BNFC 2011–20122 Cardiovascular systemEzetimibe can be used alone when statins are nottolerated, or in combination with a statin when a highdosestatin fails to control cholesterol concentrationadequately.Bile acid sequestrants are also available but tolerabilityof and compliance with these drugs is poor, and theiruse is declining.Evidence for the use of a fibrate (bezafibrate or fenofibrate)in children is limited; fibrates should be consideredonly if dietary intervention and treatment with astatin and a bile acid sequestrant is unsuccessful orcontra-indicated.In hypertriglyceridaemia which cannot be controlled byvery strict diet, omega-3 fatty acid compounds can beconsidered.StatinsThe statins (atorvastatin, fluvastatin, pravastatin,rosuvastatin and simvastatin) competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)reductase, an enzyme involved in cholesterol synthesis,especially in the liver. They are more effective thanother classes of drugs in lowering LDL-cholesterol butless effective than the fibrates in reducing triglycerides.Statins also increase concentrations of HDL-cholesterol.Statins reduce cardiovascular disease events and totalmortality in adults, irrespective of the initial cholesterolconcentration.Cautions Hypothyroidism should be managed adequatelybefore starting treatment with a statin (seeHypothyroidism, p. 125). Statins should be used withcaution in those with a history of liver disease or with ahigh alcohol intake—see also Hepatic Impairment,below. There is little information available on a rationalapproach to liver-function monitoring; however, a NICEguideline 1 suggests that liver enzymes should be measuredbefore treatment, and repeated within 3 monthsand at 12 months of starting treatment, unless indicatedat other times by signs or symptoms suggestive ofhepatotoxicity. Those with serum transaminases thatare raised, but less than 3 times the upper limit of thereference range, should not be routinely excluded fromstatin therapy. Those with serum transaminases of morethan 3 times the upper limit of the reference rangeshould discontinue statin therapy. Statins should beused with caution in those with risk factors for myopathyor rhabdomyolysis; children or their carers shouldbe advised to report unexplained muscle pain (seeMuscle Effects below). Creatine kinase concentrationshould be measured in children before treatment and ifunexplained muscle pain occurs. Statins should beavoided in acute porphyria (section 9.8.2). Interactions:Appendix 1 (statins).Hepatic impairment Statins should be used withcaution in those with a history of liver disease andavoided in active liver disease or when there are unexplainedpersistent elevations in serum transaminases.1. NICE clinical guideline 67 (May 2008). Lipid Modification—Cardiovascularrisk assessment and the modificationof blood lipids for the primary and secondary prevention ofcardiovascular diseasePregnancy Statins should be avoided in pregnancy ascongenital anomalies have been reported and thedecreased synthesis of cholesterol possibly affectsfetal development. Adequate contraception is requiredduring treatment and for 1 month afterwards.Breast-feeding The manufacturers of atorvastatin,fluvastatin, rosuvastatin, and simvastatin advise avoidinguse in mothers who are breast-feeding as there is noinformation available. The manufacturers of pravastatinadvise against use in breast-feeding mothers as a smallamount of drug is present in breast milk.Side-effects Statins can cause various muscular sideeffects,including myopathy, myositis, and rhabdomyolysis.Muscular effects are rare but often significant (seeMuscle Effects below). Statins can cause gastro-intestinaldisturbances, and very rarely pancreatitis. Theycan also cause altered liver function tests, and rarelyhepatitis and jaundice; hepatic failure has been reportedvery rarely. Other side-effects include sleep disturbance,headache, dizziness, depression, paraesthesia,hypoaesthesia, asthenia, peripheral neuropathy, amnesia,fatigue, sexual dysfunction, thrombocytopenia,arthralgia, visual disturbance, alopecia, and hypersensitivityreactions (including rash, pruritus, urticaria, andvery rarely lupus erythematosus-like reactions). In veryrare cases statins can cause interstitial lung disease; ifchildren develop symptoms such as dyspnoea, cough,and weight loss, they should seek medical attention.Muscle effects Myalgia, myositis, myopathy, and rarely rhabdomyolysishave been reported with the statins; if myopathy issuspected and creatine kinase is markedly elevated (more than5 times upper limit of reference range), or muscular symptomsare severe, treatment should be discontinued; in children atincreased risk of muscle effects, a statin should not be started ifcreatine kinase is elevated. Children at increased risk of myopathyinclude females and those with a personal or familyhistory of muscular disorders, previous history of musculartoxicity, those with a high alcohol intake, renal impairment,and, hypothyroidism (see Hypothyroidism, p. 125). There isalso an increased incidence of myopathy if a statin is given at ahigh dose or given with a fibrate, with lipid-lowering doses ofnicotinic acid, or with drugs that increase the plasma-statinconcentration, such as ciclosporin; close monitoring of liverfunction and, if symptomatic, of creatine kinase is required inchildren receiving these drugs. Rhabdomyolysis with acuterenal impairment secondary to myoglobinuria has also beenreported.Counselling Advise children or their carers to reportpromptly unexplained muscle pain, tenderness, orweakness.ATORVASTATINCautions see notes above; also haemorrhagic strokeHepatic impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also chest pain; backpain; pruritus; less commonly anorexia, malaise,weight gain, hypoglycaemia, hyperglycaemia, andtinnitus; rarely cholestatic jaundice and peripheraloedema; very rarely taste disturbances, gynaecomastia,hearing loss, Stevens-Johnson syndrome, andtoxic epidermal necrolysis

BNFC 2011–2012 2.12 Lipid-regulating drugs 127Indication and doseHyperlipidaemia including familial hypercholesterolaemia. By mouthChild 10–18 years initially 10 mg once daily,increased if necessary at intervals of at least 4weeks to usual max. 20 mg once daily (max. 80 mgonce daily in homozygous familial hypercholesterolaemia)Note Reduced dose required with concomitant ciclosporin,clarithromycin, or itraconazole—seek specialistadviceLipitor c (Pfizer) ATablets, all f/c, atorvastatin (as calcium trihydrate)10 mg, net price 28-tab pack = £13.00; 20 mg, 28-tabpack = £24.64; 40 mg, 28-tab pack = £24.64; 80 mg,28-tab pack = £28.21. Counselling, muscle effects, seenotes aboveFLUVASTATINCautions see notes aboveHepatic impairment see notes aboveRenal impairment manufacturer advises doses above40 mg daily should be initiated with caution if estimatedglomerular filtration rate is less than 30 mL/minute/1.73 m 2Pregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also very rarely vasculitisIndication and doseHeterozygous familial hypercholesterolaemia. By mouthChild 9–18 years initially 20 mg daily in theevening, adjusted in steps of 20 mg daily at intervalsof at least 6 weeks; max. 80 mg daily (40 mgtwice daily)Fluvastatin (Non-proprietary) ACapsules, fluvastatin (as sodium salt) 20 mg, net price28-cap pack = £5.03; 40 mg, 28-cap pack = £5.36.Counselling, muscle effects, see notes aboveLescol c (Novartis) ACapsules, fluvastatin (as sodium salt) 20 mg (brown/yellow), net price 28-cap pack = £15.26; 40 mg(brown/orange), 28-cap pack = £15.26, 56-cap pack =£30.53. Counselling, muscle effects, see notes aboveModified releaseFluvastatin (Non-proprietary) ATablets, m/r, fluvastatin (as sodium salt) 80 mg, netprice 28-tab pack = £19.20. Label: 25, counselling,muscle effects, see notes aboveDoseChild 9–18 years 80 mg once daily (dose form notappropriate for initial dose titration)Brands include Luvinsta c XL, Stefluvin c XLLescol c XL (Novartis) ATablets, m/r, yellow, fluvastatin (as sodium salt)80 mg, net price 28-tab pack = £19.20. Label: 25,counselling, muscle effects, see notes aboveDoseChild 9–18 years 80 mg once daily (dose form notappropriate for initial dose titration)PRAVASTATIN SODIUMCautions see notes aboveHepatic impairment see notes aboveRenal impairment start with lower doses in moderateto severe impairmentPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; less commonly abnormalurination (including dysuria, nocturia, and frequency);very rarely fulminant hepatic necrosisIndication and doseHyperlipidaemia including familial hypercholesterolaemia. By mouthChild 8–14 years 10 mg once daily at night,adjusted at intervals of at least 4 weeks to max.20 mg once daily at nightChild 14–18 years 10 mg once daily at night,adjusted at intervals of at least 4 weeks to max.40 mg once daily at nightPravastatin (Non-proprietary) ATablets, pravastatin sodium 10 mg, net price 28-tabpack = £1.72; 20 mg, 28-tab pack = £2.02; 40 mg, 28-tab pack = £2.78. Counselling, muscle effects, seenotes aboveLipostat c (Squibb) ATablets, all yellow, pravastatin sodium 10 mg, netprice 28-tab pack = £14.18; 20 mg, 28-tab pack =£26.01; 40 mg, 28-tab pack = £26.01. Counselling,muscle effects, see notes aboveROSUVASTATINCautions see notes above; children of Asian origin; uselower max. dose in children with risk factors formyopathy or rhabdomyolysis (including personal orfamily history of muscular disorders or toxicity)Hepatic impairment see notes aboveRenal impairment reduce dose if estimated glomerularfiltration rate less than 60 mL/minute/1.73 m 2 ;avoid if estimated glomerular filtration rate less than30 mL/minute/1.73 m 2Pregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also diabetes mellitus,proteinuria; very rarely haematuria; also reportedoedemaIndication and doseHyperlipidaemia including familial hypercholesterolaemia. By mouthChild 10–18 years initially 5 mg daily, increased ifnecessary at intervals of at least 4 weeks to usualmax. 20 mg once dailyNote Reduced dose required with concomitant fibrate—seek specialist adviceCrestor c (AstraZeneca) ATablets, f/c, rosuvastatin (as calcium salt) 5 mg (yellow),net price 28-tab pack = £18.03; 10 mg (pink), 28-tab pack = £18.03; 20 mg (pink), 28-tab pack = £26.02.Counselling, muscle effects, see notes above2 Cardiovascular system

128 2.12 Lipid-regulating drugs BNFC 2011–20122 Cardiovascular systemSIMVASTATINCautions see notes aboveHepatic impairment see notes aboveRenal impairment doses above 10 mg daily should beused with caution if estimated glomerular filtrationrate less than 30 mL/minute/1.73 m 2Pregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also rarely anaemiaLicensed use not licensed for use in children under10 yearsIndication and doseHyperlipidaemia including familial hypercholesterolaemia. By mouthChild 5–10 years initially 10 mg at nightincreased, if necessary, at intervals of at least 4weeks to max. 20 mg at nightChild 10–18 years initially 10 mg at nightincreased, if necessary, at intervals of at least 4weeks to max. 40 mg at nightNote Reduced dose required with concomitant ciclosporin,danazol, fibrates (except fenofibrate), amiodarone,diltiazem, or verapamil—seek specialist adviceSimvastatin (Non-proprietary) TATablets, simvastatin 10 mg, net price 28-tab pack =90p; 20 mg, 28-tab pack = £1.01; 40 mg, 28-tab pack =£1.32; 80 mg, 28-tab pack = £2.29. Counselling,muscle effects, see notes aboveBrands include Simvador cOral suspension, simvastatin 20 mg/5 mL, net price150-mL = £99.50, 40 mg/5 mL, 150-mL = £152.00.Counselling, muscle effects, see notes aboveExcipients may include propylene glycolZocor c (MSD) TATablets, all f/c, simvastatin 10 mg (peach), net price28-tab pack = £18.03; 20 mg (tan), 28-tab pack =£29.69; 40 mg (red), 28-tab pack = £29.69; 80 mg (red),28-tab pack = £29.69. Counselling, muscle effects, seenotes aboveBile acid sequestrantsColestyramine (cholestyramine) and colestipol are bileacid sequestrants used in the management of hypercholesterolaemia.They act by binding bile acids, preventingtheir reabsorption; this promotes hepatic conversionof cholesterol into bile acids; the resultantincreased LDL-receptor activity of liver cells increasesthe clearance of LDL-cholesterol from the plasma. Thusboth compounds effectively reduce LDL-cholesterol butcan aggravate hypertriglyceridaemia. Bile acid sequestrantsare not well tolerated and compliance with treatmentis poor, therefore they are rarely used in children.Cautions Bile acid sequestrants interfere with theabsorption of fat-soluble vitamins; supplements of vitaminsA, D, K, and folic acid may be required whentreatment is prolonged and the child’s growth anddevelopment should be monitored. Interactions:Appendix 1 (bile acid sequestrants).Pregnancy and breast-feeding Bile acid sequestrantsshould be used with caution as although the drugsare not absorbed, they may cause fat-soluble vitamindeficiency on prolonged use.Side-effects As bile acid sequestrants are notabsorbed, gastro-intestinal side-effects predominate.Constipation is common, but diarrhoea has occurred,as have nausea, vomiting, and gastro-intestinal discomfort.Hypertriglyceridaemia may be aggravated. Anincreased bleeding tendency has been reported due tohypoprothrombinaemia associated with vitamin K deficiency.Counselling Other drugs should be taken at least 1hour before or 4–6 hours after bile acid sequestrants toreduce possible interference with absorption.COLESTYRAMINE(Cholestyramine)Cautions see notes aboveContra-indications complete biliary obstruction (notlikely to be effective)Pregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; intestinal obstructionreported rarely and hyperchloraemic acidosisreported on prolonged useLicensed use licensed in children over 6 years toreduce cholesterol; see also section 1.9.2Indication and doseFamilial hypercholesterolaemia. By mouthChild 6–12 years initially 4 g once daily increasedto 4 g up to 3 times daily according to responseChild 12–18 years initially 4 g once dailyincreased by 4 g at weekly intervals to 12–24 gdaily in 1–4 divided doses, then adjusted accordingto response; max. 36 g dailyCholestatic pruritus section 1.9.2Diarrhoea section 1.9.2Administration The contents of each sachet should bemixed with at least 150 mL of water or other suitableliquid such as fruit juice, skimmed milk, thin soups,and pulpy fruits with a high moisture content; totaldaily dose may be given as a single dose if toleratedColestyramine (Non-proprietary) APowder, sugar-free, colestyramine (anhydrous) 4 g/sachet, net price 50-sachet pack = £18.34. Label: 13,counselling, avoid other drugs at same time (see notesabove)Excipients may include aspartame (section 9.4.1)Questran c (Bristol-Myers Squibb) APowder, colestyramine (anhydrous) 4 g/sachet, netprice 50-sachet pack = £10.76. Label: 13, counselling,avoid other drugs at same time (see notes above)Excipients include sucrose 3.79 g/sachetQuestran Light c (Bristol-Myers Squibb) APowder, sugar-free, colestyramine (anhydrous) 4 g/sachet, net price 50-sachet pack = £16.15. Label: 13,counselling, avoid other drugs at same time (see notesabove)Excipients include aspartame (section 9.4.1)

BNFC 2011–2012 2.12 Lipid-regulating drugs 129COLESTIPOL HYDROCHLORIDECautions see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseFamilial hypercholesterolaemia. By mouthChild 12–18 years initially 5 g 1–2 times dailyincreased if necessary in 5-g increments at intervalsof 1 month to max. of 30 g daily in 1–2 divideddosesAdministration the contents of each sachet should bemixed with at least 100 mL of water or other suitableliquid such as fruit juice or skimmed milk; alternativelyit can be mixed with thin soups, cereals,yoghurt, or pulpy fruits ensuring at least 100 mL ofliquid is provided; total daily dose may be given as asingle dose if toleratedColestid c (Pharmacia) AGranules, yellow, colestipol hydrochloride 5 g/sachet,net price 30 sachets = £15.05. Label: 13, counselling,avoid other drugs at same time (see notes above)Colestid Orange, granules, yellow/orange, colestipolhydrochloride 5 g/sachet, with aspartame, net price30 sachets = £15.05. Label: 13, counselling, avoidother drugs at same time (see notes above)EzetimibeEzetimibe inhibits the intestinal absorption of cholesterol.It is given in combination with a statin or alone if astatin is inappropriate. If ezetimibe is used in combinationwith a statin, there is an increased risk of rhabdomyolysis(see also Muscle Effects, p. 126)EZETIMIBECautions interactions: Appendix 1 (ezetimibe)Hepatic impairment avoid in moderate and severeimpairment—may accumulatePregnancy manufacturer advises use only if potentialbenefit outweighs risk—no information availableBreast-feeding manufacturer advises avoid—presentin milk in animal studiesSide-effects gastro-intestinal disturbances; headache,fatigue; myalgia; rarely arthralgia, hypersensitivityreactions (including rash, angioedema, and anaphylaxis),hepatitis; very rarely pancreatitis, cholelithiasis,cholecystitis, thrombocytopenia, raised creatinekinase, myopathy, and rhabdomyolysisIndication and doseAdjunct to dietary measures and statin treatmentin primary hypercholesterolaemia andhomozygous familial hypercholesterolaemia(ezetimibe alone in primary hypercholesterolaemiaif statin inappropriate or not tolerated);adjunct to dietary measures in homozygoussitosterolaemia. By mouthChild 10–18 years 10 mg once dailyEzetrol c (MSD, Schering-Plough) ATablets, ezetimibe 10 mg, net price 28-tab pack =£26.31FibratesBezafibrate and fenofibrate act mainly by decreasingserum triglycerides; they have variable effects on LDLcholesterol.Fibrates may reduce the risk of coronaryheart disease in those with low HDL-cholesterol or withraised triglycerides.Fibrates can cause a myositis-like syndrome, especiallyin children with impaired renal function. Also, combinationof a fibrate with a statin increases the risk of muscleeffects (especially rhabdomyolysis) and should be usedwith caution (see Muscle Effects, p. 126).There is limited evidence to support their use in childrenand they should only be considered if treatment with astatin and a bile acid sequestrant is unsuccessful orcontra-indicated.BEZAFIBRATECautions correct hypothyroidism before initiatingtreatment (see Hypothyroidism, p. 125); see underMyotoxicity below; interactions: Appendix 1(fibrates)Contra-indications hypoalbuminaemia, primarybiliary cirrhosis, gall bladder disease, nephroticsyndromeHepatic impairment avoid in severe liver diseaseRenal impairment reduce dose if estimated glomerularfiltration rate 15–60 mL/minute/1.73 m 2 ; avoidif estimated glomerular filtration rate less than 15 mL/minute/1.73 m 2Myotoxicity Special care needed in children with renaldisease, as progressive increases in serum-creatinine concentrationor failure to follow dosage guidelines may result inmyotoxicity (rhabdomyolysis); discontinue if myotoxicitysuspected or creatine kinase concentration increases significantlyPregnancy manufacturers advise avoid—embryotoxicityin animal studiesBreast-feeding manufacturer advises avoid—noinformation availableSide-effects gastro-intestinal disturbances, anorexia;less commonly cholestasis, weight gain, dizziness,headache, fatigue, drowsiness, renal impairment,raised serum creatinine (unrelated to renal impairment),erectile dysfunction, myotoxicity (with myastheniaor myalgia)—particular risk in renal impairment(see Cautions), urticaria, pruritus,photosensitivity reactions; very rarely gallstones,hypoglycaemia, anaemia, leucopenia, thrombocytopenia,increased platelet count, alopecia, Stevens-Johnson syndrome, and toxic epidermal necrolysisLicensed use not licensed for use in childrenIndication and doseHyperlipidaemia including familial hypercholesterolaemia(on specialist advice only). By mouthChild 10–18 years 200 mg once daily adjustedaccording to response to max. 200 mg 3 timesdaily2 Cardiovascular system

130 2.14 Drugs affecting the ductus arteriosus BNFC 2011–20122 Cardiovascular systemBezafibrate (Non-proprietary) ATablets, bezafibrate 200 mg, net price 100-tab pack =£6.86. Label: 21Bezalip c (Actavis) ATablets, f/c, bezafibrate 200 mg, net price 100-tabpack = £8.63. Label: 21FENOFIBRATECautions see under Bezafibrate; liver function testsrecommended every 3 months for first year (discontinuetreatment if significantly raised)Contra-indications gall bladder disease; photosensitivityto ketoprofenHepatic impairment avoid in severe impairmentRenal impairment reduce dose if estimated glomerularfiltration rate less than 60 mL/minute/1.73 m 2 ;avoid if estimated glomerular filtration rate less than15 mL/minute/1.73 m 2Myotoxicity Special care needed in patients with renaldisease, as progressive increases in serum-creatinine concentrationor failure to follow dosage guidelines may result inmyotoxicity (rhabdomyolysis); discontinue if myotoxicitysuspected or creatine kinase concentration increases significantlyPregnancy manufacturer advises avoid—embryotoxicityin animal studiesBreast-feeding manufacturer advises avoid—noinformation availableSide-effects see under Bezafibrate; also very rarelyhepatitis, pancreatitis, and interstitial pneumopathiesLicensed use Lipantil c Micro 67 is licensed for usein children with hypercholesterolaemiaIndication and doseHyperlipidaemias including familial hypercholesterolaemia(on specialist advice only). By mouthChild 4–15 years 1 capsule/20 kg body-weightdailyChild 15–18 years initially 3 capsules daily individed doses; usual range 2–4 capsules dailyLipantil c (Abbott Healthcare) ALipantil c Micro 67 capsules, yellow, fenofibrate(micronised) 67 mg, net price 90-cap pack = £23.30.Label: 212.13 Local sclerosantsClassification not used in BNF for Children.2.14 Drugs affecting theductus arteriosusarteriosus may increase the risk of intraventricularhaemorrhage, necrotising enterocolitis, bronchopulmonarydysplasia, and possibly death.Indometacin or ibuprofen can be used to close theductus arteriosus. Indometacin has been used formany years and is effective but it reduces cerebralblood flow, and causes a transient fall in renal andgastro-intestinal blood flow. Ibuprofen may also beused; it has little effect on renal function (there maybe a small reduction in sodium excretion) when used indoses for closure of the ductus arteriosus; gastro-intestinalproblems are uncommon.If drug treatment fails to close the ductus arteriosus,surgery may be indicated.IBUPROFENCautions may mask symptoms of infection; monitorfor bleeding; monitor gastro-intestinal function; allergicdisorders; interactions: Appendix 1 (NSAIDs)Contra-indications life-threatening infection; activebleeding especially intracranial or gastro-intestinal;thrombocytopenia or coagulation defects; markedunconjugated hyperbilirubinaemia; known or suspectednecrotising enterocolitis; pulmonary hypertensionHepatic impairment increased risk of gastro-intestinalbleeding and fluid retention; avoid in severe liverdiseaseRenal impairment use lowest effective dose andmonitor renal function; sodium and water retention;deterioration in renal function possibly leading torenal failure; avoid if possible in severe impairmentSide-effects intestinal perforation; intraventricularhaemorrhage; ischaemic brain injury; bronchopulmonarydysplasia, pulmonary haemorrhage; thrombocytopenia,neutropenia, oliguria, haematuria, fluidretention, hyponatraemia; less commonly gastrointestinalhaemorrhage; hypoxaemiaLicensed use Orphan licence for the injection forclosure of ductus arteriosus in premature neonatesless than 34 weeks gestational ageIndication and doseClosure of ductus arteriosus. By slow intravenous injectionNeonate initially 10 mg/kg as a single dose followedat 24-hour intervals by 2 doses of 5 mg/kg;course may be repeated after 48 hours if necessaryMild to moderate pain, pain and inflammationof soft tissue injuries and rheumatic disease,pyrexia section 10.1.1Administration for slow intravenous injection, giveover 15 minutes, preferably undiluted. May be dilutedwith Glucose 5% or Sodium Chloride 0.9%Pedea c (Orphan Europe) AIntravenous solution, ibuprofen 5 mg/mL, net price4 2-mL vials = £288.00Closure of the ductus arteriosusPatent ductus arteriosus is a frequent problem in prematureneonates with respiratory distress syndrome.Substantial left-to-right shunting through the ductusINDOMETACINCautions see notes above; also may mask symptomsof infection; may reduce urine output by 50% or more(monitor carefully—see also under Anuria or Oliguria,below) and precipitate renal impairment especially ifextracellular volume depleted, heart failure, sepsis, or

BNFC 2011–2012 2.14 Drugs affecting the ductus arteriosus 131concomitant use of nephrotoxic drugs; may inducehyponatraemia; inhibition of platelet aggregation(monitor for bleeding); interactions: Appendix 1(NSAIDs)Contra-indications untreated infection, bleeding(especially with active intracranial haemorrhage orgastro-intestinal bleeding); thrombocytopenia, coagulationdefects, necrotising enterocolitisHepatic impairment increased risk of gastro-intestinalbleeding and fluid retention; avoid in severeimpairmentRenal impairment use lowest effective dose andmonitor renal function; sodium and water retention;deterioration in renal function possibly leading torenal failure; avoid if possible in severe impairmentAnuria or oliguria If anuria or marked oliguria (urinaryoutput less than 0.6 mL/kg/hour), delay further doses untilrenal function returns to normalSide-effects haemorrhagic, renal, gastro-intestinal,metabolic, and coagulation disorders; pulmonaryhypertension, intracranial bleeding, fluid retention,and exacerbation of infectionIndication and doseSymptomatic ductus arteriosus. By intravenous infusion over 20–30 minutesNeonate initially 100–200 micrograms/kg as asingle dose followed by 2 doses of 100 micrograms/kgat 24-hour intervals; if residual patencypresent, give 100 micrograms/kg for a further 3doses at 24-hour intervalsNote Monitor carefully to ensure adequate urine output,see Anuria or Oliguria abovePain and inflammation in rheumatic diseasesection 10.1.1Administration for intravenous infusion, dilute eachvial with 1–2 mL Sodium Chloride 0.9% or Water forInjectionsIndometacin (Non-proprietary) AInjection, powder for reconstitution, indometacin (assodium trihydrate)Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809In the newborn with duct-dependent congenital heartdisease it is often necessary to maintain the patency ofthe ductus arteriosus whilst awaiting surgery.Alprostadil (prostaglandin E1) and dinoprostone (prostaglandinE2) are potent vasodilators that are effectivefor maintaining the patency of the ductus arteriosus.They are usually given by continuous intravenous infusion,but oral dosing of dinoprostone is still used in somecentres.During the infusion of a prostaglandin, the newbornrequires careful monitoring of heart rate, blood pressure,respiratory rate, and core body temperature. In theevent of complications such as apnoea, profound bradycardia,or severe hypotension, the infusion should betemporarily stopped and the complication dealt with;the infusion should be restarted at a lower dose. Recurrentor prolonged apnoea may require ventilatory supportin order for the prostaglandin infusion to continue.ALPROSTADILCautions see notes above; also history of haemorrhage;avoid in hyaline membrane disease; monitorarterial pressure, respiratory rate, heart rate, temperature,and venous blood pressure in arm and leg;facilities for intubation and ventilation must beimmediately available; interactions: Appendix 1(alprostadil)Side-effects apnoea (particularly in neonates under2 kg), flushing, bradycardia, hypotension, tachycardia,cardiac arrest, oedema, diarrhoea, fever, convulsions,disseminated intravascular coagulation, hypokalaemia;cortical proliferation of long bones; weakeningof the wall of the ductus arteriosus and pulmonaryartery may follow prolonged use; gastric-outletobstruction reportedIndication and doseMaintaining patency of the ductus arteriosus. By continuous intravenous infusionNeonate initially 5 nanograms/kg/minute,adjusted according to response in steps of 5 nanograms/kg/minute;max. 100 nanograms/kg/minute (but associated with increased side-effects)Note Alprostadil doses in BNFC may differ from those inproduct literatureAdministration dilute 150 micrograms/kg bodyweightto a final volume of 50 mL with Glucose 5% orSodium Chloride 0.9%; an intravenous infusion rate of0.1 mL/hour provides a dose of 5 nanograms/kg/minute. Undiluted solution must not come into contactwith the barrel of the plastic syringe; add therequired volume of alprostadil to a volume of infusionfluid in the syringe and then make up to final volumeProstin VR c (Pharmacia) AIntravenous solution, alprostadil 500 micrograms/mL in alcohol. For dilution and use as an infusion. Netprice 1–mL amp = £75.19 (hosp.only)2 Cardiovascular systemMaintenance of patencyDINOPROSTONECautions see notes above; also history of haemorrhage;avoid in hyaline membrane disease; monitorarterial oxygenation, heart rate, temperature, andblood pressure in arm and leg; facilities for intubationand ventilation must be immediately available; interactions:Appendix 1 (prostaglandins)Hepatic impairment manufacturer advises avoidRenal impairment manufacturer advises avoidSide-effects nausea, vomiting, diarrhoea; flushing,bradycardia, hypotension, cardiac arrest; respiratorydepression and apnoea, particularly with high dosesand in low birth-weight neonates, bronchospasm;pyrexia and raised white blood cell count, shivering;local reactions, erythema; if used for longer than 5days, gastric outlet obstruction; cortical hyperostosis(prolonged use)Licensed use not licensed for use in children

132 2.14 Drugs affecting the ductus arteriosus BNFC 2011–2012Indication and doseMaintaining patency of the ductus arteriosus. By continuous intravenous infusionNeonate initially 5 nanograms/kg/minute,increased as necessary in 5 nanogram/kg/minuteincrements to 20 nanograms/kg/minuteNote Doses up to 100 nanograms/kg/minute have beenused but are associated with increased side-effects. By mouth2 Cardiovascular systemNeonate 20–25 micrograms/kg every 1–2 hoursdoubled if necessary; if treatment continues formore than 1 week gradually reduce the doseAdministration for continuous intravenous infusion,dilute to a concentration of 1 microgram/mL withGlucose 5% or Sodium Chloride 0.9%.For administration by mouth, injection solution can begiven orally; dilute with waterProstin c E2 (Pharmacia) AIntravenous solution, for dilution and use as aninfusion, dinoprostone 1 mg/mL, net price 0.75-mLamp = £8.52; 10 mg/mL, 0.5-mL amp = £18.40 (bothhosp. only)Extemporaneous formulations available seeExtemporaneous Preparations, p. 6

BNFC 2011–2012 1333 Respiratory system3.1 Bronchodilators 1333.1.1 Adrenoceptor agonists 1373.1.1.1 Selective beta 2 agonists 1373.1.1.2 Other adrenoceptor agonists 1413.1.2 Antimuscarinic bronchodilators 1413.1.3 Theophylline 1423.1.4 Compound bronchodilator preparations1443.1.5 Peak flow meters, inhalerdevices, and nebulisers 1443.2 Corticosteroids 1463.3 Cromoglicate and related therapyand leukotriene receptorantagonists 1513.3.1 Cromoglicate and related therapy1513.3.2 Leukotriene receptor antagonists1523.4 Antihistamines, immunotherapy,and allergic emergencies 1533.4.1 Antihistamines 1533.4.2 Allergen immunotherapy 1573.4.3 Allergic emergencies 1593.5 Respiratory stimulants andpulmonary surfactants 1623.5.1 Respiratory stimulants 1623.5.2 Pulmonary surfactants 1623.6 Oxygen 1633.7 Mucolytics 1653.8 Aromatic inhalations 1663.9 Cough preparations 1673.9.1 Cough suppressants 1673.9.2 Expectorant and demulcentcough preparations 1673.10 Systemic nasal decongestants 168This chapter includes advice on the drug managementof the following:acute asthma, p. 134anaphylaxis, p. 159angioedema, p. 161chronic asthma, p. 135croup, p. 1373.1 Bronchodilators3.1.1 Adrenoceptor agonists3.1.2 Antimuscarinic bronchodilators3.1.3 Theophylline3.1.4 Compound bronchodilatorpreparations3.1.5 Peak flow meters, inhaler devices, andnebulisersAsthmaDrugs used in the management of asthma include beta 2agonists (section 3.1.1), antimuscarinic bronchodilators(section 3.1.2), theophylline (section 3.1.3), corticosteroids(section 3.2), cromoglicate and nedocromil (section3.3.1), leukotriene receptor antagonists (section 3.3.2),and in specialist centres, omalizumab (section 3.4.2).For tables outlining the management of chronic asthmaand management of acute asthma, see p. 135 andp. 136.Administration of drugs for asthmaInhalation This route delivers the drug directly to theairways; the dose required is smaller than when given bymouth and side-effects are reduced. See Inhaler devices,section 3.1.5.Solutions for nebulisation for use in acute severeasthma are administered over 5–10 minutes from anebuliser, usually driven by oxygen in hospital. SeeNebulisers, section 3.1.5.Oral Systemic side-effects occur more frequently whena drug is given orally rather than by inhalation. Oralcorticosteroids, theophylline, and leukotriene receptorantagonists are sometimes required for the managementof asthma. Oral administration of a beta 2 agonistis generally not recommended for children, but may benecessary in infants and young children who are unableor unwilling to use an inhaler device.Parenteral Drugs such as beta 2 agonists, corticosteroids,and aminophylline can be given by injection inacute severe asthma when drug administration by nebulisationis inadequate or inappropriate; in these circumstancesthe child should generally be treated in a highdependencyor intensive care unit.3 Respiratory systemPregnancy and breast-feedingWomen with asthma should be closely monitored duringpregnancy. Well-controlled asthma has no importanteffects on pregnancy, labour, or the fetus. Drugs for

134 3.1 Bronchodilators BNFC 2011–20123 Respiratory systemasthma should preferably be administered by inhalationto minimise fetal drug exposure. Inhaled drugs, theophylline,and prednisolone can be taken as normalduring pregnancy and breast-feeding. Women planningto become pregnant should be counselled about theimportance of taking their asthma medication regularlyto maintain good control.Severe acute exacerbations of asthma can have anadverse effect on pregnancy and should be treatedpromptly in hospital with conventional therapy, includingnebulisation of a beta 2 agonist, and oral or parenteraladministration of a corticosteroid; prednisoloneis the preferred corticosteroid for oral administrationsince very little of the drug reaches the fetus. Oxygenshould be given immediately to maintain an arterialoxygen saturation of 94–98% and prevent maternaland fetal hypoxia. An intravenous beta 2 agonist, aminophylline,or magnesium sulphate can be used duringpregnancy if necessary; parenteral beta 2 agonists canaffect the myometrium, see BNF section 7.1.3.Management of acute asthma 1ImportantRegard each emergency consultation as being forsevere acute asthma until shown otherwise.Failure to respond adequately at any time requiresimmediate transfer to hospital.Severe acute asthma can be fatal and must be treatedpromptly. Treatment of severe acute asthma is safer inhospital where resuscitation facilities are immediatelyavailable. Treatment should never be delayed for investigations,children should never be sedated, and thepossibility of a pneumothorax should be considered. Ifthe child’s condition deteriorates despite pharmacologicaltreatment, urgent transfer to a paediatric intensivecare unit should be arranged. For a table outliningthe management of severe acute asthma, see Managementof acute asthma p. 136.Mild to moderate acute asthma Administer ashort-acting beta 2 agonist using a pressurisedmetered-dose inhaler with a spacer device; for a childunder 3 years use a close-fitting facemask. Give 1 puffevery 15–30 seconds up to a maximum of 10 puffs;repeat dose after 10–20 minutes if necessary.Give prednisolone by mouth, child under 12 years 1–2 mg/kg (max. 40 mg) once daily for up to 3 days, orlonger if necessary; if the child has been taking an oralcorticosteroid for more than a few days, give prednisolone2 mg/kg (max. 60 mg) once daily. For children 12–18 years, give prednisolone 40–50 mg daily for at least 5days.1. Advice on the management of acute asthma is based onthe recommendations of the British Thoracic Society andScottish Intercollegiate Guidelines Network (updated June2009); updates available at www.brit-thoracic.org.ukIf response is poor or if a relapse occurs within 3–4hours, transfer child immediately to hospital for assessmentand further treatment.Children under 18 months often respond poorly tobronchodilators; nebulised beta 2 agonists have beenassociated with mild (but occasionally severe) paradoxicalbronchospasm and transient worsening of oxygensaturation; response to prednisolone may also be poorin this age group.Severe or life-threatening acute asthma Starttreatment below and transfer immediately to hospital.Administer high-flow oxygen (section 3.6) using a closefittingface mask or nasal prongs.Treat severe or life-threatening acute exacerbations ofasthma with an inhaled short-acting beta 2 agonist (asabove). Treatment of life-threatening asthma should beinitiated with nebulised salbutamol 2.5 mg or terbutaline5 mg (via an oxygen-driven nebuliser if available); nebuliseddoses may be doubled for children over 5 years.Repeat the dose every 20–30 minutes or as necessary,then reduce the frequency on improvement.Give prednisolone by mouth, child under 12 years 1–2 mg/kg (max. 40 mg) once daily for up to 3 days, orlonger if necessary; if the child has been taking an oralcorticosteroid for more than a few days, give prednisolone2 mg/kg (max. 60 mg) once daily. For children 12–18 years, give prednisolone 40–50 mg daily for at least 5days. If oral administration is not possible, use intravenoushydrocortisone (preferably as sodium succinate)4 mg/kg (max. 100 mg) (alternatively, if weightunavailable, child under 2 years 25 mg, 2–5 years50 mg, 5–18 years 100 mg) every 6 hours.If response is poor, add nebulised ipratropiumbromide, child under 12 years give 250 microgramsevery 20–30 minutes for the first 2 hours, then every4–6 hours as necessary. For children 12–18 years, giveipratropium bromide 500 micrograms every 4–6 hoursas necessary.If the condition does not respond or is life-threatening,transfer the child to an intensive care unit and treat withagonist (e.g. salbut-a parenteral short-acting beta 2amol, section 3.1.1.1) or parenteral aminophylline (section3.1.3). Children over 2 years with severe acuteasthma may be helped by intravenous infusion ofmagnesium sulphate 40 mg/kg (max. 2 g) over 20minutes (section 9.5.1.3), but evidence of benefit islimited.Follow-up in all cases Episodes of acute asthmashould be regarded as a failure of preventive therapy. Acareful history should be taken to establish the reasonfor the exacerbation. Inhaler technique should bechecked and regular treatment should be reviewed inaccordance with the Management of Chronic Asthmatable, p. 135. Children or their carers should be given anasthma action plan aimed at preventing relapse, optimisingtreatment, and preventing delay in seeking assistancein future exacerbations. If possible, follow-upwithin 48 hours should be arranged with the generalpractitioner or appropriate primary care health professional.Children should also be reviewed in a paediatricasthma clinic within 1–2 months of the exacerbation.

BNFC 2011–2012 3.1 Bronchodilators 135Management of chronic asthmaImportant Start at step most appropriate to initial severity; before initiating a new drug consider whetherdiagnosis is correct, check compliance and inhaler technique, and eliminate trigger factors for acute exacerbationsChild 5–18 yearsStep 1: occasional relief bronchodilatorInhaled short-acting beta 2 agonist as required (up to oncedaily)Note Move to step 2 if needed more than twice a week, or ifnight-time symptoms more than once a week, or if exacerbationin the last 2 yearsStep 2: regular inhaled preventer therapyInhaled short-acting beta 2 agonist as requiredplusRegular standard-dose 1 inhaled corticosteroid (alternatives2 are considerably less effective)Step 3: inhaled corticosteroid + inhaled long-actingbeta 2agonistInhaled short-acting beta 2 agonist as requiredplusRegular standard-dose 1 inhaled corticosteroidplusRegular inhaled long-acting beta 2 agonist (salmeterol orformoterol)If asthma not controlledIncrease dose of inhaled corticosteroid to upper end ofstandard dose range 1andEither stop long-acting beta 2 agonist if of no benefitOr continue long-acting beta 2 agonist if of some benefitIf asthma still not controlled and long-acting beta 2agonist stopped, add one ofLeukotriene receptor antagonistModified-release oral theophyllineStep 4: high-dose inhaled corticosteroid + regularbronchodilatorsInhaled short-acting beta 2 agonist as requiredwithRegular high-dose 3 inhaled corticosteroidplusInhaled long-acting beta 2 agonist (if of benefit)plusA 6-week sequential therapeutic trial of one or more ofLeukotriene receptor antagonistModified-release oral theophyllineModified-release oral beta 2 agonistStep 5: regular corticosteroid tabletsRefer to respiratory paediatricianInhaled short-acting beta 2 agonist as requiredwithRegular high-dose 3 inhaled corticosteroidandOne or more long-acting bronchodilators (see step 4)plusRegular prednisolone tablets (as single daily dose)Note In addition to regular prednisolone, continue high-doseinhaled corticosteroid (in exceptional cases may exceedlicensed doses)Stepping downReview treatment every 3 months; if control achievedstepwise reduction may be possible; reduce dose ofinhaled corticosteroid slowly (consider reduction every 3months, decreasing dose by up to 50% each time) to thelowest dose which controls asthmaChild under 5 years 4Step 1: occasional relief bronchodilatorShort-acting beta 2 agonist as required (not more thanonce daily)Note Preferably by inhalation (less effective and more sideeffectswhen given as tablets or syrup)Move to step 2 if needed more than twice a week, or if nighttimesymptoms more than once a week, or if exacerbation inthe last 2 yearsStep 2: regular preventer therapyInhaled short-acting beta 2 agonist as requiredplusRegular standard-dose 1 inhaled corticosteroidOr leukotriene receptor antagonist if inhaled corticosteroidcannot be usedStep 3: add-on therapyChild under 2 years:Refer to respiratory paediatricianChild 2–5 years:Inhaled short-acting beta 2 agonist as requiredplusRegular standard-dose 1 inhaled corticosteroidplusLeukotriene receptor antagonistStep 4: persistent poor controlRefer to respiratory paediatricianStepping downRegularly review need for treatment1. Standard doses of inhaled corticosteroidsBeclometasone dipropionate or budesonide:Child under 12 years 100–200 micrograms twice daily;Child 12–18 years 100–400 micrograms twice daily.Fluticasone propionate:Child 4–12 years 50–100 micrograms twice daily;Child 12–18 years 50–200 micrograms twice daily.Mometasone furoate:Child 12–18 years 200 micrograms twice daily.Note Dose adjustments may be required for some inhalerdevices, see under individual preparations section 3.22. Alternatives to inhaled corticosteroid are leukotrienereceptor antagonists, theophylline, inhaled nedocromil, orinhaled cromoglicate3. High doses of inhaled corticosteroidsBeclometasone dipropionate or budesonide:Child 5–12 years 200–400 micrograms twice daily;Child 12–18 years 0.4–1 mg twice daily.Fluticasone propionate:Child 5–12 years 100–200 micrograms twice daily;Child 12–18 years 200–500 micrograms twice daily.Mometasone furoate:Child 12–18 years up to 400 micrograms twice daily.Note Dose adjustments may be required for some inhalerdevices, see under individual preparations section 3.2.Failure to achieve control with these doses is unusual, seealso Side-effects of Inhaled Corticosteroids, section 3.24. Lung-function measurements cannot be used to guidemanagement in those under 5 yearsAdvice on the management of chronic asthma is based on the recommendations of the British Thoracic Society and ScottishIntercollegiate Guidelines Network (updated June 2009); updates available at www.brit-thoracic.org.uk3 Respiratory system

136 3.1 Bronchodilators BNFC 2011–2012Management of acute asthmaImportant The assessment of acute asthma in early childhood can be difficult. Children with severe or lifethreateningacute asthma may not be distressed and may not have all of these abnormalities; the presence of anyshould alert the doctor. Regard each emergency consultation as being for severe acute asthma until shown otherwiseModerate acute asthmaSevere acute asthmaLife-threatening acute asthma3 Respiratory system. Able to talk. Respiration (breaths/minute)Child 2–5 years 40, 5–12 years 30, 12–18 years < 25. Pulse (beats/minute) Child 2–5years 140, 5–12 years 125,12–18 years < 110. Arterial oxygen saturation 92%. Peak flow Child 5–12 years 50%of predicted or best, 12–18 years> 50%Treat at home or in surgery andassess response to treatmentTreatment. Inhaled short-acting beta 2 agonistvia a large-volume spacer (and aclose-fitting face mask if child under3 years) or oxygen-driven nebuliser(if available); give 2–10 puffs ofsalbutamol 100 micrograms/metered inhalation each inhaledseparately, and repeat at 10–20minute intervals if necessary or givenebulised salbutamol, Child under 5years 2.5 mg, 5–12 years 2.5–5 mg,12–18 years 5 mg or terbutaline,Child under 5 years 5 mg, 5–12years 5–10 mg, 12–18 years 10 mg,and repeat at 20–30 minute intervalsas necessary. Prednisolone by mouth Child under12 years 1–2 mg/kg (max. 40 mg)daily for up to 3 days or longer ifnecessary; if the child has beentaking an oral corticosteroid formore than a few days, give prednisolone2 mg/kg (max. 60 mg);Child 12–18 years 40–50 mg dailyfor at least 5 daysMonitor response for 15–30 minutesIf response is poor or a relapseoccurs in 3–4 hours, send immediatelyto hospital for assessment andfurther treatment. Child under 12 years too breathlessto talk or feed, 12–18 years cannotcomplete sentences in one breath. Use of accessory breathing muscles. Respiration (breaths/minute) Child2–5 years > 40, 5–12 years > 30,12–18 years 25. Pulse (beats/minute) Child 2–5 years> 140, 5–12 years >125, 12–18years 110. Arterial oxygen saturation Childunder 12 years < 92%, 12–18 years 92%. Peak flow Child 5–12 years < 50% ofpredicted or best, 12–18 years 33–50%Start treatment below and sendimmediately to hospitalTreatment. High-flow oxygen (if available). Inhaled short-acting beta 2 agonistvia a large-volume spacer (and aclose-fitting face mask if child under3 years) or oxygen-driven nebuliser (ifavailable) as for moderate acuteasthma. Prednisolone by mouth as for moderateacute asthma or intravenoushydrocortisone (preferably as sodiumsuccinate) 4 mg/kg (max.100 mg) (alternatively, if weight unavailable,Child under 2 years 25 mg,2–5 years 50 mg, 5–18 years100 mg) every 6 hours until conversionto oral prednisolone is possibleMonitor response for 15–30 minutesIf response is poor:. Inhaled ipratropium bromide via oxygen-drivennebuliser (if available),Child under 12 years, 250 microgramsrepeated every 20–30 minutesfor the first 2 hours, then every4–6 hours as necessary; Child 12–18years, 500 micrograms every 4–6hours as necessaryRefer those who fail to respond andrequire ventilatory support to apaediatric intensive care or highdependencyunit. Consider intravenous beta 2 agonists,aminophylline, or magnesium sulphate[unlicensed indication] onlyafter consultation with senior medicalstaff. Silent chest, cyanosis, poor respiratoryeffort. Arrhythmia, hypotension. Exhaustion, altered consciousness,agitation, confusion. Arterial oxygen saturation

BNFC 2011–2012 3.1.1 Adrenoceptor agonists 137CroupMild croup is largely self-limiting, but treatment with asingle dose of a corticosteroid (e.g. dexamethasone150 micrograms/kg) by mouth is of benefit.Severe croup (or mild croup that might cause complications)calls for hospital admission—a single dose ofeither dexamethasone 150 micrograms/kg or prednisolone1–2 mg/kg, can be administered by mouth beforetransfer to hospital. In hospital, dexamethasone150 micrograms/kg (by mouth or by injection) or budesonide2 mg by nebulisation (section 3.2) will oftenreduce symptoms; the dose may be repeated after 12hours if necessary.For severe croup not effectively controlled with corticosteroidtreatment, nebulised adrenaline (section 3.4.3)solution 1 in 1000 (1 mg/mL) can be given with closeclinical monitoring in a dose of 400 micrograms/kg(max. 5 mg) repeated after 30 minutes if necessary (thedose may be diluted with sterile sodium chloride 0.9%solution). The effects of nebulised adrenaline last 2–3 hours; the child needs to be carefully monitored forrecurrence of the obstruction.3.1.1 Adrenoceptor agonists(Sympathomimetics)3.1.1.1 Selective beta 2 agonists3.1.1.2 Other adrenoceptor agonistsThe selective beta 2 agonists (selective beta 2 -adrenoceptoragonists, selective beta 2 stimulants) such as salbutamolor terbutaline are the safest and most effectiveshort-acting beta 2 agonists for the treatment of asthma.Adrenaline (epinephrine), which has both alpha- andbeta-adrenoceptor agonist properties, is used in theemergency management of acute allergic and anaphylacticreactions (section 3.4.3); it is also used as anebuliser solution to treat severe croup.3.1.1.1 Selective beta 2 agonistsSelective beta 2 agonists produce bronchodilation. Ashort-acting beta 2agonist is used for immediate reliefof asthma symptoms while a long-acting beta 2agonist isused in addition to an inhaled corticosteroid in childrenrequiring prophylactic treatment.Management of Chronic Asthma table, see p. 135Management of Acute Asthma table, see p. 136For guidance on the use of inhalers and spacerdevices, see section 3.1.5Short-acting beta 2agonists Mild to moderatesymptoms of asthma respond rapidly to the inhalationof a selective short-acting beta 2 agonist such as salbutamolor terbutaline. If beta 2 agonist inhalation isneeded more often than once daily, prophylactic treatmentshould be considered, using a stepped approach asoutlined in the Management of Chronic Asthma table,p. 135. Regular treatment with an inhaled short-actingbeta 2 agonist is less effective than ‘as required’ inhalationand is not appropriate prophylactic treatment.A short-acting beta 2 agonist inhaled immediately beforeexertion reduces exercise-induced asthma; however,frequent exercise-induced asthma probably reflectspoor overall control and calls for reassessment ofasthma treatment.Long-acting beta 2 agonists Formoterol and salmeterolare longer-acting beta 2 agonists which areadministered by inhalation. They should be used forasthma only in children who regularly use an inhaledcorticosteroid (see CHM advice below). They have arole in the long-term control of chronic asthma (seeManagement of Chronic Asthma table, p. 135) and theycan be useful in nocturnal asthma. Salmeterol shouldnot be used for the relief of an asthma attack; it has aslower onset of action than salbutamol or terbutaline.Formoterol is licensed for short-term symptom reliefand for the prevention of exercise-induced bronchospasm;its speed of onset of action is similar to that ofsalbutamol.Combination inhalers that contain a long-acting beta 2agonist and a corticosteroid (section 3.2) ensure thatlong-acting beta 2 agonists are not used without concomitantcorticosteroids, but reduce the flexibility toadjust the dose of each component.CHM adviceTo ensure safe use, the CHM has advised that for themanagement of chronic asthma, long-acting beta 2agonists (formoterol and salmeterol) should:. be added only if regular use of standard-doseinhaled corticosteroids has failed to controlasthma adequately;. not be initiated in patients with rapidly deterioratingasthma;. be introduced at a low dose and the effectmonitored before considering dose increase;. be discontinued in the absence of benefit;. not be used for the relief of exercise-inducedasthma symptoms unless regular inhaled corticosteroidsare also used;. be reviewed as clinically appropriate: steppingdown therapy should be considered when goodlong-term asthma control has been achieved.A daily dose of 24 micrograms of formoterol shouldbe sufficient for the majority of children, particularlyfor younger age-groups; higher doses should be usedrarely, and only when control is not maintained onthe lower dose.Children and their carers should be advised to reportany deterioration in symptoms following initiation oftreatment with a long-acting beta 2 agonist, see Managementof Chronic Asthma table, p. 135.Inhalation A pressurised metered-dose inhaler is aneffective method of drug administration in mild tomoderate chronic asthma; to deliver the drug effectivelyparticularly in children under 12 years, a spacer deviceshould be used (see also NICE guidance, section 3.1.5).When a pressurised metered-dose inhaler with a spaceris unsuitable or inconvenient, a dry-powder inhaler orbreath-actuated inhaler may be used instead if the childis able to use the device effectively. At recommendedinhaled doses the duration of action of salbutamol andterbutaline is about 3 to 5 hours and for salmeterol andformoterol is about 12 hours. The dose, the frequency,and the maximum number of inhalations in 24 hours ofthe beta 2 agonist should be stated explicitly to the childand the child’s carer. High doses of beta 2 agonists can bedangerous in some children (see Cautions, below).Excessive use is usually an indication of inadequately3 Respiratory system

138 3.1.1 Adrenoceptor agonists BNFC 2011–20123 Respiratory systemcontrolled asthma and should be managed with aprophylactic drug such as an inhaled corticosteroid.The child and the child’s carer should be advised toseek medical advice when the prescribed dose of beta 2agonist fails to provide the usual degree of symptomaticrelief because this usually indicates a worsening of theasthma and the child may require alternative medication(see Management of Chronic Asthma table, p. 135).Children and their carers should be advised to followmanufacturers’ instructions on the care and cleansing ofinhaler devices.Nebuliser (or respirator) solutions of salbutamol andterbutaline are used for the treatment of severe acuteasthma both in hospital and in general practice. Childrenwith a severe attack of asthma should have oxygen ifpossible during nebulisation since beta 2 agonists canincrease arterial hypoxaemia, see also section 3.1.5.Oral Oral preparations of beta 2 agonists may be usedfor children if an inhaler device cannot be used butinhaled beta 2agonists are more effective and have fewerside-effects. A modified-release formulation of salbutamolmay be of value in nocturnal asthma as an alternativeto modified-release theophylline preparations(section 3.1.3), but an inhaled long-acting beta 2 agonistis preferable.Parenteral Beta 2 agonists can be given intravenouslyin children with severe or life-threatening acute asthma.Chronic asthma unresponsive to stepwise treatment(see Management of Chronic Asthma, p. 135) may benefitfrom continuous subcutaneous infusion of a beta 2agonist, but this should be used only under the supervisionof a respiratory specialist; the evidence of benefitis uncertain and it may be difficult to withdraw suchtreatment once started.Cautions Beta 2 agonists should be used with caution indiabetes—monitor blood glucose (risk of ketoacidosis,especially when a beta 2 agonist is given intravenously).Beta 2 agonists should also be used with caution inhyperthyroidism, cardiovascular disease, arrhythmias,susceptibility to QT-interval prolongation, and hypertension.Interactions: Appendix 1 (sympathomimetics,beta 2 ).Hypokalaemia Potentially serious hypokalaemia mayresult from beta 2 agonist therapy. Particular caution isrequired in severe asthma, because this effect may bepotentiated by concomitant treatment with theophyllineand its derivatives, corticosteroids, and diuretics, and byhypoxia. Plasma-potassium concentration should thereforebe monitored in severe asthma.Side-effects Side-effects of the beta 2 agonists includefine tremor (particularly in the hands), nervous tension,headache, peripheral dilatation and palpitation. Otherside-effects include tachycardia, arrhythmias, peripheralvasodilation, myocardial ischaemia, and disturbances ofsleep and behaviour. Muscle cramps and hypersensitivityreactions including paradoxical bronchospasm(occasionally severe), urticaria, angioedema, hypotension,and collapse have also been reported. Highdoses of beta 2 agonists are associated with hypokalaemia(see Hypokalaemia, above).FORMOTEROL FUMARATE(Eformoterol fumarate)Note For use in asthma only in children who regularly use aninhaled corticosteroid, see notes aboveCautions see notes abovePregnancy see p. 133Breast-feeding see p. 133Side-effects see notes above; nausea, dizziness, rash,taste disturbances, and pruritus also reportedIndication and doseReversible airways obstruction (includingnocturnal asthma and prevention of exerciseinducedbronchospasm) in patients requiringlong-term regular bronchodilator therapy seealso Management of Chronic Asthma table, p. 135;for dose see preparations belowCounselling Advise children and carers not to exceed prescribeddose, and to follow manufacturer’s directions; if apreviously effective dose of inhaled formoterol fails toprovide adequate relief, a doctor’s advice should be obtainedas soon as possibleFormoterol (Non-proprietary) ADry powder for inhalation, formoterol fumarate12 micrograms/metered inhalation, net price 120-dose unit = £23.75. Counselling, administrationBrands include Easyhaler c FormoterolDoseChronic asthma. By inhalation of powderChild 6–18 years 12 micrograms twice daily, increasedto 24 micrograms twice daily in more severe airwaysobstruction (see also CHM advice above)Atimos Modulite c (Chiesi) AAerosol inhalation, formoterol fumarate 12 micrograms/meteredinhalation, net price 100-dose unit =£30.06. Counselling, administrationDoseChronic Asthma. By aerosol inhalationChild 12–18 years 12 micrograms twice daily, increasedto max. 24 micrograms twice daily in more severe airwaysobstructionForadil c (Novartis) ADry powder for inhalation, formoterol fumarate12 micrograms/capsule, net price 60-cap pack (withinhaler device) = £23.38. Counselling, administrationDoseChronic asthma. By inhalation of powderChild 5–12 years 12 micrograms twice dailyChild 12–18 years 12 micrograms twice daily, increasedto 24 micrograms twice daily in more severe airwaysobstructionOxis c (AstraZeneca) ATurbohaler c (= dry powder inhaler), formoterolfumarate 6 micrograms/inhalation, net price 60-doseunit = £24.80; 12 micrograms/inhalation, 60-dose unit= £24.80. Counselling, administrationDoseChronic asthma. By inhalation of powderChild 6–18 years 6–12 micrograms 1–2 times daily;occasionally up to 48 micrograms daily may be needed(max. single dose 12 micrograms); reassess treatment ifadditional doses required on more than 2 days a week(see also CHM advice above)

BNFC 2011–2012 3.1.1 Adrenoceptor agonists 139Relief of bronchospasm. By inhalation of powderChild 6–18 years 6–12 microgramsPrevention of exercise-induced bronchospasm. By inhalation of powderChild 6–18 years 6–12 micrograms before exerciseChild 2–6 years 1–2 mg 3–4 times dailyChild 6–12 years 2 mg 3–4 times dailyChild 12–18 years 4 mg (sensitive patients initially2 mg) 3–4 times daily; max. single dose 8 mg(but unlikely to provide extra benefit or to betolerated)Compound preparationsFor compound preparations containing formoterol,see section 3.2SALBUTAMOL(Albuterol)Cautions see notes abovePregnancy see p. 133Breast-feeding see p. 133Side-effects see notes above; also lactic acidosis withhigh dosesLicensed use not licensed for use in hyperkalaemia;syrup not licensed for use in children under 2 years;modified-release tablets not licensed for use inchildren under 3 years; injection not licensed for usein children; Pulvinal c Salbutamol not licensed foruse in children under 6 yearsIndication and doseAcute asthma. By aerosol or nebulised solution inhalationSee Management of Acute Asthma, p. 134. By intravenous injection over 5 minutes (seealso Management of Acute Asthma, p. 134)Child 1 month–2 years 5 micrograms/kg as asingle doseChild 2–18 years 15 micrograms/kg (max.250 micrograms) as a single dose. By continuous intravenous infusionChild 1 month–18 years 1–2 micrograms/kg/minute, adjusted according to response and heartrate up to 5 micrograms/kg/minute; doses above2 micrograms/kg/minute should be given in anintensive care settingExacerbations of reversible airways obstruction(including nocturnal asthma) and prevention ofallergen- or exercise-induced bronchospasm,see also Management of Chronic Asthma, p. 135. By aerosol inhalationChild 1 month–18 years 100–200 micrograms(1–2 puffs); for persistent symptoms up to 4 timesdaily. By inhalation of powder(for Asmasal Clickhaler c , Salbulin Novolizer c ,and Ventolin Accuhaler c doses, see under preparations)Child 5–12 years 200 micrograms; for persistentsymptoms up to 4 times dailyChild 12–18 years 200–400 micrograms; forpersistent symptoms up to 4 times daily. By mouth (but use by inhalation preferred)Child 1 month–2 years 100 micrograms/kg(max. 2 mg) 3–4 times dailySevere hyperkalaemia (section 9.2.1.1). By intravenous injection over 5 minutesNeonate 4 micrograms/kg as a single dose; repeatif necessaryChild 1 month–18 years 4 micrograms/kg as asingle dose; repeat if necessary. By inhalation of nebulised solution (but intravenousinjection preferred)Neonate 2.5–5 mg as a single dose; repeat ifnecessaryChild 1 month–18 years 2.5–5 mg as a singledose; repeat if necessaryAdministration for continuous intravenous infusion,dilute to a concentration of 200 micrograms/mL withGlucose 5% or Sodium Chloride 0.9%; if fluidrestricted,can be given undiluted through centralvenous catheterFor intravenous injection, dilute to a concentration of50 micrograms/mL with Glucose 5%, Sodium Chloride0.9%, or Water for injectionsFor nebulisation, dilute nebuliser solution with asuitable volume of sterile Sodium Chloride 0.9%solution according to nebuliser type and duration ofadministration; salbutamol and ipratropium bromidesolutions are compatible and can be mixed for nebulisationOralSalbutamol (Non-proprietary) ATablets, salbutamol (as sulphate) 2 mg, net price 28-tab pack = £17.74; 4 mg, 28-tab pack = £16.40Oral solution, salbutamol (as sulphate) 2 mg/5 mL,net price 150 mL = £1.55Brands include Salapin c (sugar-free)Ventmax c SR (Chiesi) ACapsules, m/r, salbutamol (as sulphate) 4 mg (green/grey), net price 56-cap pack = £8.08; 8 mg (white), 56-cap pack = £9.69. Label: 25DoseChronic asthma (but see notes above). By mouthChild 3–12 years 4 mg twice dailyChild 12–18 years 8 mg twice dailyVentolin c (A&H) ASyrup, sugar-free, salbutamol (as sulphate) 2 mg/5 mL, net price 150 mL = 60pParenteralVentolin c (A&H) AInjection, salbutamol (as sulphate) 500 micrograms/mL, net price 1-mL amp = 38pSolution for intravenous infusion, salbutamol (assulphate) 1 mg/mL. Dilute before use. Net price 5-mLamp = £2.483 Respiratory system

140 3.1.1 Adrenoceptor agonists BNFC 2011–20123 Respiratory systemInhalationCounselling Advise children and carers not to exceed prescribeddose and to follow manufacturer’s directions; if apreviously effective dose of inhaled salbutamol fails toprovide at least 3 hours relief, a doctor’s advice should beobtained as soon as possible.Salbutamol (Non-proprietary) AAerosol inhalation, salbutamol (as sulphate)100 micrograms/metered inhalation, net price 200-dose unit = £3.19. Counselling, administrationBrands include Salamol c , Salbumalin cDry powder for inhalation, salbutamol 100 micrograms/meteredinhalation, net price 200-dose unit =£3.31; 200 micrograms/metered inhalation, 100-doseunit = £4.85, 200-dose unit = £6.63. Counselling,administrationBrands include Easyhaler c Salbutamol, Pulvinal c SalbutamolNebuliser solution, salbutamol (as sulphate) 1 mg/mL, net price 20 2.5 mL (2.5 mg) = £1.91; 2 mg/mL,20 2.5 mL (5 mg) = £3.82. May be diluted withsterile sodium chloride 0.9%Brands include Salamol Steri-Neb cAiromir c (IVAX) AAerosol inhalation, salbutamol (as sulphate)100 micrograms/metered inhalation, net price 200-dose unit = £1.97. Counselling, administrationAutohaler (breath-actuated aerosol inhalation), salbutamol(as sulphate) 100 micrograms/meteredinhalation, net price 200-dose unit = £6.02. Counselling,administrationAsmasal Clickhaler c (UCB Pharma) ADry powder for inhalation, salbutamol (as sulphate)95 micrograms/metered inhalation, net price 200-dose unit = £5.65. Counselling, administrationDoseAcute bronchospasm. By inhalation of powderChild 5–18 years 1–2 puffs; for persistent symptoms upto 4 times daily (but see also Management of ChronicAsthma, p. 135)Prophylaxis of allergen- or exercise-induced bronchospasm. By inhalation of powderChild 5–18 years 1–2 puffsSalamol Easi-Breathe c (IVAX) AAerosol inhalation, salbutamol 100 micrograms/metered inhalation, net price 200-dose breath-actuatedunit = £6.30. Counselling, administrationSalbulin Novolizer c (Meda) ADry powder for inhalation, salbutamol (as sulphate)100 micrograms/metered inhalation, net price refillable200-dose unit = £4.95; 200-dose refill = £2.75.Counselling, administrationDoseAcute bronchospasm. By inhalation of powderChild 6–12 years 100–200 micrograms; for persistentsymptoms up to 400 micrograms daily (but see alsoManagement of Chronic Asthma, p. 135)Child 12–18 years 100–200 micrograms; for persistentsymptoms up to 800 micrograms daily (but see alsoManagement of Chronic Asthma, p. 135)Prophylaxis of allergen- or exercise-induced bronchospasm. By inhalation of powderChild 6–12 years 100–200 microgramsChild 12–18 years 200 microgramsVentolin c (A&H) AAccuhaler c (dry powder for inhalation), disk containing60 blisters of salbutamol (as sulphate)200 micrograms/blister with Accuhaler c device, netprice = £4.92. Counselling, administrationDoseAcute bronchospasm. By inhalation of powderChild 5–18 years 200 micrograms; for persistentsymptoms up to 4 times daily but see also Managementof Chronic Asthma, p. 135Prophylaxis of allergen- or exercise-induced bronchospasm. By inhalation of powderChild 5–18 years 200 microgramsEvohaler c (aerosol inhalation), salbutamol (as sulphate)100 micrograms/metered inhalation, net price200-dose unit = £1.50. Counselling, administrationNebules c (for use with nebuliser), salbutamol (assulphate) 1 mg/mL, net price 20 2.5 mL (2.5 mg) =£1.68; 2 mg/mL, 20 2.5 mL (5 mg) = £2.83. May bediluted with sterile sodium chloride 0.9%Respirator solution (for use with a nebuliser orventilator), salbutamol (as sulphate) 5 mg/mL. Netprice 20 mL = £2.18 (hosp. only). May be diluted withsterile sodium chloride 0.9%SALMETEROLNote Not for immediate relief of acute attacks; for use inasthma only in children who regularly use an inhaledcorticosteroid, see notes aboveCautions see notes abovePregnancy see p. 133Breast-feeding see p. 133Side-effects see notes above; nausea, dizziness,arthralgia, and rash also reportedIndication and doseReversible airways obstruction (includingnocturnal asthma and prevention of exerciseinducedbronchospasm) in patients requiringlong-term regular bronchodilator therapy seealso Management of Chronic Asthma, p. 135. By inhalationChild 5–12 years 50 micrograms (2 puffs or 1blister) twice dailyChild 12–18 years 50 micrograms (2 puffs or 1blister) twice daily; up to 100 micrograms (4 puffsor 2 blisters) twice daily in more severe airwaysobstructionCounselling Advise children and carers that salmeterolshould not be used for relief of acute attacks, not toexceed prescribed dose, and to follow manufacturer’sdirections; if a previously effective dose of inhaled salmeterolfails to provide adequate relief, a doctor’s adviceshould be obtained as soon as possibleSerevent c (A&H) AAccuhaler c (dry powder for inhalation), disk containing60 blisters of salmeterol (as xinafoate)50 micrograms/blister with Accuhaler c device, netprice = £29.26. Counselling, administration

BNFC 2011–2012 3.1.2 Antimuscarinic bronchodilators 141Evohaler c aerosol inhalation T, salmeterol (asxinafoate) 25 micrograms/metered inhalation, netprice 120-dose unit = £29.26. Counselling, administrationDiskhaler c (dry powder for inhalation), disks containing4 blisters of salmeterol (as xinafoate)50 micrograms/blister, net price 15 disks with Diskhalerc device = £35.79, 15-disk refill = £35.15.Counselling, administrationCompound preparationsFor compound preparations containing salmeterol,see section 3.2TERBUTALINE SULPHATECautions see notes abovePregnancy see p. 133Breast-feeding see p. 133Side-effects see notes aboveLicensed use tablets not licensed for use in childrenunder 7 years; injection not licensed for use inchildren under 2 yearsIndication and doseAcute asthma. By inhalation of nebulised solutionSee Management of Acute Asthma, p. 134. By subcutaneous or slow intravenous injectionChild 2–15 years 10 micrograms/kg (max.300 micrograms) up to 4 times dailyChild 15–18 years 250–500 micrograms up to 4times daily. By continuous intravenous infusionChild 1 month–18 years initially 2–4 micrograms/kgas a loading dose, then 1–10 micrograms/kg/houraccording to response and heartrate (doses above 10 micrograms/kg/hour withclose monitoring)Exacerbations of reversible airways obstruction(including nocturnal asthma) and prevention ofexercise-induced bronchospasm see Managementof Chronic Asthma table, p. 135. By inhalation of powderChild 5–18 years 500 micrograms (1 inhalation)up to 4 times daily (for occasional use only). By mouth (but not recommended)Child 1 month–7 years 75 micrograms/kg (max.2.5 mg) 3 times dailyChild 7–15 years 2.5 mg 2–3 times dailyChild 15–18 years initially 2.5 mg 3 times daily,increased if necessary to 5 mg 3 times dailyAdministration For continuous intravenous infusion,dilute to a concentration of 5 micrograms/mL withGlucose 5% or Sodium Chloride 0.9%; if fluidrestricted,dilute to a concentration of 100 micrograms/mLFor nebulisation, dilute nebuliser solution with sterileSodium Chloride 0.9% solution according to nebulisertype and duration of administration; terbutaline andipratropium bromide solutions are compatible andmay be mixed for nebulisation.Oral and parenteralBricanyl c (AstraZeneca) ATablets, scored, terbutaline sulphate 5 mg, net price100-tab pack = £4.09Syrup, sugar-free, terbutaline sulphate 1.5 mg/5 mL,net price 100 mL = £2.00Injection, terbutaline sulphate 500 micrograms/mL,net price 1-mL amp = 30p; 5-mL amp = £1.40InhalationCounselling Advise children and carers not to exceed prescribeddose and to follow manufacturer’s directions; if apreviously effective dose of inhaled terbutaline fails toprovide at least 3 hours relief, a doctor’s advice should beobtained as soon as possibleBricanyl c (AstraZeneca) ATurbohaler c (= dry powder inhaler), terbutalinesulphate 500 micrograms/metered inhalation, netprice 100-dose unit = £6.92. Counselling, administrationRespules c (= single-dose units for nebulisation),terbutaline sulphate 2.5 mg/mL, net price 20 2-mLunits (5 mg) = £4.043.1.1.2 Other adrenoceptor agonistsAdrenaline (epinephrine) injection (1 in 1000) is usedin the emergency treatment of acute allergic and anaphylacticreactions (section 3.4.3), in angioedema (section3.4.3), and in cardiopulmonary resuscitation (section2.7.3). Adrenaline solution (1 in 1000) is used bynebulisation in the management of severe croup (section3.1).3.1.2 AntimuscarinicbronchodilatorsIpratropium by nebulisation can be added to otherstandard treatment in life-threatening acute asthma orif acute asthma fails to improve with standard therapy(see Management of Acute Asthma, p. 134). Ipratropiumcan be used to provide short-term relief inchronic asthma, but short-acting beta 2agonists actmore quickly and are preferred.The aerosol inhalation of ipratropium has a maximumeffect 30–60 minutes after use; its duration of action is 3to 6 hours.IPRATROPIUM BROMIDECautions risk of glaucoma (see below), bladder outflowobstruction; interactions: Appendix 1 (antimuscarinics)Glaucoma Acute angle-closure glaucoma reported withnebulised ipratropium, particularly when given with nebulisedsalbutamol (and possibly other beta 2 agonists); careneeded to protect the child’s eyes from nebulised drug orfrom drug powderPregnancy see p. 133Breast-feeding see p. 133Side-effects dry mouth, nausea, throat irritation,cough, headache, dizziness; less commonly diarrhoea,constipation, vomiting, palpitation, tachycardia,bronchospasm (including paradoxical bronchospasm),laryngospasm, pharyngeal oedema, urinaryretention, blurred vision, mydriasis, raised intra-ocularpressure, angle-closure glaucoma, eye pain, con-3 Respiratory system

142 3.1.3 Theophylline BNFC 2011–20123 Respiratory systemjunctival hyperaemia, corneal oedema, stomatitis,rash, pruritus; rarely atrial fibrillationIndication and doseAcute asthma. By inhalation of nebulised solutionSee Management of Acute Asthma, section 3.1Reversible airways obstruction see notes above. By aerosol inhalationChild 1 month–6 years 20 micrograms 3 timesdailyChild 6–12 years 20–40 micrograms 3 times dailyChild 12–18 years 20–40 micrograms 3–4 timesdaily. By inhalation of powderChild 12–18 years 40 micrograms 3–4 times daily(dose may be doubled in less responsive condition)Counselling Advise child and carer not to exceed prescribeddose and to follow manufacturer’s directionsRhinitis section 12.2.2Ipratropium Bromide (Non-proprietary) ANebuliser solution, ipratropium bromide 250 micrograms/mL,net price 20 1-mL (250-microgram)unit-dose vials = £6.75, 60 1-mL = £21.78; 20 2-mL (500-microgram) = £7.43, 60 2-mL = £26.97Atrovent c (Boehringer Ingelheim) AAerosol inhalationT, ipratropium bromide 20 micrograms/meteredinhalation, net price 200-dose unit =£5.05. Counselling, administrationNebuliser solution, isotonic, ipratropium bromide250 micrograms/mL, net price 20 1-mL unit-dosevials = £4.14, 60 1-mL vials = £12.44; 20 2-mLvials = £4.87, 60 2-mL vials = £14.59Ipratropium Steri-Neb c (IVAX) ANebuliser solution, isotonic, ipratropium bromide250 micrograms/mL, net price 20 1-mL (250-microgram) unit-dose vials = £8.72; 20 2-mL (500-microgram) = £9.94Respontin c (A&H) ANebuliser solution, isotonic, ipratropium bromide250 micrograms/mL, net price 20 1-mL (250-microgram) unit-dose vials = £4.78; 20 2-mL (500-microgram) = £5.603.1.3 TheophyllineTheophylline is a xanthine used as a bronchodilator inasthma, see Management of Chronic Asthma p. 135. Itmay have an additive effect when used in conjunctionwith small doses of beta 2 agonists; the combination mayincrease the risk of side-effects, including hypokalaemia(see p. 138).Theophylline is given by injection as aminophylline, amixture of theophylline with ethylenediamine, which is20 times more soluble than theophylline alone. Aminophyllineinjection is needed rarely for severe acuteasthma (see Management of Acute Asthma p. 136). Itmust be given by very slow intravenous injection (overat least 20 minutes) or by intravenous infusion; it is tooirritant for intramuscular use. Intravenous aminophyllinemay be used as a respiratory stimulant in neonateswith apnoea, but caffeine, a xanthine derivative, (section3.5.1) is usually preferred. Measurement of plasmatheophyllineconcentration may be helpful and is essentialif a loading dose of aminophylline is to be given tochildren who are already taking theophylline, becauseserious side-effects such as convulsions and arrhythmiascan occasionally precede other symptoms of toxicity.Theophylline is metabolised in the liver. The plasmatheophyllineconcentration is increased in heart failure,hepatic impairment, viral infections, and by drugs thatinhibit its metabolism. The plasma-theophylline concentrationis decreased in smokers, by alcohol consumption,and by drugs that induce its metabolism. Forinteractions of theophylline, see Appendix 1.Plasma-theophylline concentration In most individualsa plasma-theophylline concentration of 10–20 mg/litre (55–110 micromol/litre) is required forsatisfactory bronchodilation, but a lower concentrationof 5–15 mg/litre may be effective. Adverse effects canoccur within the range 10–20 mg/litre and both thefrequency and severity increase if the concentrationexceeds 20 mg/litre. In neonates, toxic symptomssometimes occur when the plasma-theophylline concentrationexceeds 14 mg/litre (78 micromol/litre). Iftheophylline is used in the treatment of neonatalapnoea, the usual target range is 8–12 mg/litre (44–66 micromol/litre).Plasma-theophylline concentration is measured 5 daysafter starting oral treatment and at least 3 days after anydose adjustment. A blood sample should be taken 1–2hours after an oral dose (after 4–6 hours in the case of amodified-release preparation). If aminophylline is givenintravenously, a blood sample should be taken 4–6 hoursafter starting treatment.THEOPHYLLINECautions see notes above; also cardiac arrhythmias orother cardiac disease, hypertension, hyperthyroidism;peptic ulcer; epilepsy; fever; hypokalaemia risk,p. 138; avoid in acute porphyria (section 9.8.2);monitor plasma-theophylline concentration (seenotes above); dose adjustment may be necessary ifsmoking started or stopped during treatment; interactions:Appendix 1 (theophylline) and notes aboveHepatic impairment reduce dosePregnancy neonatal irritability and apnoea reported;see also p. 133Breast-feeding present in milk—irritability in infantreported; modified-release preparations preferable;see also p. 133Side-effects nausea, vomiting, gastric irritation,diarrhoea, palpitation, tachycardia, arrhythmias,headache, CNS stimulation, insomnia, convulsionsoverdosage: see Emergency Treatment of Poisoning,p. 31Licensed use Slo-Phyllin c capsules not licensed foruse in children under 2 years

BNFC 2011–2012 3.1.3 Theophylline 143Indication and doseChronic asthmaSee under preparations below and Management ofChronic Asthma table p. 135Note Plasma-theophylline concentration for optimumresponse 10–20 mg/litre (55–110 micromol/litre); narrowmargin between therapeutic and toxic dose, see alsonotes aboveChild 12–18 years 200 mg every 12 hours, increasedaccording to response to 400 mg every 12 hoursNote May be appropriate to give larger evening ormorning dose to achieve optimum therapeutic effectwhen symptoms most severe; in children whose night ordaytime symptoms persist despite other therapy, who arenot currently receiving theophylline, total daily requirementmay be added as a single evening or morning doseModified releaseNote The rate of absorption from modified-release preparationscan vary between different brands. If a prescription for amodified-release oral theophylline preparation does not specifya brand name, the pharmacist should contact the prescriberand agree the brand to be dispensed. Additionally, it is essentialthat a child discharged from hospital should be maintained onthe brand on which that child was stabilised as an in-patient.Nuelin SA c (Meda)SA tablets, m/r, theophylline 175 mg. Net price 60-tab pack = £3.19. Label: 21, 25DoseChronic asthma. By mouthChild 6–12 years 175 mg every 12 hoursChild 12–18 years 175–350 mg every 12 hoursSA 250 tablets, m/r, scored, theophylline 250 mg.Net price 60-tab pack = £4.46. Label: 21, 25DoseChronic asthma. By mouthChild 6–12 years 125–250 mg every 12 hoursChild 12–18 years 250–500 mg every 12 hoursSlo-Phyllin c (Merck Serono)Capsules, m/r, theophylline 60 mg (white/clear,enclosing white pellets), net price 56-cap pack =£2.76; 125 mg (brown/clear, enclosing white pellets),56-cap pack = £3.48; 250 mg (blue/clear, enclosingwhite pellets), 56-cap pack = £4.34. Label: 25, orcounselling, see belowDoseChronic asthma. By mouthChild 6 months–2 years (body-weight under 10 kg)12 mg/kg every 12 hoursChild 2–6 years (body-weight over 10 kg) 60–120 mgevery 12 hoursChild 6–12 years 125–250 mg every 12 hoursChild 12–18 years 250–500 mg every 12 hoursAdministration Contents of the capsule (enteric-coatedgranules) may be sprinkled on to a spoonful of soft food(e.g. yoghurt) and swallowed without chewingUniphyllin Continus c (Napp)Tablets, m/r, theophylline 200 mg, net price 56-tabpack = £2.94; 300 mg, 56-tab pack = £4.77; 400 mg,56-tab pack = £5.32. Label: 25DoseChronic asthma. By mouthChild 2–12 years 9 mg/kg (up to 200 mg) every 12hours; some children with chronic asthma may require10–16 mg/kg (max. 400 mg) every 12 hoursAMINOPHYLLINENote Aminophylline is a stable mixture or combination oftheophylline and ethylenediamine; the ethylenediamine confersgreater solubility in waterCautions see under Theophylline; also rapid intravenousinjection can cause arrhythmiasHepatic impairment see under TheophyllinePregnancy see under TheophyllineBreast-feeding see under TheophyllineSide-effects see under Theophylline; also allergy toethylenediamine can cause urticaria, erythema, andexfoliative dermatitis; hypotension, arrhythmias, andconvulsions, especially if given rapidly by intravenousinjectionLicensed use Aminophylline injection not licensedfor use in children under 6 monthsIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightChronic asthma (see also Management of ChronicAsthma, p. 135). By mouthSee under preparations belowSevere acute asthma not previously treatedwith theophylline (with close monitoring; see alsoManagement of Acute Asthma, section 3.1). By intravenous injection over at least 20 minutesChild 1 month–18 years 5 mg/kg (max. 500 mg)then by intravenous infusionSevere acute asthma (with close monitoring; seealso Management of Acute Asthma, section 3.1). By intravenous infusionChild 1 month–12 years 1 mg/kg/hour adjustedaccording to plasma-theophylline concentrationChild 12–18 years 500–700 micrograms/kg/hour adjusted according to plasma-theophyllineconcentrationNote Plasma-theophylline concentration for optimumresponse in asthma 10–20 mg/litre (55–110 micromol/litre);narrow margin between therapeutic and toxic dose; childrentaking oral theophylline or aminophylline should not normallyreceive a loading dose of intravenous aminophylline; itis recommended that plasma-theophylline concentration ismeasured in all children receiving intravenous aminophylline(see notes above)3 Respiratory system

144 3.1.4 Compound bronchodilator preparations BNFC 2011–20123 Respiratory systemNeonatal apnoea (but see notes above). By intravenous injection over 20 minutesNeonate initially 6 mg/kg, then 2.5 mg/kg every12 hours (increased if necessary to 3.5 mg/kgevery 12 hours)Note Plasma-theophylline concentration for optimumresponse in neonatal apnoea 8–12 mg/litre (44–66 micromol/litre),see also notes aboveAdministration For intravenous infusion, dilute to aconcentration of 1 mg/mL with Glucose 5% or SodiumChloride 0.9%Aminophylline (Non-proprietary) AInjection, aminophylline 25 mg/mL, net price 10-mLamp = 84pInjection, aminophylline 2 mg/mL, 20-mL amp;5 mg/mL, 20-mL ampAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Modified releaseNote Advice about modified-release theophylline preparationson p. 143 also applies to modified-release aminophylline preparationsPhyllocontin Continus c (Napp)Tablets, m/r, yellow, f/c, aminophylline hydrate225 mg, net price 56-tab pack = £2.39. Label: 25DoseChronic asthma (see also Management of ChronicAsthma, p. 135). By mouthChild body-weight over 40 kg initially 1 tablet twicedaily, increased after 1 week to 2 tablets twice dailyaccording to plasma-theophylline concentrationPeak flow meters may be used to assess lung function inchildren over 5 years with asthma, but symptom monitoringis the most reliable assessment of asthma control.They are best used for short periods to assess theseverity of asthma and to monitor response to treatment;continuous use of peak flow meters may detractfrom compliance with inhalers.Standard Range Peak Flow MeterConforms to standard EN ISO 23747: 2007AirZone c , range 60–720 litres/minute, net price = £4.50,replacement mouthpiece = 38p (Clement Clarke)Medi c , range 60–800 litres/minute, net price = £4.50(Medicare)MicroPeak c , range 60–800 litres/minute, net price = £6.50,replacement mouthpiece = 38p (Micro Medical)Mini-Wright c , range 60–800 litres/minute, net price = £6.86,replacement mouthpiece = 38p (Clement Clarke)Personal Best c , range 60–800 litres/minute, net price =£6.86, replacement mouthpiece = 25p (Respironics)Piko-1 c , range 15–999 litres/minute, net price = £9.50,replacement mouthpiece = 38p (nSPIRE Health)Pinnacle c , range 60–900 litres/minute, net price = £6.50(Fyne Dynamics)Pocketpeak c , range 60–800 litres/minute, net price = £6.53,replacement mouthpiece = 38p (nSPIRE Health)Vitalograph c , range 50–800 litres/minute, net price = £4.75(a child’s peak flow meter is also available), replacementmouthpiece = 40p (Vitalograph)Note Readings from new peak flow meters are often lower thanthose obtained from old Wright-scale peak flow meters and thecorrect recording chart should be usedLow Range Peak Flow MeterCompliant to standard EN ISO 23747: 2007 except forscale rangeMedi c , range 40–420 litres/minute, net price = £6.50(Medicare)Mini-Wright c , range 30–400 litres/minute, net price = £6.90,replacement mouthpiece = 38p (Clement Clarke)Pocketpeak c , range 50–400 litres/minute, net price = £6.53,replacement mouthpiece = 38p (nSPIRE Health)Note Readings from new peak flow meters are often lower thanthose obtained from old Wright-scale peak flow meters and thecorrect recording chart should be used3.1.4 Compound bronchodilatorpreparationsIn general, children are best treated with single-ingredientpreparations, such as a selective beta 2 agonist(section 3.1.1.1) or ipratropium bromide (section3.1.2), so that the dose of each drug can be adjusted.This flexibility is lost with compound bronchodilatorpreparations.3.1.5 Peak flow meters, inhalerdevices, and nebulisersPeak flow metersDrug delivery devicesInhaler devices A pressurised metered-dose inhaler isan effective method of drug administration in mild tomoderate chronic asthma; to deliver the drug effectively,a spacer device should also be used (see also NICEguidance, below). By the age of 3 years, a child canusually be taught to use a spacer device without a mask.As soon as a child is able to use the mouthpiece, thenthis is the preferred delivery system.Dry powder inhalers may be useful in children over 5years, who are unwilling or unable to use a pressurisedmetered-dose inhaler with a spacer device; breath-actuatedinhalers may be useful in older children if they areable to use the device effectively. The child or child’scarer should be instructed carefully on the use of theinhaler. It is important to check that the inhaler is beingused correctly; poor inhalation technique may be mistakenfor a lack of response to the drug.On changing from a pressurised metered-dose inhaler toa dry powder inhaler, the child may notice a lack ofsensation in the mouth and throat previously associatedwith each actuation; coughing may occur more frequentlyfollowing use of a dry-powder inhaler.CFC-free metered-dose inhalers should be cleanedweekly according to the manufacturer’s instructions.

BNFC 2011–2012 3.1.5 Peak flow meters, inhaler devices, and nebulisers 145NICE guidanceInhaler devices for children with chronicasthma (children under 5 years, August2000; children 5–15 years, March 2002)A child’s needs, ability to develop and maintaineffective technique, and likelihood of good complianceshould govern the choice of inhaler and spacerdevice; only then should cost be considered.For children aged under 5 years:. corticosteroid and bronchodilator therapyshould be delivered by pressurised metereddoseinhaler and spacer device, with a facemaskif necessary;. if this is not effective, and depending on thechild’s condition, nebulised therapy may be consideredand, in children over 3 years, a drypowder inhaler may also be considered [butsee notes above].For children aged 5–15 years:. corticosteroid therapy should be routinely deliveredby a pressurised metered-dose inhaler andspacer device;. children and their carers should be trained in theuse of the chosen device; suitability of the deviceshould be reviewed at least annually. Inhalertechnique and compliance should be monitored.Spacer devices Spacer devices are particularly usefulfor infants, for children with poor inhalation technique,or for nocturnal asthma, because the device reduces theneed for coordination between actuation of a pressurisedmetered-dose inhaler and inhalation. The spacerdevice reduces the velocity of the aerosol and subsequentimpaction on the oropharynx and allows moretime for evaporation of the propellant so that a largerproportion of the particles can be inhaled and depositedin the lungs. Smaller-volume spacers may be moremanageable for pre-school children and infants. Thespacer device used must be compatible with the prescribedmetered-dose inhaler.Use and care of spacer devices The suitability ofthe spacer device should be carefully assessed; openingthe one-way valve is dependent on the child’s inspiratoryflow. Some devices can be tipped to 458 to open thevalve during inhaler actuation and inspiration to assistthe child.Inhalation from the spacer device should follow theactuation as soon as possible because the drug aerosolis very short-lived. The total dose (which may be morethan a single puff) should be administered as singleactuations (with tidal breathing for 10–20 seconds or5–6 breaths for each actuation) for children with goodinspiratory flow. Larger doses may be necessary for achild with acute bronchospasm; for guidance on theManagement of Acute Asthma, see section 3.1.The device should be cleansed once a month by washingin mild detergent and then allowed to dry in airwithout rinsing; the mouthpiece should be wiped cleanof detergent before use. Some manufacturers recommendmore frequent cleaning, but this should beavoided since any electrostatic charge may affect drugdelivery. Spacer devices should be replaced every 6–12months.Able Spacer c (Clement Clarke)Spacer device, small-volume device. For use with all pressurised(aerosol) inhalers, net price standard device = £4.20;with infant, child or adult mask = £6.86AeroChamber c Plus (GSK)Spacer device, medium-volume device. For use with allpressurised (aerosol) inhalers, net price standard device(blue) = £4.53, with mask (blue) = £7.56; infant device(orange) with mask = £7.56; child device (yellow) with mask= £7.56Babyhaler c (A&H) DSpacer device, paediatric use with Flixotide c , andVentolin c inhalers, net price = £11.34Haleraid c (A&H)Inhalation aid, device to place over pressurised (aerosol)inhalers to aid when strength in hands is impaired (e.g.arthritis). For use with Flixotide c , Seretide c , Serevent c , andVentolin c inhalers. Available as Haleraid c -120 for 120-doseinhalers and Haleraid c -200 for 200-dose inhalers, net price= 80pOptichamber c (Respironics)Spacer device, for use with all pressurised (aerosol) inhalers,net price = £4.28; with small, medium or large mask = £7.00PARI Vortex Spacer c (Pari) DSpacer device, medium-volume device. For use with allpressurised (aerosol) inhalers, net price with mouthpiece =£6.07D; with mask for infant or child = £7.91; with adultmask = £9.97DPocket Chamber c (nSPIRE Health)Spacer device, small-volume device. For use with all pressurised(aerosol) inhalers, net price = £4.18; with infant,small, medium, or large mask = £9.75Volumatic c (A&H)Spacer inhaler, large-volume device. For use with ClenilModulite c , Flixotide c , Seretide c , Serevent c , and Ventolin cinhalers, net price = £2.81; with paediatric mask = £2.81NebulisersIn England and Wales nebulisers and compressorsare not available on the NHS (but they are free ofVAT); some nebulisers (but not compressors) areavailable on form GP10A in Scotland (for detailsconsult Scottish Drug Tariff).A nebuliser converts a solution of a drug into an aerosolfor inhalation. It is used to deliver higher doses of drugto the airways than is usual with standard inhalers. Themain indications for use of a nebuliser are:. to deliver a beta 2 agonist or ipratropium to a childwith an acute exacerbation of asthma or of airwaysobstruction;. to deliver prophylactic medication to a child unableto use other conventional devices;. to deliver an antibacterial (such as colistimethatesodium or tobramycin) to a child with chronicpurulent infection (as in cystic fibrosis or bronchiectasis);. to deliver budesonide to a child with severe croup;The proportion of a nebuliser solution that reaches thelungs depends on the type of nebuliser and although itcan be as high as 30% it is more frequently close to 10%and sometimes below 10%. The remaining solution isleft in the nebuliser as residual volume or it is deposited3 Respiratory system

146 3.2 Corticosteroids BNFC 2011–20123 Respiratory systemin the mouthpiece and tubing. The extent to which thenebulised solution is deposited in the airways or alveolidepends on particle size. Particles with a median diameterof 1–5 microns are deposited in the airways andare therefore appropriate for asthma whereas a particlesize of 1–2 microns is needed for alveolar deposition.The type of nebuliser is therefore chosen according tothe deposition required and according to the viscosity ofthe solution (antibacterial solutions usually being moreviscous).Some jet nebulisers are able to increase drug outputduring inspiration and hence increase efficiency.Nebulised bronchodilators are appropriate for childrenwith chronic persistent asthma or those with severeacute asthma. In chronic asthma, nebulised bronchodilatorsshould only be used to relieve persistent dailywheeze, however, with the development of spacers withfacemasks, it is now unusual for a child to require longtermnebulised asthma therapy (see Management ofChronic Asthma table, p. 135). The use of nebulisersin chronic persistent asthma should be considered only:. after a review of the diagnosis and use of currentinhaler devices;. if the airflow obstruction is significantly reversibleby bronchodilators without unacceptable sideeffects;. if the child does not benefit from use of conventionalinhaler device, such as pressurised metereddoseinhaler plus spacer;. if the child is complying with the prescribed doseand frequency of anti-inflammatory treatmentincluding regular use of high-dose inhaled corticosteroid.When a nebuliser is prescribed, the child or child’s carermust:. have clear instructions from doctor, specialist nurseor pharmacist on the use of the nebuliser (and onpeak-flow monitoring—see notes above);. be instructed not to treat acute attacks without alsoseeking medical help;. have regular follow up with doctor or specialistnurse.Jet nebulisers are more widely used than ultrasonicnebulisers. Most jet nebulisers require an optimumflow rate of 6–8 litres/minute and in hospital can bedriven by piped air or oxygen; in acute asthma thenebuliser should always be driven by oxygen. Domiciliaryoxygen cylinders do not provide an adequate flowrate therefore an electrical compressor is required fordomiciliary use.Safe practiceThe Department of Health has reminded users of theneed to use the correct grade of tubing when connectinga nebuliser to a medical gas supply orcompressor.Nebuliser diluentNebulisation may be carried out using an undilutednebuliser solution or it may require dilution beforehand.The usual diluent is sterile sodium chloride 0.9%(physiological saline).Sodium Chloride (Non-proprietary) ANebuliser solution, sodium chloride 0.9%, net price20 2.5 mL = £11.50Brands include Saline Steripoule c , Saline Steri-Neb c3.2 CorticosteroidsCorticosteroids are effective in the management ofasthma; they reduce airway inflammation.An inhaled corticosteroid is used regularly for prophylaxisof asthma when a child requires a beta 2 agonistmore than twice a week, or if symptoms disturb sleepmore than once a week, or if the child has sufferedexacerbations in the last 2 years requiring a systemiccorticosteroid or a nebulised bronchodilator (see Managementof Chronic Asthma table, p. 135).In adults, current or previous smoking reduces theeffectiveness of inhaled corticosteroids and higherdoses may be necessary.Corticosteroid inhalers must be used regularly for maximumbenefit; alleviation of symptoms usually occurs 3to 7 days after initiation but may take longer. Beclometasonedipropionate, budesonide, fluticasonepropionate, and mometasone furoate appear to beequally effective. A spacer device should be used foradministering inhaled corticosteroids in children under15 years (see NICE guidance, section 3.1.5); a spacerdevice is also useful in children over 15 years, particularlyif high doses are required.In children 12–18 years using an inhaled corticosteroidand a long-acting beta 2 agonist for the prophylaxis ofasthma, but who are poorly controlled, (see step 3 of theManagement of Chronic Asthma table, p. 135)Symbicort c (budesonide with formoterol) may beused as a reliever (instead of a short-acting beta 2agonist), in addition to its regular use for the prophylaxisof asthma [unlicensed]. Symbicort c can also be used inthis way in children 12–18 years using an inhaledcorticosteroid with a dose greater than 400 microgramsbeclometasone dipropionate daily 1 , but who are poorlycontrolled [unlicensed] (see step 2 of the Managementof Chronic Asthma table, p. 135). When starting thistreatment, the total regular dose of inhaled corticosteroidshould not be reduced. Children and their carersmust be carefully instructed on the appropriate doseand management of exacerbations before initiating thistreatment, preferably by a respiratory specialist. Childrenusing budesonide with formoterol as a relieveronce a day or more should have their treatmentreviewed regularly; see also Side-effects below. Thismanagement approach has not been investigated withcombination inhalers containing other corticosteroidsand long-acting beta 2 agonists.High doses of inhaled corticosteroids can be prescribedfor children who respond only partially to standarddoses of an inhaled corticosteroid and a long-actingbeta 2 agonist or to other long-acting bronchodilators(see Management of Chronic Asthma table, p. 135).High doses should be continued only if there is clearbenefit over the lower dose. The recommended maximumdose of an inhaled corticosteroid should not1. For standard doses of other inhaled corticosteroids, seeManagement of Chronic Asthma table, p. 135

BNFC 2011–2012 3.2 Corticosteroids 147generally be exceeded; however, if a higher dose isrequired it should be initiated and supervised by arespiratory paediatrician. The use of high doses of aninhaled corticosteroid can minimise the requirement foran oral corticosteroid.Cautions of inhaled corticosteroids Systemic therapymay be required during periods of stress, such asduring severe infections, or when airways obstruction ormucus prevent drug access to smaller airways; interactions:Appendix 1 (corticosteroids).Paradoxical bronchospasm The potential for paradoxicalbronchospasm (calling for discontinuation and alternativetherapy) should be borne in mind—mild bronchospasmmay be prevented by inhalation of a shortactingbeta 2 agonist beforehand (or by transfer from anaerosol inhalation to a dry powder inhalation if suitable).CFC-free inhalers Chlorofluorocarbon (CFC) propellantsin pressurised aerosol inhalers have been replacedby hydrofluoroalkane (HFA) propellants.Doses for corticosteroid CFC-free inhalers may be differentfrom traditional CFC-containing inhalers and maydiffer between brands, see MHRA/CHM advice below.MHRA/CHM advice (July 2008)Beclometasone dipropionate CFC-free pressurisedmetered-dose inhalers (Qvar c and Clenil Modulitec ) are not interchangeable and should beprescribed by brand name; Qvar c has extra-fineparticles, is more potent than traditional beclometasonedipropionate CFC-containing inhalers, and isapproximately twice as potent as Clenil Modulite c .Side-effects of inhaled corticosteroids Inhaledcorticosteroids have considerably fewer systemiceffects than oral corticosteroids, but adverse effectshave been reported.High doses of inhaled corticosteroids (see Managementof Chronic Asthma table, p. 135) used for prolongedperiods can induce adrenal suppression. Inhaled corticosteroidshave occasionally been associated with adrenalcrisis and coma in children; excessive doses shouldbe avoided. Children using high doses of inhaled corticosteroidsshould be under the supervision of a paediatricianfor the duration of the treatment; they should begiven a ‘steroid card’ (section 6.3.2) and specific writtenadvice to consider corticosteroid replacement during anepisode of stress, such as a severe intercurrent illness oran operation.In adults, bone mineral density is sometimes reducedfollowing long-term inhalation of higher doses of corticosteroids,predisposing patients to osteoporosis (section6.6). It is, therefore, sensible to ensure that the doseof an inhaled corticosteroid is no higher than necessaryto keep a child’s asthma under good control.Growth restriction associated with systemic corticosteroidtherapy does not seem to occur with recommendeddoses of inhaled corticosteroids; although initialgrowth velocity may be reduced, there appears to beno effect on achieving normal adult height. However,the height of children receiving prolonged treatmentwith inhaled corticosteroid should be monitored; ifgrowth is slowed, referral to a paediatrician should beconsidered.Hoarseness and candidiasis of the mouth or throat havebeen reported, usually only with high doses (see alsobelow). Hypersensitivity reactions (including rash andangioedema) have been reported rarely. Other sideeffectsthat have very rarely been reported includeparadoxical bronchospasm, anxiety, depression, sleepdisturbances, and behavioural changes including hyperactivity,irritability, and aggression (particularly in children);skin thinning and bruising have also beenreported.Candidiasis The risk of oral candidiasis can be reducedby using a spacer device with the corticosteroid inhaler;rinsing the mouth with water (or cleaning the child’steeth) after inhalation of a dose may also be helpful.Antifungal oral suspension or oral gel (section 12.3.2)can be used to treat oral candidiasis while continuingcorticosteroid therapy.Oral An acute attack of asthma should be treated with ashort course (3–5 days) of oral corticosteroid, see Managementof Acute Asthma, p. 134. The dose can usuallybe stopped abruptly but it should be reduced graduallyin children under 12 years who have taken corticosteroidsfor more than 14 days. Tapering is not needed inchildren 12–18 years provided that the child receives aninhaled corticosteroid in an adequate dose (apart fromthose on maintenance oral corticosteroid treatment orwhere oral corticosteroids are required for 3 or moreweeks); see also Withdrawal of Corticosteroids, section6.3.2.In chronic continuing asthma, when the response toother drugs has been inadequate, longer term administrationof an oral corticosteroid may be necessary; insuch cases high doses of an inhaled corticosteroidshould be continued to minimise oral corticosteroidrequirements.An oral corticosteroid should normally be taken as asingle dose in the morning to reduce the disturbance tocircadian cortisol secretion. Dosage should always betitrated to the lowest dose that controls symptoms.Some clinicians use alternate-day dosing of an oralcorticosteroid.Parenteral For the use of hydrocortisone injection inthe emergency treatment of acute severe asthma, seeManagement of Acute Asthma, p. 134.BECLOMETASONE DIPROPIONATE(Beclomethasone Dipropionate)Cautions see notes abovePregnancy see p. 133Breast-feeding see p. 133Side-effects see notes aboveLicensed use Becodisk c -400, Clenil Modulite c -200and -250, and Qvar c are not licensed for use inchildren under 12 yearsIndication and doseProphylaxis of asthmaSee Management of Chronic Asthma table, p. 135Important for Asmabec Clickhaler c , Becodisks c , andQvar c doses, see under preparations belowBeclometasone (Non-proprietary) ADry powder for inhalation, beclometasonedipropionate 100 micrograms/metered inhalation, netprice 100-dose unit = £5.36; 200 micrograms/metered inhalation, 100-dose unit = £9.89, 200-dose3 Respiratory system

148 3.2 Corticosteroids BNFC 2011–20123 Respiratory systemunit = £14.93; 400 micrograms/metered inhalation,100-dose unit = £19.61. Label: 8, counselling, administration;also 10 and steroid card with high dosesBrands include Pulvinal c Beclometasone Dipropionate, Easyhalerc Beclometasone DipropionateAsmabec Clickhaler c (UCB Pharma) ADry powder for inhalation, beclometasonedipropionate 50 micrograms/metered inhalation, netprice 200-dose unit = £6.42; 100 micrograms/metered inhalation, 200-dose unit = £9.43; 250 micrograms/meteredinhalation, 100-dose unit = £11.83.Label: 8, counselling, administration; also 10 andsteroid card with high dosesDoseProphylaxis of asthma. By inhalation of powderChild 6–12 years 50–200 micrograms twice daily,adjusted as necessaryChild 12–18 years 100–400 micrograms twice daily,adjusted as necessary; max. 1 mg twice dailyBecodisks c (A&H) ADry powder for inhalation, disks containing 8 blistersof beclometasone dipropionate 100 micrograms/blister,net price 15 disks with Diskhaler c device =£11.30, 15-disk refill = £10.76; 200 micrograms/blister, 15 disks with Diskhaler c device = £21.54, 15-disk refill = £20.99; 400 micrograms/blister, 15 diskswith Diskhaler c device = £42.52, 15-disk refill =£41.98. Label: 8, counselling, administration; also 10and steroid card with high dosesDoseProphylaxis of asthma. By inhalation of powderChild 5–12 years 100–200 micrograms twice daily,adjusted as necessaryChild 12–18 years 400–800 micrograms twice daily,adjusted as necessaryClenil Modulite c (Chiesi) AAerosol inhalation, beclometasone dipropionate50 micrograms/metered inhalation, net price 200-dose unit = £3.70; 100 micrograms/metered inhalation= £7.42; 200 micrograms/metered inhalation =£16.17; 250 micrograms/metered inhalation = £16.29.Label: 8, counselling, administration; also 10 andsteroid card with high dosesDoseProphylaxis of asthma. By aerosol inhalationChild 2–12 years 100–200 micrograms twice dailyChild 12–18 years 200–400 micrograms twice dailyadjusted as necessary up to 1 mg twice dailyNote Clenil Modulite c is not interchangeable with otherCFC-free beclometasone dipropionate inhalers; the MHRAhas advised (July 2008) that CFC-free beclometasonedipropionate inhalers should be prescribed by brand name,see p. 147Dental Prescribing on NHS Clenil Modulite c 50 micrograms/meteredinhalation may be prescribedQvar c (TEVA UK) AAerosol inhalation, beclometasone dipropionate50 micrograms/metered inhalation, net price 200-dose unit = £7.87; 100 micrograms/metered inhalation,200-dose unit = £17.21. Label: 8, counselling,administration; also 10 and steroid card with highdosesAutohaler c (breath-actuated aerosol inhalation),beclometasone dipropionate 50 micrograms/meteredinhalation, net price 200-dose unit = £7.87; 100 micrograms/meteredinhalation, 200-dose unit = £17.21.Label: 8, counselling, administration; also 10 andsteroid card with high dosesEasi-Breathe c (breath-actuated aerosol inhalation),beclometasone dipropionate 50 micrograms/meteredinhalation, net price 200-dose = £7.74; 100 micrograms/meteredinhalation, 200-dose = £16.95.Label: 8, counselling, administration; also 10 andsteroid card with high dosesDoseProphylaxis of asthma. By aerosol inhalationChild 12–18 years 50–200 micrograms twice daily,increased if necessary to max. 400 micrograms twicedailyImportant When switching a child with well-controlledasthma from another corticosteroid inhaler, initially a 100-microgram metered dose of Qvar c should be prescribed for:. 200–250 micrograms of beclometasone dipropionate or budesonide. 100 micrograms of fluticasone propionateWhen switching a child with poorly controlled asthma fromanother corticosteroid inhaler, initially a 100-microgrammetered dose of Qvar c should be prescribed for 100 microgramsof beclometasone dipropionate, budesonide, orfluticasone propionate; the dose of Qvar c should beadjusted according to responseNote Qvar c is not interchangeable with other CFC-freebeclometasone dipropionate inhalers; the MHRA hasadvised (July 2008) that beclometasone dipropionate CFCfreeinhalers should be prescribed by brand name, see p. 147BUDESONIDECautions see notes abovePregnancy see p. 133Breast-feeding see p. 133Side-effects see notes aboveLicensed use Pulmicort c nebuliser solution notlicensed for use in children under 3 months; notlicensed for use in bronchopulmonary dysplasia;Symbicort c not licensed for use in children forasthma maintenance and reliever therapyIndication and doseProphylaxis of asthma see Management ofChronic Asthma table, p. 135, and preparationsbelowCroup. By inhalation of nebuliser suspensionChild over 1 month 2 mg as single dose or in 2divided doses separated by 30 minutes; dose maybe repeated after 12 hours if necessaryBronchopulmonary dysplasia with assistedventilation. By aerosol inhalationNeonate 400 micrograms twice dailyChild 1–4 months 400 micrograms twice dailyBronchopulmonary dysplasia with spontaneousrespiration. By inhalation of nebuliser suspensionNeonate 500 micrograms twice daily

BNFC 2011–2012 3.2 Corticosteroids 149Child 1–4 months 500 micrograms twice daily;for severe symptoms in child body-weight 2.5 kg orover, 1 mg twice dailyAdministration For aerosol inhalation in ventilatedbabies with bronchopulmonary dysplasia, use medium-volumespacer (section 3.1.5) attached directly toendotracheal tube; hand-ventilate through spacer,using a bag system; inflate chest 10 times betweenactivations of inhalerBudesonide (Non-proprietary) ADry powder for inhalation, budesonide 100 micrograms/meteredinhalation, net price 200-dose unit =£8.86; 200 micrograms/metered inhalation 200-doseunit = £17.71; 400 micrograms/metered inhalation100-dose unit = £17.71. Label: 8, counselling, administration;also 10 and steroid card with high dosesBrands include Easyhaler c BudesonideDoseProphylaxis of asthma. By inhalation of powderChild 6–12 years 100–400 micrograms twice daily,adjusted as necessary; alternatively, in mild to moderateasthma, 200–400 micrograms as a single dose each eveningif stabilised on daily dose given in 2 divided dosesChild 12–18 years 100–800 micrograms twice daily,adjusted as necessary; alternatively, in mild to moderateasthma, 200–400 micrograms as a single dose each eveningif stabilised on daily dose given in 2 divided doses(max. 800 micrograms)Budelin Novolizer c (Meda) ADry powder for inhalation, budesonide 200 micrograms,net price refillable inhaler device and 100-dose cartridge = £14.86; 100-dose refill cartridge =£9.59. Label: 8, counselling, administration; also 10and steroid card with high dosesDoseProphylaxis of asthma. By inhalation of powderChild 6–12 years 200–400 micrograms twice daily,adjusted as necessary; alternatively, in mild to moderateasthma, 200–400 micrograms as a single dose each eveningif stabilised on daily dose given in 2 divided dosesChild 12–18 years 200–800 micrograms twice daily,adjusted as necessary; alternatively, in mild to moderateasthma, 200–400 micrograms as a single dose each eveningif stabilised on daily dose given in 2 divided doses(max. 800 micrograms)Pulmicort c (AstraZeneca) ATurbohaler c (= dry powder inhaler), budesonide100 micrograms/metered inhalation, net price 200-dose unit = £11.84; 200 micrograms/metered inhalation,100-dose unit = £11.84; 400 micrograms/metered inhalation, 50-dose unit = £13.86. Label: 8,counselling, administration; also 10 and steroid cardwith high dosesDoseProphylaxis of asthma. By inhalation of powderChild 6–12 years 100–400 micrograms twice daily,adjusted as necessary; alternatively, in mild to moderateasthma, 200–400 micrograms as a single dose each eveningif stabilised on daily dose given in 2 divided dosesChild 12–18 years 100–800 micrograms twice daily,adjusted as necessary; alternatively, in mild to moderateasthma, 200–400 micrograms as a single dose each eveningif stabilised on daily dose given in 2 divided doses(max. 800 micrograms)Respules c (= single-dose units for nebulisation),budesonide 250 micrograms/mL, net price 20 2-mL(500-microgram) unit = £20.02; 500 micrograms/mL,20 2-mL (1-mg) unit = £30.30. May be diluted withsterile sodium chloride 0.9%. Label: 8, counselling,administration, 10, steroid cardNote Not suitable for use in ultrasonic nebulisersDoseProphylaxis of asthma. By inhalation of nebuliser suspensionChild 3 months–12 years initially 0.5–1 mg twice daily,reduced to 250–500 micrograms twice dailyChild 12–18 years initially 1–2 mg twice daily, reducedto 0.5–1 mg twice dailyCompound preparationsFor prescribing information on formoterol fumarate,see section 3.1.1.1Symbicort c (AstraZeneca) ASymbicort 100/6 Turbohaler c (= dry powderinhaler), budesonide 100 micrograms, formoterolfumarate 6 micrograms/metered inhalation, net price120-dose unit = £33.00. Label: 8, counselling,administrationDoseAsthma, maintenance therapy. By inhalation of powderChild 6–12 years 1–2 puffs twice daily reduced to 1 puffonce daily if control maintainedChild 12–18 years 1–2 puffs twice daily reduced to 1puff once daily if control maintainedAsthma, maintenance and reliever therapy (but seenotes above, p. 146). By inhalation of powderChild 12–18 years 2 puffs daily in 1–2 divided doses; forrelief of symptoms, 1 puff as needed up to max. 6 puffs ata time; max. 8 puffs dailySymbicort 200/6 Turbohaler c (= dry powderinhaler), budesonide 200 micrograms, formoterolfumarate 6 micrograms/metered inhalation, net price120-dose unit = £38.00. Label: 8, counselling,administration; also 10 and steroid card with highdosesDoseAsthma, maintenance therapy. By inhalation of powderChild 12–18 years 1–2 puffs twice daily reduced in wellcontrolledasthma to 1 puff once dailyAsthma, maintenance and reliever therapy (but seenotes above, p. 146). By inhalation of powderChild 12–18 years 2 puffs daily in 1–2 divided doses,increased if necessary to 2 puffs twice daily; for relief ofsymptoms, 1 puff as needed up to max. 6 puffs at a time;max. 8 puffs dailySymbicort 400/12 Turbohaler c (= dry powderinhaler), budesonide 400 micrograms, formoterolfumarate 12 micrograms/metered inhalation, netprice 60-dose unit = £38.00. Label: 8, counselling,administration; also 10 and steroid card with highdosesDoseAsthma, maintenance therapy. By inhalation of powderChild 12–18 years 1 puff twice daily; may be reduced inwell-controlled asthma to 1 puff once daily3 Respiratory system

150 3.2 Corticosteroids BNFC 2011–2012CICLESONIDECautions see notes abovePregnancy see p. 133Breast-feeding see p. 133Side-effects see notes aboveIndication and doseProphylaxis of asthma. By aerosol inhalationChild 12–18 years 160 micrograms daily as asingle dose reduced to 80 micrograms daily ifcontrol maintainedNebules c (= single-dose units for nebulisation)fluticasone propionate 250 micrograms/mL, net price10 2-mL (500-microgram) unit = £9.34; 1 mg/mL,10 2-mL (2-mg) unit = £37.35. May be diluted withsterile sodium chloride 0.9%. Label: 8, counselling,administration, 10, steroid cardNote Not suitable for use in ultrasonic nebulisersDoseProphylaxis of asthma. By inhalation of nebuliser suspensionChild 4–16 years 1 mg twice dailyChild 16–18 years 0.5–2 mg twice daily3 Respiratory systemAlvesco c (Nycomed) AAerosol inhalation, ciclesonide 80 micrograms/metered inhalation, net price 120-dose unit = £32.83;160 micrograms/metered inhalation, 60-dose unit =£19.31, 120-dose unit = £38.62. Label: 8, counselling,administrationFLUTICASONE PROPIONATECautions see notes abovePregnancy see p. 133Breast-feeding see p. 133Side-effects see notes above; also very rarely dyspepsia,hyperglycaemia, and arthralgiaIndication and doseProphylaxis of asthma see Management ofChronic Asthma table, p. 135, and preparationsbelowFlixotide c (A&H) AAccuhaler c (dry powder for inhalation), disk containing60 blisters of fluticasone propionate 50 micrograms/blisterwith Accuhaler c device, net price =£6.38; 100 micrograms/blister with Accuhaler cdevice = £8.93; 250 micrograms/blister withAccuhaler c device = £21.26; 500 micrograms/blisterwith Accuhaler c device = £36.14. Label: 8, counselling,administration; also 10 and steroid card with highdosesDoseProphylaxis of asthma. By inhalation of powderChild 5–16 years 50–100 micrograms twice dailyadjusted as necessary; max. 200 micrograms twice dailyChild 16–18 years 100–500 micrograms twice daily,adjusted as necessary; max. 1 mg twice daily (dosesabove 500 micrograms twice daily initiated by a specialist)Evohaler c (aerosol inhalation), fluticasone propionate50 micrograms/metered inhalation, net price 120-dose unit = £5.44; 125 micrograms/metered inhalation,120-dose unit = £21.26; 250 micrograms/metered inhalation, 120-dose unit = £36.14. Label: 8,counselling, administration; also 10 and steroid cardwith high dosesDoseProphylaxis of asthma. By aerosol inhalationChild 4–16 years 50–100 micrograms twice dailyadjusted as necessary; max. 200 micrograms twice dailyChild 16–18 years 100–500 micrograms twice dailyadjusted as necessary; max. 1 mg twice daily (dosesabove 500 micrograms twice daily initiated by a specialist)Compound preparationsFor prescribing information on salmeterol, see section3.1.1.1Seretide c (A&H) ASeretide 100 Accuhaler c (dry powder for inhalation),disk containing 60 blisters of fluticasonepropionate 100 micrograms, salmeterol (as xinafoate)50 micrograms/blister with Accuhaler c device, netprice = £31.19. Label: 8, counselling, administrationDoseProphylaxis of asthma. By inhalation of powderChild 5–18 years 1 blister twice daily, reduced to 1blister once daily if control maintainedSeretide 250 Accuhaler c (dry powder for inhalation),disk containing 60 blisters of fluticasonepropionate 250 micrograms, salmeterol (as xinafoate)50 micrograms/blister with Accuhaler c device, netprice = £35.00. Label: 8, counselling, administration,10, steroid cardDoseProphylaxis of asthma. By inhalation of powderChild 12–18 years 1 blister twice dailySeretide 500 Accuhaler c (dry powder for inhalation),disk containing 60 blisters of fluticasonepropionate 500 micrograms, salmeterol (as xinafoate)50 micrograms/blister with Accuhaler c device, netprice = £40.92. Label: 8, counselling, administration,10, steroid cardDoseProphylaxis of asthma. By inhalation of powderChild 12–18 years 1 blister twice dailySeretide 50 Evohaler c (aerosol inhalation), fluticasonepropionate 50 micrograms, salmeterol (asxinafoate) 25 micrograms/metered inhalation, netprice 120-dose unit = £18.00. Label: 8, counselling,administrationDoseProphylaxis of asthma. By aerosol inhalationChild 5–18 years 2 puffs twice daily, reduced to 2 puffsonce daily if control maintainedSeretide 125 Evohaler c (aerosol inhalation), fluticasonepropionate 125 micrograms, salmeterol (asxinafoate) 25 micrograms/metered inhalation, net

BNFC 2011–2012 3.3 Cromoglicate and related therapy 151price 120-dose unit = £35.00. Label: 8, counselling,administration, 10, steroid cardDoseProphylaxis of asthma. By aerosol inhalationChild 12–18 years 2 puffs twice dailySeretide 250 Evohaler c (aerosol inhalation), fluticasonepropionate 250 micrograms, salmeterol (asxinafoate) 25 micrograms/metered inhalation, netprice 120-dose unit = £59.48. Label: 8, counselling,administration, 10, steroid cardDoseProphylaxis of asthma. By aerosol inhalationChild 12–18 years 2 puffs twice dailyMOMETASONE FUROATECautions see notes abovePregnancy see p. 133Breast-feeding see p. 133Side-effects see notes above; also pharyngitis, headache;less commonly palpitationIndication and doseProphylaxis of asthma see also Management ofChronic Asthma table, p. 135. By inhalation of powderChild 12–18 years 200–400 micrograms as asingle dose in the evening or in 2 divided doses;dose increased to 400 micrograms twice daily ifnecessaryAsmanex c (MSD) TATwisthaler (= dry powder inhaler), mometasone furoate200 micrograms/metered inhalation, net price30-dose unit = £15.70, 60-dose unit = £23.54;400 micrograms/metered inhalation, 30-dose unit =£21.78, 60-dose unit = £36.05. Label: 8, counselling,administration, 10, steroid cardNote The Scottish Medicines Consortium has advised(November 2003) that Asmanex c is restricted for usefollowing failure of first-line inhaled corticosteroidschildren is contentious. Prophylaxis with cromoglicateor nedocromil is less effective than with inhaled corticosteroids(see Management of Chronic Asthma table).Withdrawal of sodium cromoglicate or nedocromilshould be done gradually over a period of one week—symptoms of asthma may recur.Nedocromil may be of some benefit in the prophylaxisof exercise-induced asthma.For the use of sodium cromoglicate and nedocromil inallergic conjunctivitis see section 11.4.2; sodium cromoglicateis used also in allergic rhinitis (section 12.2.1)and allergy-related diarrhoea (section 1.5.4).Paradoxical bronchospasm If paradoxical bronchospasmoccurs, a short-acting beta 2 agonist such as salbutamolor terbutaline (section 3.1.1.1) should be usedto control symptoms; treatment with sodium cromoglicateor nedocromil should be discontinued.Side-effects Side-effects associated with inhalation ofsodium cromoglicate and nedocromil include throatirritation, cough, bronchospasm (including paradoxicalbronchospasm—see above), and headache.SODIUM CROMOGLICATE(Sodium Cromoglycate)Cautions see notes above; also discontinue if eosinophilicpneumonia occursPregnancy see p. 133Breast-feeding see p. 133Side-effects see notes above; rhinitis and eosinophilicpneumonia also reportedIndication and doseProphylaxis of asthma (see also Management ofChronic Asthma, p. 135). By aerosol inhalationChild 5–18 years 10 mg (2 puffs) 4 times daily,increased if necessary to 6–8 times daily; anadditional dose may also be taken before exercise;maintenance, 5 mg (1 puff) 4 times dailyFood allergy section 1.5.43 Respiratory system3.3 Cromoglicate and relatedtherapy and leukotrienereceptor antagonists3.3.1 Cromoglicate and related therapy3.3.2 Leukotriene receptor antagonistsAllergic conjunctivitis section 11.4.2Allergic rhinitis section 12.2.1Intal c CFC-free inhaler (Sanofi-Aventis) AAerosol inhalation, sodium cromoglicate 5 mg/metered inhalation, net price 112-dose unit = £14.84.Label: 8, counselling, administration3.3.1 Cromoglicate and relatedtherapyThe mode of action of sodium cromoglicate and nedocromilis not completely understood; they may be ofvalue as prophylaxis in asthma with an allergic basis,but the evidence for benefit of sodium cromoglicate inNEDOCROMIL SODIUMCautions see notes abovePregnancy see p. 133Breast-feeding see p. 133Side-effects see notes above; also nausea, vomiting,dyspepsia, abdominal pain, pharyngitis; rarely tastedisturbancesLicensed use not licensed for use in children under 6years

152 3.3.2 Leukotriene receptor antagonists BNFC 2011–20123 Respiratory systemIndication and doseProphylaxis of asthma (but see notes above)Counselling Regular use is necessary. By aerosol inhalationChild 5–18 years 4 mg (2 puffs) 4 times daily,when control achieved may be possible to reduceto twice dailyAllergic conjunctivitis section 11.4.2Tilade c CFC-free inhaler (Sanofi-Aventis) TAAerosol inhalation, mint-flavoured, nedocromil sodium2 mg/metered inhalation. Net price 112-dose unit= £39.94. Label: 8, counselling, administration3.3.2 Leukotriene receptorantagonistsThe leukotriene receptor antagonists, montelukast andzafirlukast, block the effects of cysteinyl leukotrienes inthe airways; they can be used in children for the managementof chronic asthma with an inhaled corticosteroidor as an alternative if an inhaled corticosteroidcannot be used (see Management of Chronic Asthmatable, p. 135).Montelukast has not been shown to be more effectivethan a standard dose of inhaled corticosteroid, but thetwo drugs appear to have an additive effect. The leukotrienereceptor antagonists may be of benefit in exercise-inducedasthma and in those with concomitantrhinitis, but they are less effective in children withsevere asthma who are also receiving high doses ofother drugs.There is some limited evidence to support the intermittentuse of montelukast in children under 12 yearswith episodic wheeze associated with viral infections[unlicensed use]. Treatment is started at the onset ofeither asthma symptoms or of coryzal symptoms andcontinued for 7 days; there is no evidence to support thisuse in moderate or severe asthma.Churg-Strauss syndrome Churg-Strauss syndromehas occurred very rarely in association with the use ofleukotriene receptor antagonists; in many of thereported cases the reaction followed the reduction orwithdrawal of oral corticosteroid therapy. Prescribersshould be alert to the development of eosinophilia,vasculitic rash, worsening pulmonary symptoms, cardiaccomplications, or peripheral neuropathy.Pregnancy There is limited evidence for the safe useof leukotriene receptor antagonists during pregnancy;however, they can be taken as normal in females whohave shown a significant improvement in asthma notachievable with other drugs before becoming pregnant,see also p. 133.MONTELUKASTCautions interactions: Appendix 1 (leukotrienereceptor antagonists)Pregnancy manufacturer advises avoid unless essential;see also notes aboveBreast-feeding manufacturer advises avoid unlessessentialSide-effects abdominal pain, thirst; hyperkinesia (inyoung children), headache; very rarely Churg-Strausssyndrome (see notes above); dry mouth, diarrhoea,dyspepsia, nausea, vomiting, hepatic disorders, palpitation,oedema, increased bleeding, epistaxis, skinreactions, respiratory infections, depression, tremor,asthenia, dizziness, hallucinations, suicidal thoughtsand behaviour, paraesthesia, hypoaesthesia, sleepdisturbances, sleep walking, abnormal dreams, agitation,anxiety, aggression, seizures, pyrexia, arthralgia,and myalgia also reportedIndication and doseProphylaxis of asthma see notes above and Managementof Chronic Asthma table, p. 135. By mouthChild 6 months–6 years 4 mg once daily in theeveningChild 6–15 years 5 mg once daily in the eveningChild 15–18 years 10 mg once daily in the eveningSymptomatic relief of seasonal allergic rhinitisin children with asthma. By mouthChild 15–18 years 10 mg once daily in the eveningSingulair c (MSD) AChewable tablets, pink, cherry-flavoured, montelukast(as sodium salt) 4 mg, net price 28-tab pack =£25.69; 5 mg, 28-tab pack = £25.69. Label: 23, 24Excipients include aspartame equivalent to phenylalanine 674 micrograms/4-mgtablet and 842 micrograms/5-mg tablet (section 9.4.1)Granules, montelukast (as sodium salt) 4 mg, netprice 28-sachet pack = £25.69. Counselling, administrationCounselling Granules may be swallowed whole or mixedwith cold food (but not fluid) and taken immediatelyTablets, beige, f/c, montelukast (as sodium salt)10 mg, net price 28-tab pack = £26.97Note The Scottish Medicines Consortium has advised (June2007) that Singulair c chewable tablets and granules arerestricted for use as an alternative to low-dose inhaledcorticosteroids for children 2–14 years with mild persistentasthma who have not recently had serious asthma attacks thatrequired oral corticosteroid use, and who are not capable ofusing inhaled corticosteroids; Singulair c chewable tablets andgranules should be initiated by a specialist in paediatric asthmaZAFIRLUKASTCautions interactions: Appendix 1 (leukotrienereceptor antagonists)Hepatic disorders Children or their carers should be toldhow to recognise development of liver disorder and advisedto seek medical attention if symptoms or signs such aspersistent nausea, vomiting, malaise or jaundice developHepatic impairment manufacturer advises avoidRenal impairment manufacturer advises cautionPregnancy manufacturer advises use only if potentialbenefit outweighs risk; see also notes aboveBreast-feeding present in milk—manufactureradvises avoidSide-effects gastro-intestinal disturbances; headache;rarely bleeding disorders, hypersensitivity reactionsincluding angioedema and skin reactions, arthralgia,myalgia, hepatitis, hyperbilirubinaemia, thrombocytopenia;very rarely Churg-Strauss syndrome (seenotes above), agranulocytosis

BNFC 2011–2012 3.4 Antihistamines, immunotherapy, and allergic emergencies 153Indication and doseProphylaxis of asthma see notes above and Managementof Chronic Asthma, p. 135. By mouthChild 12–18 years 20 mg twice dailyAccolate c (AstraZeneca) ATablets, f/c, zafirlukast 20 mg, net price 56-tab pack =£17.75. Label: 233.4 Antihistamines,immunotherapy, andallergic emergencies3.4.1 Antihistamines3.4.2 Allergen immunotherapy3.4.3 Allergic emergencies3.4.1 AntihistaminesAntihistamines (histamine H 1 -receptor antagonists) areclassified as sedating or non-sedating, according to theirrelative potential for CNS depression. Antihistaminesdiffer in their duration of action, incidence of drowsiness,and antimuscarinic effects; the response to anantihistamine may vary from child to child (see Sideeffects,below). Either a sedating or a non-sedatingantihistamine may be used to treat an acute allergicreaction; for conditions with more persistent symptomswhich require regular treatment, a non-sedating antihistamineshould be used to minimise the risk of sedationand psychomotor impairment associated withsedating antihistamines.Oral antihistamines are used in the treatment of nasalallergies, particularly seasonal allergic rhinitis (hayfever), and may be of some value in vasomotor rhinitis;rhinorrhoea and sneezing is reduced, but antihistaminesare usually less effective for nasal congestion. Antihistaminesare used topically to treat allergic reactions inthe eye (section 11.4.2) and in the nose (section 12.2.1).Topical application of antihistamines to the skin is notrecommended (section 13.3).An oral antihistamine may be used to prevent urticaria,and for the treatment of acute urticarial rashes, pruritus,insect bites, and stings. Antihistamines are also used inthe management of nausea and vomiting (section 4.6),of migraine (section 4.7.4.1), and the adjunctive managementof anaphylaxis and angioedema (section 3.4.3).The non-sedating antihistamine cetirizine is safe andeffective in children. Other non-sedating antihistaminesthat are used include acrivastine, desloratadine (anactive metabolite of loratadine), fexofenadine (anactive metabolite of terfenadine), levocetirizine (anisomer of cetirizine), loratadine, mizolastine, andrupatadine. Most non-sedating antihistamines arelong-acting (usually 12–24 hours). There is little evidencethat desloratadine or levocetirizine confer anyadditional benefit—they should be reserved for childrenwho cannot tolerate other therapies.Sedating antihistamines are occasionally useful wheninsomnia is associated with urticaria and pruritus (section4.1.1). Most of the sedating antihistamines arerelatively short-acting, but promethazine may be effectivefor up to 12 hours. Alimemazine and promethazinehave a more sedative effect than chlorphenamineand cyclizine (section 4.6). Chlorphenamine isused as an adjunct to adrenaline (epinephrine) in theemergency treatment of anaphylaxis and angioedema(section 3.4.3).Cautions and contra-indications Antihistaminesshould be used with caution in children with epilepsy.Most antihistamines should be avoided in acute porphyria,but some are thought to be safe (see section9.8.2). Sedating antihistamines have significant antimuscarinicactivity—they should not be used in neonatesand should be used with caution in children withurinary retention, glaucoma, or pyloroduodenalobstruction. Phenothiazine sedating antihistamines,such as alimemazine and promethazine, should not begiven to children under 2 years, except on specialistadvice, because the safety of such use has not beenestablished. See also MHRA/CHM advice, p. 167.Interactions: see Appendix 1 (antihistamines).Hepatic impairment Sedating antihistamines shouldbe avoided in children with severe liver disease—increased risk of coma.Pregnancy Most manufacturers of antihistaminesadvise avoiding their use during pregnancy; howeverthere is no evidence of teratogenicity, except forhydroxyzine where toxicity has been reported withhigh doses in animal studies. The use of sedating antihistaminesin the latter part of the third trimester maycause adverse effects in neonates such as irritability,paradoxical excitability, and tremor.Breast-feeding Most antihistamines are present inbreast milk in varying amounts; although not known tobe harmful, most manufacturers advise avoiding theiruse in mothers who are breast-feeding.Side-effects Drowsiness is a significant side-effectwith most of the older antihistamines although paradoxicalstimulation may occur rarely in children, especiallywith high doses. Drowsiness may diminish after afew days of treatment and is considerably less of aproblem with the newer antihistamines (see also notesabove). Side-effects that are more common with theolder antihistamines include headache, psychomotorimpairment, and antimuscarinic effects such as urinaryretention, dry mouth, blurred vision, and gastro-intestinaldisturbances. Other rare side-effects of antihistaminesinclude hypotension, palpitation, arrhythmias,extrapyramidal effects, dizziness, confusion, depression,sleep disturbances, tremor, convulsions, hypersensitivityreactions (including bronchospasm, angioedema,anaphylaxis, rashes, and photosensitivity reactions),blood disorders, and liver dysfunction.Non-sedating antihistaminesSkilled tasks Although drowsiness is rare, childrenand their carers should be advised that it can occur andmay affect performance of skilled tasks (e.g. cycling ordriving); alcohol should be avoided.3 Respiratory system

154 3.4.1 Antihistamines BNFC 2011–20123 Respiratory systemACRIVASTINECautions see notes aboveContra-indications see notes above; also hypersensitivityto triprolidineRenal impairment avoid in severe impairmentPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseSymptomatic relief of allergy such as hay fever,chronic idiopathic urticaria. By mouthChild 12–18 years 8 mg 3 times dailyAcrivastine (Non-proprietary)Capsules, acrivastine 8 mg, net price 12-cap pack =£2.59, 24-cap pack = £4.49. Counselling, skilled tasksBrands include Benadryl c Allergy ReliefCETIRIZINE HYDROCHLORIDECautions see notes aboveContra-indications see notes aboveRenal impairment use half normal dose if estimatedglomerular filtration rate 30–50 mL/minute/1.73m 2 ;use half normal dose and reduce dose frequency toalternate days if estimated glomerular filtration rate10–30 mL/minute/1.73m 2 ; avoid if estimated glomerularfiltration rate less than 10 mL/minute/1.73m 2Pregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under 2yearsIndication and doseSymptomatic relief of allergy such as hay fever,chronic idiopathic urticaria, atopic dermatitis. By mouthChild 1–2 years 250 micrograms/kg twice dailyChild 2–6 years 2.5 mg twice dailyChild 6–12 years 5 mg twice dailyChild 12–18 years 10 mg once dailyCetirizine Hydrochloride (Non-proprietary)Tablets, cetirizine hydrochloride 10 mg, net price 30-tab pack = 95p. Counselling, skilled tasksDental prescribing on NHS Cetirizine 10 mg tablets may beprescribedOral solution, cetirizine hydrochloride 5 mg/5 mL,net price 200 mL = £2.03. Counselling, skilled tasksNote Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionExcipients may include propylene glycol (see Excipients p. 2)DESLORATADINENote Desloratadine is a metabolite of loratadineCautions see notes aboveContra-indications see notes above; also hypersensitivityto loratadineRenal impairment use with caution in severe impairmentPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; rarely myalgia; veryrarely hallucinationsIndication and doseSymptomatic relief of allergy such as hay fever,chronic idiopathic urticaria. By mouthChild 1–6 years 1.25 mg once dailyChild 6–12 years 2.5 mg once dailyChild 12–18 years 5 mg once dailyNeoclarityn c (Schering-Plough) ATablets, blue, f/c, desloratadine 5 mg, net price 30-tabpack = £6.77. Counselling, skilled tasksOral solution, desloratadine 2.5 mg/5 mL, net price100 mL (bubblegum-flavour) = £6.77, 150 mL =£10.15. Counselling, skilled tasksExcipients include propylene glycol (see Excipients p. 2)FEXOFENADINE HYDROCHLORIDENote Fexofenadine is a metabolite of terfenadineCautions see notes aboveContra-indications see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseSymptomatic relief of seasonal allergic rhinitis. By mouthChild 6–12 years 30 mg twice dailyChild 12–18 years 120 mg once dailySymptomatic relief of chronic idiopathic urticaria. By mouthChild 12–18 years 180 mg once dailyFexofenadine (Non-proprietary) ATablets, f/c, fexofenadine hydrochloride 120 mg, netprice 30-tab pack = £2.95; 180 mg, 30-tab pack =£3.68. Label: 5, counselling, skilled tasksTelfast c (Sanofi-Aventis) ATablets, f/c, peach, fexofenadine hydrochloride30 mg, net price 60-tab pack = £5.46; 120 mg, 30-tabpack = £5.99; 180 mg, 30-tab pack = £7.58. Label: 5,counselling, skilled tasksLEVOCETIRIZINE HYDROCHLORIDENote Levocetirizine is an isomer of cetirizineCautions see notes aboveContra-indications see notes aboveRenal impairment estimated glomerular filtrationrate 30–50 mL/minute/1.73 m 2 , reduce dose frequencyto alternate days; estimated glomerular filtrationrate 10–30 mL/minute/1.73 m 2 , reduce dosefrequency to every 3 days; estimated glomerularfiltration rate less than 10 mL/minute/1.73 m 2 , avoidPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; very rarely weight gainLicensed use tablets not licensed for use in childrenunder 6 years

BNFC 2011–2012 3.4.1 Antihistamines 155Indication and doseSymptomatic relief of allergy such as hay fever,urticaria. By mouthChild 2–6 years 1.25 mg twice dailyChild 6–18 years 5 mg once dailyLevocetirizine Hydrochloride (Non-proprietary) ATablets, levocetirizine hydrochloride 5 mg, net price30-tab pack = £4.39. Counselling, skilled tasksXyzal c (UCB Pharma) ATablets, f/c, levocetirizine hydrochloride 5 mg, netprice 30-tab pack = £4.39. Counselling, skilled tasksOral solution, sugar-free, levocetirizine hydrochloride2.5 mg/5 mL, net price 200 mL = £6.00. Counselling,skilled tasksLORATADINECautions see notes aboveContra-indications see notes aboveHepatic impairment reduce dose frequency to alternatedays in severe impairmentPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseSymptomatic relief of allergy such as hay fever,chronic idiopathic urticaria. By mouthChild 2–12 yearsBody-weight under 30 kg 5 mg once dailyBody-weight over 30 kg 10 mg once dailyChild 12–18 years 10 mg once dailyLoratadine (Non-proprietary)Tablets, loratadine 10 mg, net price 30-tab pack =£1.20. Counselling, skilled tasksDental prescribing on NHS Loratadine 10 mg tablets maybe prescribedSyrup, loratadine 5 mg/5 mL, net price 100 mL =£2.65. Counselling, skilled tasksExcipients may include propylene glycol (see Excipients, p. 2)MIZOLASTINECautions see notes aboveContra-indications see notes above; also susceptibilityto QT-interval prolongation (including cardiacdisease and hypokalaemia)Hepatic impairment manufacturer recommendsavoid in significant impairmentPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; weight gain; anxiety,asthenia; less commonly arthralgia and myalgiaIndication and doseSymptomatic relief of allergy such as hay fever,urticaria. By mouthChild 12–18 years 10 mg once dailyMizollen c (Sanofi-Aventis) ATablets, m/r, scored, mizolastine 10 mg, net price 30-tab pack = £5.77. Label: 25, counselling, skilled tasksRUPATADINECautions see notes above; also susceptibility to QTintervalprolongation (including cardiac disease andhypokalaemia)Hepatic impairment manufacturer advises avoid—noinformation availableRenal impairment manufacturer advises avoid—noinformation availablePregnancy manufacturer advises caution—limitedinformation available; see also notes aboveBreast-feeding manufacturer advises caution; seealso notes aboveSide-effects see notes above; also asthenia; lesscommonly pyrexia, irritability, increased appetite,arthralgia, and myalgiaIndication and doseSymptomatic relief of allergic rhinitis and urticaria. By mouthChild 12–18 years 10 mg once dailyRupafin c (GSK) TATablets, salmon, rupatadine (as fumarate) 10 mg, netprice 30-tab pack = £5.00. Counselling, skilled tasksSedating antihistaminesSkilled tasks Drowsiness may affect performance ofskilled tasks (e.g. cycling or driving); sedating effectsenhanced by alcohol.ALIMEMAZINE TARTRATE(Trimeprazine tartrate)Cautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment avoidPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under 2yearsIndication and doseUrticaria, pruritus. By mouthChild 6 months–2 years 250 micrograms/kg(max. 2.5 mg) 3–4 times daily—specialist use onlyChild 2–5 years 2.5 mg 3–4 times dailyChild 5–12 years 5 mg 3–4 times dailyChild 12–18 years 10 mg 2–3 times daily, insevere cases up to max. 100 mg dailyPremedication section 15.1.4. By mouthChild 2–7 years up to max. 2 mg/kg 1–2 hoursbefore operation3 Respiratory system

156 3.4.1 Antihistamines BNFC 2011–20123 Respiratory systemAlimemazine (Non-proprietary) ATablets, alimemazine tartrate 10 mg, net price 28-tabpack = £4.28. Label: 2Oral Solution, alimemazine tartrate 7.5 mg /5 mL, netprice 100 mL = £6.83; 30 mg/5 mL, 100-mL = £7.55.Label: 2CHLORPHENAMINE MALEATE(Chlorpheniramine maleate)Cautions see notes aboveContra-indications see notes aboveHepatic impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also exfoliativedermatitis and tinnitus reported; injections may causetransient hypotension or CNS stimulation and may beirritantLicensed use syrup not licensed for use in childrenunder 1 year; tablets not licensed for use in childrenunder 6 years; injection not licensed for use inneonatesIndication and doseSymptomatic relief of allergy such as hay fever,urticaria. By mouthChild 1 month–2 years 1 mg twice dailyChild 2–6 years 1 mg every 4–6 hours, max. 6 mgdailyChild 6–12 years 2 mg every 4–6 hours, max.12 mg dailyChild 12–18 years 4 mg every 4–6 hours, max.24 mg dailyEmergency treatment of anaphylactic reactions,symptomatic relief of allergy. By intramuscular or intravenous injectionChild under 6 months 250 micrograms/kg (max.2.5 mg), repeated if required up to 4 times in 24hoursChild 6 months–6 years 2.5 mg, repeated ifrequired up to 4 times in 24 hoursChild 6–12 years 5 mg, repeated if required up to4 times in 24 hoursChild 12–18 years 10 mg, repeated if required upto 4 times in 24 hoursAdministration for intravenous injection, give over 1minute; if small dose required, dilute with SodiumChloride 0.9%Chlorphenamine (Non-proprietary)Tablets, chlorphenamine maleate 4 mg, net price 28 =£1.01. Label: 2Dental prescribing on NHS Chlorphenamine tablets may beprescribedOral solution, chlorphenamine maleate 2 mg/5 mL,net price 150 mL = £2.51. Label: 2Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionDental prescribing on NHS Chlorphenamine oral solutionmay be prescribedInjection A 1 , chlorphenamine maleate 10 mg/mL,net price 1-mL amp = £1.791. A restriction does not apply where administration is forsaving life in emergencyPiriton c (GSK Consumer Healthcare)Tablets, yellow, scored, chlorphenamine maleate4 mg, net price 28 = £1.62. Label: 2Syrup, chlorphenamine maleate 2 mg/5 mL, net price150 mL = £2.39. Label: 2HYDROXYZINE HYDROCHLORIDECautions see notes above; also susceptibility to QTintervalprolongationContra-indications see notes aboveHepatic impairment reduce daily dose by one-third;see also notes aboveRenal impairment reduce daily dose by halfPregnancy toxicity in animal studies with high doses;see also notes aboveBreast-feeding see notes aboveSide-effects see notes aboveLicensed use Ucerax c syrup not licensed for use inchildren under 1 yearIndication and dosePruritus. By mouthChild 6 months–6 years initially 5–15 mg atnight, increased if necessary to 50 mg daily in 3–4divided dosesChild 6–12 years initially 15–25 mg at night,increased if necessary to 50–100 mg daily in 3–4divided dosesChild 12–18 years initially 25 mg at night,increased if necessary to 100 mg in 3–4 divideddosesAtarax c (Alliance) ATablets, both f/c, hydroxyzine hydrochloride 10 mg(orange), net price 84-tab pack = £2.18; 25 mg (green),28-tab pack = £1.17. Label: 2Ucerax c (UCB Pharma) ATabletsD, f/c, scored, hydroxyzine hydrochloride25 mg, net price 25-tab pack = £1.22. Label: 2Syrup, hydroxyzine hydrochloride 10 mg/5 mL. Netprice 200-mL pack = £1.78. Label: 2KETOTIFENCautions see notes aboveContra-indications see notes aboveHepatic impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also irritability, nervousness;less commonly cystitis; rarely weight gain;very rarely Stevens-Johnson syndromeIndication and doseSymptomatic relief of allergy such as allergicrhinitis. By mouthChild 3–18 years 1 mg twice daily

BNFC 2011–2012 3.4.2 Allergen immunotherapy 157Zaditen c (Swedish Orphan) ATablets, scored, ketotifen (as hydrogen fumarate)1 mg, net price 60-tab pack = £7.53. Label: 2, 21Elixir, ketotifen (as hydrogen fumarate), 1 mg/5 mL,net price 300 mL (strawberry-flavoured) = £8.91.Label: 2, 21PROMETHAZINE HYDROCHLORIDECautions see notes above; also severe coronary arterydiseaseContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment use with cautionPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also restlessnessIndication and doseSymptomatic relief of allergy such as hay fever,insomnia associated with urticaria and pruritus. By mouthChild 2–5 years 5 mg twice daily or 5–15 mg atnightChild 5–10 years 5–10 mg twice daily or 10–25 mg at nightChild 10–18 years 10–20 mg 2–3 times daily or25 mg at night increased to 25 mg twice daily ifnecessarySedation section 4.1.1Nausea and vomiting section 4.6Phenergan c (Sanofi-Aventis)Tablets, both blue, f/c, promethazine hydrochloride10 mg, net price 56-tab pack = £2.85; 25 mg, 56-tabpack = £4.34. Label: 2Dental prescribing on NHS May be prescribed as PromethazineHydrochloride Tablets 10 mg or 25 mgElixir, golden, promethazine hydrochloride 5 mg/5 mL. Net price 100 mL = £2.67. Label: 2Dental prescribing on NHS May be prescribed as PromethazineHydrochloride Oral Solution 5 mg/5 mL3.4.2 Allergen immunotherapyImmunotherapy using allergen vaccines containinghouse dust mite, animal dander (cat or dog), or extractsof grass and tree pollen can improve symptoms ofasthma and allergic rhino-conjunctivitis in children. Avaccine containing extracts of wasp and bee venom isused to reduce the risk of severe anaphylaxis and systemicreactions in children with hypersensitivity to waspand bee stings. An oral preparation of grass pollenextract (Grazax c ) is also licensed for grass polleninduced rhinitis and conjunctivitis. Children requiringimmunotherapy must be referred to a hospital specialistfor accurate allergy diagnosis, assessment, and treatment.In view of concerns about the safety of desensitisingvaccines, it is recommended that they are used byspecialists and only for the following indications:. seasonal allergic hay fever (caused by pollen)that has not responded to anti-allergic drugs;. hypersensitivity to wasp and bee venoms.Desensitising vaccines should generally be avoidedor used with particular care in children with asthma.Desensitising vaccines should be avoided in pregnantwomen, in children under 5 years, and in those takingbeta-blockers (adrenaline will be ineffective if a hypersensitivityreaction occurs), or ACE inhibitors (risk ofsevere anaphylactoid reactions).Hypersensitivity reactions to immunotherapy (especiallyto wasp and bee venom extracts) can be lifethreatening;bronchospasm usually develops within 1hour and anaphylaxis within 30 minutes of injection.Therefore, facilities for cardiopulmonary resuscitationmust be immediately available and the child needs to bemonitored for at least 1 hour after injection. If symptomsor signs of hypersensitivity develop (e.g. rash,urticaria, bronchospasm, faintness), even when mild,the child should be observed until these have resolvedcompletely. The first dose of oral grass pollen extract(Grazax c ) should be taken under medical supervisionand the child should be monitored for 20–30 minutes.For details on the management of anaphylaxis, seesection 3.4.3.Each set of allergen extracts usually contains vials forthe administration of graded amounts of allergen. Maintenancesets containing vials at the highest strength arealso available. Product literature must be consulted fordetails of allergens, vial strengths, and administration.BEE AND WASP ALLERGENEXTRACTSCautions see notes above and consult product literatureContra-indications see notes above and consult productliteraturePregnancy avoidSide-effects consult product literatureIndication and doseHypersensitivity to wasp or bee venom (seenotes above). By subcutaneous injectionConsult product literaturePharmalgen c (ALK-Abelló) ABee venom extract (Apis mellifera) or wasp venomextract (Vespula spp.). Net price initial treatment set =£54.81 (bee), £67.20 (wasp); maintenance treatmentset = £63.76 (bee), £82.03 (wasp)GRASS AND TREE POLLENEXTRACTSCautions see notes above and consult product literature3 Respiratory system

158 3.4.2 Allergen immunotherapy BNFC 2011–20123 Respiratory systemContra-indications see notes above and consult productliteraturePregnancy avoidSide-effects consult product literatureIndication and doseTreatment of seasonal allergic hay fever due tograss or tree pollen (see notes above)See under preparations, belowPollinex c (Allergy) AGrasses and rye or tree pollen extract, net price initialtreatment set (3 vials) and extension course treatment(1 vial) = £450.00Dose. By subcutaneous injectionConsult product literatureGrass pollen extractGrazax c (ALK-Abelló) AOral lyophilisates (= freeze-dried tablets), grasspollen extract 75 000 units, net price 30-tab pack =£66.56. Counselling, administrationDose. By mouthChild 5–18 years 1 tablet daily; start treatment at least 4months before start of pollen season and continue for upto 3 yearsCounselling Tablets should be placed under the tongue andallowed to disperse. Advise carer and child that child not toswallow for 1 minute, or eat or drink for 5 minutes, aftertaking the tabletresponse should be assessed at 16 weeks and omalizumabtreatment discontinued in patients who have notshown a marked improvement in overall asthma control.NICE guidanceOmalizumab for severe persistent allergicasthma (November 2007)Omalizumab is recommended as additional therapyfor the prophylaxis of severe persistent allergicasthma in children over 12 years, who cannot becontrolled adequately with high-dose inhaled corticosteroidsand long-acting beta 2 agonists in additionto leukotriene receptor antagonists, theophylline,oral corticosteroids, oral beta 2agonists, andsmoking cessation where clinically appropriate.The following conditions apply:. confirmation of IgE-mediated allergy to a perennialallergen by clinical history and allergyskin testing;. either 2 or more severe exacerbations of asthmarequiring hospital admission within the previousyear, or 3 or more severe exacerbations ofasthma within the previous year, at least oneof which required hospital admission, and afurther 2 which required treatment or monitoringin excess of the patient’s usual regimen, in anaccident and emergency unit.Omalizumab should be initiated and monitored by aphysician experienced in both allergy and respiratorymedicine in a specialist centre, and discontinuedat 16 weeks in patients who have not shown anadequate response to therapy.OmalizumabOmalizumab is a monoclonal antibody that binds toimmunoglobulin E (IgE). It is licensed for use as additionaltherapy in children over 6 years with proven IgEmediatedsensitivity to inhaled allergens, whose severepersistent allergic asthma cannot be controlled adequatelywith high-dose inhaled corticosteroid togetherwith a long-acting beta 2agonist. Omalizumab should beinitiated by physicians experienced in the treatment ofsevere persistent asthma.Churg-Strauss syndrome has occurred rarely in patientsgiven omalizumab; the reaction is usually associatedwith the reduction or withdrawal of oral corticosteroidtherapy. Churg-Strauss syndrome can present as eosinophilia,vasculitic rash, cardiac complications, worseningpulmonary symptoms, or peripheral neuropathy. Hypersensitivityreactions can also occur immediately followingtreatment with omalizumab or sometimes more than24 hours after the first injection.For details on the management of anaphylaxis, seesection 3.4.3.The Scottish Medicines Consortium, p. 3 has advised(September 2007 and March 2010) that omalizumab isaccepted for restricted use within NHS Scotland as addontherapy to improve asthma control in children (6 to12 years), adolescents, and adults with severe persistentallergic asthma. Omalizumab is restricted to patientswho are prescribed chronic systemic corticosteroidsand in whom all other treatments have failed. TheNICE guidanceOmalizumab for the treatment of severepersistent allergic asthma in children aged 6to 11 years (October 2010)Omalizumab is not recommended for the treatmentof severe persistent allergic asthma in children aged6 to 11 years.OMALIZUMABCautions autoimmune disease; susceptibility to helminthinfections—discontinue if infection does notrespond to anthelminticHepatic impairment manufacturer advises caution—no information availableRenal impairment manufacturer advises caution—noinformation availablePregnancy manufacturer advises avoid unless essential;no evidence of teratogenicity in animal studiesBreast-feeding manufacturer advises avoid—presentin milk in animal studiesSide-effects headache; injection-site reactions; lesscommonly nausea, diarrhoea, dyspepsia, flushing,fatigue, dizziness, drowsiness, paraesthesia, influenzalikesymptoms, photosensitivity, hypersensitivityreactions (including hypotension, bronchospasm, laryngoedema,rash, pruritus, serum sickness, andanaphylaxis); arterial thromboembolic events, Churg-Strauss syndrome (see notes above), thrombocytopenia,arthralgia, myalgia, and alopecia also reported

BNFC 2011–2012 3.4.3 Allergic emergencies 159Indication and doseProphylaxis of severe persistent allergicasthma (see notes above). By subcutaneous injectionChild 6–18 years according to immunoglobulin Econcentration and body-weight, consult productliteratureXolair c (Novartis) TAInjection, powder for reconstitution, omalizumab, netprice 150-mg vial = £256.15 (with solvent)Excipients include sucrose 108 mg/vial. administering high-flow oxygen (section 3.6) andintravenous fluids (section 9.2.2);. administering an antihistamine, such as chlorphenamine,(section 3.4.1) by slow intravenous injectionor intramuscular injection as adjunctive treatmentgiven after adrenaline. An intravenouscorticosteroid (section 6.3.2) such as hydrocortisone(preferably as sodium succinate) is of secondaryvalue in the initial management of anaphylaxisbecause the onset of action is delayed for severalhours, but should be given to prevent further deteriorationin severely affected children.3.4.3 Allergic emergenciesAdrenaline (epinephrine) provides physiological reversalof the immediate symptoms associated with hypersensitivityreactions such as anaphylaxis and angioedema.AnaphylaxisAnaphylaxis is a severe, life-threatening, generalised orsystemic hypersensitivity reaction. It is characterised bythe rapid onset of respiratory and/or circulatory problemsand is usually associated with skin and mucosalchanges; prompt treatment is required. Children withpre-existing asthma, especially poorly controlledasthma, are at particular risk of life-threatening reactions.Insect stings are a recognised risk (in particularwasp and bee stings). Latex and certain foods, includingeggs, fish, cows’ milk protein, peanuts, sesame, shellfish,soy, and tree nuts may also precipitate anaphylaxis.Medicinal products particularly associated with anaphylaxisinclude blood products, vaccines, allergen immunotherapypreparations, antibacterials, aspirin and otherNSAIDs, and neuromuscular blocking drugs. In the caseof drugs, anaphylaxis is more likely after parenteraladministration; resuscitation facilities must always beavailable when giving injections associated with specialrisk. Refined arachis (peanut) oil, which may be presentin some medicinal products, is unlikely to cause anallergic reaction—nevertheless it is wise to check thefull formula of preparations which may contain allergens.Treatment of anaphylaxisFirst-line treatment includes:. securing the airway, restoration of blood pressure(laying the child flat and raising the legs, or in therecovery position if unconscious or nauseous and atrisk of vomiting);. administering adrenaline (epinephrine) by intramuscularinjection (for doses see IntramuscularAdrenaline, below); the dose should be repeated ifnecessary at 5-minute intervals according to bloodpressure, pulse, and respiratory function [important:possible need for intravenous route usingdilute solution (Adrenaline 1 in 10 000), see IntravenousAdrenaline p. 160];Continuing respiratory deterioration requires furthertreatment with bronchodilators including inhaled orintravenous salbutamol (see p. 139), inhaled ipratropium(see p. 141), intravenous aminophylline (seep. 143), or intravenous magnesium sulphate [unlicensedindication] (see Management of Acute Asthma, p. 134).In addition to oxygen, assisted respiration and possiblyemergency tracheotomy may be necessary.When a child is so ill that there is doubt as to theadequacy of the circulation, the initial injection of adrenalinemay need to be given as a dilute solution by theintravenous route, or by the intraosseous route if venousaccess is difficult—for details of cautions, dose andstrength, see under Intravenous Adrenaline (Epinephrine),p. 160.On discharge, the child should be considered for furthertreatment with an oral antihistamine (section 3.4.1) andan oral corticosteroid (section 6.3.2) for up to 3 days toreduce the risk of further reaction. The child, or carer,should be instructed to return to hospital if symptomsrecur and to contact their general practitioner for followup.Children who are suspected of having had an anaphylacticreaction should be referred to a specialist forspecific allergy diagnosis. Avoidance of the allergen isthe principal treatment; if appropriate, an adrenalineauto-injector should be given or a replacement supplied(see Self-administration of Adrenaline, p. 160).Intramuscular adrenaline (epinephrine)The intramuscular route is the first choice route for theadministration of adrenaline in the management ofanaphylaxis. Adrenaline is best given as an intramuscularinjection into the anterolateral aspect of the middlethird of the thigh, it has a rapid onset of action afterintramuscular administration and in the shocked patientits absorption from the intramuscular site is faster andmore reliable than from the subcutaneous site. Theintravenous route should be reserved for extreme emergencywhen there is doubt about the adequacy of thecirculation; for details of cautions, dose and strength seeIntravenous Adrenaline (Epinephrine), p. 160.Children with severe allergy, and their carers, shouldideally be instructed in the self-administration of adrenalineby intramuscular injection (for details see Selfadministrationof Adrenaline (Epinephrine), p. 160).Prompt injection of adrenaline is of paramount importance.The following adrenaline doses are based on the3 Respiratory system

160 3.4.3 Allergic emergencies BNFC 2011–20123 Respiratory systemrevised recommendations of the Working Group of theResuscitation Council (UK).Dose of intramuscular injection of adrenaline(epinephrine) for anaphylaxisAge range Dose Volume ofadrenaline1 in 1000(1 mg/mL)Under 6 years 150 micrograms 0.15 mL 16–12 years 300 micrograms 0.3 mL12–18 years 500 micrograms 0.5 mL 2These doses may be repeated several times if necessaryat 5-minute intervals according to blood pressure, pulse,and respiratory function.1. Use suitable syringe for measuring small volume2. 300 micrograms (0.3 mL) if child is small or prepubertalIntravenous adrenaline (epinephrine)Intravenous adrenaline should be given only by thoseexperienced in its use, in a setting where patients can becarefully monitored.Where the child is severely ill and there is real doubtabout adequacy of the circulation and absorption fromthe intramuscular injection site, adrenaline may be givenby slow intravenous injection. Children may respond toas little as 1 microgram/kg (0.01 mL/kg) of the dilute 1in 10 000 adrenaline injection by slow intravenousinjection repeated according to response. A singledose of adrenaline by intravenous injection should notexceed 50 micrograms; if multiple doses are requiredconsider giving adrenaline by slow intravenous infusion.Great vigilance is needed to ensure that the correctstrength of adrenaline injection is used; anaphylacticshock kits need to make a very clear distinction betweenthe 1 in 10 000 strength and the 1 in 1000 strength. It isalso important that, where intramuscular injectionmight still succeed, time should not be wasted seekingintravenous access.For reference to the use of the intravenous route foracute hypotension, see section 2.7.2.Self-administration of adrenaline(epinephrine)Children at considerable risk of anaphylaxis need tocarry (or have available) adrenaline at all times andthe child, or child’s carers, need to be instructed inadvance when and how to inject it; injection techniqueis device specific. Packs for self-administration need tobe clearly labelled with instructions on how to administeradrenaline (intramuscularly, preferably at the midpointof the outer thigh, through light clothing if necessary).It is important to ensure that an adequate supplyis provided to treat symptoms until medical assistance isavailable.Adrenaline for administration by intramuscular injectionis available in ‘auto-injectors’ (e.g. Anapen c , EpiPen cor Jext c ), pre-assembled syringes fitted with a needlesuitable for very rapid administration (if necessary by abystander or a healthcare provider if it is the onlypreparation available). A syringe delivering 300 microgramsof adrenaline is recommended for a child over30 kg. A syringe delivering 150 micrograms of adrenalineis recommended for a child 15–30 kg, but on thebasis of a dose of 10 micrograms/kg, 300 microgramsmay be more appropriate for some children.ADRENALINE/EPINEPHRINECautions for cautions in non-life-threatening situations,see section 2.7.2Interactions Severe anaphylaxis in children taking betablockersmay not respond to adrenaline calling for bronchodilatortherapy, see intravenous salbutamol (section3.1.1.1); furthermore, adrenaline may cause severe hypertensionand bradycardia in those receiving non-cardioselectivebeta-blockers. Other interactions, see Appendix 1(sympathomimetics).Renal impairment section 2.7.2Pregnancy section 2.7.2Breast-feeding section 2.7.2Side-effects section 2.7.2Licensed use auto-injector delivering 150-microgramdose of adrenaline not licensed for use inchildren body-weight under 15 kgIndication and doseEmergency treatment of acute anaphylaxis,angioedema. By intramuscular injection (preferably midpointin anterolateral thigh) of 1 in 1000 (1 mg/mL)solutionSee notes and table aboveAcute anaphylaxis when there is doubt as tothe adequacy of the circulation. By slow intravenous injection of 1 in 10 000(100 micrograms/mL) solution (extreme caution—specialistuse only)See notes aboveSafe PracticeIntravenous route should be used with extreme careby specialists only, see notes aboveCroup (section 3.1). By inhalation of nebulised solution of adrenaline1 in 1000 (1 mg/mL)Child 1 month–12 years 400 micrograms/kg(max. 5 mg), repeated after 30 minutes if necessaryAdministration For nebulisation, dilute adrenaline 1 in1000 solution with sterile sodium chloride 0.9% solutionAcute hypotension, low cardiac output section2.7.2Cardiopulmonary resuscitation section 2.7.3Intramuscular or subcutaneous1Adrenaline/Epinephrine 1 in 1000 (Non-proprietary)AInjection, adrenaline (as acid tartrate) 1 mg/mL, netprice 0.5-mL amp = 52p; 1-mL amp = 57pExcipients include sulphites1. A restriction does not apply to adrenaline injection1 mg/mL where administration is for saving life inemergency

BNFC 2011–2012 3.4.3 Allergic emergencies 1611Minijet c Adrenaline 1 in 1000 (UCB Pharma) AInjection, adrenaline (as hydrochloride) 1 in 1000(1 mg/mL). Net price 1 mL (with 25 gauge 0.25 inchneedle for subcutaneous injection) = £10.79, 1 mL(with 21 gauge 1.5 inch needle for intramuscularinjection) = £6.36 (both disposable syringes)Excipients include sulphitesIntravenousExtreme caution, see notes aboveAdrenaline/Epinephrine 1 in 10 000, Dilute (Nonproprietary)AInjection, adrenaline (as acid tartrate) 100 micrograms/mL,10-mL amp, 1-mL and 10-mL prefilledsyringeExcipients include sulphitesMinijet c Adrenaline 1 in 10 000 (UCB Pharma) AInjection, adrenaline (as hydrochloride) 1 in 10 000(100 micrograms/mL), net price 3-mL prefilledsyringe = £6.27; 10-mL prefilled syringe = £6.15Excipients include sulphitesIntramuscular injection for self-administrationAnapen c (Lincoln Medical) AAnapen c 500 (delivering a single dose of adrenaline500 micrograms), adrenaline 1.7 mg/mL, net price1.05-mL auto-injector device = £30.67Excipients include sulphitesNote 0.75 mL of the solution remains in the auto-injectordevice after useDoseAcute anaphylaxis. By intramuscular injectionChild 12–18 years body-weight over 60 kg 500 microgramsrepeated after 10–15 minutes if necessary1Anapen c 300 (delivering a single dose of adrenaline300 micrograms), adrenaline 1 mg/mL (1 in 1000), netprice 1.05-mL auto-injector device = £30.67Excipients include sulphitesNote 0.75 mL of the solution remains in the auto-injectordevice after useDoseAcute anaphylaxis. By intramuscular injectionChild body-weight over 30 kg 300 microgramsrepeated after 10–15 minutes as necessaryAnapen c 150 (delivering a single dose of adrenaline150 micrograms), adrenaline 500 micrograms/mL (1in 2000), net price 1.05-mL auto-injector device =£30.67Excipients include sulphitesNote 0.75 mL of the solution remains in the auto-injectordevice after useDoseAcute anaphylaxis. By intramuscular injectionChild body-weight under 15 kg 150 microgramsrepeated after 10–15 minutes as necessaryChild body–weight 15–30 kg 150 micrograms (but onthe basis of a dose of 10 micrograms/kg, 300 microgramsmay be more appropriate for some children) repeatedafter 10–15 minutes as necessary1. A restriction does not apply to adrenaline injection1 mg/mL where administration is for saving life inemergencyEpiPen c (Meda) A1EpiPen c Auto-injector 0.3 mg (delivering a singledose of adrenaline 300 micrograms), adrenaline1 mg/mL (1 in 1000), net price 2-mL auto-injectordevice = £26.45, 2 2-mL auto-injector device =£52.90Excipients include sulphitesNote 1.7 mL of the solution remains in the auto-injectordevice after useDoseAcute anaphylaxis. By intramuscular injectionChild body-weight over 30 kg 300 microgramsrepeated after 5–15 minutes as necessaryEpiPen c Jr Auto-injector 0.15 mg (delivering a singledose of adrenaline 150 micrograms), adrenaline500 micrograms/mL (1 in 2000), net price 2-mL autoinjectordevice = £26.45, 2 2-mL auto-injectordevice = £52.90Excipients include sulphitesNote 1.7 mL of the solution remains in the auto-injectordevice after useDoseAcute anaphylaxis. By intramuscular injectionChild body-weight under 15 kg 150 microgramsrepeated after 5–15 minutes as necessaryChild body-weight 15–30 kg 150 micrograms (but onthe basis of a dose of 10 micrograms/kg, 300 microgramsmay be more appropriate for some children) repeatedafter 5–15 minutes as necessaryJext c (ALK-Abelló) A1Jext c 300 micrograms (delivering a single dose ofadrenaline (as tartrate) 300 micrograms), adrenaline1 mg/mL (1 in 1000), net price 1.4-mL auto-injectordevice = £28.77Excipients include sulphitesNote 1.1 mL of the solution remains in the auto-injectordevice after useDoseAcute anaphylaxis. By intramuscular injectionChild body-weight over 30 kg 300 microgramsrepeated after 5–15 minutes as necessary1Jext c 150 micrograms (delivering a single dose ofadrenaline (as tartrate) 150 micrograms), adrenaline1 mg/mL (1 in 1000), net price 1.4-mL auto-injectordevice = £28.77Excipients include sulphitesNote 1.25 mL of the solution remains in the auto-injectordevice after useDoseAcute anaphylaxis. By intramuscular injectionChild body-weight under 15 kg 150 microgramsrepeated after 5–15 minutes as necessaryChild body-weight 15–30 kg 150 micrograms (but onthe basis of a dose of 10 micrograms/kg, 300 microgramsmay be more appropriate for some children) repeatedafter 5–15 minutes as necessaryAngioedemaAngioedema is dangerous if laryngeal oedema is present.In this circumstance adrenaline (epinephrine)injection and oxygen should be given as describedunder Anaphylaxis (see above); antihistamines and corticosteroidsshould also be given (see again above).3 Respiratory system

162 3.5 Respiratory stimulants and pulmonary surfactants BNFC 2011–20123 Respiratory systemTracheal intubation may be necessary. In some childrenwith laryngeal oedema, adrenaline 1 in 1000 (1 mg/mL)solution may be given by nebuliser. However, nebulisedadrenaline cannot be relied upon for a systemic effect—intramuscular adrenaline should be used.Hereditary angioedema The administration of C1-esterase inhibitor (in fresh frozen plasma or in partiallypurified form) may terminate acute attacks of hereditaryangioedema, but is not practical for long-term prophylaxis;it can also be used for short-term prophylaxisbefore surgery or dental procedures [unlicensed indication].Tranexamic acid (section 2.11) is used for shorttermor long-term prophylaxis of hereditary angioedema;short-term prophylaxis is started several daysbefore planned procedures which may trigger an acuteattack of hereditary angioedema (e.g. dental work) andcontinued for 2–5 days afterwards. Danazol [unlicensedindication, see BNF section 6.7.2] is best avoided inchildren because of its androgenic effects but it can beused for short-term prophylaxis of hereditary angioedema.C1-ESTERASE INHIBITORCautions vaccination against hepatitis A (p. 607) andhepatitis B (p. 608) may be requiredPregnancy manufacturer advises avoid unless essentialBreast-feeding manufacturer advises use only ifpotential benefit outweighs risk—no informationavailableSide-effects rarely injection-site reactions, hypersensitivityreactions (including anaphylaxis)Licensed use not licensed for short-term prophylaxisof hereditary angioedemaIndication and doseAcute attacks of hereditary angioedema, shorttermprophylaxis of hereditary angioedemabefore surgery or dental procedures. By slow intravenous injection or intravenousinfusion (specialist use only)Neonate 20 units/kgChild 1 month–18 years 20 units/kgBerinert c (CSL Behring) TAInjection, powder for reconstitution C1-esteraseinhibitor, net price 500-unit vial = £550.00Electrolytes Na + 2.1 mmol/10 mL-vial3.5 Respiratory stimulantsand pulmonarysurfactants3.5.1 Respiratory stimulants3.5.2 Pulmonary surfactants3.5.1 Respiratory stimulantsRespiratory stimulants (analeptic drugs), such as caffeine,reduce the frequency of neonatal apnoea, and theneed for mechanical ventilation during the first 7 days oftreatment. They are typically used in the managementof very preterm neonates, and continued until a postmenstrualage of 34 to 35 weeks is reached (or longer ifnecessary). They should only be given under expertsupervision in hospital; it is important to rule out anyunderlying disorder, such as seizures, hypoglycaemia, orinfection, causing respiratory exhaustion before startingtreatment with a respiratory stimulant.Caffeine (as caffeine base) is licensed for the treatmentof apnoea in preterm neonates; it is used in preferenceto theophylline (section 3.1.3). Caffeine has feweradverse effects and a longer half-life than theophyllinein neonates. It is well absorbed when given orally;intravenous treatment is rarely necessary. Plasma-caffeineconcentration should be measured if the child haspreviously been treated with theophylline. The therapeuticrange for plasma-caffeine concentration is usually10–20 mg/litre (50–100 micromol/litre), but a concentrationof 25–35 mg/litre (130–180 micromol/litre)may be required.CAFFEINECautions gastro-oesophageal reflux; cardiovasculardisease; monitor plasma-caffeine concentration (seenotes above); monitor closely for 1 week after stoppingtreatmentSide-effects hypertension, tachycardia; irritability,restlessness; hypoglycaemia, hyperglycaemia; fluidand electrolyte imbalanceIndication and doseNoteDose expressed as caffeine baseNeonatal apnoea. By mouth, expressed as caffeine baseNeonate initially 10 mg/kg, then 2.5–5 mg/kgonce daily starting 24 hours after initial dose. By intravenous infusion, expressed as caffeinebaseNeonate initially 10 mg/kg over 30 minutes, then2.5–5 mg/kg over 10 minutes once daily starting24 hours after initial doseSafe practiceWhen prescribing, always state dose in terms of caffeinebaseCaffeine base 1 mg = caffeine citrate 2 mgAdministration caffeine injection may be administeredby mouth or by intravenous infusionCaffeine (Non-proprietary) AInjection, caffeine 5 mg/mL, net price 1-mL amp =£4.89Electrolytes Na + < 0.5 mmol/amp3.5.2 Pulmonary surfactantsPulmonary surfactants derived from animal lungs,beractant and poractant alfa are used to prevent andtreat respiratory distress syndrome (hyaline membranedisease) in preterm neonates. Prophylactic use of apulmonary surfactant may reduce the need for mechanicalventilation and is more effective than ‘rescue treat-

BNFC 2011–2012 3.6 Oxygen 163ment’ in preterm neonates of 29 weeks or less postmenstrualage.Pulmonary surfactants may also be of benefit in neonateswith meconium aspiration syndrome or intrapartumstreptococcal infection.Pulmonary immaturity with surfactant deficit is thecommonest reason for respiratory failure in the neonate,especially in those of less than 30 weeks post-menstrualage. Betamethasone (section 6.3.2) given to the mother(at least 12 hours but preferably 48 hours) before deliverysubstantially enhances pulmonary maturity in theneonate.Cautions Continuous monitoring is required to avoidhyperoxaemia caused by rapid improvement in arterialoxygen concentration.Side-effects Pulmonary haemorrhage and bradycardiahave been rarely associated with pulmonarysurfactants. Obstruction of the endotracheal tube bymucous secretions, and intracranial haemorrhage havealso been reported.BERACTANTCautions see notes above and consult product literatureSide-effects see notes aboveLicensed use licensed for use in respiratory distresssyndrome in newborn premature infants, birthweightover 700 g, and as prophylaxis in neonatesless than 32 weeks post-menstrual ageIndication and doseTreatment of respiratory distress syndrome inpreterm neonate; prophylaxis of respiratorydistress syndrome in preterm neonate. By endotracheal tubeNeonate phospholipid 100 mg/kg equivalent to avolume of 4 mL/kg, preferably within 8 hours ofbirth (preferably within 15 minutes of birth forprophylaxis); dose may be repeated within 48hours at intervals of at least 6 hours for up to 4dosesSurvanta c (Abbott) ASuspension, beractant (bovine lung extract) providingphospholipid 25 mg/mL, with lipids and proteins,net price 8-mL vial = £306.43PORACTANT ALFACautions see notes above and consult product literatureSide-effects see notes above; also rarely hypotensionLicensed use licensed for use in respiratory distresssyndrome in newborn premature infants, birthweightover 700 g, and as prophylaxis in neonates24–32 weeks post-menstrual ageIndication and doseTreatment of respiratory distress syndrome orhyaline membrane disease in preterm neonate;prophylaxis of respiratory distress syndrome inpreterm neonate. By endotracheal tubeNeonate treatment, 100–200 mg/kg; further dosesof 100 mg/kg may be repeated at intervals of 12hours; max. total dose 300–400 mg/kg; prophylaxis,100–200 mg/kg soon after birth (preferablywithin 15 minutes); further doses of 100 mg/kgmay be repeated 6–12 hours later and after afurther 12 hours if still intubated; max. total dose300–400 mg/kgCurosurf c (Chiesi) ASuspension, poractant alfa (porcine lung phospholipidfraction) 80 mg/mL, net price 1.5-mL vial =£281.64; 3-mL vial = £547.403.6 OxygenOxygen should be regarded as a drug. It is prescribed forhypoxaemic patients to increase alveolar oxygen tensionand decrease the work of breathing. The concentrationof oxygen required depends on the conditionbeing treated; administration of an inappropriate concentrationof oxygen may have serious or even fatalconsequences. High concentrations of oxygen cancause pulmonary epithelial damage (bronchopulmonarydysplasia), convulsions, and retinal damage, especiallyin preterm neonates.Oxygen is probably the most common drug used inmedical emergencies. It should be prescribed initially toachieve a normal or near-normal oxygen saturation. Inmost acutely ill children with an expected or knownnormal or low arterial carbon dioxide (P a CO 2 ), oxygensaturation should be maintained above 92%; someclinicians may aim for a target of 94–98%. In someclinical situations, such as carbon monoxide poisoning,(see also Emergency Treatment of Poisoning, p. 33), it ismore appropriate to aim for the highest possible oxygensaturation until the child is stable. Hypercapnic respiratoryfailure is rare in children; in those children at risk,a lower oxygen saturation target of 88–92% is indicated,see below.High concentration oxygen therapy is safe in uncomplicatedcases of conditions such as pneumonia, pulmonaryembolism, pulmonary fibrosis, shock, severe trauma,sepsis, or anaphylaxis. In such conditions, lowarterial oxygen (P a O 2 ) is usually associated with lowor normal arterial carbon dioxide (P aCO 2) and there islittle risk of hypoventilation and carbon dioxide retention.In severe acute asthma, the arterial carbon dioxide(P a CO 2 ) is usually subnormal, but as asthma deterioratesit may rise steeply. These patients usually require ahigh concentration of oxygen and if the arterial carbondioxide (P a CO 2 ) remains high despite treatment, intermittentpositive pressure ventilation needs to be consideredurgently.Oxygen should not be given to neonates except underexpert supervision. Particular care is required in pretermneonates because of the risk of hyperoxia (seeabove).Low concentration oxygen therapy (controlled oxygentherapy) is reserved for children at risk of hypercapnicrespiratory failure, which is more likely in children with:. advanced cystic fibrosis;. advanced non-cystic fibrosis bronchiectasis;3 Respiratory system

164 3.6 Oxygen BNFC 2011–20123 Respiratory system. severe kyphoscoliosis or severe ankylosingspondylitis;. severe lung scarring caused by tuberculosis;. musculoskeletal disorders with respiratory weakness,especially if on home ventilation;. an overdose of opioids, benzodiazepines, or otherdrugs causing respiratory depression.Until blood gases can be measured, initial oxygenshould be given using a controlled concentration of28% or less, titrated towards a target concentration of88–92%. The aim is to provide the child with enoughoxygen to achieve an acceptable arterial oxygen tensionwithout worsening carbon dioxide retention and respiratoryacidosis.Domiciliary oxygen Oxygen should only be prescribedfor use in the home after careful evaluation inhospital by a respiratory care specialist. Carers andchildren who smoke should be advised of the risks ofsmoking when receiving oxygen, including the risk offire. Smoking cessation therapy (section 4.10.2) shouldbe tried before home oxygen prescription.Long-term oxygen therapyThe aim of long-term oxygen therapy is to maintainoxygen saturation of at least 92%. Children (especiallythose with chronic neonatal lung disease) often requiresupplemental oxygen, either for 24-hours a day or duringperiods of sleep; many children are eventuallyweaned off long-term oxygen therapy as their conditionimproves.Long-term oxygen therapy should be considered forchildren with conditions such as:. bronchopulmonary dysplasia (chronic neonatallung disease);. congenital heart disease with pulmonary hypertension;. pulmonary hypertension secondary to pulmonarydisease;. idiopathic pulmonary hypertension;. sickle-cell disease with persistent nocturnal hypoxia;. interstitial lung disease and obliterative bronchiolitis;. cystic fibrosis;. obstructive sleep apnoea syndrome;. neuromuscular or skeletal disease requiring noninvasiveventilation;. pulmonary malignancy or other terminal diseasewith disabling dyspnoea.Increased respiratory depression is seldom a problem inchildren with stable respiratory failure treated with lowconcentrations of oxygen although it may occur duringexacerbations; children and their carers should bewarned to call for medical help if drowsiness or confusionoccurs.Short-burst oxygen therapyOxygen is occasionally prescribed for short-burst (intermittent)use for episodes of breathlessness.Ambulatory oxygen therapyAmbulatory oxygen is prescribed for children on longtermoxygen therapy who need to be away from homeon a regular basis.Oxygen therapy equipmentUnder the NHS oxygen may be supplied as oxygencylinders. Oxygen flow can be adjusted by means of anoxygen flow meter. Oxygen delivered from a cylindershould be passed through a humidifier if used for longperiods.Oxygen concentrators are more economical for childrenwho require oxygen for long periods, and in Englandand Wales can be ordered on the NHS on a regionaltendering basis (see below). A concentrator is recommendedfor a child who requires oxygen for more than 8hours a day (or 21 cylinders per month). Exceptionally, ifa higher concentration of oxygen is required the outputof 2 oxygen concentrators can be combined using a ‘Y’connection.A nasal cannula is usually preferred to a face mask forlong-term oxygen therapy from an oxygen concentrator.Nasal cannulas can, however, cause dermatitis andmucosal drying in sensitive individuals.Giving oxygen by nasal cannula allows the child to talk,eat, and drink, but the concentration is not controlledand the method may not be appropriate for acute respiratoryfailure. When oxygen is given through a nasalcannula at a rate of 1–2 litres/minute the inspiratoryoxygen concentration is usually low, but it varies withventilation and can be high if the child is underventilating.Arrangements for supplying oxygenThe following services may be ordered in England andWales:. emergency oxygen;. short-burst (intermittent) oxygen therapy;. long-term oxygen therapy;. ambulatory oxygen.The type of oxygen service (or combination of services)should be ordered on a Home Oxygen Order Form(HOOF); the amount of oxygen required (hours perday) and flow rate should be specified. The supplierwill determine the appropriate equipment to be provided.Special needs or preferences should be specifiedon the HOOF.The clinician should obtain the patient’s consent to passon the patient’s details to the supplier and the firebrigade. The supplier will contact the patient to makearrangements for delivery, installation, and maintenanceof the equipment. The supplier will also train the patientto use the equipment.The clinician should send order forms to the supplier byfacsimile (see below); a copy of the HOOF should besent to the Primary Care Trust or Local Health Board.The supplier will continue to provide the service until arevised order is received, or until notified that thepatient no longer requires the home oxygen service.

BNFC 2011–2012 3.7 Mucolytics 165HOOF and further instructions are available atwww.bprs.co.uk/oxygen.html.Eastern EnglandBOC Medicalto order:Tel: 0800 136 603Fax: 0800 169 9989North EastSouth WestSouth LondonSouth East CoastSouth CentralNorth WestYorkshire and HumbersideEast MidlandsWest MidlandsNorth LondonWalesAir Liquideto order:Tel: 0808 202 2229Fax: 0191 497 4340Air Liquideto order:Tel: 0500 823 773Fax: 0800 781 4610Air Productsto order:Tel: 0800 373 580Fax: 0800 214 709In Scotland, refer the child for assessment by a paediatricrespiratory consultant. If the need for a concentratoris confirmed the consultant will arrange for theprovision of a concentrator through the Common ServicesAgency. In Northern Ireland oxygen concentratorsand cylinders should be prescribed on form HS21;oxygen concentrators are supplied by a local contractor.In Scotland and Northern Ireland, prescriptions foroxygen cylinders and accessories can be dispensed bypharmacies contracted to provide domiciliary oxygenservices.3.7 MucolyticsMucolytics, such as carbocisteine and mecysteine, areused to facilitate mucociliary clearance and expectorationby reducing sputum viscosity but evidence ofefficacy is limited.Dornase alfa is a genetically engineered version of anaturally occurring human enzyme which cleaves extracellulardeoxyribonucleic acid (DNA); it is used toreduce sputum viscosity in children with cystic fibrosis.Dornase alfa is administered by inhalation using a jetnebuliser (section 3.1.5), usually once daily at least 1hour before physiotherapy; however, alternate-day therapymay be as effective as daily treatment. Not allchildren benefit from treatment with dornase alfa;improvement occurs within 2 weeks, but in moreseverely affected children a trial of 6–12 weeks maybe required.Nebulised hypertonic sodium chloride solution mayimprove mucociliary clearance in children with cysticfibrosis.Mesna (Mistabron c , available from ‘special-order’manufacturers or specialist importing companies, seep. 809) is used in some children with cystic fibrosiswhen other mucolytics have failed to reduce sputumviscosity; 3–6 mL of a 20% solution is nebulised twicedaily.Acetylcysteine has been used to treat meconium ileusin neonates and distal intestinal obstruction syndromein children with cystic fibrosis, but evidence of efficacyis lacking. Gastrografin c (section 1.6.5), or a bowelcleansing preparation containing macrogols (section1.6.5), is usually more effective. Acetylcysteine may beused as a mucolytic to prevent further obstruction.ACETYLCYSTEINECautions history of peptic ulceration; asthmaSide-effects hypersensitivity-like reactions includingrashes and anaphylaxisLicensed use not licensed for use in meconium ileusor for distal intestinal obstructive syndrome inchildren with cystic fibrosisIndication and doseMeconium ileus (but see notes above). By mouthNeonate 200–400 mg up to 3 times daily ifnecessaryTreatment of distal intestinal obstructivesyndrome (but see notes above). By mouthChild 1 month–2 years 0.4–3 g as a single doseChild 2–7 years 2–3 g as a single doseChild 7–18 years 4–6 g as a single dosePrevention of distal intestinal obstructionsyndrome. By mouthChild 1 month–2 years 100–200 mg 3 times dailyChild 2–12 years 200 mg 3 times dailyChild 12–18 years 200–400 mg 3 times dailyAdministration For oral administration, use oralgranules, or dilute injection solution (200 mg/mL) to aconcentration of 50 mg/mL; orange or blackcurrantjuice or cola drink may be used as a diluent to maskthe bitter tasteAcetylcysteine (Non-proprietary) AOral granules, acetylcysteine 100 mg/sachet;200 mg/sachet. Label: 13Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809InjectionSee Emergency treatment of poisoning, p. 28CARBOCISTEINECautions history of peptic ulcerationContra-indications active peptic ulcerationPregnancy manufacturer advises avoid in first trimesterBreast-feeding no information availableSide-effects rarely gastro-intestinal bleeding; hypersensitivityreactions (including rash and anaphylaxis)also reportedIndication and doseReduction of sputum viscosity. By mouthChild 2–5 years 62.5–125 mg 4 times dailyChild 5–12 years 250 mg 3 times daily3 Respiratory system

166 3.8 Aromatic inhalations BNFC 2011–20123 Respiratory systemChild 12–18 years initially 2.25 g daily in divideddoses, then 1.5 g daily in divided doses as conditionimprovesCarbocisteine (Sanofi-Aventis) ACapsules, carbocisteine 375 mg, net price 120-cappack = £16.03Brands include Mucodyne cOral liquid, carbocisteine 125 mg/5 mL, net price300 mL = £4.39; 250 mg/5 mL, 300 mL = £5.61Brands include Mucodyne c Paediatric 125 mg/5 mL (cherry- andraspberry-flavoured) and Mucodyne c 250 mg/5 mL (cinnamonandrum-flavoured)DORNASE ALFAPhosphorylated glycosylated recombinanthuman deoxyribonuclease 1 (rhDNase)Pregnancy no evidence of teratogenicity; manufactureradvises use only if potential benefit outweighsriskBreast-feeding amount probably too small to beharmful—manufacturer advises cautionSide-effects pharyngitis, voice changes, chest pain;occasionally laryngitis, rashes, urticaria, conjunctivitisIndication and doseManagement of cystic fibrosis patients with aforced vital capacity (FVC) of greater than 40%of predicted to improve pulmonary function. By inhalation of nebulised solution (by jetnebuliser)Child 5–18 years 2500 units (2.5 mg) once dailyPulmozyme c (Roche) ANebuliser solution, dornase alfa 1000 units (1 mg)/mL. Net price 2.5-mL (2500 units) vial = £16.55Note For use undiluted with jet nebulisers only; ultrasonicnebulisers are unsuitableMECYSTEINE HYDROCHLORIDE(Methyl Cysteine Hydrochloride)Cautions history of peptic ulcerationPregnancy manufacturer advises avoidBreast-feeding manufacturer advises avoidIndication and doseReduction of sputum viscosity. By mouthChild 5–12 years 100 mg 3 times dailyChild 12–18 years 200 mg 4 times daily for 2days, then 200 mg 3 times daily for 6 weeks, then200 mg twice dailyVisclair c (Ranbaxy)Tablets, yellow, s/c, e/c, mecysteine hydrochloride100 mg, net price 100= £17.65. Label: 5, 22, 25Hypertonic sodium chlorideNebulised hypertonic sodium chloride solution (3–7 %)is used to mobilise lower respiratory tract secretions inmucous consolidation (e.g. cystic fibrosis). Temporaryirritation, such as coughing, hoarseness, or reversiblebronchoconstriction may occur; an inhaled bronchodilatorcan be used before treatment with hypertonicsodium chloride to reduce the risk of these adverseeffects.MucoClear c 3% (Pari)Nebuliser solution, sodium chloride 3%, net price 20 4 mL = £12.98; 60 4 mL = £27.00Dose. By inhalation of nebulised solutionChild 4 mL 2–4 times dailyMucoClear c 6% (Pari)Nebuliser solution, sodium chloride 6%, net price 20 4 mL = £12.98; 60 4 mL = £27.00Dose. By inhalation of nebulised solutionChild 4 mL twice dailyNebusal c 7% (Forest)Nebuliser solution, sodium chloride 7%, net price 60 4 mL = £27.00Dose. By inhalation of nebulised solutionChild 4 mL up to twice daily3.8 Aromatic inhalationsInhalations containing volatile substances such aseucalyptus oil are traditionally used to relieve congestionand ease breathing. Although the vapour maycontain little of the additive, it encourages deliberateinspiration of warm moist air which is often comforting.Boiling water should not be used for inhalations owingto the risk of scalding.Strong aromatic decongestants (applied as rubs or topillows) are not recommended for infants under the ageof 3 months. Sodium chloride 0.9% solution given asnasal drops can be used to liquefy mucous secretionsand relieve nasal congestion in infants and young children.Benzoin Tincture, Compound, BP(Friars’ Balsam)Tincture, balsamic acids approx. 4.5%. Label: 15DoseNasal congestion. By inhalationAdd one teaspoonful to a pint of hot, not boiling, waterand inhale the vapourMenthol and Eucalyptus Inhalation, BP 1980Inhalation, racementhol or levomenthol 2 g,eucalyptus oil 10 mL, light magnesium carbonate 7 g,water to 100 mLDoseNasal congestion. By inhalationAdd one teaspoonful to a pint of hot, not boiling, waterand inhale the vapourDental prescribing on the NHS May be prescribed asMenthol and Eucalyptus Inhalation BP, 1980

BNFC 2011–2012 3.9 Cough preparations 1673.9 Cough preparations3.9.1 Cough suppressants3.9.2 Expectorant and demulcent coughpreparations3.9.1 Cough suppressantsCough may be a symptom of an underlying disordersuch as asthma (section 3.1), gastro-oesophageal refluxdisease (section 1.1), or rhinitis (section 12.2.1), whichshould be addressed before prescribing cough suppressants.Cough may be associated with smoking or environmentalpollutants. Cough can also result frombronchiectasis including that associated with cysticfibrosis; cough can also have a significant habit component.There is little evidence of any significant benefitfrom the use of cough suppressants in children withacute cough in ambulatory settings. Cough suppressantsmay cause sputum retention and this can be harmful inchildren with bronchiectasis.The use of cough suppressants containing pholcodineor similar opioid analgesics is not generally recommendedin children and should be avoided in childrenunder 6 years; the use of over-the-counter codeinecontainingliquids should be avoided in children under18 years, see MHRA/CHM advice below.Sedating antihistamines (section 3.4.1) are used as thecough suppressant component of many compoundcough preparations on sale to the public; all tend tocause drowsiness which may reflect their main mode ofaction.MHRA/CHM advice (March 2008 and February2009)Children under 6 years should not be given over-thecountercough and cold medicines containing thefollowing ingredients:. brompheniramine, chlorphenamine, diphenhydramine,doxylamine, promethazine, or triprolidine(antihistamines);. dextromethorphan or pholcodine (cough suppressants);. guaifenesin or ipecacuanha (expectorants);. phenylephrine, pseudoephedrine, ephedrine,oxymetazoline, or xylometazoline (decongestants).Over-the-counter cough and cold medicines can beconsidered for children aged 6–12 years after basicprinciples of best care have been tried, but treatmentshould be restricted to five days or less. Childrenshould not be given more than 1 cough or coldpreparation at a time because different brands maycontain the same active ingredient; care should betaken to give the correct dose.MHRA/CHM advice (October 2010) Over-thecountercodeine-containing liquid medicinesfor childrenChildren under 18 years should not use codeinecontainingover-the-counter liquid medicines forcough suppressionPHOLCODINECautions asthma; chronic, persistent, or productivecough; interactions: Appendix 1 (pholcodine)Contra-indications chronic bronchitis, bronchiectasis,bronchiolitis, children at risk of respiratory failureHepatic impairment avoidRenal impairment use with caution; avoid in severeimpairmentPregnancy manufacturer advises avoid unless potentialbenefit outweighs riskBreast-feeding manufacturer advises avoid unlesspotential benefit outweighs risk—no informationavailableSide-effects nausea, vomiting, constipation, sputumretention, drowsiness, dizziness, excitation, confusion,rashIndication and doseDry cough (but not generally recommended forchildren, see notes above). By mouthChild 6–12 years 2–5 mg 3–4 times dailyChild 12–18 years 5–10 mg 3–4 times dailyPholcodine Linctus, BPLinctus (= oral solution), pholcodine 5 mg/5 mL in asuitable flavoured vehicle, containing citric acidmonohydrate 1%. Net price 100 mL = 31pBrands include Pavacol-D c (sugar-free), Galenphol c (sugar-free)Pholcodine Linctus, Strong, BPLinctus (= oral solution), pholcodine 10 mg/5 mL in asuitable flavoured vehicle, containing citric acidmonohydrate 2%. Net price 100 mL = 44pBrands include Galenphol cGalenphol c (Thornton & Ross)Paediatric linctus (= oral solution), orange, sugarfree,pholcodine 2 mg/5 mL. Net price 90-mL pack =£1.203.9.2 Expectorant anddemulcent coughpreparationsSimple linctus and other demulcent cough preparationscontaining soothing substances, such as syrup or glycerol,may temporarily relieve a dry irritating cough.These preparations have the advantage of being harmlessand inexpensive and sugar-free versions are available.Expectorants are claimed to promote expulsion ofbronchial secretions but there is no evidence that anydrug can specifically facilitate expectoration.Compound cough preparations for children are onsale to the public but should not be used in childrenunder 6 years; the rationale for some is dubious. Careshould be taken to give the correct dose and to not usemore than one preparation at a time, see MHRA/CHMadvice above.3 Respiratory system

168 3.10 Systemic nasal decongestants BNFC 2011–20123 Respiratory systemSimple Linctus, Paediatric, BPLinctus (= oral solution), citric acid monohydrate0.625% in a suitable vehicle with an anise flavour. Netprice 100 mL = 72pA sugar-free version is also availableDoseCough. By mouthChild 1 month–12 years 5–10 mL 3–4 times dailySimple Linctus, BPLinctus (= oral solution), citric acid monohydrate2.5% in a suitable vehicle with an anise flavour. Netprice 100 mL = 42pA sugar-free version is also availableDoseCough. By mouthChild 12–18 years 5 mL 3–4 times daily3.10 Systemic nasaldecongestantsIndication and doseCongestion of mucous membranes of upperrespiratory tract. By mouthChild 6–12 years 30 mg 3–4 times dailyChild 12–18 years 60 mg 3–4 times daily1Galpseud c (Thornton & Ross) AUTablets, pseudoephedrine hydrochloride 60 mg, netprice 24 = £2.25Linctus, orange, sugar-free, pseudoephedrine hydrochloride30 mg/5 mL, net price 100 mL = 70pExcipients include alcohol1Sudafed c (McNeil) AUTablets, red, f/c, pseudoephedrine hydrochloride60 mg, net price 24 = £2.12Elixir, red, pseudoephedrine hydrochloride 30 mg/5 mL, net price 100 mL = £1.05Nasal congestion in children due to allergic or vasomotorrhinitis should be treated with oral antihistamines(section 3.4.1), topical nasal preparations containingcorticosteroids (section 12.2.1), or topical decongestants(section 12.2.2).There is little evidence to support the use of systemicdecongestants in children.Pseudoephedrine has few sympathomimetic effects,and is commonly combined with other ingredients(including antihistamines) in preparations intended forthe relief of cough and cold symptoms but it should notbe used in children under 6 years, see MHRA/CHMadvice, p. 167.PSEUDOEPHEDRINEHYDROCHLORIDECautions hypertension, heart disease, diabetes,hyperthyroidism, raised intra-ocular pressure; interactions:Appendix 1 (sympathomimetics)Contra-indications treatment with MAOI within previous2 weeksHepatic impairment manufacturer advises caution insevere impairmentRenal impairment manufacturer advises caution inmild to moderate impairment; avoid in severeimpairmentPregnancy defective closure of the abdominal wall(gastrochisis) reported very rarely in newborns afterfirst trimester exposureBreast-feeding amount too small to be harmfulSide-effects nausea, vomiting, hypertension, tachycardia,headache, anxiety, restlessness, insomnia;rarely hallucinations, rash; urinary retention alsoreported1. Can be sold to the public provided no more than 720 mg ofpseudoephedrine salts are supplied, and ephedrine base (orsalts) are not supplied at the same time; for details seeMedicines, Ethics and Practice, London, PharmaceuticalPress (always consult latest edtion)

BNFC 2011–2012 1694 Central nervous system4.1 Hypnotics and anxiolytics 1694.1.1 Hypnotics 1694.1.2 Anxiolytics 1714.1.3 Barbiturates 1714.2 Drugs used in psychoses andrelated disorders 1714.2.1 Antipsychotic drugs 1724.2.2 Antipsychotic depot injections 1814.2.3 Antimanic drugs 1814.3 Antidepressant drugs 1834.3.1 Tricyclic antidepressant drugs 1844.3.2 Monoamine-oxidase inhibitors 1864.3.3 Selective serotonin re-uptakeinhibitors 1864.3.4 Other antidepressant drugs 1884.4 CNS stimulants and other drugsfor attention deficit hyperactivitydisorder 1884.5 Drugs used in the treatment ofobesity 1914.6 Drugs used in nausea andvertigo 1924.7 Analgesics 1994.7.1 Non-opioid analgesics and compoundanalgesic preparations 1994.7.2 Opioid analgesics 2024.7.3 Neuropathic pain 2124.7.4 Antimigraine drugs 2124.7.4.1 Treatment of acute migraine 2124.7.4.2 Prophylaxis of migraine 2144.7.4.3 Cluster headache and the trigeminalautonomic cephalalgias 2144.8 Antiepileptics 2154.8.1 Control of the epilepsies 2154.8.2 Drugs used in status epilepticus 2314.8.3 Febrile convulsions 2354.9 Drugs used in dystonias andrelated disorders 2354.9.1 Dopaminergic drugs used indystonias 2354.9.2 Antimuscarinic drugs used indystonias 2374.9.3 Drugs used in essential tremor,chorea, tics, and related disorders2374.10 Drugs used in substance dependence2384.10.1 Alcohol dependence 2384.10.2 Nicotine dependence 2384.10.3 Opioid dependence 2414.11 Drugs for dementia 2414.1 Hypnotics and anxiolytics4.1.1 Hypnotics4.1.2 Anxiolytics4.1.3 BarbituratesMost anxiolytics (‘sedatives’) will induce sleep whengiven at night and most hypnotics will sedate whengiven during the day. Hypnotics and anxiolytics shouldbe reserved for short courses to alleviate acute conditionsafter causal factors have been established.The role of drug therapy in the management of anxietydisorders in children and adolescents is uncertain; drugtherapy should be initiated only by specialists afterpsychosocial interventions have failed. Benzodiazepinesand tricyclic antidepressants have been used butadverse effects may be problematic.Skilled tasks Hypnotics and anxiolytics may impairjudgement and increase reaction time, and so affectability to drive or perform skilled tasks; they increasethe effects of alcohol. Moreover the hangover effects ofa night dose may impair performance on the followingday.Important1. Benzodiazepines are indicated for the shorttermrelief (two to four weeks only) of anxietythat is severe, disabling or causing the childunacceptable distress, occurring alone or inassociation with insomnia or short-term psychosomatic,organic, or psychotic illness.2. The use of benzodiazepines to treat short-term‘mild’ anxiety is inappropriate.3. Benzodiazepines should be used to treat insomniaonly when it is severe, disabling, or causingthe child extreme distress.4.1.1 HypnoticsThe prescribing of hypnotics to children, except foroccasional use such as for sedation for procedures(section 15.1.4), is not justified. There is a risk ofhabituation with prolonged use. Problems settling childrenat night should be managed with behaviouraltherapy.4 Central nervous system

170 4.1.1 Hypnotics BNFC 2011–2012Dental procedures Some anxious children may benefitfrom the use of a hypnotic the night before the dentalappointment. Hypnotics do not relieve pain, and if paininterferes with sleep an appropriate analgesic should begiven.Chloral Hydrate (Non-proprietary) ASuppositories, chloral hydrate 25 mg, 50 mg, 60 mg,100 mg, 200 mg, 500 mg. Available from ‘specialorder’manufacturers or specialist importing companies,see p. 8094 Central nervous systemChloral and derivativesChloral hydrate and derivatives were formerly popularhypnotics for children.Chloral hydrate is now mainly used for sedation duringdiagnostic procedures (section 15.1.4). It accumulateson prolonged use.CHLORAL HYDRATECautions reduce dose in debilitated; avoid prolongeduse (and abrupt withdrawal thereafter); avoid contactwith skin and mucous membranes; interactions:Appendix 1 (anxiolytics and hypnotics)Skilled tasks Drowsiness may persist the next day andaffect performance of skilled tasks (e.g. driving); effects ofalcohol enhancedContra-indications severe cardiac disease; gastritis;acute porphyria (section 9.8.2)Hepatic impairment can precipitate coma; reducedose in mild to moderate hepatic impairment; avoid insevere impairmentRenal impairment avoid in severe impairmentPregnancy avoidBreast-feeding risk of sedation in infant—avoidSide-effects gastric irritation (nausea and vomitingreported), abdominal distention, flatulence, headache,tolerance, dependence, excitement, delirium (especiallyon abrupt withdrawal), ketonuria, and rashLicensed use not licensed for sedation for painlessproceduresIndication and doseSedation for painless procedures. By mouth or by rectum (if oral route not available)Neonate 30–50 mg/kg 45–60 minutes beforeprocedure; doses up to 100 mg/kg may be usedwith respiratory monitoringChild 1 month–12 years 30–50 mg/kg (max. 1 g)45–60 minutes before procedure; higher doses upto 100 mg/kg (max. 2 g) may be usedChild 12–18 years 1–2 g 45–60 minutes beforeprocedureAdministration for administration by mouth diluteliquid with plenty of water or juice to mask unpleasanttaste.Chloral Mixture, BP 2000 A(Chloral Oral Solution)Mixture, chloral hydrate 500 mg/5 mL in a suitablevehicle. Available from ‘special-order’ manufacturersor specialist importing companies, see p. 809Chloral Elixir, Paediatric, BP 2000 A(Chloral Oral Solution, Paediatric)Elixir, chloral hydrate 200 mg/5 mL (4%) in a suitablevehicle with a black currant flavour. Available from‘special-order’ manufacturers or specialist importingcompanies, see p. 809Cloral betaineWelldorm c (Alphashow) ATablets, blue-purple, f/c, cloral betaine 707 mg(: chloral hydrate 414 mg), net price 30-tab pack =£12.10. Label: 19, 27DoseShort-term treatment of insomnia. By mouthChild 12–18 years 1–2 tablets with water or milk atbedtime, max. 5 tablets (chloral hydrate 2 g) dailyElixir, red, chloral hydrate 143.3 mg/5 mL, net price150-mL pack = £8.70. Label: 19, 27DoseShort-term treatment of insomnia. By mouthChild 2–12 years 1–1.75 mL/kg (chloral hydrate 30–50 mg/kg) with water or milk at bedtime; max. 35 mL(chloral hydrate 1 g) dailyChild 12–18 years 15–45 mL (chloral hydrate 0.4–1.3 g)with water or milk at bedtime; max. 70 mL (chloralhydrate 2 g) dailyAntihistaminesSome antihistamines (section 3.4.1) such as promethazineare used for occasional insomnia in adults; theirprolonged duration of action can often cause drowsinessthe following day. The sedative effect of antihistaminesmay diminish after a few days of continuedtreatment; antihistamines are associated with headache,psychomotor impairment and antimuscarinic effects.The use of antihistamines as hypnotics in children is notusually justified.PROMETHAZINE HYDROCHLORIDEUCautions see notes in section 3.4.1; also avoid extravasationwith intravenous injectionContra-indications see Promethazine Hydrochloride,section 3.4.1Hepatic impairment see notes in section 3.4.1Renal impairment see Promethazine Hydrochloride,section 3.4.1Pregnancy see notes in section 3.4.1Breast-feeding see notes in section 3.4.1Side-effects see Promethazine Hydrochloride, section3.4.1Licensed use not licensed for use in children under 2yearsIndication and doseSedation (short-term use). By mouthChild 2–5 years 15–20 mgChild 5–10 years 20–25 mgChild 10–18 years 25–50 mg

BNFC 2011–2012 4.1.2 Anxiolytics 171Sedation in intensive care. By mouth or by slow intravenous injection or bydeep intramuscular injectionChild 1 month–12 years 0.5–1 mg/kg (max.25 mg) 4 times daily, adjusted according toresponseChild 12–18 years 25–50 mg 4 times daily,adjusted according to responseAllergy and urticaria section 3.4.1Nausea and vomiting section 4.61Promethazine (Non-proprietary) AInjection, promethazine hydrochloride 25 mg/mL,net price 1-mL amp = 68p, 2-mL amp = £1.201. A restriction does not apply where administration is forsaving life in emergency1Phenergan c (Sanofi-Aventis) AInjection, promethazine hydrochloride 25 mg/mL,net price 1-mL amp = 67p1. A restriction does not apply where administration is forsaving life in emergencyOral preparationsSection 3.4.1MelatoninMelatonin is a pineal hormone that may affect sleeppattern. Clinical experience suggests that when appropriatebehavioural sleep interventions fail, melatoninmay be of value for treating sleep onset insomnia anddelayed sleep phase syndrome in children with conditionssuch as visual impairment, cerebral palsy, attentiondeficit hyperactivity disorder, autism, and learningdifficulties. It is also sometimes used before magneticresonance imaging (MRI), computed tomography (CT),or EEG investigations. Little is known about its longtermeffects in children, and there is uncertainty as tothe effect on other circadian rhythms including endocrineor reproductive hormone secretion. Treatmentwith melatonin should be initiated and supervised by aspecialist, but may be continued by general practitionersunder a shared-care arrangement. The need to continuemelatonin therapy should be reviewed every 6 months.Melatonin is available as a modified-release tablet (Circadinc ) and also as unlicensed formulations. Circadin cis licensed for the short-term treatment of primaryinsomnia in adults over 55 years. Unlicensed immediate-releasepreparations may be more suitable forchildren; the manufacturer should be specified in theshared-care guideline because of variability in clinicaleffect of unlicensed formulations.MELATONINCautions autoimmune disease (manufacturer advisesavoid—no information available); interactions:Appendix 1 (melatonin)Hepatic impairment clearance reduced—manufactureradvises avoidRenal impairment no information available—cautionPregnancy no information available—avoidBreast-feeding present in milk—avoidSide-effects less commonly abdominal pain, dyspepsia,dry mouth, mouth ulceration, weight gain,hypertension, chest pain, malaise, dizziness, restlessness,nervousness, irritability, anxiety, migraine, proteinuria,glycosuria, pruritus, rash, dry skin; rarelythirst, flatulence, halitosis, hypersalivation, vomiting,gastritis, hypertriglyceridaemia, palpitation, syncope,hot flushes, aggression, impaired memory, restlesslegs syndrome, paraesthesia, mood changes, priapism,increased libido, prostatitis, polyuria, haematuria,leucopenia, thrombocytopenia, electrolyte disturbances,muscle spasm, arthritis, lacrimation, visualdisturbances, nail disorderLicensed use not licensed for use in childrenIndication and doseSleep onset insomnia and delayed sleep phasesyndrome (see notes above). By mouthChild 1 month–18 years initially 2–3 mg dailybefore bedtime increased if necessary after 1–2weeks to 4–6 mg daily before bedtime; max. 10 mgdailyCircadin c (Lundbeck) TATablets, m/r, melatonin 2 mg, net price 21-tab pack =£10.77. Label: 2, 21, 25Note Other formulations of melatonin are available from‘special-order’ manufacturers or specialist importing companies,see p. 8094.1.2 AnxiolyticsAnxiolytic treatment should be used in children only torelieve acute anxiety (and related insomnia) caused byfear (e.g. before surgery, section 15.1.4.1).Anxiolytic treatment should be limited to the lowestpossible dose for the shortest possible time (see p. 169).BuspironeBuspirone is thought to act at specific serotonin(5HT 1A ) receptors; safety and efficacy in children haveyet to be determined.4.1.3 BarbituratesClassification not used in BNF for Children.4.2 Drugs used in psychosesand related disorders4.2.1 Antipsychotic drugs4.2.2 Antipsychotic depot injections4.2.3 Antimanic drugsAdvice on doses of antipsychotic drugs above BNFfor Children upper limit1. Consider alternative approaches including adjuvanttherapy.4 Central nervous system

172 4.2.1 Antipsychotic drugs BNFC 2011–20124 Central nervous system2. Bear in mind risk factors, including obesity.3. Consider potential for drug interactions—see interactions:Appendix 1 (antipsychotics).4. Carry out ECG to exclude untoward abnormalitiessuch as prolonged QT interval; repeat ECG periodicallyand reduce dose if prolonged QT interval orother adverse abnormality develops.5. Increase dose slowly and not more often than onceweekly.6. Carry out regular pulse, blood pressure, and temperaturechecks; ensure that patient maintains adequatefluid intake.7. Consider high-dose therapy to be for limited periodand review regularly; abandon if no improvementafter 3 months (return to standard dosage).Important When prescribing an antipsychotic for administrationon an emergency basis, the intramuscular dose should belower than the corresponding oral dose (owing to absence offirst-pass effect), particularly if the child is very active(increased blood flow to muscle considerably increases therate of absorption). The prescription should specify the dose foreach route and should not imply that the same dose can begiven by mouth or by intramuscular injection. The dose ofantipsychotic for emergency use should be reviewed at leastdaily.4.2.1 Antipsychotic drugsThere is little information on the efficacy and safety ofantipsychotic drugs in children and adolescents andmuch of the information available has been extrapolatedfrom adult data; in particular, little is known about thelong-term effects of antipsychotic drugs on the developingnervous system. Antipsychotic drugs should beinitiated and managed under the close supervision of anappropriate specialist.Antipsychotic drugs are also known as ‘neuroleptics’and (misleadingly) as ‘major tranquillisers’. Antipsychoticdrugs generally tranquillise without impairingconsciousness and without causing paradoxical excitementbut they should not be regarded merely as tranquillisers.For conditions such as schizophrenia thetranquillising effect is of secondary importance.In the short term they are used to calm disturbedchildren whatever the underlying psychopathology,which may be schizophrenia, brain damage, mania,toxic delirium, or agitated depression. Antipsychoticdrugs are used to alleviate severe anxiety but this tooshould be a short-term measure.Schizophrenia Antipsychotic drugs relieve psychoticsymptoms such as thought disorder, hallucinations, anddelusions, and prevent relapse. Although they are usuallyless effective in apathetic withdrawn children, theysometimes appear to have an activating influence. Childrenwith acute schizophrenia generally respond betterthan those with chronic symptoms. Children shouldreceive antipsychotic drugs for 4–6 weeks before thedrug is deemed ineffective.Long-term treatment of a child with a definite diagnosisof schizophrenia may be necessary even after the firstepisode of illness in order to prevent the manifest illnessfrom becoming chronic. Withdrawal of drug treatmentrequires careful surveillance because children whoappear well on medication may suffer a disastrousrelapse if treatment is withdrawn inappropriately. Inaddition the need for continuation of treatment maynot become immediately evident because relapse isoften delayed for several weeks after cessation of treatment.Antipsychotic drugs are considered to act by interferingwith dopaminergic transmission in the brain by blockingdopamine D 2 receptors, which may give rise to theextrapyramidal effects described below, and also tohyperprolactinaemia. Antipsychotic drugs may alsoaffect cholinergic, alpha-adrenergic, histaminergic, andserotonergic receptors.Choice of drug is influenced by the potential for sideeffectsand is often guided by individual circumstancese.g. the psychological effects of potential weight gain.The drugs most commonly used in children are haloperidol,risperidone, and olanzapine.Cautions Assess child for movement disorders beforestarting treatment. Monitor neurological parameters,bowel habit, pulse, and blood pressure. Regular clinicalmonitoring of endocrine function should be consideredwhen children are taking an antipsychotic known toincrease prolactin levels; this includes measuring weightand height, assessing sexual maturation, and monitoringmenstrual function. Children with schizophrenia shouldhave physical health monitoring (including cardiovasculardisease risk assessment) at least once per year.Antipsychotic drugs should be used with caution inchildren with cardiovascular disease; an ECG may berequired (see individual drug monographs), particularlyif physical examination identifies cardiovascular riskfactors, if there is a personal history of cardiovasculardisease, or if the child is being admitted as an inpatient.Antipsychotic drugs should also be used with caution inchildren with epilepsy (and conditions predisposing toepilepsy), depression, myasthenia gravis (avoid chlorpromazine,pericyazine and prochlorperazine in theseconditions) or a susceptibility to angle-closure glaucoma.Caution is also required in severe respiratorydisease and in children with a history of jaundice orwho have blood dyscrasias (perform blood counts ifunexplained infection or fever develops). As photosensitisationmay occur with higher dosages, childrenshould avoid direct sunlight. Interactions: Appendix 1(antipsychotics).Contra-indications Antipsychotic drugs may be contra-indicatedin comatose states, CNS depression, andphaeochromocytoma.Skilled tasks Drowsiness may affect performance ofskilled tasks (e.g. driving or operating machinery), especiallyat start of treatment; effects of alcohol areenhanced.Withdrawal There is a high risk of relapse if medicationis stopped after 1–2 years. Withdrawal of antipsychoticdrugs after long-term therapy should always begradual and closely monitored to avoid the risk of acutewithdrawal syndromes or rapid relapse. Children shouldbe monitored regularly for signs and symptoms ofrelapse for 2 years after withdrawal of antipsychoticmedication.Hepatic impairment All antipsychotics can precipitatecoma if used in hepatic impairment; phenothiazinesare hepatotoxic.

BNFC 2011–2012 4.2.1 Antipsychotic drugs 173Renal impairment Start with small doses of antipsychoticdrugs in severe renal impairment because ofincreased cerebral sensitivity. Pericyazine should beavoided in renal impairment.Pregnancy Extrapyramidal effects have been reportedoccasionally in the neonate when antipsychotic drugsare taken during the third trimester of pregnancy.Breast-feeding There is limited information availableon the short- and long-term effects of antipsychotics onthe breast-fed infant. Animal studies indicate possibleadverse effects of antipsychotic medicines on the developingnervous system. Treatment with antipsychoticswhilst breast-feeding should be avoided unless absolutelynecessary.Side-effects Extrapyramidal symptoms are the mosttroublesome. They occur most frequently with thepiperazine phenothiazines (such as perphenazine, prochlorperazine,and trifluoperazine), the butyrophenones(such as haloperidol), and the depot preparations. Theyare easy to recognise but cannot be predicted accuratelybecause they depend on the dose, the type of drug, andon individual susceptibility.Extrapyramidal symptoms consist of:. parkinsonian symptoms (including tremor), whichmay appear gradually (but less commonly than inadults);. dystonia (abnormal face and body movements) anddyskinesia, which appear after only a few doses;. akathisia (restlessness), which characteristicallyoccurs after large initial doses and may resemblean exacerbation of the condition being treated; and. tardive dyskinesia (rhythmic, involuntary movementsof tongue, face, and jaw), which usuallydevelops on long-term therapy or with high dosage,but it may develop on short-term treatment withlow doses—short-lived tardive dyskinesia mayoccur after withdrawal of the drug.Parkinsonian symptoms remit if the drug is withdrawnand may be suppressed by the administration of antimuscarinicdrugs (section 4.9.2). However, routineadministration of such drugs is not justified becausenot all children are affected and because they mayunmask or worsen tardive dyskinesia.Tardive dyskinesia is of particular concern because itmay be irreversible on withdrawing therapy and treatmentis usually ineffective. In children, tardive dyskinesiais more likely to occur when the antipsychoticis withdrawn. However, some manufacturers suggestthat drug withdrawal at the earliest signs of tardivedyskinesia (fine vermicular movements of the tongue)may halt its full development. Tardive dyskinesia mayoccur and treatment must be carefully and regularlyreviewed.Hypotension and interference with temperature regulationare dose-related side-effects.Neuroleptic malignant syndrome (hyperthermia, fluctuatinglevel of consciousness, muscle rigidity, andautonomic dysfunction with pallor, tachycardia, labileblood pressure, sweating, and urinary incontinence) is arare but potentially fatal side-effect of some antipsychoticdrugs. Discontinuation of the antipsychotic isessential because there is no proven effective treatment,but cooling, bromocriptine, and dantrolene have beenused. The syndrome, which usually lasts for 5–7 daysafter drug discontinuation, may be unduly prolonged ifdepot preparations have been used.Other side-effects include: drowsiness; apathy; agitation,excitement and insomnia; convulsions; dizziness; headache;confusion; gastro-intestinal disturbances; nasalcongestion; antimuscarinic symptoms (such as drymouth, constipation, difficulty with micturition, andblurred vision; very rarely angle-closure glaucoma);cardiovascular symptoms (such as hypotension, tachycardia,and arrhythmias); ECG changes (cases of suddendeath have occurred); venous thromboembolism; endocrineeffects such as menstrual disturbances, galactorrhoea,gynaecomastia, impotence, and weight gain;blood dyscrasias (such as agranulocytosis and leucopenia),photosensitisation, contact sensitisation andrashes, and jaundice (including cholestatic); cornealand lens opacities, and purplish pigmentation of theskin, cornea, conjunctiva, and retina.Overdosage: for poisoning with phenothiazines andrelated compounds, see Emergency Treatment of Poisoning,p. 31.Classification of antipsychotics The phenothiazinederivatives can be divided into 3 main groups.Group 1: chlorpromazine, levomepromazine(methotrimeprazine), and promazine, generallycharacterised by pronounced sedative effects andmoderate antimuscarinic and extrapyramidal sideeffects.Group 2: pericyazine and pipotiazine, generallycharacterised by moderate sedative effects, markedantimuscarinic effects, but fewer extrapyramidalside-effects than groups 1 or 3.Group 3: perphenazine, prochlorperazine, and trifluoperazine,generally characterised by fewer sedativeeffects, fewer antimuscarinic effects, but morepronounced extrapyramidal side-effects thangroups 1 and 2.Drugs of other chemical groups resemble the phenothiazinesof group 3 in their clinical properties. Theyinclude the butyrophenones (e.g. haloperidol);diphenylbutylpiperidines (e.g. pimozide); thioxanthenes(flupentixol and zuclopenthixol); and thesubstituted benzamides (e.g. sulpiride).For details of the newer antipsychotic drugs amisulpride,aripiprazole, clozapine, olanzapine, quetiapine,and risperidone, see under Atypical AntipsychoticDrugs, p. 177.Choice As indicated above, the various drugs differsomewhat in predominant actions and side-effects.Selection is influenced by the degree of sedationrequired and the child’s susceptibility to extrapyramidalside-effects. However, the differences between antipsychoticdrugs are less important than the great variabilityin response; moreover, tolerance to secondary effectssuch as sedation usually develops. The atypical antipsychoticdrugs may be appropriate if extrapyramidal sideeffectsare a particular concern (see under AtypicalAntipsychotic Drugs, p. 177). Clozapine is used forschizophrenia when other antipsychotic drugs are ineffectiveor not tolerated.4 Central nervous system

174 4.2.1 Antipsychotic drugs BNFC 2011–20124 Central nervous systemPrescribing of more than one antipsychotic drug at thesame time is not recommended; it may constitute ahazard and there is no significant evidence that sideeffectsare minimised.Chlorpromazine is associated with a wide range ofadverse effects, including marked sedation.Pimozide is less sedating than chlorpromazine.Although pimozide is licensed for use in children, it isnot used because of the risk of serious cardiac sideeffects(see ECG Monitoring, p. 176).Sulpiride in high doses controls florid positive symptoms,but in lower doses it has an alerting effect onpatients with apathetic withdrawn schizophrenia.Haloperidol and trifluoperazine are also licensed foruse in children but their use is limited by the highincidence of extrapyramidal symptoms. Haloperidolmay be preferred for the rapid control of hyperactivepsychotic states; it causes less hypotension than chlorpromazine.Other uses Nausea and vomiting (section 4.6), choreas,motor tics, and intractable hiccup.Equivalent doses of oral antipsychotic drugsThese equivalences are intended only as an approximateguide; individual dosage instructions should alsobe checked; children should be carefully monitoredafter any change in medicationAntipsychotic drugChlorpromazineClozapineHaloperidolPimozideRisperidoneSulpirideTrifluoperazineDaily dose100 mg50 mg2–3 mg2 mg0.5–1 mg200 mg5 mgImportant These equivalences must not be extrapolatedbeyond the max. dose for the drug. Higher doses requirecareful titration in specialist units and the equivalencesshown here may not be appropriateDosageAfter an initial period of stabilisation, the total dailyoral dose of antipsychotic drugs can be given as asingle dose in most children. For advice on dosesabove the BNF for Children upper limit, see p. 171.CHLORPROMAZINEHYDROCHLORIDEWarning Owing to the risk of contact sensitisation, pharmacists,nurses, and other health workers should avoid directcontact with chlorpromazine; tablets should not be crushedand solutions should be handled with careCautions see notes above; also diabetes; childrenshould remain supine, with blood pressure monitoringfor 30 minutes after intramuscular injection; doseadjustment may be necessary if smoking started orstopped during treatmentContra-indications see notes above; hypothyroidismHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also hyperglycaemiaIndication and doseChildhood schizophrenia and other psychoses(under specialist supervision). By mouthChild 1–6 years 500 micrograms/kg every 4–6hours adjusted according to response (max. 40 mgdaily)Child 6–12 years 10 mg 3 times daily, adjustedaccording to response (max. 75 mg daily)Child 12–18 years 25 mg 3 times daily (or 75 mgat night), adjusted according to response, to usualmaintenance dose of 75–300 mg daily (but up to1 g daily may be required)Relief of acute symptoms of psychoses (underspecialist supervision) but see also Cautions andSide-effects. By deep intramuscular injectionChild 1–6 years 500 micrograms/kg every 6–8hours (max. 40 mg daily)Child 6–12 years 500 micrograms/kg every 6–8hours (max. 75 mg daily)Child 12–18 years 25–50 mg every 6–8 hoursChlorpromazine (Non-proprietary) ATablets, coated, chlorpromazine hydrochloride25 mg, net price 28-tab pack = £1.77; 50 mg, 28-tabpack = £2.37; 100 mg, 28-tab pack = £2.31. Label: 2,11Brands include Chloractil cOral solution, chlorpromazine hydrochloride 25 mg/5 mL, net price 150 mL = £1.79; 100 mg/5 mL,150 mL = £4.28. Label: 2, 11Injection, chlorpromazine hydrochloride 25 mg/mL,net price 1-mL amp = 60p, 2-mL amp = 63pLargactil c (Sanofi-Aventis) AInjection, chlorpromazine hydrochloride 25 mg/mL,net price 2-mL amp = 60pHALOPERIDOLCautions see notes above; also subarachnoidhaemorrhage and metabolic disturbances such ashypokalaemia, hypocalcaemia, or hypomagnesaemia;dose adjustment may be necessary if smoking startedor stopped during treatmentContra-indications see notes above; QT-intervalprolongation (avoid concomitant administration ofdrugs that prolong QT interval); bradycardiaHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above, but less sedating andfewer antimuscarinic or hypotensive symptoms; pigmentationand photosensitivity reactions rare;depression; weight loss; less commonly dyspnoea,oedema; rarely bronchospasm, hypoglycaemia, andinappropriate antidiuretic hormone secretion; Stevens-Johnsonsyndrome and toxic epidermal necrolysisalso reportedLicensed use not licensed for use in children fornausea and vomiting in palliative care

BNFC 2011–2012 4.2.1 Antipsychotic drugs 175Indication and doseSchizophrenia and other psychoses, mania,short-term adjunctive management of psychomotoragitation, excitement and violent ordangerously impulsive behaviour (under specialistsupervision). By mouthChild 12–18 years initially 0.5–3 mg 2–3 timesdaily or 3–5 mg 2–3 times daily in severely affectedor resistant disease; in resistant schizophrenia upto 30 mg daily may be needed; adjusted accordingto response to lowest effective maintenance dose(as low as 5–10 mg daily)Motor tics (including Tourette syndrome) (underspecialist supervision). By mouthChild 5–12 years 12.5–25 micrograms/kg twicedaily, adjusted according to response up to 10 mgdailyChild 12–18 years 1.5 mg 3 times daily, adjustedaccording to response up to 10 mg dailyNausea and vomiting in palliative care. By mouthChild 12–18 years 1.5 mg once daily at night,increased to 1.5 mg twice daily if necessary; max.5 mg twice daily. By continuous intravenous or subcutaneousinfusionChild 1 month–12 years 25–85 micrograms/kgover 24 hoursChild 12–18 years 1.5–5 mg over 24 hoursHaloperidol (Non-proprietary) ATablets, haloperidol 500 micrograms, net price 28-tabpack = 91p; 1.5 mg, 28-tab pack = £1.39; 5 mg, 28-tabpack = £2.15; 10 mg, 28-tab pack = £5.53; 20 mg, 28-tab pack = £14.07. Label: 2Injection, haloperidol 5 mg/mL, net price 1-mL amp= 49pDozic c (Rosemont) AOral liquid, sugar-free, haloperidol 1 mg/mL, netprice 100-mL pack = £6.86. Label: 2Haldol c (Janssen) ATablets, both scored, haloperidol 5 mg (blue), netprice 100-tab pack = £7.21; 10 mg (yellow), 100-tabpack = £14.08. Label: 2Oral liquid, sugar-free, haloperidol 2 mg/mL, netprice 100-mL pack (with pipette) = £4.45. Label: 2Injection, haloperidol 5 mg/mL, net price 1-mL amp= 37pSerenace c (IVAX) ACapsules, green, haloperidol 500 micrograms, netprice 30-cap pack = 98p. Label: 2Tablets, haloperidol 1.5 mg, net price 30-tab pack =£1.74; 5 mg (pink), 30-tab pack = £3.95; 10 mg (palepink), 30-tab pack = £6.76. Label: 2Oral liquid, sugar-free, haloperidol 2 mg/mL, netprice 500-mL pack = £34.48. Label: 2LEVOMEPROMAZINE(Methotrimeprazine)Cautions see notes above; diabetes; children receivinglarge initial doses should remain supineContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; occasionally raisederythrocyte sedimentation rate occurs; hyperglycaemiaalso reportedIndication and doseRestlessness and confusion in palliative care. By continuous subcutaneous infusionChild 1–12 years 0.35–3 mg/kg over 24 hoursChild 12–18 years 12.5–200 mg over 24 hoursNausea and vomiting in palliative care. By continuous intravenous or subcutaneousinfusionChild 1 month–12 years 100–400 micrograms/kg over 24 hoursChild 12–18 years 5–25 mg over 24 hoursAdministration for administration by subcutaneousinfusion dilute with a suitable volume of SodiumChloride 0.9%Nozinan c (Sanofi-Aventis) ATablets, scored, levomepromazine maleate 25 mg, netprice 84-tab pack = £20.26. Label: 2Injection, levomepromazine hydrochloride 25 mg/mL, net price 1-mL amp = £2.01PERICYAZINE(Periciazine)Cautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; more sedating; hypotensioncommon when treatment initiated; respiratorydepressionLicensed use tablets not licensed for use in childrenIndication and doseSchizophrenia, psychoses (severe mental orbehavioural disorders only) (under specialistsupervision). By mouthChild 1–12 years initially 500 micrograms dailyfor 10-kg child, increased by 1 mg for each additional5 kg to max. total daily dose of 10 mg; dosemay be gradually increased according to responsebut maintenance should not exceed twice initialdoseChild 12–18 years initially 25 mg 3 times dailyincreased at weekly intervals by steps of 25 mgaccording to response; usual max. 100 mg 3 timesdaily; total daily dose may alternatively be given in2 divided doses4 Central nervous system

176 4.2.1 Antipsychotic drugs BNFC 2011–20124 Central nervous systemPericyazine (Non-proprietary) ATablets, yellow, scored, pericyazine 2.5 mg, net price84-tab pack = £9.23; 10 mg, 84-tab pack = £24.95.Label: 2Syrup, brown, pericyazine 10 mg/5 mL, net price 100-mL pack = £12.08. Label: 2PERPHENAZINECautions see notes above; hypothyroidismContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; less sedating; extrapyramidalsymptoms, especially dystonia, more frequent,particularly at high dosage; rarely systemiclupus erythematosusIndication and doseSchizophrenia and other psychoses, mania,short-term adjunctive management of anxiety,severe psychomotor agitation, excitement,violent or dangerously impulsive behaviour(under specialist supervision). By mouthChild 14–18 years initially 4 mg 3 times dailyadjusted according to the response; max. 24 mgdailyFentazin c (Goldshield) ATablets, both s/c, perphenazine 2 mg, net price 100-tab pack = £22.38; 4 mg, 100-tab pack = £26.34.Label: 2PIMOZIDECautions see notes aboveECG monitoring Following reports of sudden unexplaineddeath, an ECG is recommended before treatment. It is alsorecommended that patients taking pimozide should have anannual ECG (if the QT interval is prolonged, treatmentshould be reviewed and either withdrawn or dose reducedunder close supervision) and that pimozide should not begiven with other antipsychotic drugs (including depot preparations),tricyclic antidepressants or other drugs whichprolong the QT interval, such as certain antimalarials, antiarrhythmicdrugs and certain antihistamines and should notbe given with drugs which cause electrolyte disturbances(especially diuretics)Contra-indications see notes above; history ofarrhythmias or congenital QT prolongationHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; less sedating; seriousarrhythmias, venous thromboembolism, glycosuria,and rarely, hyponatraemia reportedLicensed use not licensed for use in TourettesyndromeIndication and doseSchizophrenia (under specialist supervision). By mouthChild 12–18 years initially 1 mg daily, increasedaccording to response in steps of 2–4 mg at intervalsof not less than 1 week; usual dose range 2–20 mg dailyTourette syndrome (under specialist supervision). By mouthChild 2–12 years 1–4 mg dailyChild 12–18 years 2–10 mg dailyOrap c (Janssen) ATablets, scored, green, pimozide 4 mg, net price 100-tab pack = £26.87. Label: 2SULPIRIDECautions see notes above; also excited, agitated, oraggressive children (even low doses may aggravatesymptoms)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also hepatitis andvenous thromboembolismLicensed use not licensed for use in TourettesyndromeIndication and doseSchizophrenia (under specialist supervision). By mouthChild 14–18 years 200–400 mg twice daily; max.800 mg daily in predominantly negative symptoms,dose increased to max. 2.4 g daily in mainlypositive symptomsTourette syndrome (under specialist supervision). By mouthChild 2–12 years 50–400 mg twice dailyChild 12–18 years 100–400 mg twice dailySulpiride (Non-proprietary) ATablets, sulpiride 200 mg, net price 30-tab pack =£8.09; 56-tab pack = £6.46; 400 mg, 30-tab pack =£18.57. Label: 2Dolmatil c (Sanofi-Aventis) ATablets, both scored, sulpiride 200 mg, net price 100-tab pack = £13.31; 400 mg (f/c), 100-tab pack =£34.87. Label: 2Sulpor c (Rosemont) AOral solution, sugar-free, lemon- and aniseed-flavoured,sulpiride 200 mg/5 mL, net price 150 mL =£25.38. Label: 2TRIFLUOPERAZINECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; extrapyramidal symptomsmore frequent, especially at doses exceeding6 mg daily; anorexia; muscle weakness

BNFC 2011–2012 4.2.1 Antipsychotic drugs 177Indication and doseSchizophrenia and other psychoses, short-termadjunctive management of psychomotor agitation,excitement and violent or dangerouslyimpulsive behaviour (under specialist supervision). By mouthChild 12–18 years initially 5 mg twice daily,increased by 5 mg daily after 1 week, then atintervals of 3 days, according to responseShort-term adjunctive management of severeanxiety (under specialist supervision). By mouthChild 3–6 years up to 500 micrograms twice dailyChild 6–12 years up to 2 mg twice dailyChild 12–18 years 1–2 mg twice daily, increasedif necessary to 3 mg twice dailyAntiemetic section 4.6Trifluoperazine (Non-proprietary) ATablets, coated, trifluoperazine (as hydrochloride)1 mg, net price 112-tab pack = £7.22; 5 mg, 112-tabpack = £4.65. Label: 2Oral solution, trifluoperazine (as hydrochloride)5 mg/5 mL, net price 150-mL pack = £10.84. Label: 2Stelazine c (Goldshield) ATablets, blue, f/c, trifluoperazine (as hydrochloride)1 mg, net price 112-tab pack = £3.43; 5 mg, 112-tabpack = £4.89. Label: 2Syrup, sugar-free, yellow, trifluoperazine (as hydrochloride)1 mg/5 mL, net price 200-mL pack = £2.95.Label: 2Atypical antipsychotic drugsThe ‘atypical antipsychotic’ drugs amisulpride, aripiprazole,clozapine, olanzapine, quetiapine, and risperidonemay be better tolerated than other antipsychoticdrugs; extrapyramidal symptoms may be lessfrequent than with older antipsychotic drugs.Clozapine, olanzapine, and quetiapine cause little or noelevation of prolactin concentration; when changingfrom other antipsychotic drugs, a reduction in prolactinmay increase fertility.Clozapine is used for the treatment of schizophreniaonly in children unresponsive to, or intolerant of, conventionalantipsychotic drugs. It can cause agranulocytosisand its use is restricted to patients registeredwith a clozapine Patient Monitoring Service (see underClozapine).NICE guidanceAripiprazole for the treatment ofschizophrenia in people aged 15 to 17 years(January 2011)Aripiprazole is recommended as an option for thetreatment of schizophrenia in adolescents aged 15 to17 years who have not responded adequately to, orwho are intolerant of, risperidone, or for whomrisperidone is contra-indicated.Cautions and contra-indications While atypicalantipsychotic drugs have not generally been associatedwith clinically significant prolongation of the QT interval,they should be used with care if prescribed withother drugs that increase the QT interval. Atypical antipsychoticdrugs should be used with caution in childrenwith cardiovascular disease, or a history of epilepsy;interactions: Appendix 1 (antipsychotics).Skilled tasks Atypical antipsychotic drugs may affectperformance of skilled tasks (e.g. driving); effects ofalcohol are enhanced.Withdrawal Withdrawal of antipsychotic drugs afterlong-term therapy should always be gradual and closelymonitored to avoid the risk of acute withdrawal syndromesor rapid relapse.Side-effects Side-effects of the atypical antipsychoticdrugs include weight gain, dizziness, postural hypotension(especially during initial dose titration) whichmay be associated with syncope or reflex tachycardia insome children, extrapyramidal symptoms (usually mildand transient and which respond to dose reduction or toan antimuscarinic drug), and occasionally tardive dyskinesiaon long-term administration (discontinue drugon appearance of early signs); venous thromboembolismhas been reported. Hyperglycaemia and sometimesdiabetes can occur, particularly with clozapine, olanzapine,quetiapine, and risperidone; monitoring weightand plasma-glucose concentration may identify thedevelopment of hyperglycaemia. Neuroleptic malignantsyndrome has been reported rarely. Hypersalivationassociated with clozapine therapy can be treated withhyoscine hydrobromide (p. 198), provided that thepatient is not at particular risk from the additive antimuscarinicside-effects of hyoscine and clozapine.AMISULPRIDECautions see notes aboveContra-indications see notes above; phaeochromocytoma,prolactin-dependent tumoursRenal impairment halve dose if estimated glomerularfiltration rate 30–60 mL/minute/1.73 m 2 ; use onethirddose if estimated glomerular filtration rate 10–30 mL/minute/1.73 m 2 ; no information available ifestimated glomerular filtration rate less than 10 mL/minute/1.73 m 2Pregnancy avoidBreast-feeding avoid—no information availableSide-effects see notes above; also insomnia, anxiety,agitation, drowsiness, gastro-intestinal disorders suchas constipation, nausea, vomiting, and dry mouth;hyperprolactinaemia; occasionally bradycardia;rarely seizuresIndication and doseAcute psychotic episode (under specialist supervision). By mouthChild 15–18 years 200–400 mg twice dailyadjusted according to response; max. 1.2 g dailyPredominantly negative symptoms (under specialistsupervision). By mouthChild 15–18 years 50–300 mg daily4 Central nervous system

178 4.2.1 Antipsychotic drugs BNFC 2011–20124 Central nervous systemAmisulpride (Non-proprietary) ATablets, amisulpride 50 mg, net price 60-tab pack =£7.18; 100 mg, 60-tab pack = £31.74; 200 mg, 60-tabpack = £16.47; 400 mg, 60-tab pack = £105.68.Label: 2Solian c (Sanofi-Aventis) ATablets, scored, amisulpride 50 mg, net price 60-tabpack = £22.76; 100 mg, 60-tab pack = £35.29; 200 mg,60-tab pack = £58.99, 400 mg, 60-tab pack = £117.97.Label: 2Solution, 100 mg/mL, net price 60 mL (caramel flavour)= £33.76. Label: 2ARIPIPRAZOLECautions see notes above; cerebrovascular diseaseContra-indications see notes aboveHepatic impairment use with caution in severeimpairmentPregnancy use only if potential benefit outweighsrisk—no information availableBreast-feeding avoid—present in milk in animalstudiesSide-effects see notes above; gastro-intestinal disturbances;tachycardia; fatigue, insomnia, agitation,akathesia, drowsiness, restlessness, tremor, headache,asthenia; blurred vision; less commonly depression;very rarely anorexia, dysphagia, oropharangealspasm, laryngospasm, hepatitis, jaundice, hypersalivation,pancreatitis, oedema, thromboembolism,arrhythmias, bradycardia, hypertension, chest pain,anxiety, speech disorder, suicidal ideation, seizures,hyponatraemia, stiffness, myalgia, rhabdomyolysis,priapism, urinary retention and incontinence, blooddisorders, sweating, alopecia, photosensitivity reactions,rash, and impaired temperature regulationLicensed use not licensed for use in children under15 years; not licensed for mania in childrenIndication and doseSchizophrenia and treatment and recurrenceprevention of mania (under specialist supervision). By mouthChild 13–18 years 2 mg once daily, increased to5 mg once daily after 2 days, then further increasedto 10 mg once daily after a further 2 days; furtherincreased if necessary in steps of 5 mg to max.30 mg dailyAbilify c (Bristol-Myers Squibb) ATablets, aripiprazole 5 mg (blue), net price 28-tabpack = £95.74; 10 mg (pink), 28-tab pack = £95.74;15 mg (yellow), 28-tab pack = £95.74; 30 mg (pink),28-tab pack = £191.47. Label: 2Orodispersible tablets, aripiprazole 10 mg (pink), netprice 28-tab pack = £95.74; 15 mg (yellow), 28-tabpack = £95.74. Label: 2, counselling, administrationExcipients include aspartame (section 9.4.1)Counselling Tablets should be placed on the tongue andallowed to dissolve, or be dispersed in water and swallowedOral solution, aripiprazole 1 mg/mL, net price150 mL with measuring cup = £102.57. Label: 2CLOZAPINECautions see notes above; monitor leucocyte and differentialblood counts (see Agranulocytosis, below);susceptibility to angle-closure glaucoma; taper offother antipsychotics before starting; close medicalsupervision during initiation (risk of collapse becauseof hypotension); dose adjustment may be necessary ifsmoking started or stopped during treatmentWithdrawal On planned withdrawal reduce dose over 1–2weeks to avoid risk of rebound psychosis. If abrupt withdrawalnecessary observe child carefullyAgranulocytosis Neutropenia and potentially fatalagranulocytosis reported. Leucocyte and differential bloodcounts must be normal before starting; monitor counts everyweek for 18 weeks then at least every 2 weeks and if clozapinecontinued and blood count stable after 1 year at leastevery 4 weeks (and 4 weeks after discontinuation); if leucocytecount below 3000/mm 3 or if absolute neutrophil countbelow 1500/mm 3 discontinue permanently and refer tohaematologist. Patients who have a low white blood cellcount because of benign ethnic neutropenia may be startedon clozapine with the agreement of a haematologist. Avoiddrugs which depress leucopoiesis; children (or carers) shouldreport immediately symptoms of infection, especially influenza-likeillnessMyocarditis and cardiomyopathy Fatal myocarditis (mostcommonly in first 2 months) and cardiomyopathy reported.. Perform physical examination and take full medicalhistory before starting;. Specialist examination required if cardiac abnormalitiesor history of heart disease found—clozapine initiatedonly in absence of severe heart disease and if benefitoutweighs risk;. Persistent tachycardia especially in first 2 monthsshould prompt observation for other indicators for myocarditisor cardiomyopathy;. If myocarditis or cardiomyopathy suspected clozapineshould be stopped and child evaluated urgently bycardiologist;. Discontinue permanently in clozapine-induced myocarditisor cardiomyopathyGastro-intestinal obstruction Reactions resembling gastrointestinalobstruction reported. Clozapine should be usedcautiously with drugs which cause constipation (e.g. antimuscarinicdrugs) or in children with history of colonicdisease or bowel surgery. Monitor for constipation andprescribe laxative if requiredContra-indications severe cardiac disorders (e.g.myocarditis; see Cautions); history of neutropenia oragranulocytosis (see Cautions); bone-marrow disorders;paralytic ileus (see Cautions); alcoholic and toxicpsychoses; history of circulatory collapse; drugintoxication; coma or severe CNS depression;uncontrolled epilepsyHepatic impairment monitor hepatic function regularly;avoid in symptomatic or progressive liver diseaseor hepatic failureRenal impairment avoid in severe impairmentPregnancy use with cautionBreast-feeding avoidSide-effects see notes above; also constipation (seeCautions), hypersalivation, dry mouth, nausea, vomiting,anorexia; tachycardia, ECG changes, hypertension;drowsiness, dizziness, headache, tremor, seizures,fatigue, impaired temperature regulation;urinary incontinence and retention; leucopenia,eosinophilia, leucocytosis; blurred vision; sweating;less commonly agranulocytosis (important: see Cautions);rarely dysphagia, hepatitis, cholestatic jaundice,pancreatitis, circulatory collapse, arrhythmia,myocarditis (important: see Cautions), pericarditis,thromboembolism, agitation, confusion, delirium,anaemia; very rarely parotid gland enlargement,intestinal obstruction (see Cautions), cardiomyopathy,myocardial infarction, respiratory depression, priapism,interstitial nephritis, thrombocytopenia, throm-

BNFC 2011–2012 4.2.1 Antipsychotic drugs 179bocythaemia, hypertriglyceridaemia, hypercholesterolaemia,hyperlipidaemia, fulminant hepaticnecrosis, angle-closure glaucoma, and skin reactionsLicensed use not licensed for use in children under16 yearsIndication and doseSchizophrenia in children unresponsive to, orintolerant of, conventional antipsychotic drugs(under specialist supervision). By mouthChild 12–18 years 12.5 mg once or twice on firstday then 25–50 mg on second day then increasedgradually (if well tolerated) in steps of 25–50 mgdaily over 14–21 days up to 300 mg daily in divideddoses (larger dose at night, up to 200 mg daily maybe taken as a single dose at bedtime); if necessarymay be further increased in steps of 50–100 mgonce (preferably) or twice weekly; usual dose 200–450 mg daily (max. 900 mg daily)Note Restarting after interval of more than 2 days,12.5 mg once or twice on first day (but may be feasible toincrease more quickly than on initiation)—extreme cautionif previous respiratory or cardiac arrest with initialdosingClozaril c (Novartis) ATablets, yellow, clozapine 25 mg (scored), net price28-tab pack = £5.40, 84-tab pack (hosp. only) =£16.18, 100-tab pack (hosp. only) = £19.26; 100 mg,28-tab pack = £21.56, 84-tab pack (hosp. only) =£64.68, 100-tab pack (hosp. only) = £77.00. Label: 2,10, patient information leafletNote Child, prescriber, and supplying pharmacist must beregistered with the Clozaril Patient Monitoring Service—takes several days to do thisDenzapine c (Merz) ATablets, yellow, scored, clozapine 25 mg, net price 84-tab pack = £16.64, 100-tab pack = £19.80; 50 mg, 50-tab pack = £19.80; 100 mg, 84-tab pack = £66.53, 100-tab pack = £79.20; 200 mg, 50-tab pack = £79.20.Label: 2, 10, patient information leafletSuspension, clozapine 50 mg/mL, net price 100 mL= £39.60. Label: 2, 10, patient information leaflet,counselling, administrationCounselling Shake well for 90 seconds when dispensing or ifvisibly settled; otherwise shake well for 10 seconds beforeuseNote May be diluted in waterNote Child, prescriber, and supplying pharmacist must beregistered with the Denzapine Patient Monitoring Service—takes several days to do thisZaponex c (TEVA UK) ATablets, yellow, scored, clozapine 25 mg, net price 84-tab pack = £8.28; 100 mg, 84-tab pack = £33.88.Label: 2, 10, patient information leafletNote Child, prescriber, and supplying pharmacist must beregistered with the Zaponex Treatment Access System—takes several days to do thisHepatic impairment initial dose 5 mg daily, increasedslowlyRenal impairment initial dose 5 mg daily, increasedslowlyPregnancy use only if potential benefit outweighs risk;neonatal lethargy, tremor and hypertonia reportedwhen used in third trimesterBreast-feeding avoid—present in milkSide-effects see notes above; also mild, transientantimuscarinic effects; drowsiness, speech difficulty,abnormal gait, hallucinations, akathisia, asthenia,increased appetite, increased body temperature,raised triglyceride concentration, oedema, hyperprolactinaemia(but clinical manifestations uncommon);eosinophilia; less commonly hypotension, bradycardia,QT interval prolongation, urinary incontinence,and photosensitivity; rarely seizures, leucopenia,and rash; very rarely hepatitis, pancreatitis,hypercholesterolaemia, hypothermia, urinary retention,priapism, thrombocytopenia, neutropenia, rhabdomyolysis,and angle-closure glaucoma; with injection,sinus pause and hypoventilationLicensed use not licensed for use in childrenIndication and doseSchizophrenia, combination therapy for mania(under specialist supervision). By mouthChild 12–18 years initially 5–10 mg dailyadjusted to usual range of 5–20 mg daily; dosesgreater than 10 mg daily only after reassessment;max. 20 mg dailyMonotherapy for mania (under specialist supervision). By mouthChild 12–18 years 15 mg daily adjusted to usualrange of 5–20 mg daily; doses greater than 15 mgonly after reassessment; max. 20 mg dailyNote When one or more factors present that might result inslower metabolism (e.g. female gender, non-smoker) considerlower initial dose and more gradual dose increaseZyprexa c (Lilly) ATablets, f/c, olanzapine 2.5 mg, net price 28-tab pack= £21.85; 5 mg, 28-tab pack = £43.70; 7.5 mg, 56-tabpack = £131.10; 10 mg, 28-tab pack = £87.40, 15 mg(blue), 28-tab pack = £119.18; 20 mg (pink), 28-tabpack = £158.90. Label: 2Orodispersible tablet (Velotab c ), yellow, olanzapine5 mg, net price 28-tab pack = £48.07; 10 mg, 28-tabpack = £87.40; 15 mg, 28-tab pack = £131.10; 20 mg,28-tab pack = £174.79. Label: 2, counselling, administrationExcipients include aspartame (section 9.4.1)Counselling Velotab c may be placed on the tongue andallowed to dissolve, or dispersed in water, orange juice, applejuice, milk, or coffee4 Central nervous systemOLANZAPINECautions see notes above; also susceptibility to angleclosureglaucoma, paralytic ileus, diabetes mellitus(risk of exacerbation or ketoacidosis), low leucocyteor neutrophil count, bone-marrow depression, hypereosinophilicdisorders, myeloproliferative disease;dose adjustment may be necessary if smoking startedor stopped during treatmentQUETIAPINECautions see notes above; cerebrovascular disease;children at risk of aspiration pneumoniaHepatic impairment for immediate-release tablets,initially 25 mg daily, increased daily in steps of 25–50 mgPregnancy use only if potential benefit outweighs riskBreast-feeding avoid—no information available

180 4.2.1 Antipsychotic drugs BNFC 2011–20124 Central nervous systemSide-effects see notes above; also drowsiness, dyspepsia,constipation, dry mouth, hypertension, mildasthenia, rhinitis, tachycardia, irritability; leucopenia,neutropenia and occasionally eosinophilia reported;elevated plasma-triglyceride and cholesterol concentrations,hypothyroidism; possible QT interval prolongation;restless legs syndrome; rarely oedema;very rarely priapismLicensed use not licensed for use in childrenIndication and doseSchizophrenia (under specialist supervision). By mouthChild 12–18 years initially 25 mg twice dailyadjusted in steps of 25–50 mg according toresponse; max. 750 mg dailyTreatment of mania in bipolar disorder (underspecialist supervision). By mouthChild 12–18 years 25 mg twice daily on day 1,then 50 mg twice daily on day 2, then 100 mg twicedaily on day 3, then 150 mg twice daily on day 4,then 200 mg twice daily on day 5; thereafter doseadjusted according to response in steps no greaterthan 100 mg daily, usual dose 400–600 mg daily in2 divided dosesSeroquel c (AstraZeneca) TATablets, f/c, quetiapine (as fumarate) 25 mg (peach),net price 60-tab pack = £33.83; 100 mg (yellow), 60-tab pack = £113.10; 150 mg (pale yellow), 60-tab pack= £113.10; 200 mg (white), 60-tab pack = £113.10;300 mg (white), 60-tab pack = £170.00. Label: 2Modified releaseSeroquel c XL (AstraZeneca) TATablets, m/r, quetiapine (as fumarate) 50 mg (peach),net price 60-tab pack = £67.66; 150 mg (white), 60-tabpack = £113.10; 200 mg (yellow), 60-tab pack =£113.10; 300 mg (pale yellow), 60-tab pack = £170.00;400 mg (white), 60-tab pack = £226.20. Label: 2, 23,25DoseSchizophrenia (under specialist supervision). By mouthChild 12–18 years initially 50 mg once daily adjusted insteps of 50 mg daily according to response, usual dose400–800 mg once daily; max. 800 mg once dailyNote Patients can be switched from immediate-release tomodified-release tablets at the equivalent daily dose; tomaintain clinical response, dose titration may be requiredRISPERIDONECautions see notes above; hyperprolactinaemia, prolactin-dependenttumours; dehydration; family historyof sudden cardiac death (perform ECG); avoid in acuteporphyria (section 9.8.2)Hepatic impairment initial and subsequent oral dosesshould be halvedRenal impairment initial and subsequent oral dosesshould be halvedPregnancy use only if potential benefit outweighs risk;extrapyramidal effects reported in neonate whentaken in third trimesterBreast-feeding use only if potential benefit outweighsrisk—small amount present in milkSide-effects see notes above; also gastro-intestinaldisturbances (including diarrhoea, constipation,nausea and vomiting, dyspepsia, abdominal pain), drymouth; dyspnoea; drowsiness, asthenia, tremor, sleepdisturbances, agitation, anxiety, headache; urinaryincontinence; hyperprolactinaemia (less commonlygalactorrhoea, menstrual disturbances, gynaecomastia);arthralgia, myalgia; abnormal vision; epistaxis;rash; less commonly anorexia, ECG changes,hypoaesthesia, impaired concentration, sexual dysfunction,blood disorders, tinnitus, angioedema; rarelyintestinal obstruction, pancreatitis, jaundice, seizures,hyponatraemia, abnormal temperature regulation;oedema and priapism also reportedLicensed use not licensed for use in children forpsychosis, mania, or autismIndication and doseAcute and chronic psychosis (under specialistsupervision). By mouthChild 12–18 years 2 mg in 1–2 divided doses onfirst day then 4 mg in 1–2 divided doses on secondday (slower titration appropriate in some children);usual dose range 4–6 mg daily; doses above 10 mgdaily only if benefit considered to outweigh risk(max. 16 mg daily)Short-term monotherapy of mania in bipolardisorder (under specialist supervision). By mouthChild 12–18 years initially 500 micrograms oncedaily adjusted in steps of 0.5–1 mg daily accordingto response; usual dose 2.5 mg daily in 1–2 divideddoses, max. 6 mg dailyShort-term treatment (up to 6 weeks) of persistentaggression in conduct disorder (underspecialist supervision). By mouthChild 5–18 years and body-weight under 50 kginitially 250 micrograms once daily increasedaccording to response in steps of 250 microgramson alternate days; usual dose 500 micrograms daily(up to 750 micrograms once daily has beenrequired)Child 5–18 years and body-weight over 50 kginitially 500 micrograms once daily increasedaccording to response in steps of 500 microgramson alternate days; usual dose 1 mg daily (up to1.5 mg once daily has been required)Short-term treatment of severe aggression inautism (under specialist supervision). By mouthChild over 5 years and 15–20 kg 250 microgramsdaily increased if necessary after at least 4days to 500 micrograms daily; thereafter increasedby 250 micrograms daily at 2-week intervals tomax. 1 mg dailyChild over 5 years and over 20 kg 500 microgramsdaily increased if necessary after at least 4days to 1 mg daily; thereafter increased by500 micrograms daily at 2-week intervals; max.daily dose 2.5 mg if under 45 kg; max. daily dose3 mg if over 45 kg

BNFC 2011–2012 4.2.2 Antipsychotic depot injections 181Risperidone (Non-proprietary) TATablets, risperidone 500 micrograms, net price 20-tabpack = 97p; 1 mg, 20-tab pack = £1.18, 60-tab pack =£1.70; 2 mg, 60-tab pack = £2.13; 3 mg, 60-tab pack =£2.71; 4 mg, 60-tab pack = £31.52; 6 mg, 28-tab pack =£24.12. Label: 2Orodispersible tablets, risperidone 0.5 mg, net price28-tab pack = £16.88; 1 mg, 28-tab pack = £20.51;2 mg, 28-tab pack = £37.72; 3 mg, 28-tab pack =£14.39; 4 mg, 28-tab pack = £15.20. Label: 2, counselling,administrationCounselling Tablets should be placed on the tongue,allowed to dissolve and swallowedLiquid, risperidone 1 mg/mL, net price 100-mL pack= £57.40. Label: 2, counselling, use of dose syringeNote Liquid may be diluted with any non-alcoholic drink,except teaRisperdal c (Janssen) TATablets, f/c, scored, risperidone 500 micrograms(brown-red), net price 20-tab pack = £5.08; 1 mg(white), 20-tab pack = £8.36, 60-tab pack = £25.08;2 mg (orange), 60-tab pack = £49.46; 3 mg (yellow),60-tab pack = £72.73; 4 mg (green), 60-tab pack =£96.00; 6 mg (yellow), 28-tab pack = £67.88. Label: 2Orodispersible tablets (Quicklet c ), pink, risperidone500 micrograms, net price 28-tab pack = £8.23; 1 mg,28-tab pack = £17.32; 2 mg, 28-tab pack = £32.65;3 mg, 28-tab pack = £36.24; 4 mg, 28-tab pack =£46.68. Label: 2, counselling, administrationExcipients include aspartame (section 9.4.1)Counselling Tablets should be placed on the tongue,allowed to dissolve and swallowedLiquid, risperidone 1 mg/mL, net price 100-mL pack= £52.87. Label: 2, counselling, use of dose syringeNote Liquid may be diluted with any non-alcoholic drink,except tea4.2.2 Antipsychotic depotinjectionsThere is limited information on the use of antipsychoticdepot injections in children and use should be restrictedto specialist centres.4.2.3 Antimanic drugsAntimanic drugs are used in mania to control acuteattacks and to prevent recurrence of episodes of maniaor hypomania. Long-term treatment of bipolar disordershould continue for at least two years from the lastmanic episode and up to five years if the patient hasrisk factors for relapse.An antidepressant drug (section 4.3) may also berequired for the treatment of co-existing depression,but should be avoided in patients with rapid-cyclingbipolar disorder, recent history of hypomania, or rapidmood fluctuations.BenzodiazepinesUse of benzodiazepines (section 4.1) may be helpful inthe initial stages of treatment for behavioural disturbanceor agitation; they should not be used for longperiods because of the risk of dependence.Antipsychotic drugsAtypical antipsychotic drugs (normally olanzapine,quetiapine, or risperidone) (section 4.2.1) are usefulin acute episodes of mania and hypomania; if theresponse to antipsychotic drugs is inadequate, lithiumor valproate may be added. An antipsychotic drug maybe used concomitantly with lithium or valproate in theinitial treatment of severe acute mania.Atypical antipsychotics are the treatment of choice forthe long-term management of bipolar disorder in childrenand adolescents; if the patient has frequentrelapses or continuing functional impairment, considerconcomitant therapy with lithium or valproate. An atypicalantipsychotic that causes less weight gain anddoes not increase prolactin levels is preferred.When discontinuing antipsychotics, the dose should bereduced gradually over at least 4 weeks if the child iscontinuing on other antimanic drugs; if the child is notcontinuing on other antimanic drugs, or has a history ofmanic relapse, a withdrawal period of up to 3 months isrequired.High doses of haloperidol may be hazardous when usedwith lithium; irreversible toxic encephalopathy has beenreported.CarbamazepineCarbamazepine (section 4.8.1) may be used under specialistsupervision for the prophylaxis of bipolar disorder(manic-depressive disorder) in children unresponsive toa combination of other prophylactic drugs; it is used inthose with rapid-cycling manic-depressive illness (4 ormore affective episodes per year). The dose of carbamazepineshould not normally be increased if an acuteepisode of mania occurs. When stopping treatment withcarbamazepine, reduce the dose gradually over a periodof at least 4 weeks.ValproateValproic acid (as the semisodium salt) is licensed inadults for the treatment of manic episodes associatedwith bipolar disorder. Sodium valproate (section 4.8.1) isunlicensed for the treatment of bipolar disorder.Valproate can be used for the prophylaxis of bipolardisorder [unlicensed use]; however, it should not normallybe prescribed for women of child-bearing potential.In patients with frequent relapse or continuingfunctional impairment, consider switching therapy tolithium or an atypical antipsychotic, or adding lithium oran atypical antipsychotic to valproate. If a patient takingvalproate experiences an acute episode of mania that isnot ameliorated by increasing the valproate dose, considerconcomitant therapy with olanzapine, quetiapine,or risperidone. When stopping valproate reduce thedose gradually over at least 4 weeks.LithiumLithium salts are used in the prophylaxis and treatmentof mania, in the prophylaxis of bipolar disorder (manicdepressivedisorder), as concomitant therapy with antidepressantmedication in children who have had anincomplete response to treatment for acute depressionin bipolar disorder, and in the prophylaxis of recurrentdepression (unipolar illness or unipolar depression).4 Central nervous system

182 4.2.3 Antimanic drugs BNFC 2011–20124 Central nervous systemLithium is used to treat acute episodes of mania inchildren who have responded to lithium before andwhose symptoms are not severe.The decision to give prophylactic lithium usuallyrequires specialist advice, and must be based on carefulconsideration of the likelihood of recurrence in theindividual child, and the benefit of treatment weighedagainst the risks. The full prophylactic effect of lithiummay not occur for six to twelve months after the initiationof therapy. An atypical antipsychotic or valproate(given alone or as adjunctive therapy with lithium) arealternative prophylactic treatments in patients whoexperience frequent relapses or continuing functionalimpairment. Long-term use of lithium has been associatedwith thyroid disorders and mild cognitive andmemory impairment. Long-term treatment shouldtherefore be undertaken only with careful assessmentof risk and benefit, and with monitoring of thyroidfunction at baseline and every 6 months (more often ifthere is evidence of deterioration). Renal functionshould be monitored at baseline and every 6 monthsthereafter (more often if there is evidence of deteriorationor the patient has other risk factors, such as startingACE inhibitors, NSAIDs, or diuretics). The need forcontinued therapy should be assessed regularly andchildren should be maintained on lithium after 3 to 5years only if benefit persists.Serum concentrations Lithium salts have a narrowtherapeutic/toxic ratio and should not be prescribedunless facilities for monitoring serum-lithium concentrationsare available. Samples should be taken 12 hoursafter the dose to achieve a serum-lithium concentrationof 0.4–1 mmol/litre. A target serum-lithium concentrationof 0.8–1 mmol/litre is recommended for acuteepisodes of mania, and for patients who have previouslyrelapsed or have sub-syndromal symptoms. It is importantto determine the optimum range for each individualchild. Serum-lithium monitoring should be performedweekly after initiation and after each dose change untilconcentrations are stable, then every 3 months thereafter.Additional serum-lithium measurements should bemade if a child develops significant intercurrent diseaseor if there is a significant change in a child’s sodium orfluid intake.Overdosage, usually with serum-lithium concentrationof over 1.5 mmol/litre, may be fatal and toxic effectsinclude tremor, ataxia, dysarthria, nystagmus, renalimpairment, and convulsions. If these potentially hazardoussigns occur, treatment should be stopped, serumlithiumconcentrations redetermined, and steps taken toreverse lithium toxicity. In mild cases withdrawal oflithium and administration of sodium and fluid willreverse the toxicity. A serum-lithium concentration inexcess of 2 mmol/litre requires urgent treatment asdescribed under Emergency Treatment of Poisoning,p. 30.Interactions Lithium toxicity is made worse by sodiumdepletion, therefore concurrent use of diuretics(particularly thiazides) is hazardous and should beavoided. For other interactions with lithium, seeAppendix 1 (lithium).Withdrawal While there is no clear evidence of withdrawalor rebound psychosis, abrupt discontinuation oflithium increases the risk of relapse. If lithium is to bediscontinued, the dose should be reduced gradually overa period of at least 4 weeks (preferably over a period ofup to 3 months). Children and carers should be warnedof the risk of relapse if lithium is discontinued abruptly.If lithium is stopped or has to be discontinued abruptly,consider changing therapy to an atypical antipsychoticor valproate.Lithium treatment packsA lithium treatment pack may be given to patientson initiation of treatment with lithium. The packconsists of a patient information booklet, lithiumalert card, and a record book for tracking serumlithiumconcentration.Packs may be purchased from 3MTel: 0845 610 1112nhsforms@spsl.uk.comLITHIUM CARBONATECautions measure serum-lithium concentration regularly(every 3 months on stabilised regimens), measurerenal function and thyroid function every 6months on stabilised regimens and advise childrenand carers to seek attention if symptoms of hypothyroidismdevelop (females are at greater risk) e.g.lethargy, feeling cold; maintain adequate sodium andfluid intake; test renal function before initiating and ifevidence of toxicity, avoid in cardiac disease, andconditions with sodium imbalance such as Addison’sdisease; reduce dose or discontinue in diarrhoea,vomiting, and intercurrent infection (especially ifsweating profusely); psoriasis (risk of exacerbation);diuretic treatment, myasthenia gravis; surgery (section15.1); if possible avoid abrupt withdrawal (seenotes above); interactions: Appendix 1 (lithium)Counselling Children should maintain adequate fluid intakeand avoid dietary changes which reduce or increase sodiumintake; lithium treatment packs are available (see above)Renal impairment avoid if possible or reduce doseand closely monitor serum-lithium concentrationPregnancy avoid if possible in first trimester (risk ofteratogenicity, including cardiac abnormalities); doserequirements increased in second and third trimesters(but on delivery, return abruptly to normal); closemonitoring of serum-lithium concentration advised(risk of toxicity in neonate)Breast-feeding present in milk and risk of toxicity ininfant—avoidSide-effects gastro-intestinal disturbances, fine tremor,renal impairment (particularly impaired urinaryconcentration and polyuria), polydipsia, leucocytosis;also weight gain and oedema (may respond to dosereduction); hyperparathyroidism and hypercalcaemiareported; signs of intoxication are blurred vision,increasing gastro-intestinal disturbances (anorexia,vomiting, diarrhoea), muscle weakness, increasedCNS disturbances (mild drowsiness and sluggishnessincreasing to giddiness with ataxia, coarse tremor,lack of coordination, dysarthria), and require withdrawalof treatment; with severe overdosage (serumlithiumconcentration above 2 mmol/litre) hyperreflexiaand hyperextension of limbs, convulsions, toxicpsychoses, syncope, renal failure, circulatory failure,coma, and occasionally, death; goitre, raised antidiuretichormone concentration, hypothyroidism,hypokalaemia, ECG changes, and kidney changesmay also occur; see also Emergency Treatment ofPoisoning, p. 30

BNFC 2011–2012 4.3 Antidepressant drugs 183Indication and doseTreatment and prophylaxis of mania, bipolardisorder, recurrent depression (see also notesabove), aggressive or self-mutilating behaviour. By mouthSee under preparations below, adjusted to achievea serum-lithium concentration of 0.6–1 mmol/litre12 hours after a dose on days 4–7 of treatment,then every week until dosage has remained constantfor 4 weeks and every 3 months thereafter;doses are initially divided throughout the day, butonce daily administration is preferred whenserum-lithium concentration stabilisedNote Preparations vary widely in bioavailability;changing the preparation requires the same precautionsas initiation of treatmentCamcolit c (Norgine) ACamcolit 250 c tablets, f/c, scored, lithium carbonate250 mg (Li + 6.8 mmol), net price 100-tab pack =£3.09 Label: 10, lithium card, counselling, see aboveCamcolit 400 c tablets, m/r, f/c, scored, lithiumcarbonate 400 mg (Li + 10.8 mmol), net price 100-tabpack = £4.13. Label: 10, lithium card, 25, counselling,see aboveDoseTreatment. By mouth(see above for advice on bioavailability and serum-lithiummonitoring)Child 12–18 years initially 1–1.5 g dailyProphylaxis. By mouth(see above for advice on bioavailability and serum-lithiummonitoring)Child 12–18 years initially 300–400 mg dailyLiskonum c (GSK) ATablets, m/r, f/c, scored, lithium carbonate 450 mg(Li + 12.2 mmol), net price 60-tab pack = £2.88.Label: 10, lithium card, 25, counselling, see aboveDoseTreatment. By mouth(see above for advice on bioavailability and serum-lithiummonitoring)Child 12–18 years initially 225–675 mg twice dailyProphylaxis. By mouth(see above for advice on bioavailability and serum-lithiummonitoring)Child 12–18 years initially 225–450 mg twice dailyLITHIUM CITRATECautions see under Lithium Carbonate and notesaboveCounselling Patients should maintain an adequate fluidintake and should avoid dietary changes which might reduceor increase sodium intake; lithium treatment cards areavailable from pharmacies (see above)Side-effects see under Lithium Carbonate and notesaboveLicensed use not licensed for use in childrenIndication and doseSee under Lithium Carbonate and notes above. By mouthAdjust to achieve serum-lithium concentration of0.6–1 mmol/litre as described under LithiumCarbonate aboveNote Preparations vary widely in bioavailability;changing the preparation requires the same precautionsas initiation of treatmentLi-Liquid c (Rosemont) AOral solution, lithium citrate 509 mg/5 mL (Li +5.4 mmol/5 mL), yellow, net price 150-mL pack =£5.79; 1.018 g/5 mL (Li + 10.8 mmol/5 mL), orange,150-mL pack = £11.58. Label: 10, lithium card,counselling, see aboveNote 5-mL dose of 509 mg/5 mL oral solution is equivalentto 200 mg lithium carbonatePriadel c (Sanofi-Aventis) ALiquid, sugar-free, lithium citrate 520 mg/5 mL(approx. Li + 5.4 mmol/5 mL), net price 150-mL pack= £5.61. Label: 10, lithium card, counselling, seeaboveNote 5-mL dose is equivalent to 204 mg lithium carbonate4.3 Antidepressant drugs4.3.1 Tricyclic antidepressant drugs4.3.2 Monoamine-oxidase inhibitors4.3.3 Selective serotonin re-uptakeinhibitors4.3.4 Other antidepressant drugsDepression in children should be managed by anappropriate specialist and treatment should involvepsychological therapy.The major classes of antidepressant drugs include thetricyclics and related antidepressant drugs (section4.3.1), the selective serotonin re-uptake inhibitors(SSRIs) (section 4.3.3), and the monoamine oxidaseinhibitors (MAOIs).Antidepressant drugs should not be used routinely inmild depression, and psychological therapy should beconsidered initially; however, a trial of antidepressanttherapy may be considered in cases refractory to psychologicaltreatments or in those associated with psychosocialor medical problems. Drug treatment of milddepression may also be considered in children with ahistory of moderate or severe depression.Choice of antidepressant drug should be based on theindividual child’s requirements, including the presenceof concomitant disease, existing therapy, suicide risk,and previous response to antidepressant therapy.When drug treatment of depression is considerednecessary in children, the SSRIs should be consideredfirst-line treatment; following a safety and efficacyreview, fluoxetine is licensed to treat depression inchildren.4 Central nervous system

184 4.3.1 Tricyclic antidepressant drugs BNFC 2011–20124 Central nervous systemTricyclic antidepressant drugs should be avoided for thetreatment of depression in children.St John’s wort (Hypericum perforatum) is a popularherbal remedy on sale to the public for treating milddepression in adults. It should not be used for thetreatment of depression in children because St John’swort can induce drug metabolising enzymes and anumber of important interactions with conventionaldrugs, including conventional antidepressants, havebeen identified (see Appendix 1, St John’s wort).Furthermore, the amount of active ingredient variesbetween different preparations of St John’s wort andswitching from one to another can change the degree ofenzyme induction. If a child stops taking St John’s wort,the concentration of interacting drugs may increase,leading to toxicity.Hyponatraemia and antidepressant therapyHyponatraemia (possibly due to inappropriate secretionof antidiuretic hormone) has been associatedwith all types of antidepressants; however, it hasbeen reported more frequently with SSRIs thanwith other antidepressant drugs. Hyponatraemiashould be considered in all children who developdrowsiness, confusion, or convulsions while takingan antidepressant drug.Suicidal behaviour and antidepressant therapyThe use of antidepressant drugs has been linkedwith suicidal thoughts and behaviour. Where necessary,children should be monitored for suicidal behaviour,self-harm, and hostility, particularly at thebeginning of treatment or if the dose is changed.Management Children should be reviewed every 1–2weeks at the start of antidepressant treatment. Treatmentshould be continued for at least 4 weeks beforeconsidering whether to switch antidepressant due tolack of efficacy. In cases of partial response, continuefor a further 2–4 weeks. Following remission, antidepressanttreatment should be continued at the samedose for at least 6 months. Children with a history ofrecurrent depression should continue treatment for atleast 2 years.Withdrawal Withdrawal effects may occur within 5days of stopping treatment with antidepressant drugs;they are usually mild and self-limiting, but in some casesmay be severe. The risk of withdrawal symptoms isincreased if the antidepressant is stopped suddenlyafter regular administration for 8 weeks or more. Thedose should preferably be reduced gradually over about4 weeks, or longer if withdrawal symptoms emerge (6months in children who have been on long-term maintenancetreatment). See also section 4.3.1, and section4.3.3.Anxiety Management of acute anxiety in children withdrug treatment is contentious (section 4.1.2). Forchronic anxiety (of longer than 4 weeks’ duration), itmay be appropriate to use an antidepressant drugbefore a benzodiazepine.4.3.1 Tricyclic antidepressantdrugsStudies have shown that tricyclic antidepressants arenot effective for treating depression in children.For reference to the role of some tricyclic antidepressantdrugs in some forms of neuralgia, see section 4.7.3,and in nocturnal enuresis in children, see section 7.4.2.Dosage It is important to use doses that are sufficientlyhigh for effective treatment but not so high as to causetoxic effects. Low doses should be used for initial treatment.In most children the long half-life of tricyclic antidepressantdrugs allows once-daily administration, usually atnight; the use of modified-release preparations is thereforeunnecessary.Cautions Tricyclic antidepressant drugs should beused with caution in children with cardiovascular disease(see also Contra-indications, below); because of therisk of arrhythmias, children with concomitant conditionssuch as hyperthyroidism and phaeochromocytomashould be treated with care. Care is also needed inchildren with epilepsy and diabetes.Tricyclic antidepressant drugs have antimuscarinicactivity, and therefore caution is needed in childrenwith chronic constipation, urinary retention, or thosewith a susceptibility to angle-closure glaucoma. Tricyclicantidepressant drugs should be used with cautionin children with a significant risk of suicide, or a historyof psychosis or bipolar disorder, because antidepressanttherapy may aggravate these conditions; treatmentshould be stopped if the child enters a manic phase.Skilled tasks Drowsiness may affect the performanceof skilled tasks (e.g. driving); effects of alcoholenhanced.Contra-indications Tricyclic antidepressants are contra-indicatedin arrhythmias (particularly heart block),and in the manic phase of bipolar disorder. Avoid treatmentwith tricyclic antidepressant drugs in acute porphyria(section 9.8.2).Hepatic impairment The sedative effects of tricyclicantidepressant drugs are increased in children withhepatic impairment. They should be avoided in severeliver disease.Breast-feeding The amount of tricyclic antidepressantssecreted into breast milk is too small to be harmful(but see Doxepin, p. 185).Side-effects Arrhythmias and heart block occasionallyfollow the use of tricyclic antidepressants, particularlyamitriptyline, and may be a factor in the suddendeath of children with cardiac disease; other cardiovascularside-effects include postural hypotension, tachycardia,and ECG changes.Central nervous system side-effects are common, andinclude anxiety, dizziness, agitation, confusion, sleepdisturbances, irritability, and paraesthesia; drowsiness

BNFC 2011–2012 4.3.1 Tricyclic antidepressant drugs 185is associated with some of the tricyclic antidepressants.Convulsions, hallucinations, delusions, mania, andhypomania may occur (see also under Cautions,above), and, rarely, extrapyramidal symptoms includingtremor and dysarthria.Antimuscarinic side-effects include dry mouth, blurredvision (very rarely precipitation of angle-closure glaucoma),constipation (rarely leading to paralytic ileus),and urinary retention.Endocrine effects include breast enlargement, galactorrhoea,and gynaecomastia. Sexual dysfunction mayoccur. Changes in blood sugar, increased appetite, andweight gain can accompany treatment with tricyclicantidepressant drugs, but anorexia and weight loss arealso seen. Hepatic and haematological reactions mayoccur. Hyponatraemia has been associated with antidepressanttreatment (see Hyponatraemia and AntidepressantTherapy, p. 184). Other class side-effectsinclude nausea, vomiting, taste disturbance, tinnitus,rash, urticaria, pruritus, photosensitivity, alopecia, andsweating.Neuroleptic malignant syndrome (section 4.2.1) may,very rarely, occur in the course of antidepressant drugtreatment.Suicidal behaviour has been linked with antidepressantdrugs (see p. 184).Overdosage Limited quantities of tricyclic antidepressantdrugs should be prescribed at any one time becausetheir cardiovascular and epileptogenic effects are dangerousin overdosage. In particular, overdosage withamitriptyline is associated with a relatively high rateof fatality. For advice on overdosage see EmergencyTreatment of Poisoning, p. 29.Withdrawal Withdrawal symptoms include influenzalikesymptoms (chills, myalgia, sweating, headache,nausea), insomnia, vivid dreams, and may occasionallyinclude movement disorders and mania. If possible tricyclicantidepressant drugs should be withdrawn slowly(see also section 4.3).AMITRIPTYLINE HYDROCHLORIDECautions see notes above; interactions: Appendix 1(antidepressants, tricyclic)Contra-indications see notes aboveHepatic impairment see notes abovePregnancy use only if potential benefit outweighs riskBreast-feeding see notes aboveSide-effects see notes above; also abdominal pain,stomatitis, palpitation, oedema, hypertension, restlessness,fatigue, mydriasis, and increased intra-ocularpressure; overdosage: see Emergency Treatment ofPoisoning, p. 29 (high rate of fatality—see Overdosage,above)Licensed use not licensed for use in neuropathicpainIndication and doseDepression (but see notes above). By mouthChild 16–18 years 10–25 mg 3 times daily (totaldaily dose may alternatively be given as a singledose at bedtime) increased gradually as necessaryto 150–200 mg dailyNeuropathic pain. By mouthChild 2–12 years initially 200–500 micrograms/kg (max. 10 mg) once daily at night, increased ifnecessary; max. 1 mg/kg twice daily on specialistadviceChild 12–18 years initially 10 mg once daily atnight, increased gradually if necessary to usualdose 75 mg at night; higher doses on specialistadviceAmitriptyline (Non-proprietary) ATablets, coated, amitriptyline hydrochloride 10 mg,net price 28 = 90p; 25 mg, 28 = 90p; 50 mg, 28 =£1.00. Label: 2Oral solution, amitriptyline hydrochloride 25 mg/5 mL, net price 150 mL = £15.47; 50 mg/5 mL,150 mL = £16.82. Label: 2DOXEPINCautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment use with cautionPregnancy use with caution—limited informationavailableBreast-feeding see notes above; accumulation ofdoxepin metabolite may cause sedation and respiratorydepressionSide-effects see notes above; also abdominal pain,stomatitis, diarrhoea, flushing, and oedemaIndication and doseDepressive illness, particularly where sedationis required (but see notes above). By mouthChild 12–18 years initially 75 mg daily in divideddoses or as a single dose at bedtime, adjustedaccording to response; usual maintenance 30–300 mg daily (doses above 100 mg given in 3divided doses)Sinepin c (Marlborough) ACapsules, doxepin (as hydrochloride) 25 mg, net price28-cap pack = £3.77; 50 mg, 28-cap pack = £5.71.Label: 2IMIPRAMINE HYDROCHLORIDECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment use with caution in severe impairmentPregnancy colic, tachycardia, dyspnoea, irritability,and muscle spasms reported in neonates when usedin third trimesterBreast-feeding see notes aboveSide-effects see notes above; also palpitation, flushing,restlessness, headache, fatigue; very rarelyabdominal pain, stomatitis, diarrhoea, hypertension,oedema, cardiac decompensation, allergic alveolitis,aggression, myoclonus, peripheral vasospasm, andmydriasisLicensed use not licensed for use for attention deficithyperactivity disorder4 Central nervous system

186 4.3.3 Selective serotonin re-uptake inhibitors BNFC 2011–20124 Central nervous systemIndication and doseNocturnal enuresis. By mouthChild 6–8 years 25 mg at bedtimeChild 8–11 years 25–50 mg at bedtimeChild 11–18 years 50–75 mg at bedtimeNote Max. period of treatment (including gradual withdrawal)3 months—full physical examination beforefurther course, see also section 7.4.2Attention deficit hyperactivity disorder (underspecialist supervision). By mouthChild 6–18 years 10–30 mg twice dailyImipramine (Non-proprietary) ATablets, coated, imipramine hydrochloride 10 mg, netprice 28-tab pack = £1.30; 25 mg, 28-tab pack = £1.24.Label: 2Oral solution, imipramine hydrochloride 25 mg/5 mL, net price 150-mL = £20.00. Label: 2NORTRIPTYLINECautions see notes above; manufacturer advisesplasma-nortriptyline concentration monitoring if doseabove 100 mg daily, but evidence of practical valueuncertainContra-indications see notes aboveHepatic impairment see notes abovePregnancy use only if potential benefit outweighs riskBreast-feeding see notes aboveSide-effects see notes above; also abdominal pain,stomatitis, diarrhoea, hypertension, oedema, flushing,restlessness, fatigue, and mydriasisIndication and doseDepression (but see notes above). By mouthChild 12–18 years low dose initially increased asnecessary to 30–50 mg daily in divided doses or asa single dose (max. 150 mg daily)Allegron c (King) ATablets, nortriptyline (as hydrochloride) 10 mg, netprice 100-tab pack = £12.06; 25 mg (orange, scored),100-tab pack = £24.02. Label: 24.3.2 Monoamine-oxidaseinhibitors(MAOIs)Classification not used in BNF for Children.4.3.3 Selective serotonin reuptakeinhibitorsCitalopram, fluoxetine, fluvoxamine, and sertralineselectively inhibit the re-uptake of serotonin (5-hydroxytryptamine,5-HT); they are termed selective serotoninre-uptake inhibitors (SSRIs).Depressive illness in children and adolescentsThe balance of risks and benefits for the treatment ofdepressive illness in individuals under 18 years isconsidered unfavourable for the SSRIs citalopram,escitalopram, paroxetine, and sertraline, and formirtazapine and venlafaxine. Clinical trials havefailed to show efficacy and have shown an increasein harmful outcomes. However, it is recognised thatspecialists may sometimes decide to use these drugsin response to individual clinical need; children andadolescents should be monitored carefully for suicidalbehaviour, self-harm or hostility, particularly atthe beginning of treatment. Only fluoxetine hasbeen shown in clinical trials to be effective fortreating depressive illness in children and adolescents.However, it is possible that, in common withthe other SSRIs, it is associated with a small risk ofself-harm and suicidal thoughts. Overall, the balanceof risks and benefits for fluoxetine in the treatment ofdepressive illness in individuals under 18 years isconsidered favourable, but children and adolescentsmust be carefully monitored as above.Cautions SSRIs should be used with caution in childrenwith epilepsy (avoid if poorly controlled, discontinueif convulsions develop), cardiac disease, diabetesmellitus, susceptibility to angle-closure glaucoma, ahistory of mania or bleeding disorders (especially gastro-intestinalbleeding), and if used together with otherdrugs that increase the risk of bleeding. They shouldalso be used with caution in those receiving concurrentelectroconvulsive therapy (prolonged seizures reportedwith fluoxetine). SSRIs may also impair performance ofskilled tasks (e.g. driving). Interactions: Appendix 1(antidepressants, SSRI).Withdrawal Gastro-intestinal disturbances, headache,anxiety, dizziness, paraesthesia, electric shock sensationin the head, neck, and spine, tinnitus, sleep disturbances,fatigue, influenza-like symptoms, and sweating are themost common features of abrupt withdrawal of an SSRIor marked reduction of the dose; palpitation and visualdisturbances can occur less commonly. The dose shouldbe tapered over a few weeks to avoid these effects. Itmay be necessary to withdraw treatment over a longerperiod; consider obtaining specialist advice if symptomspersist.Contra-indications SSRIs should not be used if thechild enters a manic phase.Pregnancy Manufacturers advise that SSRIs shouldnot be used during pregnancy unless the potentialbenefit outweighs the risk. There is a small increasedrisk of congenital heart defects when SSRIs are takenduring early pregnancy. If SSRIs are used during thethird trimester there is a risk of neonatal withdrawalsymptoms, and persistent pulmonary hypertension inthe newborn has been reported.Side-effects SSRIs are less sedating and have fewerantimuscarinic and cardiotoxic effects than tricyclicantidepressant drugs (section 4.3.1). Side-effects of theSSRIs include gastro-intestinal effects (dose-related andfairly common—include nausea, vomiting, dyspepsia,abdominal pain, diarrhoea, constipation), anorexiawith weight loss (increased appetite and weight gain

BNFC 2011–2012 4.3.3 Selective serotonin re-uptake inhibitors 187also reported) and hypersensitivity reactions includingrash (consider discontinuation—may be sign of impendingserious systemic reaction, possibly associated withvasculitis), urticaria, angioedema, anaphylaxis, arthralgia,myalgia and photosensitivity; other side-effectsinclude dry mouth, nervousness, anxiety, headache,insomnia, tremor, dizziness, asthenia, hallucinations,drowsiness, convulsions (see Cautions above), galactorrhoea,sexual dysfunction, urinary retention, sweating,hypomania or mania (see Cautions above), movementdisorders and dyskinesias, visual disturbances, hyponatraemia(see Hyponatraemia and AntidepressantTherapy, p. 184), and bleeding disorders includingecchymoses and purpura. Suicidal behaviour has beenlinked with antidepressants, see p. 184. Angle-closureglaucoma may very rarely be precipitated by treatmentwith SSRIs.CITALOPRAMCautions see notes aboveContra-indications see notes aboveHepatic impairment use doses at lower end of rangeRenal impairment no information available for estimatedglomerular filtration rate less than 20 mL/minute/1.73 m 2Pregnancy see notes aboveBreast-feeding present in milk—avoidSide-effects see notes above; also hepatitis, palpitation,tachycardia, oedema, bradycardia, posturalhypotension, coughing, yawning, confusion, impairedconcentration, aggression, malaise, amnesia,migraine, paraesthesia, abnormal dreams, euphoria,mydriasis, taste disturbance, increased salivation,rhinitis, tinnitus, polyuria, micturition disorders, andpruritusLicensed use not licensed for use in childrenIndication and doseMajor depression (but see Depressive Illness inChildren and Adolescents, above). By mouth as tabletsChild 12–18 years initially 10 mg once daily,increased if necessary to 20 mg once daily over 2–4 weeks; max. 60 mg once daily. By mouth as oral dropsChild 12–18 years initially 8 mg once dailyincreased if necessary to 16 mg once daily over 2–4 weeks; max. 48 mg once dailyCitalopram (Non-proprietary) ATablets, citalopram (as hydrobromide) 10 mg, netprice 28-tab pack = £1.03; 20 mg, 28-tab pack = £1.30;40 mg, 28-tab pack = £1.37. Counselling, drivingOral drops, citalopram (as hydrochloride) 40 mg/mL,net price 15-mL pack = £17.92. Counselling, driving,administrationNote 4 drops (8 mg) can be considered equivalent in therapeuticeffect to 10-mg tabletMix with water, orange juice, or apple juice before takingCipramil c (Lundbeck) ATablets, f/c, citalopram (as hydrobromide) 10 mg, netprice 28-tab pack = £5.38; 20 mg (scored), 28-tab pack= £8.95; 40 mg, 28-tab pack = £15.12. Counselling,drivingOral drops, sugar-free, citalopram (as hydrochloride)40 mg/mL, net price 15-mL pack = £10.08. Counselling,driving, administrationNote 4 drops (8 mg) can be considered equivalent in therapeuticeffect to 10-mg tabletMix with water, orange juice, or apple juice before takingFLUOXETINECautions see notes aboveContra-indications see notes aboveHepatic impairment reduce dose or increase doseintervalPregnancy see notes aboveBreast-feeding present in breast milk, avoidSide-effects see notes above; also vasodilatation,postural hypotension, pharyngitis, dyspnoea, chills,taste disturbance, sleep disturbances, euphoria, confusion,yawning, impaired concentration, changes inblood sugar, alopecia, urinary frequency; rarelypulmonary inflammation and fibrosis; very rarelyhepatitis, toxic epidermal necrolysis, and neurolepticmalignant syndrome-like eventIndication and doseMajor depression. By mouthChild 8–18 years 10 mg once daily increasedafter 1–2 weeks if necessary, max. 20 mg oncedailyLong duration of action Consider the long half-life offluoxetine when adjusting dosage (or in overdosage)Fluoxetine (Non-proprietary) ACapsules, fluoxetine (as hydrochloride) 20 mg, netprice 30-cap pack = £1.90; 60 mg, 30-cap pack =£54.43. Counselling, drivingBrands include Oxactin cLiquid, fluoxetine (as hydrochloride) 20 mg/5 mL, netprice 70 mL = £5.04. Counselling, drivingBrands include Prozep cProzac c (Lilly) ACapsules, fluoxetine (as hydrochloride) 20 mg(green/yellow), net price 30-cap pack = £1.50.Counselling, drivingLiquid, fluoxetine (as hydrochloride) 20 mg/5 mL, netprice 70 mL = £11.12. Counselling, drivingFLUVOXAMINE MALEATECautions see notes aboveContra-indications see notes aboveHepatic impairment start with low doseRenal impairment start with low dosePregnancy see notes aboveBreast-feeding present in milk—avoidSide-effects see notes above; palpitation, tachycardia,malaise; less commonly postural hypotension, confusion,ataxia; rarely abnormal liver function (usuallysymptomatic—discontinue treatment); also reportedparaesthesia, taste disturbance, neuroleptic malignantsyndrome-like eventIndication and doseObsessive-compulsive disorder. By mouthChild 8–18 years initially 25 mg dailyincreased if necessary in steps of 25 mg every4 Central nervous system

188 4.4 CNS stimulants and other drugs for ADHD BNFC 2011–20124–7 days according to response (total daily dosesabove 50 mg in 2 divided doses); max. 100 mgtwice dailyNote If no improvement in obsessive-compulsive disorderwithin 10 weeks, treatment should be reconsidered4.3.4 Other antidepressantdrugsClassification not used in BNF for Children.4 Central nervous systemFluvoxamine (Non-proprietary) ATablets, fluvoxamine maleate 50 mg, net price 60-tabpack = £10.81; 100 mg, 30-tab pack = £11.67. Counselling,drivingFaverin c (Abbott Healthcare) ATablets, f/c, scored, fluvoxamine maleate 50 mg, netprice 60-tab pack = £17.10; 100 mg, 30-tab pack =£17.10. Counselling, drivingSERTRALINECautions see notes aboveContra-indications see notes aboveHepatic impairment reduce dose or increase doseinterval in mild or moderate impairment; avoid insevere impairmentRenal impairment use with cautionPregnancy see notes aboveBreast-feeding not known to be harmful but considerdiscontinuing breast-feedingSide-effects see notes above; pancreatitis, hepatitis,jaundice, liver failure, stomatitis, palpitation, hypertension,hypercholesterolaemia, tachycardia, posturalhypotension, bronchospasm, amnesia, paraesthesia,aggression, hypoglycaemia, hypothyroidism, hyperprolactinaemia,urinary incontinence, menstrual irregularities,leucopenia, and tinnitus also reportedLicensed use not licensed for use in children fordepressionIndication and doseObsessive-compulsive disorder. By mouthChild 6–12 years initially 25 mg daily increased to50 mg daily after 1 week, further increased ifnecessary in steps of 50 mg at intervals of at least 1week; max. 200 mg dailyChild 12–18 years initially 50 mg daily increasedif necessary in steps of 50 mg over several weeks;max. 200 mg dailyMajor depression (but see Depressive Illness inChildren and Adolescents, above). By mouthChild 12–18 years initially 50 mg once dailyincreased if necessary in steps of 50 mg daily atintervals of at least a week; max. 200 mg once dailySertraline (Non-proprietary) ATablets, sertraline (as hydrochloride) 50 mg, net price28-tab pack = £1.15; 100 mg, 28-tab pack = £1.53.Counselling, drivingLustral c (Pfizer) ATablets, both f/c, sertraline (as hydrochloride) 50 mg(scored), net price 28-tab pack = £17.82; 100 mg, 28-tab pack = £29.16. Counselling, driving4.4 CNS stimulants and otherdrugs for attention deficithyperactivity disorderCNS stimulants should be prescribed for children withsevere and persistent symptoms of attention deficithyperactivity disorder (ADHD), when the diagnosishas been confirmed by a specialist; children with moderatesymptoms of ADHD can be treated with CNSstimulants when psychological interventions havebeen unsuccessful or are unavailable. Prescribing ofCNS stimulants may be continued by general practitionersunder a shared-care arrangement. Treatment ofADHD often needs to be continued into adolescence,and may need to be continued into adulthood.Drug treatment of ADHD should be part of a comprehensivetreatment programme. The choice of medicationshould take into consideration co-morbid conditions(such as tic disorders, Tourette syndrome, andepilepsy), the adverse effect profile, potential for drugmisuse, and preferences of the child and carers. Methylphenidateand atomoxetine are used for the managementof ADHD; dexamfetamine is an alternative inchildren who do not respond to these drugs. Beforeinitiation of drug therapy, and every 6 months thereafter,pulse, blood pressure, weight, and height should bemeasured.The need to continue drug treatment for ADHD shouldbe reviewed at least annually. This may involve suspendingtreatment.A tricyclic antidepressant such as imipramine (section4.3.1) is sometimes used in the treatment of ADHD; itshould not be prescribed concomitantly with a CNSstimulant.Modafinil is used for the treatment of daytime sleepinessassociated with narcolepsy; dependence with longtermuse cannot be excluded and it should therefore beused with caution.Dexamfetamine and methylphenidate [both unlicensed]are also used to treat narcolepsy.ATOMOXETINECautions see notes above; also cardiovascular diseaseincluding hypertension and tachycardia; structuralcardiac abnormalities; QT-interval prolongation(avoid concomitant use of drugs that prolong QTinterval); psychosis or mania; history of seizures;aggressive behaviour, hostility, or emotional lability;susceptibility to angle-closure glaucoma; interactions:Appendix 1 (atomoxetine)Hepatic disorders Following rare reports of hepatic disorders,children and carers should be advised of the risk and betold how to recognise symptoms; prompt medical attention

BNFC 2011–2012 4.4 CNS stimulants and other drugs for ADHD 189should be sought in case of abdominal pain, unexplainednausea, malaise, darkening of the urine or jaundiceSuicidal ideation Following reports of suicidal thoughts andbehaviour, children and carers should be informed about therisk and told to report clinical worsening, suicidal thoughts orbehaviour, irritability, agitation, or depressionHepatic impairment halve dose in moderate impairment;quarter dose in severe impairment; see alsoHepatic Disorders abovePregnancy no information available; avoid unlesspotential benefit outweighs riskBreast-feeding avoid—present in milk in animalstudiesSide-effects anorexia, dry mouth, nausea, vomiting,abdominal pain, constipation, dyspepsia, flatulence;palpitation, tachycardia, increased blood pressure,postural hypotension, hot flushes; sleep disturbance,dizziness, headache, fatigue, lethargy, depression,psychotic or manic symptoms, aggression, hostility,emotional lability, drowsiness, anxiety, irritability,tremor, rigors; urinary retention, prostatitis, sexualdysfunction, menstrual disturbances; mydriasis, conjunctivitis;dermatitis, pruritus, rash, sweating; lesscommonly suicidal ideation (see Suicidal Ideation,above), cold extremities; very rarely hepatic disorders(see Hepatic Disorders, above), seizures, Raynaud’sphenomenon, and angle-closure glaucomaLicensed use doses above 100 mg daily not licensedIndication and doseAttention deficit hyperactivity disorder initiatedby specialist. By mouthChild over 6 years (body-weight under 70 kg)initially 500 micrograms/kg daily for 7 days,increased according to response; usual maintenancedose 1.2 mg/kg daily, but may be increasedto 1.8 mg/kg daily (max. 120 mg daily) under thedirection of a specialistChild over 6 years (body-weight over 70 kg)initially 40 mg daily for 7 days, increased accordingto response; usual maintenance dose 80 mg daily,but may be increased to max. 120 mg daily underthe direction of a specialistNote Total daily dose may be given either as a single dose inthe morning or in 2 divided doses with last dose no later thanearly eveningStrattera c (Lilly) TACapsules, atomoxetine (as hydrochloride) 10 mg(white), net price 7-cap pack = £15.62, 28-cap pack =£62.46; 18 mg (gold/white), 7-cap pack = £15.62, 28-cap pack = £62.46; 25 mg (blue/white), 7-cap pack =£15.62, 28-cap pack = £62.46; 40 mg (blue), 7-cappack = £15.62, 28-cap pack = £62.46; 60 mg (blue/gold), 28-cap pack = £62.46; 80 mg (brown/white),28-cap pack = £83.28. Label: 3DEXAMFETAMINE SULPHATE(Dexamphetamine sulphate)Cautions see notes above; also anorexia; mild hypertension(contra-indicated if moderate or severe);psychosis or bipolar disorder; monitor for aggressivebehaviour or hostility during initial treatment; historyof epilepsy (discontinue if convulsions occur); tics andTourette syndrome (use with caution)—discontinue iftics occur; susceptibility to angle-closure glaucoma;avoid abrupt withdrawal; data on safety and efficacyof long-term use not complete; acute porphyria (seesection 9.8.2); interactions: Appendix 1 (sympathomimetics)Growth restriction Monitor height and weight as growthrestriction may occur during prolonged therapy (drug-freeperiods may allow catch-up in growth but withdraw slowly toavoid inducing depression or renewed hyperactivity).Contra-indications cardiovascular disease includingmoderate to severe hypertension, structural cardiacabnormalities, hyperexcitability or agitated states,hyperthyroidism, history of drug or alcohol abuseSkilled tasks May affect performance of skilled tasks (e.g.driving); effects of alcohol unpredictableRenal impairment use with cautionPregnancy avoid (retrospective evidence of uncertainsignificance suggesting possible embryotoxicity)Breast-feeding significant amount in milk—avoidSide-effects nausea, diarrhoea, dry mouth, abdominalcramps, anorexia (increased appetite also reported),weight loss, taste disturbance, ischaemic colitis, palpitation,tachycardia, chest pain, hypertension, hypotension,cardiomyopathy, myocardial infarction, cardiovascularcollapse, cerebral vasculitis, stroke,headache, restlessness, depression, hyperreflexia,hyperactivity, impaired concentration, ataxia, anxiety,aggression, dizziness, confusion, sleep disturbances,dysphoria, euphoria, irritability, nervousness, malaise,obsessive-compulsive behaviour, paranoia, psychosis,panic attack, tremor, convulsions (see also Cautions),neuroleptic malignant syndrome, anhedonia, growthrestriction in children (see also Cautions and notesabove), hyperpyrexia, renal impairment, sexual dysfunction,acidosis, rhabdomyolysis, mydriasis, visualdisturbances, alopecia, rash, sweating, urticaria; centralstimulants have provoked choreoathetoid movementsand dyskinesia, tics and Tourette syndrome inpredisposed individuals (see also Cautions); veryrarely angle-closure glaucoma; overdosage: seeEmergency Treatment of Poisoning, p. 31Indication and doseRefractory attention deficit hyperactivity disorderinitiated by specialist. By mouthChild 6–18 years initially 2.5 mg 2–3 times daily,increased if necessary at weekly intervals by 5 mg;usual max. 1 mg/kg daily, up to 20 mg (40 mg dailyhas been required in some children); maintenancedose given in 2–4 divided dosesAdministration tablets can be halvedDexamfetamine (Non-proprietary) 2Tablets, scored, dexamfetamine sulphate 5 mg, netprice 28-tab pack = £15.60. Counselling, drivingMETHYLPHENIDATEHYDROCHLORIDECautions see notes above; also monitor for psychiatricdisorders; anxiety or agitation; tics or a family historyof Tourette syndrome; drug or alcohol dependence;epilepsy (discontinue if increased seizure frequency);avoid abrupt withdrawal; interactions: Appendix 1(sympathomimetics)Contra-indications severe depression, suicidal ideation;anorexia nervosa; psychosis; uncontrolled bipolardisorder; hyperthyroidism; cardiovascular disease(including heart failure, cardiomyopathy, severehypertension, and arrhythmias), structural cardiac4 Central nervous system

190 4.4 CNS stimulants and other drugs for ADHD BNFC 2011–20124 Central nervous systemabnormalities; phaeochromocytoma; vasculitis; cerebrovasculardisordersPregnancy limited experience—avoid unless potentialbenefit outweighs riskBreast-feeding limited information available—avoidSide-effects abdominal pain, nausea, vomiting, diarrhoea,dyspepsia, dry mouth, anorexia, reduced weightgain; tachycardia, palpitation, arrhythmias, changes inblood pressure; tics (very rarely Tourette syndrome),insomnia, nervousness, asthenia, depression, irritability,aggression, headache, drowsiness, dizziness,movement disorders; fever, arthralgia; rash, pruritus,alopecia; growth restriction; less commonly constipation,abnormal dreams, confusion, suicidal ideation,urinary frequency, haematuria, muscle cramps, epistaxis;rarely sweating and visual disturbances; veryrarely hepatic dysfunction, cerebral arteritis, psychosis,seizures, neuroleptic malignant syndrome, toleranceand dependence, blood disorders includingleucopenia and thrombocytopenia, exfoliativedermatitis, and erythema multiforme; supraventriculartachycardia, bradycardia, and convulsions alsoreportedLicensed use not licensed for use in children under 6years; doses over 60 mg daily not licensed; doses ofConcerta c XL over 54 mg daily not licensedIndication and doseAttention deficit hyperactivity disorder initiatedby specialist. By mouthChild 4–6 years 2.5 mg twice daily increased ifnecessary at weekly intervals by 2.5 mg daily tomax. 1.4 mg/kg daily in 2–3 divided doses; discontinueif no response after 1 monthChild 6–18 years initially 5 mg 1–2 times daily,increased if necessary at weekly intervals by 5–10 mg daily; licensed max. 60 mg daily in 2–3divided doses but may be increased to 2.1 mg/kgdaily in 2–3 divided doses (max. 90 mg daily) underthe direction of a specialist; discontinue if noresponse after 1 monthEvening dose If effect wears off in evening (withrebound hyperactivity) a dose at bedtime may beappropriate (establish need with trial bedtime dose)Note Treatment may be started using a modified-releasepreparationAdministration Ritalin c tablets may be halved; contentsof Equasym XL c capsules, and Medikinet XL ccapsules, can be sprinkled on a tablespoon of applesauce, then swallowed immediately without chewingMethylphenidate Hydrochloride (Non-proprietary)2Tablets, methylphenidate hydrochloride 5 mg, netprice 30-tab pack = £2.67; 10 mg, 30-tab pack = £6.74;20 mg, 30-tab pack = £9.59Brands include Medikinet c30-tab pack = £36.81; 36 mg (white), 30-tab pack =£42.45. Label: 25Counselling Tablet membrane may pass through gastrointestinaltract unchangedCautions dose form not appropriate for use in dysphagia or ifgastro-intestinal lumen restrictedDoseAttention deficit hyperactivity disorder. By mouthChild 6–18 years initially 18 mg once daily (in themorning), increased if necessary at weekly intervals by18 mg according to response; licensed max. 54 mg oncedaily, but may be increased to 2.1 mg/kg daily (max.108 mg daily) under the direction of a specialist; discontinueif no response after 1 monthNote Total daily dose of 15 mg of standard-release formulationis considered equivalent to Concerta c XL18 mg once dailyNote Concerta c XL tablets consist of an immediatereleasecomponent (22% of the dose) and a modifiedreleasecomponent (78% of the dose)Equasym XL c (Shire) 2Capsules, m/r, methylphenidate hydrochloride 10 mg(white/green), net price 30-cap pack = £25.00; 20 mg(white/blue), 30-cap pack = £30.00; 30 mg (white/brown), 30-cap pack = £35.00. Label: 25DoseAttention deficit hyperactivity disorder. By mouthChild 6–18 years initially 10 mg once daily in themorning before breakfast, increased gradually at weeklyintervals if necessary; licensed max. 60 mg daily, but maybe increased to 2.1 mg/kg daily (max. 90 mg daily) underthe direction of a specialist; discontinue if no responseafter 1 monthNote Contents of capsule can be sprinkled on a tablespoonof apple sauce (then swallowed immediatelywithout chewing)Note Equasym XL c capsules consist of an immediatereleasecomponent (30% of the dose) and a modifiedreleasecomponent (70% of the dose)Medikinet XL c (Flynn) 2Capsules, m/r, methylphenidate hydrochloride 10 mg(lilac/white), net price 28-cap pack = £20.18; 20 mg(lilac), 28-cap pack = £26.91; 30 mg (purple/lightgrey), 28-cap pack = £31.39; 40 mg (purple/grey), 28-cap pack = £43.20. Label: 25DoseAttention deficit hyperactivity disorder. By mouthChild 6–18 years 10 mg once daily in the morning withbreakfast, adjusted at weekly intervals according toresponse; licensed max. 60 mg daily, but may beincreased to 2.1 mg/kg daily (max. 90 mg daily) underthe direction of a specialist; discontinue if no responseafter 1 monthNote Contents of capsule can be sprinkled on a tablespoonof apple sauce (then swallowed immediatelywithout chewing)Note Medikinet XL c capsules consist of an immediatereleasecomponent (50% of the dose) and a modifiedreleasecomponent (50% of the dose)Ritalin c (Novartis) 2Tablets, scored, methylphenidate hydrochloride10 mg, net price 30-tab pack = £5.57Modified releaseConcerta c XL (Janssen) 2Tablets, m/r, methylphenidate hydrochloride 18 mg(yellow), net price 30-tab pack = £31.19; 27 mg (grey),MODAFINILCautions monitor blood pressure and heart rate inhypertension (see Contra-indications); ECG requiredbefore initiation; possibility of dependence; bipolardisorder or history of psychiatric disorders; alcohol ordrug abuse; interactions: Appendix 1 (modafinil)Contra-indications moderate to severe uncontrolledhypertension, arrhythmia; history of left ventricular

BNFC 2011–2012 4.5 Drugs used in the treatment of obesity 191hypertrophy, of cor pulmonale, or of clinically significantstimulant-induced mitral-valve prolapse(including ischaemic ECG changes, chest pain andarrhythmias)Hepatic impairment halve dose in severe impairmentRenal impairment use with caution—no informationavailablePregnancy avoidBreast-feeding avoid—present in milk in animalstudiesSide-effects dry mouth, appetite changes, gastrointestinaldisturbances (including nausea, diarrhoea,constipation, and dyspepsia), abdominal pain; tachycardia,vasodilation, chest pain, palpitation; headache(uncommonly migraine), anxiety, sleep disturbances,dizziness, depression, confusion, paraesthesia, asthenia;visual disturbances; less commonly mouth ulcers,glossitis, pharyngitis, dysphagia, taste disturbance,increased thirst, hypertension, hypotension, bradycardia,arrhythmia, peripheral oedema, hypercholesterolaemia,rhinitis, dyspnoea, agitation, dyskinesia,amnesia, emotional lability, abnormal dreams,suicidal ideation, tremor, decreased libido, weightchanges, hyperglycaemia, urinary frequency, menstrualdisturbances, eosinophilia, leucopenia, myasthenia,muscle cramps, dry eye, sinusitis, epistaxis,myalgia, arthralgia, acne, sweating, rash, and pruritus;rarely hallucinations, mania, psychosis; very rarely,multi-organ hypersensitivity reaction, Stevens-Johnsonsyndrome, and toxic epidermal necrolysisLicensed use not licensed for use in childrenIndication and doseNarcolepsy. By mouthChild 5–12 years initially 100 mg daily in themorning, dose adjusted according to response to100–400 mg daily either in 2 divided doses morningand at noon or as a single dose in the morningChild 12–18 years 200 mg daily, either in 2divided doses morning and at noon or as a singledose in the morning, dose adjusted according toresponse to 200–400 mg daily in 2 divided doses oras a single doseProvigil c (Cephalon) TATablets, modafinil 100 mg, net price 30-tab pack =£52.60; 200 mg, 30-tab pack = £105.204.5 Drugs used in thetreatment of obesityObesity is associated with many health problems includingcardiovascular disease, diabetes mellitus, gallstones,and osteoarthritis. Factors that aggravate obesity mayinclude depression, other psychosocial problems, andsome drugs.The main treatment of the obese individual is a suitablediet, carefully explained to the individual or carer, withappropriate support and encouragement; increasedphysical activity should also be encouraged. If appropriate,smoking cessation (while maintaining bodyweight) may be worthwhile before attempting supervisedweight loss, since cigarette smoking may be moreharmful than obesity.Obesity should be managed in an appropriate setting bystaff who have been trained in the management ofobesity in children; the individual or carer shouldreceive advice on diet and lifestyle modification andshould be monitored for changes in weight as well as inblood pressure, blood lipids, and other associated conditions.NICE has recommended (December 2006) that drugtreatment should only be considered for obese childrenafter dietary, exercise, and behavioural approaches havebeen started, and who have associated conditions suchas orthopaedic problems or sleep apnoea; treatment isintended both to facilitate weight loss and to maintainreduced weight. Initial treatment should involve a 6–12month trial of orlistat, with regular reviews of effectiveness,tolerance, and adherence.Choice Orlistat, a lipase inhibitor, reduces the absorptionof dietary fat. Some weight loss in those takingorlistat probably results from a reduction in fat intake toavoid severe gastro-intestinal effects including steatorrhoea.Vitamin supplementation (especially of vitaminD) should be considered.Thyroid hormones have no place in the treatment ofobesity except in biochemically proven hypothyroidchildren. The use of diuretics, chorionic gonadotrophin,or amfetamines is not appropriate for weight reduction.ORLISTATCautions may impair absorption of fat-soluble vitamins;chronic kidney disease or volume depletion;interactions: Appendix 1 (orlistat)Multivitamins If a multivitamin supplement is required, itshould be taken at least 2 hours after orlistat doseContra-indications chronic malabsorption syndrome;cholestasisPregnancy use with cautionBreast-feeding avoid—no information availableSide-effects oily leakage from rectum, flatulence,faecal urgency, liquid or oily stools, faecal incontinence,abdominal distension and pain (gastro-intestinaleffects minimised by reduced fat intake), toothand gingival disorders, respiratory infections, malaise,anxiety, headache, menstrual disturbances, urinarytractinfection, hypoglycaemia; also reported rectalbleeding, diverticulitis, cholelithiasis, hepatitis, hypothyroidism,oxalate nephropathy, bullous eruptionsLicensed use not licensed for use in childrenIndication and doseAdjunct in obesity initiated by specialist. By mouthChild 12–18 years 120 mg taken immediatelybefore, during, or up to 1 hour after each mainmeal (max. 120 mg 3 times daily); continue treatmentbeyond 12 weeks only under specialistrecommendationNote If a meal is missed or contains no fat, the dose oforlistat should be omittedXenical c (Roche) ACapsules, turquoise, orlistat 120 mg, net price 84-cappack = £31.634 Central nervous system

192 4.6 Drugs used in nausea and vertigo BNFC 2011–20124 Central nervous system4.6 Drugs used in nausea andvertigoAntiemetics should be prescribed only when the causeof vomiting is known because otherwise they may delaydiagnosis. Antiemetics are unnecessary and sometimesharmful when the cause can be treated, such as indiabetic ketoacidosis, or in digoxin or antiepileptic overdose.If antiemetic drug treatment is indicated, the drug ischosen according to the aetiology of vomiting.Antihistamines are effective against nausea and vomitingresulting from many underlying conditions. There isno evidence that any one antihistamine is superior toanother but their duration of action and incidence ofadverse effects (drowsiness and antimuscarinic effects)differ.The phenothiazines are dopamine antagonists and actcentrally by blocking the chemoreceptor trigger zone.They may be considered for the prophylaxis and treatmentof nausea and vomiting associated with diffuseneoplastic disease, radiation sickness, and the emesiscaused by drugs such as opioids, general anaesthetics,and cytotoxics. Prochlorperazine, perphenazine, andtrifluoperazine are less sedating than chlorpromazine;severe dystonic reactions sometimes occur with phenothiazines(see below). Some phenothiazines are availableas rectal suppositories, which can be useful inchildren with persistent vomiting or with severe nausea;for children over 12 years prochlorperazine can also beadministered as a buccal tablet which is placed betweenthe upper lip and the gum.Droperidol is a butyrophenone, structurally related tohaloperidol, which blocks dopamine receptors in thechemoreceptor trigger zone.Other antipsychotic drugs including haloperidol andlevomepromazine (section 4.2.1) are also used for therelief of nausea in palliative care (see p. 19 and p. 20).Metoclopramide is an effective antiemetic and itsactivity closely resembles that of the phenothiazines.Metoclopramide also acts directly on the gastro-intestinaltract and it may be superior to the phenothiazinesfor emesis associated with gastroduodenal, hepatic, andbiliary disease. In postoperative nausea and vomiting,metoclopramide has limited efficacy. For the role ofmetoclopramide in cytotoxic-induced nausea and vomitingsee section 8.1.Acute dystonic reactionsPhenothiazines and metoclopramide can all induceacute dystonic reactions such as facial and skeletalmuscle spasms and oculogyric crises; children (especiallygirls, young women, and those under 10 kg) areparticularly susceptible. With metoclopramide, dystoniceffects usually occur shortly after startingtreatment and subside within 24 hours of stoppingit. An antimuscarinic drug such as procyclidine (section4.9.2) is used to abort dystonic attacks.Domperidone acts at the chemoreceptor trigger zone; ithas the advantage over metoclopramide and the phenothiazinesof being less likely to cause central effects suchas sedation and dystonic reactions because it does notreadily cross the blood-brain barrier. For the role ofdomperidone in cytotoxic-induced nausea and vomitingsee section 8.1. Domperidone is also used to treatvomiting due to emergency hormonal contraception(section 7.3.5).Granisetron and ondansetron are specific 5HT 3 -receptorantagonists which block 5HT 3 receptors in thegastro-intestinal tract and in the CNS. They are ofvalue in the management of nausea and vomiting inchildren receiving cytotoxics and in postoperativenausea and vomiting.Nabilone is a synthetic cannabinoid with antiemeticproperties. It may be used for nausea and vomitingcaused by cytotoxic chemotherapy that is unresponsiveto conventional antiemetics. Side-effects such as drowsinessand dizziness occur frequently with standarddoses.Dexamethasone (section 6.3.2) has antiemetic effects.For the role of dexamethasone in cytotoxic-inducednausea and vomiting see section 8.1.Vomiting during pregnancyNausea in the first trimester of pregnancy is generallymild and does not require drug therapy. On rare occasionsif vomiting is severe, short-term treatment with anantihistamine, such as promethazine, may be required.Prochlorperazine or metoclopramide may be consideredas second-line treatments. If symptoms do notsettle in 24 to 48 hours then specialist opinion shouldbe sought. Hyperemesis gravidarum is a more seriouscondition, which requires intravenous fluid and electrolytereplacement and sometimes nutritional support.Supplementation with thiamine must be considered inorder to reduce the risk of Wernicke’s encephalopathy.Postoperative nausea and vomitingThe incidence of postoperative nausea and vomitingdepends on many factors including the anaestheticused, and the type and duration of surgery. Other riskfactors include female sex, a history of postoperativenausea and vomiting or motion sickness, and intraoperativeand postoperative use of opioids. Therapy toprevent postoperative nausea and vomiting should bebased on the assessed risk. Drugs used include 5HT 3 -receptor antagonists, droperidol, dexamethasone,some phenothiazines (e.g. prochlorperazine), and antihistamines(e.g. cyclizine). A combination of two ormore antiemetic drugs that have different mechanismsof action is often indicated in those at high risk ofpostoperative nausea and vomiting or where postoperativevomiting presents a particular danger (e.g. in sometypes of surgery). When a prophylactic antiemetic drughas failed, postoperative nausea and vomiting should betreated with one or more drugs from a different class.Opioid-induced nausea and vomitingCyclizine, ondansetron, and prochlorperazine are usedto relieve opioid-induced nausea and vomiting; ondansetronhas the advantage of not producing sedation.

BNFC 2011–2012 4.6 Drugs used in nausea and vertigo 193Motion sicknessAntiemetics should be given to prevent motion sicknessrather than after nausea or vomiting develop. The mosteffective drug for the prevention of motion sickness ishyoscine hydrobromide. For children over 10 yearsold, a transdermal hyoscine patch provides prolongedactivity but it needs to be applied several hours beforetravelling. The sedating antihistamines are slightly lesseffective against motion sickness, but are generallybetter tolerated than hyoscine. If a sedative effect isdesired promethazine is useful, but generally a slightlyless sedating antihistamine such as cyclizine or cinnarizineis preferred. The 5HT 3 -receptor antagonists,domperidone, metoclopramide, and the phenothiazines(except the antihistamine phenothiazine promethazine)are ineffective in motion sickness.Other vestibular disordersManagement of vestibular diseases is aimed at treatingthe underlying cause as well as treating symptoms of thebalance disturbance and associated nausea and vomiting.Antihistamines (such as cinnarizine), and phenothiazines(such as prochlorperazine) are effective forprophylaxis and treatment of nausea and vertigo resultingfrom vestibular disorders; however, when nauseaand vertigo are associated with middle ear surgery,treatment can be difficult.Cytotoxic chemotherapyFor the management of nausea and vomiting induced bycytotoxic chemotherapy, see section 8.1.Palliative careFor the management of nausea and vomiting in palliativecare, see p. 19 and p. 20.MigraineFor the management of nausea and vomiting associatedwith migraine, see p. 214.AntihistaminesCINNARIZINECautions section 3.4.1Contra-indications section 3.4.1Hepatic impairment section 3.4.1Renal impairment use with caution—no informationavailablePregnancy section 3.4.1Breast-feeding section 3.4.1Side-effects section 3.4.1; also rarely weight gain,sweating, lichen planus, and lupus-like skin reactionsIndication and doseRelief of symptoms of vestibular disorders. By mouthChild 5–12 years 15 mg 3 times dailyChild 12–18 years 30 mg 3 times dailyMotion sickness. By mouthChild 5–12 years 15 mg 2 hours before travel then7.5 mg every 8 hours during journey if necessaryChild 12–18 years 30 mg 2 hours before travelthen 15 mg every 8 hours during journey ifnecessaryCinnarizine (Non-proprietary)Tablets, cinnarizine 15 mg, net price 84-tab pack =£8.84. Label: 2Stugeron c (Janssen)Tablets, scored, cinnarizine 15 mg, net price 15-tabpack = £1.55, 100-tab pack = £4.18. Label: 2CYCLIZINECautions section 3.4.1; severe heart failure; maycounteract haemodynamic benefits of opioids; interactions:Appendix 1 (antihistamines)Skilled tasks Drowsiness may affect performance of skilledtasks (e.g. driving); effects of alcohol enhancedContra-indications section 3.4.1Hepatic impairment section 3.4.1Pregnancy section 3.4.1Breast-feeding no information availableSide-effects section 3.4.1Licensed use tablets not licensed for use in childrenunder 6 years; injection not licensed for use inchildrenIndication and doseNausea and vomiting of known cause; nauseaand vomiting associated with vestibular disordersand palliative care. By mouth or by intravenous injection over 3–5minutesChild 1 month–6 years 0.5–1 mg/kg up to 3times daily; max. single dose 25 mgChild 6–12 years 25 mg up to 3 times dailyChild 12–18 years 50 mg up to 3 times dailyNote For motion sickness, take 1–2 hours before departure. By rectumChild 2–6 years 12.5 mg up to 3 times dailyChild 6–12 years 25 mg up to 3 times dailyChild 12–18 years 50 mg up to 3 times daily. By continuous intravenous or subcutaneousinfusionChild 1 month–2 years 3 mg/kg over 24 hoursChild 2–5 years 50 mg over 24 hoursChild 6–12 years 75 mg over 24 hoursChild 12–18 years 150 mg over 24 hoursAdministration for administration by mouth, tabletsmay be crushedValoid c (Amdipharm)Tablets, scored, cyclizine hydrochloride 50 mg, netprice 100-tab pack = £7.41. Label: 2InjectionA, cyclizine lactate 50 mg/mL, net price 1-mL amp = 51p4 Central nervous system

194 4.6 Drugs used in nausea and vertigo BNFC 2011–20124 Central nervous systemCyclizine (Non-proprietary)Suppositories, 12.5 mg, 25 mg, 50 mg, 100 mg.Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809PROMETHAZINE HYDROCHLORIDECautions see notes in section 3.4.1Contra-indications see Promethazine Hydrochloride,section 3.4.1Hepatic impairment see notes in section 3.4.1Renal impairment see Promethazine Hydrochloride,section 3.4.1Pregnancy see notes in section 3.4.1Breast-feeding see notes in section 3.4.1Side-effects see Promethazine Hydrochloride, section3.4.1 but more sedatingIndication and doseNausea and vomiting. By mouthChild 2–5 years 5 mg at bedtime on night beforetravel, repeat following morning if necessaryChild 5–10 years 10 mg at bedtime on nightbefore travel, repeat following morning if necessaryChild 10–18 years 20–25 mg at bedtime on nightbefore travel, repeat following morning if necessaryAllergy and urticaria section 3.4.1Sedation section 4.1.1PreparationsSection 3.4.1PROMETHAZINE TEOCLATECautions section 3.4.1; severe coronary artery disease;asthma, bronchitis, bronchiectasis, Reye’ssyndromeContra-indications section 3.4.1Hepatic impairment section 3.4.1Renal impairment use with cautionPregnancy section 3.4.1Breast-feeding section 3.4.1Side-effects section 3.4.1Licensed use not licensed to treat vomiting ofpregnancyIndication and doseNausea, vomiting, labyrinthine disorders. By mouthChild 5–10 years 12.5–37.5 mg dailyChild 10–18 years 25–75 mg daily (max. 100 mg)Motion sickness prevention. By mouthChild 5–10 years 12.5 mg at bedtime on nightbefore travel or 12.5 mg 1–2 hours before travelChild 10–18 years 25 mg at bedtime on nightbefore travel or 25 mg 1–2 hours before travelMotion sickness treatment. By mouthChild 5–10 years 12.5 mg at onset, then 12.5 mgat bedtime for 2 daysChild 10–18 years 25 mg at onset, then 25 mg atbedtime for 2 daysSevere vomiting during pregnancy. By mouth25 mg at bedtime increased if necessary to max.100 mg daily (but see also Vomiting DuringPregnancy, p. 192)Avomine c (Manx)Tablets, scored, promethazine teoclate 25 mg, netprice 10-tab pack = £1.13; 28-tab pack = £3.13.Label: 2Phenothiazines and related drugsCHLORPROMAZINEHYDROCHLORIDECautions see Chlorpromazine Hydrochloride, section4.2.1Contra-indications see notes in section 4.2.1Hepatic impairment see notes in section 4.2.1Renal impairment see notes in section 4.2.1Pregnancy see notes in section 4.2.1Breast-feeding see notes in section 4.2.1Side-effects see Chlorpromazine Hydrochloride, section4.2.1Indication and doseNausea and vomiting of terminal illness (whereother drugs are unsuitable). By mouthChild 1–6 years 500 micrograms/kg every 4–6hours; max. 40 mg dailyChild 6–12 years 500 micrograms/kg every 4–6hours; max. 75 mg dailyChild 12–18 years 10–25 mg every 4–6 hours. By deep intramuscular injectionChild 1–6 years 500 micrograms/kg every 6–8hours; max. 40 mg dailyChild 6–12 years 500 micrograms/kg every 6–8hours; max. 75 mg dailyChild 12–18 years initially 25 mg then 25–50 mgevery 3–4 hours until vomiting stopsPreparationsSection 4.2.1DROPERIDOLCautions section 4.2.1; also chronic obstructivepulmonary disease or respiratory failure; electrolytedisturbances; history of alcohol abuse; continuouspulse oximetry required if risk of ventricular arrhythmia—continuefor 30 minutes following administration;interactions: Appendix 1 (droperidol)Contra-indications section 4.2.1; QT-interval prolongation(avoid concomitant administration of drugs

BNFC 2011–2012 4.6 Drugs used in nausea and vertigo 195that prolong QT interval); hypokalaemia; hypomagnesaemia;bradycardiaHepatic impairment max. 625 micrograms repeatedevery 6 hours as requiredRenal impairment max. 625 micrograms repeatedevery 6 hours as requiredPregnancy section 4.2.1Breast-feeding limited information available—avoidrepeated administrationSide-effects section 4.2.1; also anxiety, cardiac arrest,hallucinations, and inappropriate secretion of antidiuretichormoneIndication and dosePrevention and treatment of postoperativenausea and vomiting. By intravenous injectionChild 2–18 years 20–50 micrograms/kg (max.1.25 mg) 30 minutes before the end of surgery,repeated every 6 hours as necessaryXomolix c (ProStrakan) TAInjection, droperidol 2.5 mg/mL, net price 1-mL amp= £3.94PERPHENAZINECautions see notes in section 4.2.1Contra-indications see notes in section 4.2.1Hepatic impairment see notes in section 4.2.1Renal impairment see notes in section 4.2.1Pregnancy see notes in section 4.2.1Breast-feeding see notes in section 4.2.1Side-effects see Perphenazine, section 4.2.1Indication and doseSevere nausea and vomiting unresponsive toother antiemetics. By mouthChild 14–18 years 4 mg 3 times daily, adjustedaccording to response, max. 24 mg dailyPreparationsSection 4.2.1PROCHLORPERAZINECautions see notes in section 4.2.1; hypotension morelikely after intramuscular injectionContra-indications see notes in section 4.2.1Hepatic impairment see notes in section 4.2.1Renal impairment see notes in section 4.2.1Pregnancy see notes in section 4.2.1Breast-feeding see notes in section 4.2.1Side-effects see notes in section 4.2.1; respiratorydepression may occur in susceptible childrenLicensed use injection not licensed for use in childrenIndication and dosePrevention and treatment of nausea and vomiting. By mouthChild 1–12 years and over 10 kg 250 micrograms/kg2–3 times dailyChild 12–18 years 5–10 mg, repeated if necessaryup to 3 times daily. By intramuscular injectionChild 2–5 years, 1.25–2.5 mg, repeated if necessaryup to 3 times dailyChild 5–12 years 5–6.25 mg, repeated if necessaryup to 3 times dailyChild 12–18 years 12.5 mg, repeated if necessaryup to 3 times dailyNote Doses are expressed as prochlorperazine maleate ormesilate; 1 mg prochlorperazine maleate : 1 mg prochlorperazinemesilateProchlorperazine (Non-proprietary) ATablets, prochlorperazine maleate 5 mg, net price 28-tab pack = £1.25, 84-tab pack = £2.28. Label: 2Injection, prochlorperazine mesilate 12.5 mg/mL, netprice 1-mL amp = 52pStemetil c (Sanofi-Aventis) ATablets, prochlorperazine maleate 5 mg (off-white),net price 28-tab pack = £1.98, 84-tab pack = £5.94.Label: 2Syrup, straw-coloured, prochlorperazine mesilate5 mg/5 mL, net price 100-mL pack = £3.34. Label: 2Injection, prochlorperazine mesilate 12.5 mg/mL, netprice 1-mL amp = 52pBuccal preparationBuccastem c (Alliance) ATablets (buccal), pale yellow, prochlorperazine maleate3 mg, net price 5 10-tab pack = £5.89. Label: 2,counselling, administration, see under Dose belowDose. By mouthChild 12–18 years 1–2 tablets twice daily; tablets areplaced high between upper lip and gum and left todissolveTRIFLUOPERAZINECautions see notes in section 4.2.1Contra-indications see notes in section 4.2.1Hepatic impairment see notes in section 4.2.1Renal impairment see notes in section 4.2.1Pregnancy see notes in section 4.2.1Breast-feeding see notes in section 4.2.1Side-effects see Trifluoperazine section 4.2.1Indication and doseSevere nausea and vomiting unresponsive toother antiemetics. By mouthChild 3–5 years up to 500 micrograms twice dailyChild 6–12 years up to 2 mg twice dailyChild 12–18 years 1–2 mg twice daily; max. 3 mgtwice dailyPreparationsSection 4.2.1Domperidone and metoclopramideDOMPERIDONECautions children; interactions: Appendix 1 (domperidone)Contra-indications prolactinaemia; if increased gastro-intestinalmotility harmful4 Central nervous system

196 4.6 Drugs used in nausea and vertigo BNFC 2011–20124 Central nervous systemHepatic impairment avoidRenal impairment reduce dose in renal impairmentPregnancy use only if potential benefit outweighs riskBreast-feeding amount too small to be harmfulSide-effects rarely gastro-intestinal disturbances(including cramps), and hyperprolactinaemia; veryrarely ventricular arrhythmias, agitation, drowsiness,nervousness, seizures, extrapyramidal effects, headache,and rashes; also reported QT-interval prolongationIndication and doseNausea and vomiting. By mouthChild over 1 month and body-weight up to35 kg 250–500 micrograms/kg 3–4 times daily;max. 2.4 mg/kg in 24 hoursBody-weight 35 kg and over 10–20 mg 3–4 timesdaily, max. 80 mg daily. By rectumBody-weight 15–35 kg 30 mg twice dailyBody-weight over 35 kg 60 mg twice dailyGastro-intestinal stasis section 1.21Domperidone (Non-proprietary) ATablets, 10 mg (as maleate), net price 30-tab pack =£1.12; 100-tab pack = £1.90Suspension, domperidone 5 mg/5 mL, net price 200-mL pack = £12.001. Domperidone can be sold to the public for children over 16years (provided packs do not contain more than 200 mg) forthe relief of postprandial symptoms of excessive fullness,nausea, epigastric bloating and belching occasionallyaccompanied by epigastric discomfort and heartburn, andfor the relief of nausea and vomiting of less than 48 hours’duration (max. single dose 10 mg, max. daily dose 40 mg)Motilium c (Sanofi-Aventis) ATablets, f/c, domperidone 10 mg (as maleate), netprice 30-tab pack = £2.71; 100-tab pack = £9.04Suppositories, domperidone 30 mg, net price 10 =£3.06METOCLOPRAMIDEHYDROCHLORIDECautions atopic allergy (including asthma); cardiacconduction disturbances (and concomitant use ofother drugs affecting cardiac conduction); may maskunderlying disorders such as cerebral irritation; epilepsy;acute porphyria (section 9.8.2); interactions:Appendix 1 (metoclopramide)Contra-indications gastro-intestinal obstruction, perforationor haemorrhage; 3–4 days after gastro-intestinalsurgery; phaeochromocytomaHepatic impairment reduce doseRenal impairment avoid or use small dose in severeimpairment; increased risk of extrapyramidal reactionsPregnancy not known to be harmfulBreast-feeding small amount present in milk; avoidSide-effects extrapyramidal effects (see p. 192),hyperprolactinaemia, occasionally tardive dyskinesiaon prolonged administration; also reported, dyspnoea,anxiety, confusion, drowsiness, dizziness, tremor,restlessness, diarrhoea, depression, neurolepticmalignant syndrome, visual disturbances, rashes,pruritus, oedema; cardiac conduction abnormalitiesreported following intravenous administration; rarelymethaemoglobinaemia (more severe in G6PD deficiency)Licensed use not licensed for use in neonates as aprokineticIndication and doseSevere intractable vomiting of known cause,vomiting associated with radiotherapy andcytotoxics, aid to gastro-intestinal intubation,as a prokinetic in neonates. By mouth, or by intramuscular injection or byintravenous injection over 1–2 minutesNeonate 100 micrograms/kg every 6–8 hours (bymouth or by intravenous injection only)Child 1 month–1 year and body-weight up to10 kg 100 micrograms/kg (max. 1 mg) twice dailyChild 1–3 years and body-weight 10–14 kg1 mg 2–3 times dailyChild 3–5 years and body-weight 15–19 kg2 mg 2–3 times dailyChild 5–9 years and body-weight 20–29 kg2.5 mg 3 times dailyChild 9–18 years and body-weight 30–60 kg5 mg 3 times dailyChild 15–18 years and body-weight over 60 kg10 mg 3 times dailyNote Daily dose of metoclopramide should not normallyexceed 500 micrograms/kgPremedication in diagnostic procedures. By mouth as a single dose 5–10 minutes beforeexaminationChild 1 month–3 years and body-weight up to14 kg 100 micrograms/kg, max. 1 mgChild 3–5 years and body-weight 15–19 kg2 mgChild 5–9 years and body-weight 20–29 kg2.5 mgChild 9–15 years and body-weight 30–60 kg5 mgChild 15–18 years and body-weight over 60 kg10 mgMetoclopramide (Non-proprietary) ATablets, metoclopramide hydrochloride 10 mg, netprice 28-tab pack = £1.01Oral solution, metoclopramide hydrochloride 5 mg/5 mL, net price 150-mL pack = £6.51. Counselling, useof pipetteNote Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionInjection, metoclopramide hydrochloride 5 mg/mL,net price 2-mL amp = 26pMaxolon c (Amdipharm) ATablets, scored, metoclopramide hydrochloride10 mg, net price 84-tab pack = £5.24Injection, metoclopramide hydrochloride 5 mg/mL,net price 2-mL amp = 27pCompound preparations (for migraine)Section 4.7.1

BNFC 2011–2012 4.6 Drugs used in nausea and vertigo 1975HT 3 -receptor antagonistsGRANISETRONCautions QT-interval prolongation (avoid concomitantuse of drugs that prolong QT interval)Pregnancy use only when compelling reasons—noinformation availableBreast-feeding avoid—no information availableSide-effects constipation, nausea, diarrhoea, vomiting,abdominal pain; headache, drowsiness, asthenia;fever; rarely hepatic dysfunction, chest pain,arrhythmia; very rarely anorexia, dizziness, insomnia,agitation, movement disorders, and rashLicensed use sterile solution not licensed for use inchildren under 2 yearsIndication and doseTreatment and prevention of nausea and vomitinginduced by cytotoxic chemotherapy orradiotherapy. By mouthChild 12–18 years 1–2 mg within 1 hour beforestart of treatment, then 1 mg twice daily duringtreatment (total daily dose may alternatively begiven as a single dose); when intravenous infusionalso used, max. combined total 9 mg in 24 hours. By intravenous infusionChild 1 month–12 years prevention, 40 micrograms/kg(max. 3 mg) before start of cytotoxictherapy; treatment, 40 micrograms/kg (max. 3 mg)repeated within 24 hours if necessary (not lessthan 10 minutes after initial dose). By intravenous injection or by intravenousinfusionChild 12–18 years prevention, 3 mg before startof cytotoxic therapy (up to 2 additional 3-mg dosesmay be given within 24 hours); treatment, 3 mgrepeated if necessary (doses must not be given lessthan 10 minutes apart), max. 9 mg in 24 hoursAdministration for intravenous infusion, dilute up to3 mL in Glucose 5% or Sodium Chloride 0.9% to atotal volume of 10–30 mL; give over 5 minutesGranisetron (Non-proprietary) ATablets, granisetron (as hydrochloride) 1 mg, net price10-tab pack = £51.20Injection, granisetron (as hydrochloride) 1 mg/mL,for dilution before use, net price 1-mL amp = £1.20, 3-mL amp = £4.80Kytril c (Roche) ATablets, f/c, granisetron (as hydrochloride) 1 mg, netprice 10-tab pack = £52.39; 2 mg, 5-tab pack = £52.39Injection, granisetron (as hydrochloride) 1 mg/mL,for dilution before use, net price 1-mL amp = £6.88, 3-mL amp = £20.63ONDANSETRONCautions QT-interval prolongation (avoid concomitantuse of drugs that prolong QT interval); subacuteintestinal obstruction; adenotonsillar surgeryHepatic impairment reduce dose in moderate orsevere impairmentPregnancy no information available; avoid unlesspotential benefit outweighs riskBreast-feeding present in milk in animal studies—avoidSide-effects constipation; headache; flushing; injection-sitereactions; less commonly hiccups, hypotension,bradycardia, chest pain, arrhythmias, movementdisorders, seizures; on intravenousadministration, rarely dizziness, transient visual disturbances(very rarely transient blindness)Licensed use not licensed for radiotherapy-inducednausea and vomiting in childrenIndication and dosePrevention and treatment of chemotherapyandradiotherapy-induced nausea and vomiting. By intravenous infusion over at least 15 minutesChild 6 months–18 years either 5 mg/m 2immediately before chemotherapy (max. singledose 8 mg), then give by mouth, or 150 micrograms/kgimmediately before chemotherapy(max. single dose 8 mg) repeated every 4 hours for2 further doses, then give by mouth; max. totaldaily dose 32 mg. By mouth following intravenous administrationNote Oral dosing can start 12 hours after intravenousadministrationChild 6 months–18 yearsBody surface area less than 0.6 m 2 or bodyweight10 kg or less 2 mg every 12 hours for upto 5 days (max. total daily dose 32 mg)Body surface area 0.6 m 2 or greater or bodyweightover 10 kg 4 mg every 12 hours for up to 5days (max. total daily dose 32 mg)Treatment and prevention of postoperativenausea and vomiting. By slow intravenous injection over at least 30secondsChild 1 month–18 years 100 micrograms/kg(max. 4 mg), as a single dose before, during, orafter induction of anaesthesiaAdministration for intravenous infusion, dilute to aconcentration of 320–640 micrograms/mL with Glucose5% or Sodium Chloride 0.9%; give over at least15 minutesOndansetron (Non-proprietary) ATablets, ondansetron (as hydrochloride) 4 mg, netprice 30-tab pack = £66.85; 8 mg, 10-tab pack =£49.92Brands include Ondemet cOral solution, ondansetron (as hydrochloride) 4 mg/5 mL, net price 50-mL pack = £35.97Brands include Demorem cInjection, ondansetron (as hydrochloride) 2 mg/mL,net price 2-mL amp = £5.39, 4-mL amp = £10.79Brands include Ondemet cZofran c (GSK) ATablets, yellow, f/c, ondansetron (as hydrochloride)4 mg, net price 30-tab pack = £107.91; 8 mg, 10-tabpack = £71.944 Central nervous system

198 4.6 Drugs used in nausea and vertigo BNFC 2011–20124 Central nervous systemOral lyophilisates (Zofran Melt c ), ondansetron 4 mg,net price 10-tab pack = £35.97; 8 mg, 10-tab pack =£71.94. Counselling, administrationExcipients include aspartame (section 9.4.1)Counselling Tablets should be placed on the tongue,allowed to disperse and swallowedOral solution, sugar-free, strawberry-flavoured,ondansetron (as hydrochloride) 4 mg/5 mL, net price50-mL pack = £35.97Injection, ondansetron (as hydrochloride) 2 mg/mL,net price 2-mL amp = £5.99; 4-mL amp = £11.99CannabinoidNABILONECautions history of psychiatric disorder; hypertension;heart disease; adverse effects on mental state canpersist for 48–72 hours after stopping; interactions:Appendix 1 (nabilone)Skilled tasks Drowsiness may affect performance of skilledtasks (e.g. driving); effects of alcohol enhancedHepatic impairment avoid in severe impairmentPregnancy avoid unless essentialBreast-feeding avoid—no information availableSide-effects drowsiness, vertigo, euphoria, drymouth, ataxia, visual disturbance, concentration difficulties,sleep disturbance, dysphoria, hypotension,headache and nausea; also confusion, disorientation,hallucinations, psychosis, depression, decreasedcoordination, tremors, tachycardia, decreased appetite,and abdominal painBehavioural effects Children and carers should be madeaware of possible changes of mood and other adversebehavioural effectsLicensed use not licensed for use in childrenIndication and doseNausea and vomiting caused by cytotoxicchemotherapy, unresponsive to conventionalantiemetics (under close observation, preferably inhospital setting). By mouthConsult local treatment protocol for detailsNabilone (Meda) 2Capsules, blue/white, nabilone 1 mg, net price 20-cap pack = £125.84. Label: 2, counselling,behavioural effectsHyoscineHYOSCINE HYDROBROMIDE(Scopolamine Hydrobromide)Cautions section 1.2; also epilepsySkilled tasks Drowsiness may affect performance of skilledtasks (e.g. driving) and may persist for up to 24 hours orlonger after removal of patch; effects of alcohol enhancedContra-indications section 1.2Hepatic impairment use with cautionRenal impairment use with cautionPregnancy use only if potential benefit outweighs risk;injection may depress neonatal respirationBreast-feeding amount too small to be harmfulSide-effects section 1.2Licensed use not licensed for use in excessiverespiratory secretions or hypersalivation associatedwith clozapine therapyIndication and doseMotion sickness. By mouthChild 4–10 years 75–150 micrograms 30 minutesbefore start of journey, repeated every 6 hours ifrequired; max. 3 doses in 24 hoursChild 10–18 years 150–300 micrograms 30 minutesbefore start of journey, repeated every 6 hoursif required; max. 3 doses in 24 hours. By topical applicationChild 10–18 years apply 1 patch (1 mg) to hairlessarea of skin behind ear 5–6 hours beforejourney; replace if necessary after 72 hours, sitingreplacement patch behind the other earExcessive respiratory secretions. By mouth or by sublingual administrationChild 2–12 years 10 micrograms/kg, max.300 micrograms 4 times dailyChild 12–18 years 300 micrograms 4 times daily. By transdermal routeChild 1 month–3 years 250 micrograms every 72hours (quarter of a patch)Child 3–10 years 500 micrograms every 72 hours(half a patch)Child 10–18 years 1 mg every 72 hours (onepatch). By subcutaneous injection, intravenous injection,intravenous infusion, or subcutaneousinfusionSee Prescribing in Palliative Care, p. 19 and p. 20Hypersalivation associated with clozapinetherapy. By mouthChild 12–18 years 300 micrograms up to 3 timesdaily; max. 900 micrograms dailyPremedication section 15.1.3Administration patch applied to hairless area of skinbehind ear; if less than whole patch required eithercut with scissors along full thickness ensuring membraneis not peeled away or cover portion to preventcontact with skinFor administration by mouth, injection solution maybe given orallyJoy-Rides c (GSK Consumer Healthcare)Tablets, chewable, hyoscine hydrobromide 150 micrograms,net price 12-tab pack = £1.49. Label: 2, 24Kwells c (Bayer Consumer Care)Tablets, chewable, hyoscine hydrobromide 150 micrograms(Kwells c Kids), net price 12-tab pack = £1.67;300 micrograms, 12-tab pack = £1.67. Label: 2

BNFC 2011–2012 4.7 Analgesics 199Scopoderm TTS c (Novartis Consumer Health) APatch, self-adhesive, pink, releasing hyoscine approx.1 mg/72 hours when in contact with skin. Net price 2= £4.30. Label: 19, counselling, see belowCounselling Explain accompanying instructions to child andcarer, in particular emphasise advice to wash hands afterhandling and to wash application site after removing, and touse one patch at a time4.7 Analgesics4.7.1 Non-opioid analgesics and compoundanalgesic preparations4.7.2 Opioid analgesics4.7.3 Neuropathic pain4.7.4 Antimigraine drugsThe non-opioid drugs (section 4.7.1), paracetamol andibuprofen (and other NSAIDs), are particularly suitablefor pain in musculoskeletal conditions, whereas theopioid analgesics (section 4.7.2) are more suitable formoderate to severe pain, particularly of visceral origin.Pain in palliative care For advice on pain relief inpalliative care, see p. 17.Pain in sickle-cell disease The pain of mild sicklecellcrises is managed with paracetamol, an NSAID(section 10.1.1), codeine, or dihydrocodeine. Severecrises may require the use of morphine or diamorphine;concomitant use of an NSAID may potentiate analgesiaand allow lower doses of the opioid to be used. Amixture of nitrous oxide and oxygen (Entonox c ,Equanox c ) may also be used.Dental and orofacial pain Analgesics should be usedjudiciously in dental care as a temporary measure untilthe cause of the pain has been dealt with.Dental pain of inflammatory origin, such as that associatedwith pulpitis, apical infection, localised osteitis(dry socket) or pericoronitis is usually best managed bytreating the infection, providing drainage, restorativeprocedures, and other local measures. Analgesicsprovide temporary relief of pain (usually for about 1 to7 days) until the causative factors have been broughtunder control. In the case of pulpitis, intra-osseousinfection or abscess, reliance on analgesics alone isusually inappropriate.Similarly the pain and discomfort associated with acuteproblems of the oral mucosa (e.g. acute herpetic gingivostomatitis,erythema multiforme) may be relieved bybenzydamine (p. 543) or topical anaesthetics until thecause of the mucosal disorder has been dealt with.However, where a child is febrile, the antipyretic actionof paracetamol (p. 200) or ibuprofen (p. 503) is oftenhelpful.The choice of an analgesic for dental purposes should bebased on its suitability for the child. Most dental pain isrelieved effectively by non-steroidal anti-inflammatorydrugs (NSAIDs) e.g. ibuprofen (section 10.1.1). Paracetamolhas analgesic and antipyretic effects but noanti-inflammatory effect.Opioid analgesics (section 4.7.2) such as dihydrocodeineact on the central nervous system and are traditionallyused for moderate to severe pain. However,opioid analgesics are relatively ineffective in dentalpain and their side-effects can be unpleasant.Combining a non-opioid with an opioid analgesic canprovide greater relief of pain than either analgesic givenalone. However, this applies only when an adequatedose of each analgesic is used. Most combinationanalgesic preparations have not been shown to providegreater relief of pain than an adequate dose of the nonopioidcomponent given alone. Moreover, combinationpreparations have the disadvantage of an increasednumber of side-effects.Any analgesic given before a dental procedure shouldhave a low risk of increasing postoperative bleeding. Inthe case of pain after the dental procedure, taking ananalgesic before the effect of the local anaesthetic hasworn off can improve control. Postoperative analgesiawith ibuprofen is usually continued for about 24 to 72hours.Dysmenorrhoea Paracetamol or a NSAID (section10.1.1) will generally provide adequate relief of painfrom dysmenorrhoea. Alternatively use of a combinedhormonal contraceptive in adolescent girls may preventthe pain.4.7.1 Non-opioid analgesicsand compound analgesicpreparationsParacetamol has analgesic and antipyretic propertiesbut no demonstrable anti-inflammatory activity; unlikeopioid analgesics, it does not cause respiratory depressionand is less irritant to the stomach than the NSAIDs.Overdosage with paracetamol is particularly dangerousas it may cause hepatic damage which is sometimes notapparent for 4 to 6 days (see Emergency Treatment ofPoisoning, p. 26).Non-steroidal anti-inflammatory analgesics(NSAIDs, section 10.1.1) are particularly useful for thetreatment of children with chronic disease accompaniedby pain and inflammation. Some of them are also usedin the short-term treatment of mild to moderate painincluding transient musculoskeletal pain but paracetamolis now often preferred. They are also suitable for therelief of pain in dysmenorrhoea and to treat pain causedby secondary bone tumours, many of which producelysis of bone and release prostaglandins (see Prescribingin Palliative Care, p. 17). Due to an association withReye’s syndrome (section 2.9), aspirin should beavoided in children under 16 years except in Kawasakisyndrome or for its antiplatelet action (section 2.9).NSAIDs are also used for peri-operative analgesia (section15.1.4.2).Dental and orofacial pain Most dental pain isrelieved effectively by NSAIDs (section 10.1.1).Paracetamol is less irritant to the stomach than NSAIDs.Paracetamol is a suitable analgesic for children; sugarfreeversions can be requested by specifying ‘sugar-free’on the prescription.For further information on the management of dentaland orofacial pain, see above.4 Central nervous system

200 4.7.1 Non-opioid analgesics BNFC 2011–20124 Central nervous systemCompound analgesic preparationsCompound analgesic preparations that contain a simpleanalgesic (such as aspirin or paracetamol) with anopioid component reduce the scope for effective titrationof the individual components in the management ofpain of varying intensity.Compound analgesic preparations containing paracetamolor aspirin with a low dose of an opioid analgesic(e.g. 8 mg of codeine phosphate per compound tablet)may be used in older children but the advantages havenot been substantiated. The low dose of the opioid maybe enough to cause opioid side-effects (in particular,constipation) and can complicate the treatment of overdosage(see p. 28) yet may not provide significantadditional relief of pain.A full dose of the opioid component (e.g. 60 mg codeinephosphate) in compound analgesic preparations effectivelyaugments the analgesic activity but is associatedwith the full range of opioid side-effects (includingnausea, vomiting, severe constipation, drowsiness, respiratorydepression, and risk of dependence on long-termadministration). For details of the side-effects of opioidanalgesics, see p. 203.PARACETAMOL(Acetaminophen)Cautions alcohol dependence; max. daily infusiondose 3 g in patients with hepatocellular insufficiency,chronic alcoholism, chronic malnutrition, or dehydration;high risk of liver toxicity with high doses;interactions: Appendix 1 (paracetamol)Hepatic impairment dose-related toxicity—avoidlarge doses; see also CautionsRenal impairment increase infusion dose interval toevery 6 hours if estimated glomerular filtration rateless than 30 mL/minute/1.73m 2Pregnancy not known to be harmfulBreast-feeding amount too small to be harmfulSide-effects side-effects rare, but rashes, blood disorders(including thrombocytopenia, leucopenia,neutropenia) reported; hypotension, flushing, andtachycardia also reported on infusion; important:liver damage (and less frequently renal damage) followingoverdosage, see Emergency Treatment ofPoisoning, p. 26Licensed use not licensed for use in children under 2months by mouth; not licensed for use in pretermneonates by intravenous infusion; doses for severesymptoms not licensed; co-codamol 8/500 tabletsnot licensed for use in children under 12 yearsIndication and dosePain; pyrexia with discomfort. By mouthNeonate 28–32 weeks postmenstrual age20 mg/kg as a single dose then 10–15 mg/kgevery 8–12 hours as necessary; max. 30 mg/kgdaily in divided dosesNeonate over 32 weeks postmenstrual age20 mg/kg as a single dose then 10–15 mg/kgevery 6–8 hours as necessary; max. 60 mg/kgdaily in divided dosesChild 1–3 months 30–60 mg every 8 hours asnecessaryChild 3–12 months 60–120 mg every 4–6 hours(max. 4 doses in 24 hours)Child 1–6 years 120–250 mg every 4–6 hours(max. 4 doses in 24 hours)Child 6–12 years 250–500 mg every 4–6 hours(max. 4 doses in 24 hours)Child 12–18 years 500 mg every 4–6 hours. By rectumNeonate 28–32 weeks postmenstrual age20 mg/kg as a single dose then 15 mg/kg every 12hours as necessary; max. 30 mg/kg daily individed dosesNeonate over 32 weeks postmenstrual age30 mg/kg as a single dose then 20 mg/kg every 8hours as necessary; max. 60 mg/kg daily individed dosesChild 1–3 months 30–60 mg every 8 hours asnecessaryChild 3–12 months 60–125 mg every 4–6 hoursas necessary (max. 4 doses in 24 hours)Child 1–5 years 125–250 mg every 4–6 hours asnecessary (max. 4 doses in 24 hours)Child 5–12 years 250–500 mg every 4–6 hours asnecessary (max. 4 doses in 24 hours)Child 12–18 years 500 mg every 4–6 hours. By intravenous infusion over 15 minutesPreterm neonate over 32 weeks postmenstrualage 7.5 mg/kg every 8 hours; max. 25 mg/kg dailyNeonate 10 mg/kg every 4–6 hours; max. 30 mg/kg dailyChild body-weight under 50 kg 15 mg/kg every4–6 hours; max. 60 mg/kg dailyChild body-weight over 50 kg 1 g every 4–6hours; max. 4 g dailySevere postoperative pain (but see Cautions). By mouthChild 1 month–6 years 20–30 mg/kg as a singledose then 15–20 mg/kg every 4–6 hours; max.90 mg/kg daily in divided dosesChild 6–12 years 20–30 mg/kg (max. 1 g) as asingle dose then 15–20 mg/kg every 4–6 hours;max. 90 mg/kg (max. 4 g) daily in divided dosesChild 12–18 years 1 g every 4–6 hours (max. 4doses in 24 hours). By rectumChild 1–3 months 30 mg/kg as a single dose then15–20 mg/kg every 4–6 hours; max. 90 mg/kgdaily in divided dosesChild 3 months–6 years 30–40 mg/kg as a singledose then 15–20 mg/kg every 4–6 hours; max.90 mg/kg daily in divided dosesChild 6–12 years 30–40 mg/kg (max. 1 g) as asingle dose then 15–20 mg/kg every 4–6 hours;max. 90 mg/kg (max. 4 g) daily in divided dosesChild 12–18 years 1 g every 4–6 hours (max. 4doses in 24 hours)

BNFC 2011–2012 4.7.1 Non-opioid analgesics 201Post-immunisation pyrexia in infants (see alsop. 600). By mouthChild 2–3 months 60 mg as a single doserepeated once after 4–6 hours if necessaryParacetamol (Non-proprietary)Tablets and capletsA 1 , paracetamol 500 mg, netprice 16-tab pack = 17p, 32-tab pack = £1.00, 100-tabpack = £1.44. Label: 29, 30Brands include Panadol c D,Dental prescribing on NHS Paracetamol Tablets may beprescribedCapsulesA 1 , paracetamol 500 mg, net price 32-cappack = £1.00, 100-cap pack = £3.34. Label: 29, 30Brands include Panadol Capsules c DSoluble tablets (= Dispersible tablets)A 2 , paracetamol500 mg, net price 60-tab pack = £4.39.Label: 13, 29, 30Brands include Panadol Soluble c D (contains Na + 18.6 mmol/tablet), Paracetamol Seltzer c (contains Na + 16.9 mmol/tablet)Dental prescribing on NHS Paracetamol Soluble Tablets500 mg may be prescribedPaediatric soluble tablets (= Paediatric dispersibletablets), paracetamol 120 mg, net price 16-tab pack =89p. Label: 13, 30Brands include Disprol c Soluble Paracetamol DOral suspension 120 mg/5 mL (= Paediatric Mixture),paracetamol 120 mg/5 mL, net price 100 mL =72p, 150 mL = 84p, 200 mL = £1.05, 500 mL = £2.00.Label: 30Note BP directs that when Paediatric Paracetamol OralSuspension or Paediatric Paracetamol Mixture is prescribedParacetamol Oral Suspension 120 mg/5 mL should be dispensed;sugar-free versions can be ordered by specifying‘sugar-free’on the prescriptionBrands include Calpol c Paediatric, Calpol c Paediatric sugarfree,Disprol c Paediatric, Medinol c Paediatric sugar-free,Panadol c sugar-freeOral suspension 250 mg/5 mL (= Mixture), paracetamol250 mg/5 mL, net price 100 mL = 82p,200 mL = £1.10, 500 mL = £3.29. Label: 30Brands include Calpol c 6 Plus D, Medinol c Over 6 DDental prescribing on NHS Paracetamol Oral Suspensionmay be prescribedSuppositories, paracetamol 60 mg, net price 10 =£9.96; 125 mg, 10 = £11.50; 250 mg, 10 = £23.00;500 mg, 10 = £36.80; 1 g, 12 = £60.00. Label: 30Brands include Alvedon cNote Other strengths available from ‘special-order’ manufacturersor specialist importing companies, see p. 809Perfalgan c (Bristol-Myers Squibb) TAIntravenous infusion, paracetamol 10 mg/mL, netprice 50-mL vial = £1.39, 100-mL vial = £1.52Administration give undiluted or dilute to a concentration of1 mg/mL in Glucose 5% or Sodium Chloride 0.9%; use within 1hour of dilutionWith codeineFor prescribing information on codeine, see p. 204.When co-codamol tablets, dispersible (or effervescent)tablets, or capsules are prescribed and nostrength is stated, tablets, dispersible (or effervescent)tablets, or capsules, respectively, containingcodeine phosphate 8 mg and paracetamol 500 mgshould be dispensed.2Co-codamol 8/500 (Non-proprietary) AUTablets, co-codamol 8/500 (codeine phosphate 8 mg,paracetamol 500 mg), net price 30-tab pack = £1.25,32-tab pack = 50p, 100-tab pack = £1.35. Label: 29, 30DosePain, pyrexia. By mouthChild 6–12 years ½–1 tablet every 4–6 hours; max. 4tablets dailyChild 12–18 years 1–2 tablets every 4–6 hours; max. 8tablets dailyEffervescent or dispersible tablets, co-codamol 8/500 (codeine phosphate 8 mg, paracetamol 500 mg),net price 32-tab pack = £1.00, 100-tab pack = £4.32.Label: 13, 29, 30Brands include Paracodol c DNote The Drug Tariff allows tablets of co-codamol labelled‘dispersible’ to be dispensed against an order for ‘effervescent’and vice versaDosePain, pyrexia. By mouthChild 6–12 years ½–1 tablet in water every 4–6 hours;max. 4 tablets dailyChild 12–18 years 1–2 tablets in water every 4–6 hours;max. 8 tablets dailyCapsules, co-codamol 8/500 (codeine phosphate8 mg, paracetamol 500 mg), net price 10-cap pack =£1.10, 20-cap pack = £1.71. Label: 29, 30Brands include Paracodol c DDosePain, pyrexia. By mouthChild 12–18 years 1–2 capsules every 4 hours; max. 8capsules daily4 Central nervous systemPanadol OA c (GSK) ATablets, f/c, paracetamol 1 g, net price 100-tab pack= £3.30. Label: 30DosePain, pyrexia. By mouthChild 12–18 years 1 tablet up to 4 times daily, not moreoften than every 4 hours1. Can be sold to the public provided packs contain no morethan 32 capsules or tablets; pharmacists can sell multiplepacks up to a total quantity of 100 capsules or tablets injustifiable circumstances; for details see Medicines, Ethicsand Practice, London, Pharmaceutical Press (alwaysconsult latest edition)2. Can be sold to the public under certain circumstances; forexemptions see Medicines, Ethics and Practice, London,Pharmaceutical Press (always consult latest edition)With dihydrocodeine tartrate 10 mgFor prescribing information on dihydrocodeine, seep. 205See notes, p. 200When co-dydramol tablets are prescribed and no strength isstated, tablets containing dihydrocodeine tartrate 10 mg andparacetamol 500 mg should be dispensedCo-dydramol (Non-proprietary) AUTablets, scored, co-dydramol 10/500 (dihydrocodeinetartrate 10 mg, paracetamol 500 mg), net price30-tab pack = £1.21. Label: 29, 30DoseMild to moderate pain. By mouthChild 12–18 years 1–2 tablets every 4–6 hours; max. 8tablets daily

202 4.7.2 Opioid analgesics BNFC 2011–20124 Central nervous systemWith dihydrocodeine tartrate 20 or 30 mgSee warnings and notes, p. 200When co-dydramol tablets are prescribed and no strength isstated, tablets containing dihydrocodeine tartrate 10 mg andparacetamol 500 mg should be dispensedRemedeine c (Napp) AUTablets, paracetamol 500 mg, dihydrocodeine tartrate20 mg, net price 112-tab pack = £10.57. Label: 2, 29,30DoseSevere pain. By mouthChild 12–18 years 1–2 tablets every 4–6 hours; max. 8tablets dailyForte tablets, paracetamol 500 mg, dihydrocodeinetartrate 30 mg, net price 56-tab pack = £6.53. Label: 2,29, 30DoseSevere pain. By mouthChild 12–18 years 1–2 tablets every 4–6 hours; max. 8tablets dailyWith tramadolFor prescribing information on tramadol, see section4.7.2Tramacet c (Grünenthal) ATablets, f/c, yellow, tramadol hydrochloride 37.5 mg,paracetamol 325 mg, net price 60-tab pack = £9.68.Label: 2, 25, 29, 30DoseModerate to severe pain. By mouthChild 12–18 years 2 tablets not more often than every 6hours; max. 8 tablets dailyEffervescent tablets, pink, tramadol hydrochloride37.5 mg, paracetamol 325 mg, net price 60-tab pack =£9.68. Label: 2, 13, 29, 30 (contains Na + 7.8 mmol/tablet)DoseModerate to severe pain. By mouthChild 12–18 years 2 tablets not more often than every 6hours; max. 8 tablets dailyWith antiemeticsMigraleve c (McNeil) UTablets, all f/c, pink tablets, buclizine hydrochloride6.25 mg, paracetamol 500 mg, codeine phosphate8 mg; yellow tablets, paracetamol 500 mg, codeinephosphate 8 mg, net price 48-tab Migraleve A (32pink + 16 yellow) = £4.81; 48 pink (Migraleve Pink)=£5.24. Label: 2, (Migraleve Pink), 17, 30DoseTreatment of acute migraine. By mouthChild under 10 years only under close medical supervisionChild 10–14 years 1 pink tablet at onset of attack, or if itis imminent, then 1 yellow tablet every 4 hours ifnecessary; max. 1 pink and 3 yellow tablets in 24 hoursChild 14–18 years 2 pink tablets at onset of attack, or ifit is imminent, then 2 yellow tablets every 4 hours ifnecessary; max. in 24 hours 2 pink and 6 yellowParamax c (Sanofi-Aventis) ATablets, scored, paracetamol 500 mg, metoclopramidehydrochloride 5 mg, net price 42-tab pack =£9.64. Label: 17, 30Sachets, effervescent powder, sugar-free, the contentsof 1 sachet = 1 tablet; to be dissolved in ¼tumblerful of liquid before administration, net price42-sachet pack = £12.52. Label: 13, 17, 30DoseTreatment of acute migraine. By mouthChild 12–18 years 1 at onset of attack then 1 every 4hours when necessary to max. of 3 in 24 hours (max.dose of metoclopramide 500 micrograms/kg daily)Important Metoclopramide can cause severe extrapyramidaleffects (for further details, see p. 192 andp. 196)4.7.2 Opioid analgesicsOpioid analgesics are usually used to relieve moderateto severe pain particularly of visceral origin. Repeatedadministration may cause tolerance, but this is no deterrentin the control of pain in terminal illness, for guidelinessee Prescribing in Palliative Care, p. 17. Regularuse of a potent opioid may be appropriate for certaincases of chronic non-malignant pain; treatment shouldbe supervised by a specialist and the child should beassessed at regular intervals.Cautions Opioids should be used with caution inchildren with impaired respiratory function and asthma(avoid during an acute attack), hypotension, shock,obstructive or inflammatory bowel disorders, diseasesof the biliary tract, and convulsive disorders. A reduceddose is recommended in hypothyroidism or adrenocorticalinsufficiency. Repeated use of opioid analgesics isassociated with the development of psychological andphysical dependence; although this is rarely a problemwith therapeutic use, caution is advised if prescribing forpatients with a history of drug dependence. Avoidabrupt withdrawal after long-term treatment. Transdermalpreparations (fentanyl or buprenorphine patches)are not suitable for acute pain or in those children whoseanalgesic requirements are changing rapidly, becausethe long time to steady state prevents rapid titration ofthe dose.Palliative care In the control of pain in terminal illness,the cautions listed above should not necessarily be adeterrent to the use of opioid analgesics.Contra-indications Opioid analgesics should beavoided in children with acute respiratory depression,and when there is a risk of paralytic ileus. They are alsocontra-indicated in conditions associated with raisedintracranial pressure, and in head injury (opioid analgesicsinterfere with pupillary responses vital for neurologicalassessment). Comatose children should not betreated with opioid analgesics.Hepatic impairment Opioid analgesics may precipitatecoma in children with hepatic impairment; avoiduse or reduce dose.Renal impairment The effects of opioid analgesia areincreased and prolonged and there is increased cerebralsensitivity when children with renal impairment aretreated with opioid analgesics; avoid use or reduce dose.

BNFC 2011–2012 4.7.2 Opioid analgesics 203Pregnancy Respiratory depression and withdrawalsymptoms can occur in the neonate if opioid analgesicsare used during delivery; also gastric stasis and inhalationpneumonia has been reported in the mother ifopioid analgesics are used during labour.Side-effects Opioid analgesics share many sideeffects,although qualitative and quantitative differencesexist. The most common side-effects include nauseaand vomiting (particularly in initial stages), constipation,dry mouth and biliary spasm; larger doses producemuscle rigidity, hypotension and respiratory depression(for reversal of opioid-induced respiratory depression,see section 15.1.7); neonates, particularly if preterm,may be more susceptible. Other common side-effectsof opioid analgesics include bradycardia, tachycardia,palpitation, oedema, postural hypotension, hallucinations,vertigo, euphoria, dysphoria, mood changes, dependence,dizziness, confusion, drowsiness, sleep disturbances,headache, sexual dysfunction, difficulty withmicturition, urinary retention, ureteric spasm, miosis,visual disturbances, sweating, flushing, rash, urticaria,and pruritus. Overdosage: see Emergency Treatment ofPoisoning, p. 28.Long-term use of opioid analgesics can lead to hypogonadismand adrenal insufficiency in both boys andgirls. This is thought to be dose related and can lead toamenorrhoea, reduced libido, infertility, depression, anderectile dysfunction. Long-term use of opioid analgesicshas also been associated with a state of abnormal painsensitivity (hyperalgesia). Pain associated with hyperalgesiais usually distinct from pain associated with diseaseprogression or breakthrough pain, and is oftenmore diffuse and less defined. Treatment of hyperalgesiainvolves reducing the dose of opioid medication orswitching therapy; cases of suspected hyperalgesiashould be referred to a specialist pain team.Interactions See Appendix 1 (opioid analgesics)(important: special hazard with pethidine and possiblyother opioids and MAOIs).Skilled tasks Drowsiness may affect performance ofskilled tasks (e.g. driving); effects of alcohol enhanced.Driving at the start of therapy with opioid analgesics,and following dose changes, should be avoided.Strong opioids Morphine remains the most valuableopioid analgesic for severe pain although it frequentlycauses nausea and vomiting. It is the standard againstwhich other opioid analgesics are compared. In additionto relief of pain, morphine also confers a state ofeuphoria and mental detachment.Morphine is the opioid of choice for the oral treatmentof severe pain in palliative care. It is given regularlyevery 4 hours (or every 12 or 24 hours as modifiedreleasepreparations). For guidelines on dosage adjustmentin palliative care, see p. 17.Buprenorphine has both opioid agonist and antagonistproperties and may precipitate withdrawal symptoms,including pain, in children dependent on other opioids.It has abuse potential and may itself cause dependence.It has a much longer duration of action than morphineand sublingually is an effective analgesic for 6 to 8hours. Unlike most opioid analgesics, the effects ofbuprenorphine are only partially reversed by naloxone.It is used rarely in children.Diamorphine (heroin) is a powerful opioid analgesic. Itmay cause less nausea and hypotension than morphine.In palliative care the greater solubility of diamorphineallows effective doses to be injected in smaller volumesand this is important in the emaciated child.Diamorphine is sometimes given by the intranasal routeto treat acute pain in children, for example, in accidentand emergency units; however, as yet, there is limitedsafety and efficacy data to support this practice.Alfentanil, fentanyl and remifentanil are used byinjection for intra-operative analgesia (section15.1.4.3). Fentanyl is available in a transdermal drugdelivery system as a self-adhesive patch which is changedevery 72 hours.Methadone is less sedating than morphine and acts forlonger periods. In prolonged use, methadone should notbe administered more often than twice daily to avoid therisk of accumulation and opioid overdosage. Methadonemay be used instead of morphine when excitation (orexacerbation of pain) occurs with morphine. Methadonemay also be used to treat children with neonatal abstinencesyndrome (section 4.10).Papaveretum should not be used in children; morphineis easier to prescribe and less prone to error with regardto the strength and dose.Pethidine produces prompt but short-lasting analgesia;it is less constipating than morphine, but even in highdoses is a less potent analgesic. Its use in children is notrecommended. Pethidine is used for analgesia in labour;however, other opioids, such as morphine or diamorphine,are often preferred for obstetric pain.Tramadol is used in older children and producesanalgesia by two mechanisms: an opioid effect and anenhancement of serotonergic and adrenergic pathways.It has fewer of the typical opioid side-effects (notably,less respiratory depression, less constipation and lessaddiction potential); psychiatric reactions have beenreported.Weak opioids Codeine is used for the relief of mild tomoderate pain but is too constipating for long-term use.Dihydrocodeine has an analgesic efficacy similar tothat of codeine; doses may be given every 4 hours.Dose Doses of opioids may need to be adjustedindividually according to the degree of analgesia andside-effects; response to opioids varies widely, particularlyin the neonatal period. Opioid overdosage can haveserious consequences and the dose should be calculatedand checked with care.Postoperative analgesia A combination of opioidand non-opioid analgesics is used to treat postoperativepain (section 15.1.4.2). The use of intra-operativeopioids affects the prescribing of postoperative analgesics.A postoperative opioid analgesic should be givenwith care since it may potentiate any residual respiratorydepression (for the treatment of opioid-inducedrespiratory depression, see section 15.1.7).Morphine is used most widely. Tramadol is not aseffective in severe pain as other opioid analgesics.Buprenorphine may antagonise the analgesic effect ofpreviously administered opioids and is generally notrecommended. Pethidine is unsuitable for post-operativepain because it is metabolised to norpethidinewhich may accumulate, particularly in neonates and inrenal impairment; norpethidine stimulates the centralnervous system and may cause convulsions.4 Central nervous system

204 4.7.2 Opioid analgesics BNFC 2011–20124 Central nervous systemOpioids are also given epidurally [unlicensed route] inthe postoperative period but are associated with sideeffectssuch as pruritus, urinary retention, nausea andvomiting; respiratory depression can be delayed, particularlywith morphine.For details of patient-controlled analgesia (PCA) andnurse-controlled analgesia (NCA) to relieve postoperativepain, consult hospital protocols. Formulationsspecifically designed for PCA are available (Pharma-Ject c Morphine Sulphate).Dental and orofacial pain Opioid analgesics arerelatively ineffective in dental pain. Like other opioids,dihydrocodeine often causes nausea and vomitingwhich limits its value in dental pain; if taken for morethan a few doses it is also liable to cause constipation.Dihydrocodeine is not very effective in postoperativedental pain.For the management of dental and orofacial pain, seep. 199.Pain management and opioid dependenceAlthough caution is necessary, patients who are dependenton opioids or have a history of drug dependencemay be treated with opioid analgesics when there is aclinical need. Treatment with opioid analgesics in thispatient group should normally be carried out with theadvice of specialists. However, doctors do not require aspecial license to prescribe opioid analgesics to patientswith opioid dependence for relief of pain due to organicdisease or injury.Dependence and withdrawal Psychological dependencerarely occurs when opioids are used for painrelief but tolerance can develop during long-term treatment;they should be withdrawn gradually to avoidabstinence symptoms. For information on the treatmentof neonatal abstinence syndrome, see section 4.10.BUPRENORPHINECautions see notes above; also impaired consciousness;effects only partially reversed by naloxoneContra-indications see notes above; also myastheniagravisHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding present in low levels in breast milk—monitor neonate for drowsiness, adequate weightgain, and developmental milestonesSide-effects see notes above; can induce mild withdrawalsymptoms in children dependent on opioids;also diarrhoea, abdominal pain, anorexia, dyspepsia;vasodilatation; dyspnoea; paraesthesia, asthenia, fatigue,agitation, anxiety; less commonly flatulence,taste disturbance, hypertension, syncope, hypoxia,wheezing, cough, restlessness, depersonalisation,dysarthria, impaired memory, hypoaesthesia, tremor,influenza-like symptoms, pyrexia, rhinitis, rigors,muscle cramp, myalgia, tinnitus, dry eye, and dry skin;rarely paralytic ileus, dysphagia, diverticulitis,impaired concentration, and psychosis; very rarelyretching, hyperventilation, hiccups, and muscle fasciculationLicensed use sublingual tablets not licensed for usein children under 6 years; injection not licensed foruse in children under 6 monthsIndication and doseModerate to severe pain. By sublingual administrationChild body-weight 16–25 kg 100 microgramsevery 6–8 hoursChild body-weight 25–37.5 kg 100–200 microgramsevery 6–8 hoursChild body-weight 37.5–50 kg 200–300 microgramsevery 6–8 hoursChild body-weight over 50 kg 200–400 microgramsevery 6–8 hours. By intramuscular or by slow intravenous injectionChild 6 months–12 years 3–6 micrograms/kgevery 6–8 hours, max. 9 micrograms/kgChild 12–18 years 300–600 micrograms every 6–8 hoursAdministration for administration by mouth, tabletsmay be halvedTemgesic c (Reckitt Benckiser) 3Tablets (sublingual), buprenorphine (as hydrochloride),200 micrograms, net price 50-tab pack =£5.13; 400 micrograms, 50-tab pack = £10.26. Label: 2,26Injection, buprenorphine (as hydrochloride)300 micrograms/mL, net price 1-mL amp = 48pCODEINE PHOSPHATECautions see notes above; also cardiac arrhythmias;myasthenia gravis; acute abdomen; gallstonesVariation in metabolism The capacity to metabolise codeinecan vary considerably between individuals and lead toeither reduced therapeutic effect or marked increase in sideeffectsContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding amount usually too small to beharmful; however, mothers vary considerably in theircapacity to metabolise codeine—risk of morphineoverdose in infantSide-effects see notes above; also abdominal pain,anorexia, seizures, malaise, hypothermia, antidiureticeffect, and muscle fasciculation; pancreatitis alsoreportedLicensed use tablets not licensed for use in children;injection not licensed for use in children under 1yearIndication and doseMild to moderate pain. By mouth or by rectum or by subcutaneousinjection or by intramuscular injectionNeonate 0.5–1 mg/kg every 4–6 hoursChild 1 month–12 years 0.5–1 mg/kg every 4–6hours, max. 240 mg dailyChild 12–18 years 30–60 mg every 4–6 hours,max. 240 mg daily

BNFC 2011–2012 4.7.2 Opioid analgesics 205Codeine Phosphate (Non-proprietary)Tablets A, codeine phosphate 15 mg, net price 28-tab pack = £1.14; 30 mg, 28-tab pack = £1.22; 60 mg,28-tab pack = £1.84. Label: 2Syrup A, codeine phosphate 25 mg/5 mL, net price100 mL = 93p. Label: 2Injection 2, codeine phosphate 60 mg/mL, netprice 1-mL amp = £2.44With paracetamolSection 4.7.1DIAMORPHINE HYDROCHLORIDE(Heroin Hydrochloride)Cautions see notes above; also severe diarrhoea; toxicpsychosis, CNS depression; severe cor pulmonaleContra-indications see notes above; also delayedgastric emptying; phaeochromocytomaHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding therapeutic doses unlikely to affectinfant; withdrawal symptoms in infants of dependentmothers; breast-feeding not best method of treatingdependence in offspringSide-effects see notes above; also anorexia, tastedisturbance; syncope; asthenia, raised intracranialpressure; myocardial infarction also reportedLicensed use intranasal route not licensedIndication and doseAcute or chronic pain. By mouthChild 1 month–12 years 100–200 micrograms/kg (max. 10 mg) every 4 hours, adjusted accordingto responseChild 12–18 years 5–10 mg every 4 hours,adjusted according to response. By intravenous administrationNeonate (ventilated) initially by intravenousinjection over 30 minutes, 50 micrograms/kg thenby continuous intravenous infusion, 15 micrograms/kg/hour,adjusted according to responseNeonate (non-ventilated) by continuous intravenousinfusion 2.5–7 micrograms/kg/hour,adjusted according to responseChild 1 month–12 years by continuous intravenousinfusion 12.5–25 micrograms/kg/hour,adjusted according to response. By intravenous injectionChild 1–3 months 20 micrograms/kg every 6hours, adjusted according to responseChild 3–6 months 25–50 micrograms/kg every 6hours, adjusted according to responseChild 6–12 months 75 micrograms/kg every 4hours, adjusted according to responseChild 1–12 years 75–100 micrograms/kg (max.5 mg) every 4 hours, adjusted according toresponseChild 12–18 years 2.5–5 mg every 4 hours,adjusted according to response. By continuous subcutaneous infusionSee Prescribing in Palliative Care, p. 17. By subcutaneous or by intramuscular injectionChild 12–18 years 5 mg every 4 hours, adjustedaccording to responseAcute pain in an emergency setting; shortpainful procedures. Intranasally (but see p. 203)Child over 10 kg 100 micrograms/kg, max. 10 mgAdministration for intravenous infusion, dilute inGlucose 5% or Sodium Chloride 0.9%; Glucose 5% ispreferableFor intranasal administration, diamorphine powdershould be dissolved in sufficient volume of Water forInjections to provide the requisite dose in 0.2 mL ofsolution; use solution immediately after preparationDiamorphine (Non-proprietary) 2Tablets, diamorphine hydrochloride 10 mg, net price100-tab pack = £16.42. Label: 2Injection, powder for reconstitution, diamorphinehydrochloride, net price 5-mg amp = £2.57, 10-mgamp = £3.59, 30-mg amp = £3.82, 100-mg amp =£9.34, 500-mg amp = £42.07Extemporaneous formulations available seeExtemporaneous Preparations, p. 6DIHYDROCODEINE TARTRATECautions see notes above; also pancreatitis; severe corpulmonaleContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding use only if potential benefit outweighsriskSide-effects see notes above; also paralytic ileus,abdominal pain, diarrhoea, seizures, and paraesthesiaLicensed use most preparations not licensed for usein children under 4 yearsIndication and doseModerate to severe pain. By mouth or by intramuscular injection or bysubcutaneous injectionChild 1–4 years 500 micrograms/kg every 4–6hoursChild 4–12 years 0.5–1 mg/kg (max. 30 mg)every 4–6 hoursChild 12–18 years 30 mg (max. 50 mg by intramuscularor deep subcutaneous injection) every 4–6 hoursDihydrocodeine (Non-proprietary)Tablets A, dihydrocodeine tartrate 30 mg, net price28-tab pack = £1.58. Label: 2Dental prescribing on NHS Dihydrocodeine Tablets 30 mgmay be prescribedOral solution A, dihydrocodeine tartrate 10 mg/5 mL, net price 150 mL = £3.50. Label: 2Injection 2, dihydrocodeine tartrate 50 mg/mL, netprice 1-mL amp = £3.174 Central nervous system

206 4.7.2 Opioid analgesics BNFC 2011–20124 Central nervous systemDF 118 Forte c (Martindale) ATablets, dihydrocodeine tartrate 40 mg, net price 100-tab pack = £11.51. Label: 2DoseSevere pain. By mouthChild 12–18 years 40–80 mg 3 times daily; max. 240 mgdailyModified releaseDHC Continus c (Napp) ATablets, m/r, dihydrocodeine tartrate 60 mg, net price56-tab pack = £5.18; 90 mg, 56-tab pack = £8.66;120 mg, 56-tab pack = £10.89. Label: 2, 25DoseChronic severe pain. By mouthChild 12–18 years 60–120 mg every 12 hoursWith paracetamolSection 4.7.1FENTANYLCautions see notes above; also diabetes mellitus,impaired consciousness, cerebral tumour, myastheniagravis, see also Transdermal Fentanyl, belowContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding monitor infant for opioid-inducedside-effectsSide-effects see notes above; also abdominal pain,dyspepsia, diarrhoea, gastro-oesophageal reflux disease,stomatitis, anorexia, hypertension, vasodilatation,dyspnoea, aesthenia, myoclonus, anxiety, tremor,appetite changes, rhinitis, pharyngitis, paraesthesia,application-site reactions; less commonly ileus, flatulence,hypoventilation, impaired concentration,impaired coordination, amnesia, speech disorder,malaise, seizure, pyrexia, thirst, blood disorders(including thrombocytopenia), chills; rarely hiccups,very rarely arrhythmia, apnoea, haemoptysis, ataxia,delusions, bladder painIndication and doseSevere chronic pain. By transdermal routeChild 2–16 years currently treated with strongopioid analgesic, initial dose based on previous 24-hour opioid requirement (consult product literature)Child 16–18 years child not currently treatedwith strong opioid analgesic (but see TransdermalFentanyl, below), one ‘12’ or ‘25 micrograms/hour’patch replaced after 72 hours; child currentlytreated with strong opioid analgesic, initial dosebased on previous 24-hour opioid requirement(consult product literature)Dose adjustment When starting, evaluation of theanalgesic effect should not be made before the systemhas been worn for 24 hours (to allow for the gradualincrease in plasma-fentanyl concentration)—previousanalgesic therapy should be phased out gradually fromtime of first patch application; if necessary dose shouldbe adjusted at 48–72-hour intervals in steps of 12–25 micrograms/hour. More than one patch may be usedat a time (but applied at same time to avoid confusion)—consider additional or alternative analgesic therapy ifdose required exceeds 300 micrograms/hour (important:it may take up to 25 hours for the plasma-fentanylconcentration to decrease by 50%—replacement opioidtherapy should be initiated at a low dose and increasedgradually).Long duration of action In view of the long duration ofaction, children who have had severe side-effects shouldbe monitored for up to 24 hours after patch removalBreakthrough pain and premedication analgesia,see under preparation belowPeri-operative analgesia section 15.1.4.3Conversion (from oral morphine to transdermal fentanyl),see Prescribing in Palliative Care, p. 18Administration For patches, apply to dry, non-irritated,non-irradiated, non-hairy skin on torso or upperarm, removing after 72 hours and siting replacementpatch on a different area (avoid using the same areafor several days).LozengesActiq c (Flynn) 2Lozenge, (with oromucosal applicator), fentanyl (ascitrate) 200 micrograms, net price 3 = £17.52, 30 =£175.16; 400 micrograms, 3 = £17.52, 30 = £175.16;600 micrograms, 3 = £17.52, 30 = £175.16; 800 micrograms,3 = £17.52, 30 = £175.16; 1.2 mg, 3 = £17.52,30 = £175.16; 1.6 mg, 3 = £17.52, 30 = £175.16.Label: 2DoseBreakthrough pain. By transmucosal application (lozenge withoromucosal applicator)Child 16–18 years initially 200 micrograms (over 15minutes) repeated if necessary 15 minutes after first dose(no more than 2 dose units for each pain episode); ifadequate pain relief not achieved with 1 dose unit forconsecutive breakthrough pain episodes, increase thestrength of the dose unit until adequate pain reliefachieved with 4 lozenges or less dailyNote If more than 4 episodes of breakthrough pain eachday, adjust dose of background analgesicPatchesTransdermal fentanylFever or external heat Monitor patients using patchesfor increased side-effects if fever present (increasedabsorption possible); avoid exposing application site toexternal heat, for example a hot bath or sauna (mayalso increase absorption)Respiratory depression Risk of fatal respiratorydepression, particularly in patients not previouslytreated with a strong opioid analgesic; manufacturerrecommends use only in opioid tolerant patientsCounselling Patients and carers should be informedabout safe use, including correct administration anddisposal, strict adherence to dosage instructions, andthe symptoms and signs of opioid overdosage. Patchesshould be removed immediately in case of breathingdifficulties, marked drowsiness, confusion, dizziness, orimpaired speech, and patients and carers should seekprompt medical attention.Prescriptions Prescriptions for fentanyl patches can bewritten to show the strength in terms of the release rate andit is acceptable to write ‘Fentanyl 25 patches’ to prescribepatches that release fentanyl 25 micrograms per hour. Thedosage should be expressed in terms of the interval betweenapplying a patch and replacing it with a new one, e.g. ‘onepatch to be applied every 72 hours’. The total quantity ofpatches should be written in words and figures.Fentanyl (Non-proprietary) 2Patches, self-adhesive, fentanyl, ‘12’ patch (releasingapprox. 12 micrograms/hour for 72 hours), net price 5

BNFC 2011–2012 4.7.2 Opioid analgesics 207= £17.76; ‘25’ patch (releasing approx. 25 micrograms/hourfor 72 hours), 5 = £25.38; ‘50’ patch(releasing approx. 50 micrograms/hour for 72 hours),5 = £47.40; ‘75’ patch (releasing approx. 75 micrograms/hourfor 72 hours), 5 = £66.08; ‘100’ patch(releasing approx. 100 micrograms/hour for 72hours), 5 = £81.45. Label: 2, counselling, administrationBrands include Fentalis c , Matrifen c , Mezolar c , Osmanil c ,Tilofyl c , Victanyl cDurogesic DTrans c (Janssen) 2Patches, self-adhesive, transparent, fentanyl, ‘12’patch (releasing approx. 12 micrograms/hour for 72hours), net price 5 = £17.76; ‘25’ patch (releasingapprox. 25 micrograms/hour for 72 hours), 5 =£25.38; ‘50’ patch (releasing approx. 50 micrograms/hour for 72 hours), 5 = £47.40; ‘75’ patch (releasingapprox. 75 micrograms/hour for 72 hours), 5 =£66.08; ‘100’ patch (releasing approx. 100 micrograms/hourfor 72 hours), 5 = £81.45. Label: 2,counselling, administrationHYDROMORPHONEHYDROCHLORIDECautions see notes above; also pancreatitis; toxicpsychosisContra-indications see notes above; also acuteabdomenHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding avoid—no information availableSide-effects see notes above; also paralytic ileus,peripheral oedema, seizures, asthenia, dyskinesia,agitation, and tremorIndication and doseSevere pain in cancer. By mouthChild 12–18 years 1.3 mg every 4 hours,increased if necessary according to severity of painAdministration Swallow whole capsule or sprinklecontents on soft foodPalladone c (Napp) 2Capsules, hydromorphone hydrochloride 1.3 mg(orange/clear), net price 56-cap pack = £8.82; 2.6 mg(red/clear), 56-cap pack = £17.64. Label: 2, counselling,see belowModified releasePalladone c SR (Napp) 2Capsules, m/r, hydromorphone hydrochloride 2 mg(yellow/clear), net price 56-cap pack = £20.98; 4 mg(pale blue/clear), 56-cap pack = £28.75; 8 mg (pink/clear), 56-cap pack = £56.08; 16 mg (brown/clear),56-cap pack = £106.53; 24 mg (dark blue/clear), 56-cap pack = £159.82. Label: 2, counselling, see belowDoseSevere pain in cancer. By mouthChild 12–18 years 4 mg every 12 hours, increased ifnecessary according to severity of painCounselling Swallow whole or open capsule and sprinklecontents on soft foodMETHADONE HYDROCHLORIDECautions see notes above; also myasthenia gravis;history of cardiac conduction abnormalities, familyhistory of sudden death (ECG monitoring recommended;see also QT Interval Prolongation, below)QT interval prolongation Children with the following riskfactors for QT interval prolongation should be carefullymonitored while taking methadone: heart or liver disease,electrolyte abnormalities, or concomitant treatment withdrugs that can prolong QT interval; children requiring morethan 100 mg daily should also be monitoredContra-indications see notes above; also phaeochromocytomaHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding withdrawal symptoms in infant;breast-feeding permissible during maintenance butdose should be as low as possible and infant monitoredto avoid sedationSide-effects see notes above; also QT interval prolongation;torsade de pointes, hypothermia, restlessness,raised intracranial pressure, dysmenorrhoea, dryeyes, and hyperprolactinaemiaLicensed use not licensed for use in childrenIndication and doseNeonatal opioid withdrawal dose may vary, consultlocal guidelines. By mouthNeonate initially 100 micrograms/kg increased by50 micrograms/kg every 6 hours until symptomsare controlled; for maintenance, total daily dosethat controls symptoms given in 2 divided doses;to withdraw, reduce dose over 7–10 daysMethadone (Non-proprietary) 2Oral solution 1 mg/mL, methadone hydrochloride1 mg/mL, net price 30 mL = 62p, 50 mL = £1.04,100 mL = £1.27, 500 mL = £11.34. Label: 2Brands include Eptadone c ,Metharose c (sugar-free), Physeptone(also as sugar-free)Safe PracticeThis preparation is 2½ times the strength of MethadoneLinctus; many preparations of this strength arelicensed for opioid dependence only but some are alsolicensed for analgesia in severe painMORPHINE SALTSCautions see notes above; also pancreatitis, myastheniagravis, cardiac arrhythmias, severe cor pulmonaleContra-indications see notes above; also delayedgastric emptying, acute abdomen; heart failure secondaryto chronic lung disease; phaeochromocytomaHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding therapeutic doses unlikely to affectinfant; withdrawal symptoms in infants of dependentmothers; breast-feeding not best method of treatingdependence in offspringSide-effects see notes above; also paralytic ileus,abdominal pain, anorexia, dyspepsia, exacerbation ofpancreatitis, taste disturbance, hypertension, hypothermia,syncope, bronchospasm, inhibition of cough4 Central nervous system

208 4.7.2 Opioid analgesics BNFC 2011–20124 Central nervous systemreflex, restlessness, seizures, paraesthesia, asthenia,malaise, disorientation, excitation, agitation, delirium,raised intracranial pressure, amenorrhoea, myoclonus,muscle fasciculation, rhabdomyolysis, nystagmusLicensed use Oramorph c solution not licensed foruse in children under 1 year; Oramorph c unit dosevials not licensed for use in children under 6 years;Sevredol c tablets not licensed for use in childrenunder 3 years; MST Continus c preparationslicensed to treat children with cancer pain (agerangenot specified by manufacturer); MXL ccapsules not licensed for use in children under 1year; suppositories not licensed for use in childrenIndication and dosePain. By subcutaneous injectionNeonate initially 100 micrograms/kg every 6hours, adjusted according to responseChild 1–6 months initially 100–200 micrograms/kg every 6 hours, adjusted according to responseChild 6 months–2 years initially 100–200 micrograms/kgevery 4 hours, adjusted according toresponseChild 2–12 years initially 200 micrograms/kgevery 4 hours, adjusted according to responseChild 12–18 years initially 2.5–10 mg every 4hours, adjusted according to response. By intravenous injection over at least 5 minutesNeonate initially 50 micrograms/kg every 6 hours,adjusted according to responseChild 1–6 months initially 100 micrograms/kgevery 6 hours, adjusted according to responseChild 6 months–12 years initially 100 micrograms/kgevery 4 hours, adjusted according toresponseChild 12–18 years initially 5 mg every 4 hours,adjusted according to response. By intravenous administrationNeonate initially by intravenous injection (over atleast 5 minutes) 50 micrograms/kg then by continuousintravenous infusion 5–20 micrograms/kg/hour adjusted according to responseChild 1–6 months initially by intravenous injection(over at least 5 minutes) 100 micrograms/kgthen by continuous intravenous infusion 10–30 micrograms/kg/hour adjusted according toresponseChild 6 months–12 years initially by intravenousinjection (over at least 5 minutes) 100 micrograms/kgthen by continuous intravenous infusion20–30 micrograms/kg/hour adjusted accordingto responseChild 12–18 years initially by intravenous injection(over at least 5 minutes) 5 mg then by continuousintravenous infusion 20–30 micrograms/kg/hour adjusted according to response. By mouth or by rectumChild 1–3 months initially 50–100 micrograms/kg every 4 hours, adjusted according to responseChild 3–6 months 100–150 micrograms/kg every4 hours, adjusted according to responseChild 6–12 months 200 micrograms/kg every 4hours, adjusted according to responseChild 1–2 years initially 200–300 micrograms/kgevery 4 hours, adjusted according to responseChild 2–12 years initially 200–300 micrograms/kg (max. 10 mg) every 4 hours, adjusted accordingto responseChild 12–18 years initially 5–10 mg every 4hours, adjusted according to response. By continuous subcutaneous infusionChild 1–3 months 10 micrograms/kg/hour,adjusted according to responseChild 3 months–18 years 20 micrograms/kg/hour, adjusted according to responseNeonatal opioid withdrawal under specialistsupervision. By mouthNeonate initially 40 micrograms/kg every 4 hoursuntil symptoms controlled, increase dose ifnecessary; reduce frequency gradually over 6–10days, and stop when 40 micrograms/kg once dailyachieved; dose may vary, consult local guidelinesAdministration for continuous intravenous infusion,dilute with Glucose 5% or 10% or Sodium Chloride0.9%Neonatal intensive care, dilute 2.5 mg/kg bodyweightto a final volume of 50 mL with infusion fluid;an intravenous infusion rate of 0.1 mL/hour providesa dose of 5 micrograms/kg/hourOral solutionsNote For advice on transfer from oral solutions of morphine tomodified-release preparations of morphine, see Prescribing inPalliative Care, p. 17Morphine Oral SolutionsA or 2Oral solutions of morphine can be prescribed by writing theformula:Morphine hydrochloride 5 mgChloroform water to 5 mLNote The proportion of morphine hydrochloride may bealtered when specified by the prescriber; if above 13 mg per5 mL the solution becomes 2. For sample prescription seeControlled Drugs and Drug Dependence, p. 9. It is usual toadjust the strength so that the dose volume is 5 or 10 mL.Oramorph c (Boehringer Ingelheim)Oramorph c oral solution A, morphine sulphate10 mg/5 mL, net price 100-mL pack = £1.78; 300-mLpack = £4.95; 500-mL pack = £7.47. Label: 2Oramorph c concentrated oral solution 2, sugarfree,morphine sulphate 100 mg/5 mL, net price 30-mL pack = £4.98; 120-mL pack = £18.59 (both withcalibrated dropper). Label: 2TabletsSevredol c (Napp) 2Tablets, f/c, scored, morphine sulphate 10 mg (blue),net price 56-tab pack = £5.28; 20 mg (pink), 56-tabpack = £10.55; 50 mg (pale green), 56-tab pack =£28.02. Label: 2

BNFC 2011–2012 4.7.2 Opioid analgesics 209Modified-release 12-hourly oral preparationsMST Continus c (Napp) 2Tablets, m/r, f/c, morphine sulphate 5 mg (white), netprice 60-tab pack = £3.29; 10 mg (brown), 60-tab pack= £5.16; 15 mg (green), 60-tab pack = £9.61; 30 mg(purple), 60-tab pack = £12.40; 60 mg (orange), 60-tabpack = £24.20; 100 mg (grey), 60-tab pack = £38.30;200 mg (green), 60-tab pack = £76.62. Label: 2, 25Suspension (= sachet of granules to mix with water),m/r, pink, morphine sulphate 20 mg/sachet, net price30-sachet pack = £24.58; 30 mg/sachet, 30-sachetpack = £25.54; 60 mg/sachet, 30-sachet pack =£51.09; 100 mg/sachet, 30-sachet pack = £85.15;200 mg/sachet pack, 30-sachet pack = £170.30.Label: 2, 13Dose. By mouthEvery 12 hours, dose adjusted according to daily morphinerequirements; for further advice on determiningdose, see Prescribing in Palliative Care, p. 17; dosagerequirements should be reviewed if the brand is alteredNote Prescriptions must also specify ‘tablets’ or ‘suspension’(i.e. ‘MST Continus tablets’ or ‘MST Continus suspension’)Modified-release 24-hourly oral preparationsMXL c (Napp) 2Capsules, m/r, morphine sulphate 30 mg (light blue),net price 28-cap pack = £10.91; 60 mg (brown), 28-cappack = £14.95; 90 mg (pink), 28-cap pack = £22.04;120 mg (green), 28-cap pack = £29.15; 150 mg (blue),28-cap pack = £36.43; 200 mg (red-brown), 28-cappack = £46.15. Label: 2, counselling, see belowDose. By mouthEvery 24 hours, dose adjusted according to daily morphinerequirements; for further advice on determiningdose, see Prescribing in Palliative Care, p. 17; dosagerequirements should be reviewed if the brand is alteredCounselling Swallow whole or open capsule and sprinklecontents on soft foodNote Prescriptions must also specify ‘capsules’ (i.e. ‘MXLcapsules’)SuppositoriesMorphine (Non-proprietary) 2Suppositories, morphine hydrochloride or sulphate10 mg, net price 12 = £11.21; 15 mg, 12 = £8.85;20 mg, 12 = £33.22; 30 mg, 12 = £13.47. Label: 2Note Both the strength of the suppositories and the morphinesalt contained in them must be specified by theprescriberMorphine sulphate 5 mg suppositories available from‘special-order’ manufacturers or specialist importingcompanies, see p. 809InjectionsMorphine Sulphate (Non-proprietary) 2Injection, morphine sulphate 10, 15, 20, and 30 mg/mL, net price 1- and 2-mL amp (all) = 72p–£1.40Intravenous infusion, morphine sulphate 1 mg/mL,net price 50-mL vial = £5.00; 2 mg/mL, 50-mL vial =£5.89Injection with antiemeticFor prescribing information on cyclizine, see section4.6Caution Not recommended in palliative care, see Nausea andVomiting, p. 19Cyclimorph c (Amdipharm) 2Cyclimorph-10 c Injection, morphine tartrate 10 mg,cyclizine tartrate 50 mg/mL, net price 1-mL amp =£1.75DoseModerate to severe pain (short-term use only). By subcutaneous, intramuscular, or intravenous injectionChild 12–18 years 1 mL, repeated not more often thanevery 4 hours, max. 3 doses in any 24-hour periodCyclimorph-15 c Injection, morphine tartrate 15 mg,cyclizine tartrate 50 mg/mL, net price 1-mL amp =£1.82DoseModerate to severe pain (short-term use only). By subcutaneous, intramuscular, or intravenous injectionChild 12–18 years 1 mL, repeated not more often thanevery 4 hours, max. 3 doses in any 24-hour periodOXYCODONE HYDROCHLORIDECautions see notes above; also toxic psychosis; pancreatitisContra-indications see notes above; also acuteabdomen; delayed gastric emptying; chronic constipation;cor pulmonale; acute porphyria (section 9.8.2)Hepatic impairment avoid in moderate to severeimpairment; see also notes aboveRenal impairment avoid if estimated glomerular filtrationrate less than 10 mL/minute/1.73m 2 ; see alsonotes abovePregnancy see notes aboveBreast-feeding present in milk—avoidSide-effects see notes above; also diarrhoea, abdominalpain, anorexia, dyspepsia; bronchospasm, dyspnoea,impaired cough reflex; asthenia, anxiety; chills;muscle fasciculation; less commonly paralytic ileus,cholestasis, gastritis, flatulence, dysphagia, taste disturbance,belching, hiccups, vasodilatation, supraventriculartachycardia, syncope, amnesia,hypoaesthesia, restlessness, seizures, pyrexia, amenorrhoea,hypotonia, paraesthesia, disorientation,malaise, agitation, speech disorder, tremor, thirst, anddry skinLicensed use not licensed for use in childrenIndication and doseModerate to severe pain in palliative care (seealso Prescribing in Palliative Care, p. 17). By mouthChild 1 month–12 years initially 200 micrograms/kg(up to 5 mg) every 4–6 hours, doseincreased if necessary according to severity of painChild 12–18 years initially 5 mg every 4–6 hours,dose increased if necessary according to severityof pain4 Central nervous systemMinijet c Morphine Sulphate (UCB Pharma) 2Injection, morphine sulphate 1 mg/mL, net price 10-mL disposable syringe = £15.00Oxynorm c (Napp) 2Capsules, oxycodone hydrochloride 5 mg (orange/beige), net price 56-cap pack = £11.36; 10 mg (white/

210 4.7.2 Opioid analgesics BNFC 2011–20124 Central nervous systembeige), 56-cap pack = £22.73; 20 mg (pink/beige), 56-cap pack = £45.47. Label: 2Liquid (= oral solution), sugar-free, oxycodonehydrochloride 5 mg/5 mL, net price 250 mL = £9.66.Label: 2Concentrate (= concentrated oral solution), sugarfree,oxycodone hydrochloride 10 mg/mL, net price120 mL = £46.39. Label: 2Modified releaseOxyContin c (Napp) 2Tablets, f/c, m/r, oxycodone hydrochloride 5 mg(blue), net price 28-tab pack = £12.46; 10 mg (white),56-tab pack = £24.91; 15 mg (grey), 56-tab pack =£37.41; 20 mg (pink), 56-tab pack = £49.82; 30 mg(brown), 56-tab pack = £74.81; 40 mg (yellow), 56-tabpack = £99.66; 60 mg (red), 56-tab pack = £149.66;80 mg (green), 56-tab pack = £199.33; 120 mg (purple),56-tab pack = £299.31. Label: 2, 25DoseModerate to severe pain in palliative care. By mouthChild 8–12 years initially, 5 mg every 12 hours,increased if necessary according to severity of painChild 12–18 years initially, 10 mg every 12 hours,increased if necessary according to severity of painPAPAVERETUM USafe PracticeDo not confuse with papaverineA mixture of 253 parts of morphine hydrochloride, 23parts of papaverine hydrochloride and 20 parts ofcodeine hydrochlorideTo avoid confusion, the figures of 7.7 mg/mL or15.4 mg/mL should be used for prescribing purposesCautions see notes above; supraventricular tachycardiaContra-indications see notes above; heart failuresecondary to chronic lung disease; phaeochromocytomaHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding therapeutic doses unlikely to affectinfant; withdrawal symptoms in infants of dependentmothers; breast-feeding not best method of treatingdependence in offspringSide-effects see notes above; also hypothermiaIndication and dosePremedication, postoperative analgesia, severechronic pain. By subcutaneous or intramuscular injectionNeonate 115 micrograms/kg repeated every 4hours if necessaryChild 1–12 months 154 micrograms/kg repeatedevery 4 hours if necessaryChild 1–6 years 1.93–3.85 mg repeated every 4hours if necessaryChild 6–12 years 3.85–7.7 mg repeated every 4hours if necessaryChild 12–18 years 7.7–15.4 mg repeated every 4hours if necessary. By intravenous injectionGenerally 25–50% of the corresponding subcutaneousor intramuscular dosePapaveretum (Non-proprietary) 2UInjection, papaveretum 15.4 mg/mL (providing theequivalent of 10 mg of anhydrous morphine/mL), netprice 1-mL amp = £1.64PETHIDINE HYDROCHLORIDECautions see notes above; not suitable for severecontinuing pain; accumulation of metabolites mayresult in neurotoxicity; myasthenia gravis; cardiacarrhythmias, severe cor pulmonaleContra-indications see notes above; phaeochromocytomaHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding present in milk but not known to beharmfulSide-effects see notes above; also restlessness, tremor,and hypothermia; convulsions reported inoverdosageIndication and doseObstetric analgesia. By subcutaneous or by intramuscular injectionChild 12–18 years 1 mg/kg (max. 100 mg),repeated 1–3 hours later if necessary; max. 400 mgin 24 hoursPethidine (Non-proprietary) 2Injection, pethidine hydrochloride 50 mg/mL, netprice 1-mL amp = 48p, 2-mL amp = 51p; 10 mg/mL,5-mL amp = £3.17, 10-mL amp = £2.18TRAMADOL HYDROCHLORIDECautions see notes above; impaired consciousness;excessive bronchial secretions; not suitable as substitutein opioid-dependent patientsGeneral anaesthesia Not recommended for analgesia duringpotentially light planes of general anaesthesia (possiblyincreased intra-operative recall reported)Contra-indications see notes above; uncontrolledepilepsyHepatic impairment see notes aboveRenal impairment see notes abovePregnancy embryotoxic in animal studies—manufactureradvises avoid; see also notes aboveBreast-feeding amount probably too small to beharmful, but manufacturer advises avoidSide-effects see notes above; also diarrhoea, retching,fatigue, paraesthesia; less commonly gastritis, andflatulence; rarely anorexia, syncope, hypertension,bronchospasm, dyspnoea, wheezing, seizures, andmuscle weakness; blood disorders also reportedLicensed use not licensed for use in children under12 yearsIndication and doseModerate to severe pain. By mouthChild 12–18 years 50–100 mg not more oftenthan every 4 hours; total of more than 400 mg dailynot usually required

BNFC 2011–2012 4.7.2 Opioid analgesics 211. By intravenous injection (over 2–3 minutes) orby intravenous infusion or by intramuscularinjectionChild 12–18 years 50–100 mg every 4–6 hoursPostoperative pain. By intravenous injection (over 2–3 minutes)Child 12–18 years 100 mg initially then 50 mgevery 10–20 minutes if necessary up to total max.250 mg (including initial dose) in first hour, then50–100 mg every 4–6 hours; max. 600 mg dailyAdministration for intravenous infusion, dilute withGlucose 5% or Sodium Chloride 0.9%Tramadol Hydrochloride (Non-proprietary) ACapsules, tramadol hydrochloride 50 mg, net price30-cap pack = £1.22, 100-cap pack = £2.07. Label: 2Brands include Tramake cInjection, tramadol hydrochloride 50 mg/mL, netprice 2-mL amp = 95pMarol c (Morningside) ATablets, m/r, tramadol hydrochloride 100 mg, netprice 60-tab pack = £9.12; 150 mg, 60-tab pack =£13.68; 200 mg, 60-tab pack = £18.24. Label: 2, 25DoseModerate to severe pain. By mouthChild 12–18 years 100 mg twice daily increased ifnecessary; usual max. 200 mg twice dailyMaxitram SR c (Chiesi) ACapsules, m/r, tramadol hydrochloride 50 mg(white), net price 60-cap pack = £4.55; 100 mg (yellow),60-cap pack = £12.14; 150 mg (yellow), 60-cappack = £18.21; 200 mg (yellow), 60-cap pack = £24.28.Label: 2, 25DoseModerate to severe pain. By mouthChild 12–18 years initially 100 mg twice dailyincreased if necessary; usual max. 200 mg twice dailyZamadol c (Meda) ACapsules, tramadol hydrochloride 50 mg, net price100-cap pack = £8.00. Label: 2Orodispersible tablets (Zamadol Melt c ), tramadolhydrochloride 50 mg, net price 60-tab pack = £7.12.Label: 2, counselling, administrationExcipients include aspartame (section 9.4.1)Counselling Zamadol Melt c should be sucked and thenswallowed. May also be dispersed in waterInjection, tramadol hydrochloride 50 mg/mL, netprice 2-mL amp = £1.10Zydol c (Grünenthal) ACapsules, green/yellow, tramadol hydrochloride50 mg, net price 30-cap pack = £2.29, 100-cap pack =£7.63. Label: 2Soluble tablets, tramadol hydrochloride 50 mg, netprice 20-tab pack = £2.79, 100-tab pack = £13.33.Label: 2, 13Injection, tramadol hydrochloride 50 mg/mL, netprice 2-mL amp = 80pModified-release 12-hourly preparationsLarapam c SR (Sandoz) ATablets, m/r, tramadol hydrochloride 100 mg, netprice 60-tab pack = £17.55; 150 mg, 60-tab pack =£27.35; 200 mg, 60-tab pack = £36.50. Label: 2, 25DoseModerate to severe pain. By mouthChild 12–18 years initially 100 mg twice daily increasedif necessary; usual max. 200 mg twice dailyMabron c (Morningside) ATablets, m/r, tramadol hydrochloride 100 mg, netprice 60-tab pack = £18.26; 150 mg, 60-tab pack =£27.39; 200 mg, 60-tab pack = £36.52. Label: 2, 25DoseModerate to severe pain. By mouthChild 12–18 years 100 mg twice daily increased ifnecessary; usual max. 200 mg twice dailyTramquel SR c (Meda) ACapsules, m/r, tramadol hydrochloride 50 mg (darkgreen), net price 60-cap pack = £7.20; 100 mg (white),60-cap pack = £14.39; 150 mg (dark green), 60-cappack = £21.59; 200 mg (yellow), 60-cap pack = £28.78.Label: 2, counselling, administrationDoseModerate to severe pain. By mouthChild 12–18 years 50–100 mg twice daily increased ifnecessary; usual max. 200 mg twice dailyAdministration Swallow whole or open capsule and swallowcontents immediately without chewingZamadol c SR (Meda) ACapsules, m/r, tramadol hydrochloride 50 mg(green), net price 60-cap pack = £7.20; 100 mg, 60-cappack = £14.39; 150 mg (dark green), 60-cap pack =£21.59; 200 mg (yellow), 60-cap pack = £28.78.Label: 2, counselling, administrationDoseModerate to severe pain. By mouthChild 12–18 years 50–100 mg twice daily increased ifnecessary to 150–200 mg twice daily; total of more than400 mg daily not usually requiredAdministration Swallow whole or open capsule and swallowcontents immediately without chewingZeridame c SR (Actavis) ATablets, m/r, tramadol hydrochloride 100 mg, netprice 60-tab pack = £17.21; 150 mg, 60-tab pack =£25.82; 200 mg, 60-tab pack = £34.43. Label: 2, 25DoseModerate to severe pain. By mouthChild 12–18 years 100 mg twice daily, increased ifnecessary; usual max. 200 mg twice dailyZydol SR c (Grünenthal) ATablets, m/r, f/c, tramadol hydrochloride 50 mg(yellow), net price 60-tab pack = £4.60; 100 mg, 60-tab4 Central nervous system

212 4.7.3 Neuropathic pain BNFC 2011–20124 Central nervous systempack = £18.26; 150 mg (beige), 60-tab pack = £27.39;200 mg (orange), 60-tab pack = £36.52. Label: 2, 25DoseModerate to severe pain. By mouthChild 12–18 years 50–100 mg twice daily increased ifnecessary to 150–200 mg twice daily; total of more than400 mg daily not usually requiredModified-release 24-hourly preparationsTradorec XL c (MSD) ATablets, m/r, tramadol hydrochloride 100 mg, netprice 30-tab pack = £14.10; 200 mg, 30-tab pack =£14.98; 300 mg, 30-tab pack = £22.47. Label: 2, 25DoseModerate to severe pain. By mouthChild 12–18 years initially 100 mg once daily, increasedif necessary to max. 400 mg once dailyZamadol c 24hr (Meda) ATablets, f/c, m/r, tramadol hydrochloride 150 mg, netprice 28-tab pack = £10.70; 200 mg, 28-tab pack =£14.26; 300 mg, 28-tab pack = £21.39; 400 mg, 28-tabpack = £28.51. Label: 2, 25DoseModerate to severe pain. By mouthChild 12–18 years initially 150 mg once daily increasedif necessary; max. 400 mg once dailyZydol XL c (Grünenthal) ATablets, m/r, f/c, tramadol hydrochloride 150 mg, netprice 30-tab pack = £12.18; 200 mg, 30-tab pack =£17.98; 300 mg, 30-tab pack = £24.94; 400 mg, 30-tabpack = £32.47. Label: 2, 25DoseModerate to severe pain. By mouthChild 12–18 years 150 mg once daily increased ifnecessary; more than 400 mg once daily not usuallyrequiredWith paracetamolsection 4.7.14.7.3 Neuropathic painNeuropathic pain, which occurs as a result of damage toneural tissue, includes compression neuropathies, peripheralneuropathies (e.g. due to diabetes, HIV infection,chemotherapy), trauma, idiopathic neuropathy,central pain (e.g. pain following spinal cord injury andsyringomyelia), postherpetic neuralgia, and phantomlimb pain. The pain may occur in an area of sensorydeficit and may be described as burning, shooting orscalding; it may be accompanied by pain that is evokedby a non-noxious stimulus (allodynia).Children with chronic neuropathic pain require multidisciplinarymanagement, which may include physiotherapyand psychological support. Neuropathicpain is generally managed with a tricyclic antidepressantsuch as amitriptyline (p. 185) or antiepilepticdrugs such as carbamazepine (p. 218). Children withlocalised pain may benefit from topical local anaestheticpreparations section 15.2, particularly whileawaiting specialist review. Neuropathic pain mayrespond only partially to opioid analgesics. A corticosteroidmay help to relieve pressure in compressionneuropathy and thereby reduce pain.For the management of neuropathic pain in palliativecare, see p. 18.Chronic facial pain Chronic oral and facial painincluding persistent idiopathic facial pain (also termed‘atypical facial pain’) and temporomandibular dysfunction(previously termed temporomandibular joint paindysfunction syndrome) may call for prolonged use ofanalgesics or for other drugs. Tricyclic antidepressants(section 4.3.1) may be useful for facial pain [unlicensedindication], but are not on the Dental Practitioners’ List.Disorders of this type require specialist referral andpsychological support to accompany drug treatment.Children on long-term therapy need to be monitoredboth for progress and for side-effects.4.7.4 Antimigraine drugs4.7.4.1 Treatment of acute migraine4.7.4.2 Prophylaxis of migraine4.7.4.3 Cluster headache and the trigeminalautonomic cephalalgias4.7.4.1 Treatment of acute migraineTreatment of a migraine attack should be guided byresponse to previous treatment and the severity of theattacks. A simple analgesic such as paracetamol (preferablyin a soluble or dispersible form) or an NSAID,usually ibuprofen, is often effective; concomitant antiemetictreatment may be required. If treatment with ananalgesic is inadequate, an attack may be treated with aspecific antimigraine compound such as the 5HT 1 -receptor agonist sumatriptan. Ergot alkaloids areassociated with many side-effects and should beavoided.Excessive use of acute treatments for migraine (opioidand non-opioid analgesics, 5HT 1 -receptor agonists, andergotamine) is associated with medication-overuseheadache (analgesic-induced headache); therefore,increasing consumption of these medicines needs carefulmanagement.5HT 1 -receptor agonists5HT 1 -receptor agonists are used in the treatment ofacute migraine attacks; treatment of children shouldbe initiated by a specialist. The 5HT 1 -receptor agonists(‘triptans’) act on the 5HT (serotonin) 1B/1D receptorsand they are therefore sometimes referred to as5HT 1B=1D -receptor agonists. A 5HT 1 -receptor agonistmay be used during the established headache phase ofan attack and is the preferred treatment in those who failto respond to conventional analgesics. 5HT 1 -receptoragonists are not indicated for the treatment of hemiplegic,basilar, or opthalmoplegic migraine.If a child does not respond to one 5HT 1 -receptor agonist,an alternative 5HT 1 -receptor agonist should betried. For children who have prolonged attacks thatfrequently recur despite treatment with a 5HT 1 -receptoragonist, combination therapy with an NSAID such as

BNFC 2011–2012 4.7.4 Antimigraine drugs 213naproxen can be considered. Sumatriptan and zolmitriptanare used for migraine in children. They may alsobe of value in cluster headache (see also section 4.7.4.3).Cautions See interactions: Appendix 1 (5HT 1 agonists).SUMATRIPTANCautions see under 5HT 1 -receptor agonists above;pre-existing cardiac disease; history of seizures; sensitivityto sulfonamides; interactions: Appendix 1(5HT 1agonists)Skilled tasks Drowsiness may affect performance of skilledtasks (e.g. driving)Contra-indications vasospasm; previous cerebrovascularaccident or transient ischaemic attack; peripheralvascular disease; moderate and severehypertensionHepatic impairment reduce dose of oral therapy;avoid in severe impairmentRenal impairment use with cautionPregnancy limited experience—avoid unless potentialbenefit outweighs riskBreast-feeding present in milk but amount probablytoo small to be harmful; withhold breast-feeding for12 hoursSide-effects nausea, vomiting; sensations of tingling,heat, heaviness, pressure, or tightness of any part ofthe body (including throat and chest—discontinue ifintense, may be due to coronary vasoconstriction orto anaphylaxis), transient increase in blood pressure,flushing; dyspnoea; drowsiness, dizziness, weakness;myalgia; also reported diarrhoea, ischaemic colitis,hypotension, bradycardia or tachycardia, palpitation,arrhythmias, myocardial infarction, Raynaud’ssyndrome, anxiety, seizures, tremor, dystonia, nystagmus,arthralgia, visual disturbances, sweating;epistaxis with nasal sprayLicensed use tablets and injection not licensed foruse in children; not licensed for treating clusterheadache in childrenIndication and doseTreatment of acute migraine. By mouthChild 6–10 years 25 mg as a single dose, repeatedonce after at least 2 hours if migraine recursChild 10–12 years 50 mg as a single dose,repeated once after at least 2 hours if migrainerecursChild 12–18 years 50–100 mg as a single dose,repeated once after at least 2 hours if migrainerecurs. By subcutaneous injection (using auto-injector)Child 10–18 years 6 mg as a single dose, repeatedonce after at least 1 hour if migraine recurs; max.12 mg in 24 hours. IntranasallyChild 12–18 years 10–20 mg as a single dose,repeated once after at least 2 hours if migrainerecurs; max. 40 mg in 24 hoursTreatment of acute cluster headache (underspecialist supervision). By subcutaneous injection (using auto-injector)Child 10–18 years 6 mg as a single dose, repeatedonce after at least 1 hour if headache recurs; max.12 mg in 24 hours. IntranasallyChild 12–18 years 10–20 mg as a single dose,repeated once after at least 2 hours if headacherecurs; max. 40 mg in 24 hoursNote Child not responding to initial dose should not takesecond dose for same attack1Sumatriptan (Non-proprietary) ATablets, sumatriptan (as succinate) 50 mg, net price 6-tab pack = £1.71, 12-tab pack = £2.49; 100 mg, 6-tabpack = £2.43. Label: 3, 10, patient information leaflet1. Sumatriptan 50 mg tablets can be sold to the public to treatpreviously diagnosed migraine; max. daily dose 100 mgImigran c (GSK) ATablets, sumatriptan (as succinate) 50 mg, net price 6-tab pack = £26.54; 100 mg, 6-tab pack = £42.90.Label: 3, 10, patient information leafletInjection, sumatriptan (as succinate) 12 mg/mL (=6 mg/0.5-mL syringe), net price, treatment pack (2 0.5-mL prefilled syringes and auto-injector) = £42.47;refill pack 2 0.5-mL prefilled cartridges = £40.41.Label: 3, 10, patient information leafletNasal spray, sumatriptan 10 mg/0.1-mL actuation,net price 2 unit-dose spray device = £11.80; 20 mg/0.1-mL actuation, 2 unit-dose spray device = £11.80, 6unit-dose spray device = £35.39. Label: 3, 10, patientinformation leafletImigran Radis c (GSK) ATablets, f/c, sumatriptan (as succinate) 50 mg (pink),net price 6-tab pack = £23.90; 100 mg (white), 6-tabpack = £42.90. Label: 3, 10, patient information leafletZOLMITRIPTANCautions see under 5HT 1 -receptor agonists above;should not be taken within 12 hours of any other5HT 1 -receptor agonist; interactions: Appendix 1(5HT 1agonists)Contra-indications vasospasm; Wolff-Parkinson-White syndrome or arrhythmias associated withaccessory cardiac conduction pathways; previouscerebrovascular accident or transient ischaemicattack; ischaemic heart disease; uncontrolled hypertensionHepatic impairment max. 5 mg in 24 hours in moderateor severe impairmentPregnancy limited experience—avoid unless potentialbenefit outweighs riskBreast-feeding use with caution—present in milk inanimal studiesSide-effects abdominal pain, dry mouth, nausea,vomiting; palpitation, sensations of tingling, heat,heaviness, pressure, or tightness of any part of thebody (including throat and chest—discontinue ifintense, may be due to coronary vasoconstriction orto anaphylaxis); dizziness, drowsiness, headache,paraesthesia, asthenia; myalgia, muscle weakness; lesscommonly tachycardia, transient increase in bloodpressure, polyuria; rarely urticaria; very rarely gastrointestinaland splenic infarction, ischaemic colitis,4 Central nervous system

214 4.7.4 Antimigraine drugs BNFC 2011–20124 Central nervous systemangina pectoris, myocardial infarction; with nasalspray, taste disturbance, and epistaxisLicensed use not licensed for use in childrenIndication and doseTreatment of acute migraine. By mouthChild 12–18 years 2.5 mg, repeated after not lessthan 2 hours if migraine recurs (if response unsatisfactoryafter 3 attacks consider increasing doseto 5 mg or switching to alternative treatment);max. 10 mg in 24 hours. IntranasallyChild 12–18 years 5 mg (1 spray) into 1 nostril,repeated after not less than 2 hours if migrainerecurs; max. 10 mg in 24 hoursTreatment of acute cluster headache. IntranasallyChild 12–18 years 5 mg (1 spray) into 1 nostril,repeated after not less than 2 hours if headacherecurs; max. 10 mg in 24 hoursZomig c (AstraZeneca) ATablets, f/c, yellow, zolmitriptan 2.5 mg, net price 6-tab pack = £18.00, 12-tab pack = £36.00Orodispersible tablets (Zomig Rapimelt c ), zolmitriptan2.5 mg, net price 6-tab pack = £17.90; 5 mg, 6-tab pack = £22.80. Counselling, administrationCounselling Zomig Rapimelt c should be placed on thetongue, allowed to disperse and swallowedExcipients include aspartame equivalent to phenylalanine 2.81 mg/tablet (section 9.4.1)Nasal spray, zolmitriptan 5 mg/0.1-mL unit-dosespray device, net price 6 unit-dose sprays = £36.50AntiemeticsAntiemetics (section 4.6), including metoclopramide,domperidone, phenothiazines, and antihistamines,relieve the nausea associated with migraine attacks.Antiemetics may be given by intramuscular injectionor rectally if vomiting is a problem. Metoclopramide anddomperidone have the added advantage of promotinggastric emptying and normal peristalsis; a single doseshould be given at the onset of symptoms (important:for warnings relating to extrapyramidal effects of metoclopramidesee p. 192 and p. 196).4.7.4.2 Prophylaxis of migraineWhere migraine attacks are frequent, possible provokingfactors such as stress should be sought; combinedoral contraceptives may also provoke migraine. Preventivetreatment should be considered if migraine attacksinterfere with school and social life, particularly forchildren who:. suffer at least two attacks a month;. suffer an increasing frequency of headaches;. suffer significant disability despite suitable treatmentfor migraine attacks;. cannot take suitable treatment for migraine attacks.In children it is often possible to stop prophylaxis after aperiod of treatment.Propranolol (section 2.4) may be effective in preventingmigraine in children but it is contra-indicated in thosewith asthma. Side-effects such as depression and posturalhypotension can further limit its use.Pizotifen, an antihistamine and serotonin antagonist,taken at night or twice daily, may also be used but itsefficacy in children has not been clearly established.Common side-effects include drowsiness and weightgain.Topiramate (section 4.8.1) is licensed for migraineprophylaxis.PIZOTIFENCautions urinary retention; susceptibility to angleclosureglaucoma; history of epilepsy; interactions:Appendix 1 (pizotifen)Skilled tasks Drowsiness may affect performance of skilledtasks (e.g. driving); effects of alcohol enhancedRenal impairment use with cautionPregnancy avoid unless potential benefit outweighsriskBreast-feeding amount probably too small to beharmful but manufacturer advises avoidSide-effects dry mouth, nausea, dizziness, drowsiness,increased appetite, weight gain; less commonlyconstipation; rarely anxiety, aggression, insomnia,paraesthesia, hallucination, depression, arthralgia,myalgia; very rarely seizuresLicensed use 1.5-mg tablets not licensed for use inchildrenIndication and doseProphylaxis of migraine. By mouthChild 5–10 years initially 500 micrograms at nightincreased according to response up to 500 micrograms3 times daily; max. single dose at night1 mg; max. 1.5 mg in 24 hoursChild 10–12 years initially 1 mg at nightincreased according to response up to 500 micrograms3 times daily; max. single dose at night1 mg; max. 1.5 mg in 24 hoursChild 12–18 years initially 1.5 mg at nightincreased according to response to 1.5 mg 3 timesdaily; max. single dose 3 mg; max. 4.5 mg in 24hoursPizotifen (Non-proprietary) ATablets, pizotifen (as hydrogen malate), 500 micrograms,net price 28-tab pack = £1.28; 1.5 mg, 28-tabpack = £2.17. Label: 2Sanomigran c (Novartis) ATablets, both ivory-yellow, s/c, pizotifen (as hydrogenmalate), 500 micrograms, net price 60-tab pack =£2.06; 1.5 mg, 28-tab pack = £3.42. Label: 2Elixir, pizotifen (as hydrogen malate) 250 micrograms/5mL, net price 300 mL = £3.61. Label: 24.7.4.3 Cluster headache and thetrigeminal autonomiccephalalgiasCluster headache rarely responds to standard analgesics.Sumatriptan given by subcutaneous injectionis the drug of choice for the treatment of cluster head-

BNFC 2011–2012 4.8 Antiepileptics 215ache. If an injection is unsuitable, sumatriptan nasalspray or zolmitriptan nasal spray may be used. Treatmentshould be initiated by a specialist. Alternatively,100% oxygen at a rate of 10–15 litres/minute for 10–20minutes is useful in aborting an attack.The other trigeminal autonomic cephalalgias, paroxysmalhemicrania (sensitive to indometacin), and shortlastingunilateral neuralgiform headache attacks withconjunctival injection and tearing, are seen rarely andare best managed by a specialist.4.8 Antiepileptics4.8.1 Control of the epilepsies4.8.2 Drugs used in status epilepticus4.8.3 Febrile convulsionsof adverse effects and drug interactions (see below). Ifcombination therapy does not bring about worthwhilebenefits, revert to the regimen (monotherapy or combinationtherapy) that provided the best balance betweentolerability and efficacy.Interactions Interactions between antiepileptics arecomplex and may increase toxicity without a correspondingincrease in antiepileptic effect. Interactionsare usually caused by hepatic enzyme induction orhepatic enzyme inhibition; displacement from proteinbinding sites is not usually a problem. These interactionsare highly variable and unpredictable.For interactions of antiepileptic drugs, see Appendix 1;for advice on hormonal contraception and enzymeinducingdrugs, see section 7.3.1 and section 7.3.2.Significant interactions that occur between antiepilepticsand that may affect dosing requirements are asfollows:Note Check under each drug for possible interactions whentwo or more antiepileptic drugs are used4.8.1 Control of the epilepsiesThe decision about when to start treatment with anantiepileptic drug and the choice of medication dependson frequency and type of seizures, neurological findings,the identification of an epilepsy syndrome, and thewishes of the child and carers. For the majority ofchildren, epilepsy is controlled with a single antiepilepticdrug.The object of treatment is to prevent the occurrence ofseizures by maintaining an effective dose of one or moreantiepileptic drugs. Careful adjustment of doses isnecessary, starting with low doses and increasing graduallyuntil seizures are controlled or there are significantadverse effects.When choosing an antiepileptic drug to use, the seizuretype, epilepsy syndrome, concomitant medication, comorbidity,age, and sex should be taken into account.For women of child-bearing age, see Pregnancy, p. 216and Breast-feeding, p. 217.The frequency of administration is often determined bythe plasma-drug half-life, and should be kept as low aspossible to encourage better adherance. Most antiepileptics,when used in usual dosage, can be giventwice daily. Lamotrigine, phenobarbital and phenytoin,which have long half-lives, can be given as a daily doseat bedtime. However, with large doses, some antiepilepticsmay need to be given 3 times daily to avoid adverseeffects associated with high peak plasma-drug concentrations.Young children metabolise some antiepilepticsmore rapidly than adults and therefore may requiremore frequent doses and a higher amount per kilogrambody-weight.Management When monotherapy with a first-lineantiepileptic drug has failed, monotherapy with a seconddrug should be tried; the diagnosis should bechecked before starting an alternative drug if the firstdrug showed lack of efficacy. The change from oneantiepileptic drug to another should be cautious, slowlywithdrawing the first drug only when the new regimenhas been established. Combination therapy with two ormore antiepileptic drugs may be necessary, but theconcurrent use of antiepileptic drugs increases the riskCarbamazepineoften lowers plasma concentration of clobazam, clonazepam,lamotrigine, phenytoin (but may also raiseplasma-phenytoin concentration), tiagabine, topiramate,valproate, and an active metabolite of oxcarbazepinesometimes lowers plasma concentration of ethosuximide,primidone (but tendency for correspondingincrease in plasma-phenobarbital concentration), andrufinamidesometimes raises plasma concentration of phenobarbitaland primidone-derived phenobarbitalEthosuximidesometimes raises plasma concentration of phenytoinLamotriginesometimes raises plasma concentration of an activemetabolite of carbamazepine (but evidence is conflicting)Oxcarbazepinesometimes lowers plasma concentration of carbamazepine(but may raise plasma concentration of an activemetabolite of carbamazepine)sometimes raises plasma concentration of phenytoinoften raises plasma concentration of phenobarbital andprimidone-derived phenobarbitalPhenobarbital or Primidoneoften lowers plasma concentration of clonazepam, lamotrigine,phenytoin (but may also raise plasma-phenytoinconcentration), tiagabine, valproate, and an activemetabolite of oxcarbazepinesometimes lowers plasma concentration of ethosuximide,rufinamide, and topiramatePhenytoinoften lowers plasma concentration of clonazepam,carbamazepine, lamotrigine, tiagabine, topiramate, valproate,and an active metabolite of oxcarbazepineoften raises plasma concentration of phenobarbital andprimidone-derived phenobarbitalsometimes lowers plasma concentration of ethosuximide,primidone (by increasing conversion to phenobarbital),and rufinamide4 Central nervous system

216 4.8.1 Control of the epilepsies BNFC 2011–20124 Central nervous systemRufinamidesometimes lowers plasma concentration of carbamazepinesometimes raises plasma concentration of phenytoinStiripentoloften raises plasma concentration of carbamazepine,clobazam, phenobarbital, primidone-derived phenobarbital,and phenytoinTopiramatesometimes raises plasma concentration of phenytoinValproatesometimes lowers plasma concentration of an activemetabolite of oxcarbazepineoften raises plasma concentration of lamotrigine, phenobarbital,primidone-derived phenobarbital, phenytoin(but may also lower), and an active metabolite of carbamazepinesometimes raises plasma concentration of ethosuximideand rufinamideVigabatrinoften lowers plasma concentration of phenytoinWithdrawal Antiepileptics should be withdrawn underspecialist supervision. Avoid abrupt withdrawal, particularlyof barbiturates and benzodiazepines because thiscan precipitate severe rebound seizures. Reduction indosage should be gradual and, in the case of barbiturates,the withdrawal process may take months.The decision to withdraw antiepileptics from a seizurefreechild, and its timing, depends on individual circumstancessuch as the type of epilepsy and its cause. Evenin children who have been seizure-free for several years,there is a significant risk of seizure recurrence on drugwithdrawal.Drugs should be gradually withdrawn over at least 2–3months by reducing the daily dose by 10–25% at intervalsof 1–2 weeks. Benzodiazepines may need to bewithdrawn over 6 months or longer.In children receiving several antiepileptic drugs, onlyone drug should be withdrawn at a time.Monitoring Routine measurement of plasma concentrationsof antiepileptic drugs is not usually justified,because the target concentration ranges are arbitraryand often vary between individuals. However, plasmadrugconcentrations may be measured in children withworsening seizures, status epilepticus, suspected noncompliance,or suspected toxicity. Similarly, haematologicaland biochemical monitoring should not be undertakenunless clinically indicated.Driving Older children with epilepsy may drive a motorvehicle (but not a large goods or passenger carryingvehicle) provided that they have been seizure-free forone year or, if subject to attacks only while asleep, haveestablished a 3-year period of asleep attacks withoutawake attacks. Those affected by drowsiness should notdrive or operate machinery.Guidance issued by the Drivers Medical Unit of theDriver and Vehicle Licensing Agency (DVLA) recommendsthat patients should be advised not to driveduring medication changes or withdrawal of antiepilepticdrugs, and for 6 months afterwards.Patients who have had a first or single epileptic seizuremust not drive for 6 months (5 years in the case of largegoods or passenger carrying vehicles) after the event;driving may then be resumed, provided the patient hasbeen assessed by a specialist as fit to drive because noabnormality was detected on investigation.Pregnancy Young women of child-bearing potentialshould discuss with a specialist, the impact of bothepilepsy, and its treatment, on the outcome ofpregnancy.There is an increased risk of teratogenicity associatedwith the use of antiepileptic drugs (especially if usedduring the first trimester and if the patient takes two ormore antiepileptic drugs). Valproate is associated withthe highest risk of major and minor congenital malformations,and with developmental delay. Valproateshould not be prescribed unless there is no safer alternativeand only after a careful discussion of the risks;doses greater than 1 g daily are associated with anincreased risk of teratogenicity. There is also anincreased risk of teratogenicity with phenytoin, primidone,phenobarbital, lamotrigine, and carbamazepine.There is not enough evidence to establish the risk ofteratogenicity with other antiepileptic drugs.Prescribers should also consider carefully the choice ofantiepileptic therapy in pre-pubescent girls who maylater become pregnant.Young women of child-bearing potential who take antiepilepticdrugs should be given contraceptive advice.Some antiepileptic drugs can reduce the efficacy ofhormonal contraceptives, and the efficacy of some antiepilepticsmay be affected by hormonal contraceptives(see section 7.3.1 and interactions of antiepileptics,Appendix 1).Young women who want to become pregnant should bereferred to a specialist for advice in advance of conception.For some women, the severity of seizure or theseizure type may not pose a serious threat, and drugwithdrawal may be considered; therapy may beresumed after the first trimester. If treatment with antiepilepticdrugs must continue throughout pregnancy,then monotherapy is preferable at the lowest effectivedose.Once an unplanned pregnancy is discovered it is usuallytoo late for changes to be made to the treatment regimen;the risk of harm to the mother and fetus fromconvulsive seizures outweighs the risk of continuedtherapy. The likelihood of a young woman who is takingantiepileptic drugs having a baby with no malformationsis at least 90%, and it is important that women do notstop taking essential treatment because of concern overharm to the fetus.To reduce the risk of neural tube defects, folate supplementation(section 9.1.2) is advised before conceptionand throughout the first trimester.The concentration of antiepileptic drugs in the plasmacan change during pregnancy. Doses of phenytoinp. 224, carbamazepine, and lamotrigine should beadjusted on the basis of plasma-drug concentrationmonitoring; the dose of other antiepileptic drugs shouldbe monitored carefully during pregnancy and after birth,and adjustments made on a clinical basis. Plasma-drugconcentration monitoring during pregnancy is also usefulto check compliance. Additionally, in patients takingtopiramate or levetiracetam, it is recommended thatfetal growth is monitored.

BNFC 2011–2012 4.8.1 Control of the epilepsies 217Young women who have seizures in the second half ofpregnancy should be assessed for eclampsia before anychange is made to antiepileptic treatment. Status epilepticusshould be treated according to the standardprotocol, see section 4.8.2.Routine injection of vitamin K (section 9.6.6) at birthminimises the risk of neonatal haemorrhage associatedwith antiepileptics.Withdrawal effects in the newborn may occur with someantiepileptic drugs, in particular benzodiazepines andphenobarbital, and can take several days to diminish.Epilepsy and Pregnancy RegisterAll pregnant women with epilepsy, whether takingmedication or not, should be encouraged to notifythe UK Epilepsy and Pregnancy Register (Tel: 0800389 1248).Breast-feeding Breast-feeding is acceptable with allantiepileptic drugs taken in normal doses, with thepossible exception of the barbiturates and some of thenewer antiepileptics (see under individual drugs).Focal seizures with or withoutsecondary generalisationCarbamazepine, lamotrigine, oxcarbazepine, andsodium valproate are the drugs of choice for focalseizures; second-line drugs include clobazam, gabapentin,levetiracetam, tiagabine, and topiramate.Generalised seizuresTonic-clonic seizures The drugs of choice for tonicclonicseizures are carbamazepine, lamotrigine, levetiracetam,and sodium valproate. For children whohave tonic-clonic seizures as part of the syndrome ofprimary generalised epilepsy, sodium valproate is thedrug of choice. Second-line drugs include clobazam,oxcarbazepine, and topiramate.Absence seizures Ethosuximide and sodium valproateare the drugs of choice in typical absenceseizures; lamotrigine can be used if these are unsuitable.Sodium valproate is also highly effective in treatingthe generalised tonic-clonic seizures which can co-existwith absence seizures in idiopathic primary generalisedepilepsy.Myoclonic seizures Myoclonic seizures (myoclonicjerks) occur in a variety of syndromes, and response totreatment varies considerably. Sodium valproate is thedrug of choice, and clobazam, clonazepam, ethosuximide,lamotrigine, levetiracetam, or topiramate aresecond-line drugs.Atypical absence, atonic, and tonic seizuresAtypical absence and atonic seizures can be managedwith sodium valproate, lamotrigine, or ethosuximide.Tonic seizures can be treated with sodium valproate.Second-line drugs for atypical absence, atonic, and tonicseizures include clobazam, clonazepam, levetiracetam,and topiramate; tonic seizures are rarely aggravated bybenzodiazepines.Epilepsy syndromesInfantile spasms Vigabatrin is the drug of choice forinfantile spasms associated with tuberous sclerosis. Inspasms of other causes, high doses of corticosteroids,such as prednisolone (section 6.3.2) or tetracosactide(section 6.5.1), may be more effective. Second-linealternatives include clobazam, clonazepam, sodium valproate,and topiramate; nitrazepam is used but it issedating.Lennox-Gastaut syndrome Lamotrigine, sodiumvalproate, and topiramate are first-line drugs for treatingLennox-Gastaut syndrome. Clobazam, clonazepam,ethosuximide, levetiracetam, and rufinamide are alsoused.Landau-Kleffner syndrome Prednisolone, lamotrigine,and sodium valproate are commonly used totreat Landau-Kleffner syndrome. Alternatives includeclobazam, levetiracetam, and topiramate.Neonatal seizures Seizures can occur before delivery,but they are most common up to 24 hours afterbirth. Seizures in neonates occur as a result of biochemicaldisturbances, inborn errors of metabolism, hypoxicischaemic encephalopathy, drug withdrawal, meningitis,stroke, cerebral haemorrhage or malformation, orsevere jaundice (kernicterus).Seizures caused by biochemical imbalance and those inneonates with inherited abnormal pyridoxine or biotinmetabolism should be corrected by treating the underlyingcause (section 9.6.2). Seizures caused by drugwithdrawal following intra-uterine exposure are treatedwith a drug withdrawal regimen.Phenobarbital can be used to manage neonatal seizureswhere there is a risk of recurrence; phenytoin isan alternative. Benzodiazepines (such as clonazepam(p. 232) and midazolam (p. 234)) and rectal paraldehyde(p. 234) may also be useful in the managementof acute neonatal seizures. Lidocaine (p. 86) maybe used if other treatments are unsuccessful; lidocaineshould not be given to neonates who have receivedphenytoin infusion because of the risk of cardiac toxicity.Severe myoclonic epilepsy of infancy Stiripentolis licensed to treat severe myoclonic epilepsy of infancy(Dravet Syndrome).Carbamazepine and oxcarbazepineCarbamazepine is a drug of choice for simple andcomplex focal seizures and for tonic-clonic seizuressecondary to a focal discharge. It can exacerbate myoclonicand absence seizures. It is essential to initiatecarbamazepine therapy at a low dose and build this upslowly in small increments every 3–7 days. Some sideeffects(such as headache, ataxia, drowsiness, nausea,vomiting, blurring of vision, dizziness, unsteadiness, andallergic skin reactions) are dose-related, and may bedose-limiting. These side-effects are more common atthe start of treatment. They may be reduced by alteringthe timing of medication or by using a modified-releasepreparation.Oxcarbazepine is licensed as monotherapy or adjunctivetherapy for the treatment of focal seizures with orwithout secondary generalised tonic-clonic seizures.4 Central nervous system

218 4.8.1 Control of the epilepsies BNFC 2011–20124 Central nervous systemCARBAMAZEPINECautions cardiac disease (see also Contra-indications);skin reactions (see also Blood, Hepatic, or Skin disorders,below and under Side-effects); test for HLA-B*1502 allele in individuals of Han Chinese or Thaiorigin (avoid unless no alternative—risk of Stevens-Johnson syndrome in the presence of HLA-B*1502allele); history of haematological reactions to otherdrugs; manufacturer recommends blood counts andhepatic and renal function tests (but evidence ofpractical value uncertain); may exacerbate absenceand myoclonic seizures; consider vitamin D supplementationin patients who are immobilised for longperiods or who have inadequate sun exposure ordietary intake of calcium; susceptibility to angle-closureglaucoma; cross-sensitivity reported with oxcarbazepine,and with phenytoin; avoid abrupt withdrawal;interactions: see p. 215 and Appendix 1(carbamazepine)Blood, hepatic, or skin disorders Children or their carersshould be told how to recognise signs of blood, liver, or skindisorders, and advised to seek immediate medical attention ifsymptoms such as fever, rash, mouth ulcers, bruising, orbleeding develop. Carbamazepine should be withdrawnimmediately in cases of aggravated liver dysfunction or acuteliver disease. Leucopenia that is severe, progressive, orassociated with clinical symptoms requires withdrawal (ifnecessary under cover of a suitable alternative).Contra-indications AV conduction abnormalities(unless paced); history of bone marrow depression,acute porphyria (section 9.8.2)Hepatic impairment metabolism impaired inadvanced liver disease; see also Blood, Hepatic, orSkin Disorders, aboveRenal impairment use with cautionPregnancy see Pregnancy, p. 216Breast-feeding amount probably too small to beharmful but monitor infant for possible adversereactions; see also Breast-feeding, p. 217Side-effects see notes above; also dry mouth, nausea,vomiting, oedema, ataxia, dizziness, drowsiness, fatigue,headache, hyponatraemia (leading in rare casesto water intoxication), blood disorders (includingeosinophilia, leucopenia, thrombocytopenia, haemolyticanaemia, and aplastic anaemia), dermatitis,urticaria; less commonly diarrhoea, constipation,involuntary movements (including nystagmus), visualdisturbances; rarely abdominal pain, anorexia,hepatitis, jaundice, vanishing bile duct syndrome,cardiac conduction disorders, hypertension, hypotension,peripheral neuropathy, dysarthria, aggression,agitation, confusion, depression, hallucinations,restlessness, paraesthesia, lymph node enlargement,muscle weakness, systemic lupus erythematosus,delayed multi-organ hypersensitivity disorder; veryrarely pancreatitis, stomatitis, hepatic failure, tastedisturbance, exacerbation of coronary artery disease,AV block with syncope, circulatory collapse, hypercholesterolaemia,thrombophlebitis, thromboembolism,pulmonary hypersensitivity (with dyspnoea,pneumonitis, or pneumonia), psychosis, neurolepticmalignant syndrome, osteomalacia (see Cautions),osteoporosis, galactorrhoea, gynaecomastia,impaired male fertility, interstitial nephritis, renalfailure, sexual dysfunction, urinary frequency, urinaryretention, arthralgia, muscle pain, muscle spasm,conjunctivitis, angle-closure glaucoma, hearing disorders,acne, alterations in skin pigmentation, alopecia,hirsutism, sweating, photosensitivity, purpura,Stevens-Johnson syndrome, toxic epidermal necrolysis,aseptic meningitis; suicidal ideationPharmacokinetics plasma concentration for optimumresponse 4–12 mg/litre (20–50 micromol/litre) measured after 1–2 weeksLicensed use suppositories not licensed for use intrigeminal neuralgia or prophylaxis of bipolar disorderIndication and doseFocal and generalised tonic-clonic seizures,trigeminal neuralgia, prophylaxis of bipolardisorder. By mouthChild 1 month–12 years initially 5 mg/kg at nightor 2.5 mg/kg twice daily, increased as necessaryby 2.5–5 mg/kg every 3–7 days; usual maintenancedose 5 mg/kg 2–3 times daily; doses up to20 mg/kg daily have been usedChild 12–18 years initially 100–200 mg 1–2 timesdaily, increased slowly to usual maintenance dose200–400 mg 2–3 times daily; in some cases dosesup to 1.8 g daily may be needed. By rectumChild 1 month–18 years use approx. 25% morethan the oral dose (max. 250 mg) up to 4 timesdailyNote Different preparations may vary in bioavailability; toavoid reduced effect or excessive side-effects, it may beprudent to avoid changing the formulationAdministration Oral liquid has been used rectally—should be retained for at least 2 hours (but may havelaxative effect)Carbamazepine (Non-proprietary) ATablets, carbamazepine 100 mg, net price 28 = £5.69;200 mg, 28 = £4.99; 400 mg, 28 = £6.59. Label: 3, 8,counselling, blood, hepatic or skin disorder symptoms(see above), driving (see notes above)Brands include Epimaz cDental prescribing on NHS Carbamazepine Tablets may beprescribedTegretol c (Novartis) ATablets, scored, carbamazepine 100 mg, net price 84-tab pack = £2.07; 200 mg, 84-tab pack = £3.83;400 mg, 56-tab pack = £5.02. Label: 3, 8, counselling,blood, hepatic or skin disorder symptoms (see above),driving (see notes above)Chewtabs, orange, carbamazepine 100 mg, net price56-tab pack = £3.16; 200 mg, 56-tab pack = £5.88.Label: 3, 8, 21, 24, counselling, blood, hepatic or skindisorder symptoms (see above), driving (see notesabove)Liquid, sugar-free, carbamazepine 100 mg/5 mL. Netprice 300-mL pack = £6.12. Label: 3, 8, counselling,blood, hepatic or skin disorder symptoms (see above),driving (see notes above)Suppositories, carbamazepine 125 mg, net price 5 =£8.03; 250 mg, 5 = £10.71. Label: 3, 8, counselling,blood, hepatic or skin disorder symptoms (see above),driving (see notes above)DoseEpilepsy for short-term use (max. 7 days) when oraltherapy temporarily not possibleNote Suppositories of 125 mg may be considered to beapproximately equivalent in therapeutic effect to tablets of100 mg but final adjustment should always depend on clin-

BNFC 2011–2012 4.8.1 Control of the epilepsies 219ical response (plasma concentration monitoring recommended);max. dose by rectum 250 mg 4 times dailyModified releaseCarbagen c SR (Generics) ATablets, m/r, f/c, scored, carbamazepine 200 mg, netprice 56-tab pack = £5.20; 400 mg, 56-tab pack =£10.24. Label: 3, 8, 25, counselling, blood, hepatic orskin disorder symptoms (see above), driving (seenotes above)DoseChild 5–18 years as above; total daily dose given in 1–2divided dosesTegretol c Prolonged Release (Novartis) ATablets, m/r, scored, carbamazepine 200 mg (beigeorange),net price 56-tab pack = £5.20; 400 mg(brown-orange), 56-tab pack = £10.24. Label: 3, 8, 25,counselling, blood, hepatic or skin disorder symptoms(see above), driving (see notes above)DoseChild 5–18 years as above; total daily dose given in 2divided dosesAdministration Tegretol c Prolonged Release tablets can behalved but should not be chewedOXCARBAZEPINECautions hypersensitivity to carbamazepine; avoidabrupt withdrawal; hyponatraemia (monitor plasmasodiumconcentration in patients at risk), heart failure(monitor body-weight), cardiac conduction disorders;avoid in acute porphyria (section 9.8.2); interactions:see p. 215 and Appendix 1 (oxcarbazepine)Blood, hepatic, or skin disorders Children or their carersshould be told how to recognise signs of blood, liver, or skindisorders, and advised to seek immediate medical attention ifsymptoms such as lethargy, confusion, muscular twitching,fever, rash, blistering, mouth ulcers, bruising, or bleedingdevelopHepatic impairment caution in severe impairment—no information availableRenal impairment halve initial dose if estimatedglomerular filtration rate less than 30 mL/minute/1.73 m 2 , increase according to response at intervals ofat least 1 weekPregnancy see Pregnancy, p. 216Breast-feeding amount probably too small to beharmful but manufacturer advises avoid; see alsoBreast-feeding, p. 217Side-effects nausea, vomiting, constipation, diarrhoea,abdominal pain, dizziness, headache, drowsiness,agitation, amnesia, asthenia, ataxia, confusion,impaired concentration, depression, tremor, hyponatraemia,acne, alopecia, rash, nystagmus, visualdisorders including diplopia; less commonly urticaria,leucopenia; very rarely hepatitis, pancreatitis, arrhythmias,blood disorders, systemic lupus erythematosus,Stevens-Johnson syndrome, and toxic epidermalnecrolysis; hypertension and hypothyroidism alsoreported; suicidal ideationIndication and doseMonotherapy and adjunctive therapy of focalseizures with or without secondary generalisedtonic-clonic seizures. By mouthChild 6–18 years initially 4–5 mg/kg (max.300 mg) twice daily, increased according toresponse in steps of up to 5 mg/kg twice daily atweekly intervals (usual maintenance dose foradjunctive therapy 15 mg/kg twice daily); max.23 mg/kg twice dailyNote In adjunctive therapy the dose of concomitant antiepilepticsmay need to be reduced when using high doses ofoxcarbazepineOxcarbazepine (Non-proprietary) ATablets, oxcarbazepine 150 mg, net price 50-tab pack= £11.02; 300 mg, 50-tab pack = £22.38; 600 mg, 50-tab pack = £44.72. Label: 3, 8, counselling, blood,hepatic or skin disorders (see above), driving (seenotes above)Trileptal c (Novartis) ATablets, f/c, scored, oxcarbazepine 150 mg (green),net price 50-tab pack = £8.50; 300 mg (yellow), 50-tabpack = £17.00; 600 mg (pink), 50-tab pack = £34.00.Label: 3, 8, counselling, blood, hepatic or skin disorders(see above), driving (see notes above)Oral suspension, sugar-free, oxcarbazepine 300 mg/5 mL, net price 250 mL (with oral syringe) = £34.00.Label: 3, 8, counselling, blood, hepatic or skin disorders(see above), driving (see notes above)Excipients include propylene glycol (see Excipients, p. 2)EthosuximideEthosuximide is used for typical absence seizures; itmay also be used for myoclonic seizures and for atypicalabsence, atonic, and tonic seizures.ETHOSUXIMIDECautions avoid abrupt withdrawal; avoid in acuteporphyria (section 9.8.2); interactions: see p. 215 andAppendix 1 (ethosuximide)Blood disorders Children or their carers should be told howto recognise signs of blood disorders, and advised to seekimmediate medical attention if symptoms such as fever,mouth ulcers, bruising, or bleeding developHepatic impairment use with cautionRenal impairment use with cautionPregnancy see Pregnancy, p. 216Breast-feeding present in milk; hyperexcitability andsedation reported; see also Breast-feeding, p. 217Side-effects gastro-intestinal disturbances (includingnausea, vomiting, diarrhoea, abdominal pain, andanorexia), weight loss; less frequently headache, fatigue,drowsiness, dizziness, hiccup, ataxia, euphoria,irritability, aggression, and impaired concentration;rarely tongue swelling, sleep disturbances, depression,psychosis, photophobia, dyskinesia, increasedlibido, vaginal bleeding, myopia, gingival hypertrophy,rash; also reported hyperactivity, increase in seizurefrequency, blood disorders (including leucopenia,agranulocytosis, pancytopenia, and aplastic anaemia—bloodcounts required if features of infection),systemic lupus erythematosus, and Stevens-Johnsonsyndrome; suicidal ideationIndication and doseAbsence seizures, atypical absence, myoclonicseizures. By mouthChild 1 month–6 years initially 5 mg/kg (max.125 mg) twice daily, increased gradually over 2–3weeks up to maintenance dose of 10–20 mg/kg(max. 500 mg) twice daily; total daily dose mayrarely be given in 3 divided doses4 Central nervous system

220 4.8.1 Control of the epilepsies BNFC 2011–20124 Central nervous systemChild 6–18 years initially 250 mg twice daily,increased by 250 mg at intervals of 4–7 days tousual dose of 500–750 mg twice daily; occasionallyup to 1 g twice daily may be neededEthosuximide (Non-proprietary) ACapsules, ethosuximide 250 mg, net price 56-cappack = £38.23. Label: 8, counselling, blood disorders(see above), driving (see notes above)Emeside c (Chemidex) ASyrup, black currant, ethosuximide 250 mg/5 mL, netprice 200-mL pack = £6.60. Label: 8, counselling,blood disorders (see above), driving (see notes above)Zarontin c (Pfizer) ASyrup, yellow, ethosuximide 250 mg/5 mL, net price200-mL pack = £4.22. Label: 8, counselling, blooddisorders (see above), driving (see notes above)GabapentinGabapentin is used as adjunctive therapy for the treatmentof focal seizures with or without secondary generalisation;it can be used as monotherapy in childrenover 12 years.GABAPENTINCautions avoid abrupt withdrawal (may cause anxiety,insomnia, nausea, pain, and sweating—taper off overat least 1 week); diabetes mellitus, false positivereadings with some urinary protein tests; history ofpsychotic illness; interactions: Appendix 1 (gabapentin)Renal impairment reduce dose if estimated glomerularfiltration rate less than 80 mL/minute/1.73 m 2 ;consult product literaturePregnancy see Pregnancy, p. 216Breast-feeding present in milk—manufactureradvises use only if potential benefit outweighs risk;see also Breast-feeding, p. 217Side-effects diarrhoea, dry mouth, dyspepsia, nausea,vomiting, constipation, abdominal pain, flatulence,appetite changes, gingivitis, weight gain; hypertension,vasodilation, oedema; dyspnoea, cough,rhinitis; confusion, depression, hostility, sleep disturbances,headache; dizziness, anxiety, amnesia, ataxia,dysarthria, nystagmus, tremor, asthenia, paraesthesia,hyperkinesia; influenza-like symptoms; impotence,urinary incontinence; leucopenia; myalgia, arthralgia;diplopia, amblyopia; rash, purpura, pruritus, acne;rarely pancreatitis, hepatitis, jaundice, palpitation,hallucinations, movement disorders, thrombocytopenia,blood-glucose fluctuations in patients with diabetes,tinnitus, acute renal failure, Stevens-Johnsonsyndrome, and alopecia; suicidal ideation; alsoreported psychosisLicensed use not licensed for use in children under 6years; not licensed at doses over 50 mg/kg daily inchildren under 12 yearsIndication and doseAdjunctive treatment of focal seizures with orwithout secondary generalisation. By mouthChild 2–6 years 10 mg/kg once daily on day 1,then 10 mg/kg twice daily on day 2, then 10 mg/kg3 times daily on day 3, increased according toresponse to usual dose of 30–70 mg/kg daily in 3divided dosesChild 6–12 years 10 mg/kg (max. 300 mg) oncedaily on day 1, then 10 mg/kg (max. 300 mg) twicedaily on day 2, then 10 mg/kg (max. 300 mg) 3times daily on day 3; usual dose 25–35 mg/kg dailyin 3 divided doses; max. 70 mg/kg daily in 3divided dosesChild 12–18 years 300 mg once daily on day 1,then 300 mg twice daily on day 2, then 300 mg 3times daily on day 3 or initially 300 mg 3 timesdaily on day 1; then increased according toresponse in steps of 300 mg (in 3 divided doses)every 2–3 days; usual dose 0.9–3.6 g daily in 3divided dosesMonotherapy for focal seizures with or withoutsecondary generalisation. By mouthChild 12–18 years 300 mg once daily on day 1,then 300 mg twice daily on day 2, then 300 mg 3times daily on day 3 or initially 300 mg 3 timesdaily on day 1; then increased according toresponse in steps of 300 mg (in 3 divided doses)every 2–3 days; usual dose 0.9–3.6 g daily in 3divided dosesNote Some children may not tolerate daily increments;longer intervals (up to weekly) may be more appropriateAdministration capsules can be opened but the bittertaste is difficult to maskGabapentin (Non-proprietary) ACapsules, gabapentin 100 mg, net price 100-cap pack= £3.57; 300 mg, 100-cap pack = £8.83; 400 mg, 100-cap pack = £5.53. Label: 3, 5, 8, counselling, driving(see notes above)Tablets, gabapentin 600 mg, net price 100-tab pack =£24.85; 800 mg, 100-tab pack= £36.42. Label: 3, 5, 8,counselling, driving (see notes above)Neurontin c (Pfizer) ACapsules, gabapentin 100 mg (white), net price 100-cap pack = £18.29; 300 mg (yellow), 100-cap pack =£42.40; 400 mg (orange), 100-cap pack = £49.06.Label: 3, 5, 8, counselling, driving (see notes above)Tablets, f/c, gabapentin 600 mg, net price 100-tabpack = £84.80; 800 mg, 100-tab pack = £98.13.Label: 3, 5, 8, counselling, driving (see notes above)LacosamideLacosamide is licensed for adjunctive treatment offocal seizures with or without secondary generalisation.The Scottish Medicines Consortium (p. 3) has advised(January 2009) that lacosamide (Vimpat c ) is acceptedfor restricted use within NHS Scotland as adjunctivetreatment for focal seizures with or without secondarygeneralisation in patients from 16 years. It is restrictedfor specialist use in refractory epilepsy.

BNFC 2011–2012 4.8.1 Control of the epilepsies 221LACOSAMIDECautions risk of PR-interval prolongation (includingconduction problems, severe cardiac disease, andconcomitant use of drugs that prolong PR interval),elderly; interactions: Appendix 1 (lacosamide)Contra-indications second- or third-degree AV blockHepatic impairment caution in severe impairment—no information availableRenal impairment titrate dose with caution; max.250 mg daily if estimated glomerular filtration rate isless than 30 mL/minute/1.73 m 2Pregnancy see Pregnancy, p. 216Breast-feeding manufacturer advises avoid—presentin milk in animal studies; see also Breast-feeding,p. 217Side-effects nausea, vomiting, constipation, flatulence,dizziness, headache, impaired coordination,cognitive disorder, drowsiness, tremor, depression,fatigue, abnormal gait, blurred vision, nystagmus,pruritus; also reported dyspepsia, dry mouth, firstdegreeAV block, bradycardia, PR-interval prolongation,confusion, hypoesthesia, dysarthria, irritability,muscle spasm, tinnitus, rash; suicidal ideationIndication and doseAdjunctive treatment of focal seizures with orwithout secondary generalisation. By intravenous infusion over 15–60 minutes(for up to 5 days) or by mouthChild 16–18 years initially 50 mg twice daily,increased in steps of 50 mg twice daily every week;max. 200 mg twice dailyAdministration for intravenous infusion, give undilutedor dilute with Glucose 5% or Sodium Chloride0.9%Vimpat c (UCB Pharma) TATablets, f/c, lacosamide 50 mg (pink), net price 14-tabpack = £10.81; 100 mg (yellow), 14-tab pack = £21.62,56-tab pack = £86.50; 150 mg (salmon), 14-tab pack =£32.44, 56-tab pack £129.74; 200 mg (blue), 56-tabpack = £144.16. Label: 8, counselling, driving (seenotes above)Syrup, lacosamide 15 mg/mL, net price 200 mL =£38.61. Label: 8, counselling, driving (see notes above)Excipients include aspartame (section 9.4.1)Intravenous infusion, lacosamide 10 mg/mL netprice 200-mg vial = £29.70Electrolytes Na + 2.6 mmol/200-mg vialLamotrigineLamotrigine is an antiepileptic for focal seizures, primaryand secondary generalised tonic-clonic seizures,and for typical absence seizures. Efficacy may not bemaintained in all children treated for typical absenceseizures. It may be tried for atypical absence, atonic, andtonic seizures. Lamotrigine may cause serious skinreactions; dose recommendations should be adheredto closely.Lamotrigine is used either as sole treatment or as anadjunct to treatment with other antiepileptic drugs. Valproateincreases plasma-lamotrigine concentration,whereas the enzyme-inducing antiepileptics reduce it;care is therefore required in choosing the appropriateinitial dose and subsequent titration. When the potentialfor interaction is not known, treatment should beinitiated with lower doses, such as those used withvalproate.LAMOTRIGINECautions closely monitor and consider withdrawal ifrash, fever, or signs of hypersensitivity syndromedevelop; avoid abrupt withdrawal (taper off over 2weeks or longer) unless serious skin reaction occurs;myoclonic seizures (may be exacerbated); interactions:see p. 215 and Appendix 1 (lamotrigine)Blood disorders Children and their carers should be alert forsymptoms and signs suggestive of bone-marrow failure, suchas anaemia, bruising, or infection. Aplastic anaemia, bonemarrowdepression, and pancytopenia have been associatedrarely with lamotrigineHepatic impairment halve dose in moderate impairment;quarter dose in severe impairmentRenal impairment caution in renal failure; metabolitemay accumulate; consider reducing maintenancedose in significant impairmentPregnancy see Pregnancy, p. 216Breast-feeding present in milk, but limited data suggestno harmful effect on infant; see also Breastfeeding,p. 217Side-effects nausea, vomiting, diarrhoea, dry mouth,aggression, agitation, headache, drowsiness, dizziness,tremor, insomnia, ataxia, back pain, arthralgia,nystagmus, diplopia, blurred vision, rash (see SkinReactions, below); rarely conjunctivitis; very rarelyhepatic failure, movement disorders, unsteadiness,increase in seizure frequency, confusion, hallucination,blood disorders (including anaemia, leucopenia,thrombocytopenia, pancytopenia—see Blood Disorders,above), hypersensitivity syndrome (possiblyincluding rash, fever, facial oedema, lymphadenopathy,hepatic dysfunction, blood disorders, disseminatedintravascular coagulation, and multi-organdysfunction), lupus erythematosus-like reactions; alsoreported suicidal ideation, aseptic meningitisSkin reactions Serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis havedeveloped especially in children; most rashes occur in thefirst 8 weeks. Rash is sometimes associated with hypersensitivitysyndrome (see Side-effects, above) and is morecommon in patients with history of allergy or rash from otherantiepileptic drugs. Consider withdrawal if rash or signs ofhypersensitivity syndrome develop. Factors associated withincreased risk of serious skin reactions include concomitantuse of valproate, initial lamotrigine dosing higher thanrecommended, and more rapid dose escalation thanrecommended.Counselling Warn children and their carers to see theirdoctor immediately if rash or signs or symptoms of hypersensitivitysyndrome developIndication and doseMonotherapy and adjunctive treatment of focalseizures and primary and secondary generalisedtonic-clonic seizures; seizures associatedwith Lennox-Gastaut syndrome. By mouthAdjunctive therapy of seizures with valproateChild 2–12 years initially 150 micrograms/kgonce daily for 14 days (those weighing under 13 kgmay receive 2 mg on alternate days for first 14days) then 300 micrograms/kg once daily forfurther 14 days, thereafter increased by max. of300 micrograms/kg every 7–14 days; usual maintenance1–5 mg/kg daily in 1–2 divided doses(max. single dose 100 mg)4 Central nervous system

222 4.8.1 Control of the epilepsies BNFC 2011–20124 Central nervous systemChild 12–18 years initially 25 mg on alternatedays for 14 days then 25 mg daily for further 14days, thereafter increased by max. 50 mg every 7–14 days; usual maintenance 100–200 mg daily in1–2 divided dosesAdjunctive therapy of seizures (with enzymeinducing drugs) without valproateChild 2–12 years initially 300 micrograms/kgtwice daily for 14 days then 600 micrograms/kgtwice daily for further 14 days, thereafter increasedby max. 1.2 mg/kg every 7–14 days; usual maintenance2.5–7.5 mg/kg (max. single dose 200 mg)twice dailyChild 12–18 years initially 50 mg daily for 14days then 50 mg twice daily for further 14 days,thereafter increased by max. 100 mg every 7–14days; usual maintenance 100–200 mg twice daily(up to 700 mg daily has been required)Adjunctive therapy of seizures (withoutenzyme inducing drugs) without valproateChild 2–12 years initially 300 micrograms/kgdaily in 1–2 divided doses for 14 days then600 micrograms/kg daily in 1–2 divided doses forfurther 14 days, thereafter increased by max.600 micrograms/kg every 7–14 days; usual maintenance1–10 mg/kg daily in 1–2 divided doses;max. 200 mg dailyChild 12–18 years initially 25 mg daily for 14days, increased to 50 mg daily for further 14 days,then increased by max. 100 mg every 7–14 days;usual maintenance 100–200 mg daily in 1–2divided dosesMonotherapy of seizuresChild 12–18 years initially 25 mg daily for 14days, increased to 50 mg daily for further 14 days,then increased by max. 100 mg every 7–14 days;usual maintenance as monotherapy, 100–200 mgdaily in 1–2 divided doses (up to 500 mg daily hasbeen required)Monotherapy of typical absence seizures. By mouthChild 2–12 years initially 300 micrograms/kgdaily in 1–2 divided doses for 14 days, then600 micrograms/kg daily in 1–2 divided doses forfurther 14 days, thereafter increased by max.600 micrograms/kg every 7–14 days; usual maintenance1–10 mg/kg daily in 1–2 divided doses (upto 15 mg/kg daily has been required)Note Dose titration should be repeated if restarting afterinterval of more than 5 daysSafe PracticeDo not confuse the different combinations; see alsonotes aboveLamotrigine (Non-proprietary) TATablets, lamotrigine 25 mg, net price 56-tab pack =£2.25; 50 mg, 56-tab pack = £3.07; 100 mg, 56-tabpack = £4.53; 200 mg, 30-tab pack = £27.53, 56-tabpack = £7.51. Label: 8, counselling, driving (see notesabove), skin reactions (see above)Dispersible tablets, lamotrigine 5 mg, net price 28-tab pack = £2.27; 25 mg, 56-tab pack = £2.91; 100 mg,56-tab pack = £5.86. Label: 8, 13, counselling, driving(see notes above), skin reactions (see above)Lamictal c (GSK) TATablets, yellow, lamotrigine 25 mg, net price 56-tabpack = £19.61; 50 mg, 56-tab pack = £33.35; 100 mg,56-tab pack = £57.53; 200 mg, 56-tab pack = £97.79.Label: 8, counselling, driving (see notes above), skinreactions (see above)Dispersible tablets, chewable, lamotrigine 2 mg, netprice 30-tab pack = £10.45; 5 mg, 28-tab pack = £7.82;25 mg, 56-tab pack = £19.61; 100 mg, 56-tab pack =£57.53. Label: 8, 13, counselling, driving (see notesabove), skin reactions (see above)LevetiracetamLevetiracetam is used for monotherapy and adjunctivetreatment of focal seizures with or without secondarygeneralisation, and for adjunctive treatment of myoclonicseizures in children with juvenile myoclonic epilepsy,and primary generalised tonic-clonic seizures.LEVETIRACETAMCautions avoid abrupt withdrawal; interactions:Appendix 1 (levetiracetam)Hepatic impairment halve dose in severe hepaticimpairment if estimated glomerular filtration rate lessthan 60 mL/minute/1.73 m 2Renal impairment reduce dose if estimated glomerularfiltration rate less than 80 mL/minute/1.73 m 2(consult product literature)Pregnancy see Pregnancy, p. 216Breast-feeding present in milk—manufactureradvises avoid; see also Breast-feeding, p. 217Side-effects anorexia, weight changes, abdominalpain, nausea, vomiting, dyspepsia, diarrhoea, cough,drowsiness, amnesia, ataxia, convulsion, dizziness,headache, tremor, hyperkinesia, malaise, impairedattention, aggression, agitation, depression, insomnia,anxiety, irritability, personality disorder, thrombocytopenia,myalgia, diplopia, blurred vision, rash; alsoreported pancreatitis, hepatic failure, paraesthesia,confusion, hallucinations, psychosis, suicidal ideation,leucopenia, neutropenia, pancytopenia, alopecia,toxic epidermal necrolysis, Stevens-JohnsonsyndromeIndication and doseMonotherapy of focal seizures with or withoutsecondary generalisation. By mouth or by intravenous infusionNote If switching between oral therapy and intravenoustherapy (for those temporarily unable to take oral medication),the intravenous dose should be the same as theestablished oral doseChild 16–18 years initially 250 mg once dailyincreased after 1 week to 250 mg twice daily;thereafter, increased according to response insteps of 250 mg twice daily every 2 weeks; max.1.5 g twice dailyAdjunctive therapy of focal seizures with orwithout secondary generalisation. By mouthChild 1–6 months initially 7 mg/kg once daily,increased gradually by max. 7 mg/kg twice dailyevery 2 weeks; max. 21 mg/kg twice daily

BNFC 2011–2012 4.8.1 Control of the epilepsies 223Child 6 months–18 years, body-weight under50 kg initially 10 mg/kg once daily, increasedgradually by max. 10 mg/kg twice daily every 2weeks; max. 30 mg/kg twice dailyChild 12–18 years, body-weight over 50 kginitially 250 mg twice daily, increased gradually by500 mg twice daily every 2 weeks; max. 1.5 g twicedaily. By intravenous infusionNote If switching between oral therapy and intravenoustherapy (for those temporarily unable to take oral medication),the intravenous dose should be the same as theestablished oral doseChild 4–18 years, body-weight under 50 kginitially 10 mg/kg once daily, increased graduallyby max. 10 mg/kg twice daily every 2 weeks; max.30 mg/kg twice dailyChild 12–18 years, body-weight over 50 kginitially 250 mg twice daily, increased gradually by500 mg twice daily every 2 weeks; max. 1.5 g twicedailyAdjunctive therapy of myoclonic seizures andtonic-clonic seizures. By mouth or by intravenous infusionNote If switching between oral therapy and intravenoustherapy (for those temporarily unable to take oral medication),the intravenous dose should be the same as theestablished oral doseChild 12–18 years, body-weight under 50 kginitially 10 mg/kg once daily, increased graduallyby max. 10 mg/kg twice daily every 2 weeks; max.30 mg/kg twice dailyChild 12–18 years, body-weight over 50 kginitially 250 mg twice daily, increased gradually by500 mg twice daily every 2 weeks; max. 1.5 g twicedailyAdministration for intravenous infusion, dilute requisitedose with at least 100 mL Glucose 5% or SodiumChloride 0.9%; give over 15 minutesFor administration of oral solution, requisite dosemay be diluted in a glass of waterKeppra c (UCB Pharma) ATablets, f/c, levetiracetam 250 mg (blue), net price60-tab pack = £29.70; 500 mg (yellow), 60-tab pack =£52.30; 750 mg (orange), 60-tab pack = £89.10; 1 g(white), 60-tab pack = £101.10. Label: 8Oral solution, sugar-free, levetiracetam 100 mg/mL,net price 150 mL (with 1-mL or 3-mL syringe) =£42.60, 300 mL (with 10-ml syringe) = £71.00. Label: 8Concentrate for intravenous infusion, levetiracetam100 mg/mL, net price 5-mL vial = £13.50Electrolytes Na + 0.83 mmol/vialNote For dilution before usePhenobarbital and primidonePhenobarbital is effective for tonic-clonic, focal seizuresand neonatal seizures but may cause behaviouraldisturbances and hyperkinesia. It may be tried for atypicalabsence, atonic, and tonic seizures. For therapeuticpurposes phenobarbital and phenobarbital sodiumshould be considered equivalent in effect. Reboundseizures may be a problem on withdrawal. Monitoringthe plasma concentration is less useful than with otherdrugs because tolerance occurs.Primidone is largely converted to phenobarbital andthis is probably responsible for its antiepileptic action. Itis used rarely in children. A low initial dose of primidoneis essential.PHENOBARBITAL(Phenobarbitone)Cautions see also notes above; debilitated; respiratorydepression (avoid if severe); avoid abrupt withdrawal(dependence with prolonged use); history of drug andalcohol abuse; consider vitamin D supplementation inpatients who are immobilised for long periods or whohave inadequate sun exposure or dietary intake ofcalcium; avoid in acute porphyria (see section 9.8.2);interactions: see p. 215 and Appendix 1 (barbiturates)Hepatic impairment may precipitate coma; avoid insevere impairmentRenal impairment use with cautionPregnancy see Pregnancy, p. 216Breast-feeding avoid if possible; drowsiness mayoccur; see also Breast-feeding, p. 217Side-effects hepatitis, cholestasis; hypotension; respiratorydepression; drowsiness, lethargy, depression,ataxia, behavioural disturbances, nystagmus, irritability,hallucinations, impaired memory and cognition,hyperactivity; osteomalacia (see Cautions);megaloblastic anaemia (may be treated with folicacid), agranulocytosis, thrombocytopenia; allergicskin reactions; very rarely Stevens-Johnson syndromeand toxic epidermal necrolysis; suicidal ideation;overdosage: see Emergency Treatment of Poisoning,p. 25Pharmacokinetics trough plasma concentration foroptimum response 15–40 mg/litre (60–180 micromol/litre)Indication and doseAll forms of epilepsy except typical absenceseizures. By mouth or by intravenous injectionNeonate initially 20 mg/kg by slow intravenousinjection then 2.5–5 mg/kg once daily either byslow intravenous injection or by mouth; dose andfrequency adjusted according to response. By mouthChild 1 month–12 years initially 1–1.5 mg/kgtwice daily, increased by 2 mg/kg daily as required;usual maintenance dose 2.5–4 mg/kg once ortwice dailyChild 12–18 years 60–180 mg once dailyStatus epilepticus section 4.8.2Note For therapeutic purposes phenobarbital and phenobarbitalsodium may be considered equivalent in effectAdministration for administration by mouth, tabletsmay be crushedFor intravenous injection, dilute to a concentration of20 mg/mL with Water for Injections; give over 20minutes (no faster than 1 mg/kg/minute)4 Central nervous system

224 4.8.1 Control of the epilepsies BNFC 2011–20124 Central nervous systemPhenobarbital (Non-proprietary) 3Tablets, phenobarbital 15 mg, net price 28-tab pack =95p; 30 mg, 28-tab pack = 96p; 60 mg, 28-tab pack =71p. Label: 2, 8, counselling, driving (see notes above)Elixir, phenobarbital 15 mg/5 mL in a suitable flavouredvehicle, containing alcohol 38%, net price100 mL = 78p. Label: 2, 8, counselling, driving (seenotes above)Note Some hospitals supply alcohol-free formulations ofvarying phenobarbital strengthsInjection, phenobarbital sodium 15 mg/mL, net price1-mL amp = £1.64; 30 mg/mL, 1-mL amp = £2.04;60 mg/mL, 1-mL amp = £2.14; 200 mg/mL, 1-mLamp = £2.00Excipients include propylene glycol (see Excipients, p. 2)Note Must be diluted before intravenous administration (seeAdministration)PRIMIDONECautions see Phenobarbital; interactions: see p. 215and Appendix 1 (primidone)Hepatic impairment reduce dose, may precipitatecomaRenal impairment see PhenobarbitalPregnancy see PhenobarbitalBreast-feeding see PhenobarbitalSide-effects see Phenobarbital; also nausea, visualdisturbances; less commonly vomiting, headache,dizziness; rarely psychosis, lupus erythematosus,arthralgia; also reported Dupuytren’s contracturePharmacokinetics monitor plasma concentrationsof derived phenobarbital. Optimum range as forphenobarbitalIndication and doseAll forms of epilepsy except absence seizures(but see notes above). By mouthChild under 2 years initially 125 mg daily atbedtime, increased by 125 mg every 3 daysaccording to response; usual maintenance, 125–250 mg twice dailyChild 2–5 years initially 125 mg daily at bedtime,increased by 125 mg every 3 days according toresponse; usual maintenance, 250–375 mg twicedailyChild 5–9 years initially 125 mg daily at bedtime,increased by 125 mg every 3 days according toresponse; usual maintenance, 375–500 mg twice adayChild 9–18 years initially 125 mg daily at bedtime,increased by 125 mg every 3 days to 250 mgtwice daily, then increased according to responseby 250 mg every 3 days to max. 750 mg twice dailyMysoline c (Acorus) ATablets, scored, primidone 50 mg, net price 100-tabpack = £12.60; 250 mg, 100-tab pack = £12.60.Label: 2, 8, counselling, driving (see notes above)PhenytoinPhenytoin is effective for tonic-clonic, focal, and neonatalseizures but it may worsen myoclonus. It has anarrow therapeutic index and the relationship betweendose and plasma-drug concentration is non-linear; smalldosage increases in some children may produce largeincreases in plasma concentration with acute toxic sideeffects.Similarly, a few missed doses or a small changein drug absorption may result in a marked change inplasma concentration. Monitoring of plasma concentrationimproves dosage adjustment. Symptoms of phenytointoxicity include nystagmus, diplopia, slurredspeech, ataxia, confusion, and hyperglycaemia.Phenytoin may cause coarsening of the facial appearance,acne, hirsutism, and gingival hyperplasia and somay be particularly undesirable in adolescent patients.When only parenteral administration is possible,fosphenytoin (section 4.8.2), a pro-drug of phenytoin,may be convenient to give. Whereas phenytoin shouldbe given intravenously only, fosphenytoin may also begiven by intramuscular injection.PHENYTOINCautions see notes above; cross-sensitivity reportedwith cabamazepine; avoid abrupt withdrawal; HLA-B*1502 allele in individuals of Han Chinese or Thaiorigin – avoid unless essential (increased risk of Stevens–Johnsonsyndrome); manufacturer recommendsblood counts (but evidence of practical value uncertain);consider vitamin D supplementation in patientsthat are immobilised for long periods or who haveinadequate sun exposure or dietary intake of calcium;enteral feeding (interrupt feeding for 2 hours beforeand after dose; more frequent monitoring may benecessary); avoid in acute porphyria (section 9.8.2);interactions: see p. 215 and Appendix 1 (phenytoin)Blood or skin disorders Children and their carers should betold how to recognise signs of blood or skin disorders, andadvised to seek immediate medical attention if symptomssuch as fever, rash, mouth ulcers, bruising, or bleedingdevelop. Leucopenia which is severe, progressive, or associatedwith clinical symptoms requires withdrawal (ifnecessary under cover of a suitable alternative)Hepatic impairment reduce dosePregnancy changes in plasma-protein binding makeinterpretation of plasma-phenytoin concentrationsdifficult—monitor unbound fraction; see alsoPregnancy, p. 216Breast-feeding small amounts present in milk, but notknown to be harmful; see also Breast-feeding, p. 217Side-effects nausea, vomiting, constipation; drowsiness,insomnia, transient nervousness, tremor,paraesthesia, dizziness, headache, anorexia; gingivalhypertrophy and tenderness (maintain good oralhygiene); rash (discontinue; if mild reintroduce cautiouslybut discontinue immediately if recurrence),acne, hirsutism, coarsening of facial appearance;rarely hepatoxicity (discontinue immediately and donot readminister), peripheral neuropathy, dyskinesia,lymphadenopathy, osteomalacia (see Cautions), blooddisorders (including megaloblastic anaemia, leucopenia,thrombocytopenia, and aplastic anaemia),polyarteritis nodosa, lupus erythematosus, Stevens-Johnson syndrome, and toxic epidermal necrolysis;also reported polyarthropathy, pneumonitis, interstitialnephritis; suicidal ideationPharmacokinetics therapeutic plasma-phenytoinconcentrations reduced in first 3 months of lifebecause of reduced protein bindingTrough plasma concentration for optimumresponse:Neonate–3 months, 6–15 mg/litre (25–60 micromol/litre)

BNFC 2011–2012 4.8.1 Control of the epilepsies 225Child 3 months–18 years, 10–20 mg/litre (40–80 micromol/litre)Licensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseAll forms of epilepsy except absence seizures. By intravenous injection (over 20–30 minutes)and by mouthNeonate initial loading dose by slow intravenousinjection (section 4.8.2) 18 mg/kg then by mouth2.5–5 mg/kg twice daily adjusted according toresponse and plasma-phenytoin concentration(usual max. 7.5 mg/kg twice daily). By mouthChild 1 month–12 years initially 1.5–2.5 mg/kgtwice daily, then adjusted according to responseand plasma-phenytoin concentration to 2.5–5 mg/kg twice daily (usual max. 7.5 mg/kg twice daily or300 mg daily)Child 12–18 years initially 75–150 mg twice dailythen adjusted according to response and plasmaphenytoinconcentration to 150–200 mg twicedaily (usual max. 300 mg twice daily)Status epilepticus, acute symptomatic seizuresassociated with head trauma or neurosurgerysection 4.8.2Administration for administration by mouth, interruptenteral feeds for at least 1–2 hours before and aftergiving phenytoin; give with water to enhanceabsorptionFor administration by intravenous injection andintravenous infusion, see p. 235Phenytoin (Non-proprietary) ATablets, coated, phenytoin sodium 100 mg, net price28-tab pack = £30.00. Label: 8, counselling, administration,blood or skin disorder symptoms (seeabove), driving (see notes above)Note On the basis of single dose tests there are no clinicallyrelevant differences in bioavailability between availablephenytoin sodium tablets and capsules but there may be apharmacokinetic basis for maintaining the same brand ofphenytoin in some patientsEpanutin c (Pfizer) ACapsules, phenytoin sodium 25 mg (white/purple),net price 28-cap pack = 66p; 50 mg (white/pink), 28-cap pack = 67p; 100 mg (white/orange), 84-cap pack= £2.83; 300 mg (white/green), 28-cap pack = £2.83.Label: 8, counselling, administration, blood or skindisorder symptoms (see above), driving (see notesabove)Chewable tablets (Infatabs c ), yellow, scored,phenytoin 50 mg, net price 112 = £7.38. Label: 8, 24,counselling, blood or skin disorder symptoms (seeabove), driving (see notes above)Note Contain phenytoin 50 mg (as against phenytoin sodium)therefore care is needed on changing to capsules ortablets containing phenytoin sodiumSuspension, red, phenytoin 30 mg/5 mL, net price500 mL = £4.27. Label: 8, counselling, administration,blood or skin disorder symptoms (see above), driving(see notes above)Note Suspension of phenytoin 90 mg in 15 mL may beconsidered to be approximately equivalent in therapeuticeffect to capsules or tablets containing phenytoin sodium100 mg, but nevertheless care is needed in making changesParenteral preparationsSection 4.8.2RufinamideRufinamide is licensed for the adjunctive treatment ofseizures in Lennox-Gastaut syndrome.The Scottish Medicines Consortium (p. 3) has advised(October 2008) that rufinamide (Inovelon c ) is acceptedfor restricted use within NHS Scotland as adjunctivetherapy in the treatment of seizures associated withLennox-Gastaut syndrome in patients 4 years andabove. It is restricted for use when alternative traditionalantiepileptic drugs are unsatisfactory.RUFINAMIDECautions closely monitor and consider withdrawal ifrash, fever, or other signs of hypersensitivitysyndrome (see Side-effects) develop; avoid abruptwithdrawal; interactions: see p. 215 and Appendix 1(rufinamide)Hepatic impairment caution and careful dose titrationin mild to moderate impairment; avoid in severeimpairmentPregnancy see Pregnancy, p. 216Breast-feeding manufacturer advises avoid—noinformation available; see also Breast-feeding, p. 217Side-effects nausea, vomiting, constipation, diarrhoea,dyspepsia, abdominal pain; rhinitis, epistaxis;weight loss, anorexia, dizziness, headache, drowsiness,insomnia, anxiety, fatigue, increase in seizurefrequency, impaired coordination, hyperactivity, tremor,gait disturbances; influenza-like symptoms; oligomenorrhoea;back pain; nystagmus, diplopia,blurred vision; rash, and acne; hypersensitivitysyndrome (possibly including rash, fever, lymphadenopathy,hepatic dysfunction, haematuria, and multiorgandysfunction) also reportedHypersensitivity syndrome Serious hypersensitivitysyndrome (see above) has developed especially in childrenand upon initiation of therapy; consider withdrawal if rash orsigns or symptoms of hypersensitivity syndrome developCounselling Warn children and their carers to seekimmediate medical attention if signs or symptoms ofhypersensitivity syndrome developIndication and doseAdjunctive treatment of seizures in Lennox-Gastaut syndrome. By mouthChild 4–18 years body-weight less than 30 kg,initially 100 mg twice daily increased according toresponse in steps of 100 mg twice daily up to every2 days; max. 500 mg twice daily (max. 300 mgtwice daily if adjunctive therapy with valproate)Child 4–18 years body-weight over 30 kg, initially200 mg twice daily increased according toresponse in steps of 200 mg twice daily up to every2 days; body-weight 30–50 kg max. 900 mg twicedaily; body-weight 50–70 kg max. 1.2 g twice daily;body-weight over 70 kg max. 1.6 g twice dailyAdministration Tablets may be crushed and given in half aglass of waterInovelon c (Eisai) TATablets, pink, f/c, scored, rufinamide 100 mg, netprice 10-tab pack = £5.15; 200 mg, 60-tab pack =4 Central nervous system

226 4.8.1 Control of the epilepsies BNFC 2011–20124 Central nervous system£61.77; 400 mg, 60-tab pack = £102.96. Label: 21,counselling, driving (see notes above), hypersensitivitysyndrome (see above)StiripentolStiripentol is licensed for use in combination with clobazamand valproate as adjunctive therapy of refractorygeneralised tonic-clonic seizures in children with severemyoclonic epilepsy in infancy (Dravet Syndrome). Itshould be used under specialist supervision.STIRIPENTOLCautions perform full blood count and liver functiontests prior to initiating treatment and every 6 monthsthereafter; monitor growth; interactions: Appendix 1(stiripentol)Contra-indications history of psychosisHepatic impairment avoid—no information availableRenal impairment avoid—no information availablePregnancy see Pregnancy, p. 216Breast-feeding present in milk in animal studies; seealso Breast-feeding, p. 217Side-effects nausea, vomiting; aggression, anorexia,ataxia, drowsiness, dystonia, hyperexcitability, hyperkinesia,hypotonia, irritability, sleep disorders, weightloss; neutropenia; less commonly fatigue, photosensitivity,rash, and urticariaIndication and doseSevere myoclonic epilepsy in infancy. By mouthChild 3–18 years initially 10 mg/kg in 2–3divided doses; titrate dose over minimum of 3 daysto max. 50 mg/kg/day in 2–3 divided dosesDiacomit c (Alan Pharmaceuticals) TACapsules, stiripentol 250 mg (pink), net price 60-cappack = £284.00; 500 mg (white), 60-cap pack =£493.00. Label: 1, 8, 21, counselling, administrationPowder, stiripentol 250 mg, net price 60-sachet pack= £284.00; 500 mg, 60-sachet pack = £493.00.Label: 1, 8, 13, 21, counselling, administrationExcipients include aspartame (section 9.4.1)Counselling Do not take with milk, diary products, carbonateddrinks, fruit juice, or with food or drink that contains caffeineTiagabineTiagabine is used as adjunctive treatment for focalseizures with or without secondary generalisation thatare not satisfactorily controlled by other antiepileptics.TIAGABINECautions avoid in acute porphyria (section 9.8.2);avoid abrupt withdrawal; interactions: Appendix 1(tiagabine)Driving May impair performance of skilled tasks (e.g. driving)Hepatic impairment in mild to moderate impairmentreduce dose, prolong the dose interval, or both; avoidin severe impairmentPregnancy see Pregnancy, p. 216Breast-feeding manufacturer advises use only ifpotential benefit outweighs risk; see also Breastfeeding,p. 217Side-effects diarrhoea; dizziness, tiredness, nervousness,tremor, impaired concentration, emotional lability,speech impairment; rarely confusion, depression,drowsiness, psychosis, non-convulsive status epilepticus,bruising, and visual disturbances; suicidalideation; leucopenia also reportedIndication and doseAdjunctive treatment for focal seizures with orwithout secondary generalisation not satisfactorilycontrolled by other antiepileptics. By mouthWith enzyme-inducing drugsChild 12–18 years initially 5–10 mg in 1–2divided doses, increased in steps of 5–10 mg dailyat weekly intervals; usual maintenance dose 30–45 mg daily in 2–3 divided dosesWithout enzyme-inducing drugsChild 12–18 years initially 5–10 mg in 1–2divided doses, increased in steps of 5–10 mg dailyat weekly intervals; initial maintenance dose 15–30 mg daily in 2–3 divided dosesGabitril c (Cephalon) ATablets, f/c, tiagabine (as hydrochloride) 5 mg, netprice 100-tab pack = £40.89; 10 mg, 100-tab pack =£81.77; 15 mg, 100-tab pack = £122.66. Label: 21TopiramateTopiramate can be given alone or as adjunctive treatmentin generalised tonic-clonic seizures or focal seizureswith or without secondary generalisation. It canalso be used as adjunctive treatment for seizures associatedwith Lennox-Gastaut syndrome. Topiramate isalso licensed for prophylaxis of migraine (section4.7.4.2).TOPIRAMATECautions avoid abrupt withdrawal; risk of metabolicacidosis; risk of nephrolithiasis—ensure adequatehydration (especially in strenuous activity or warmenvironment); avoid in acute porphyria (section 9.8.2);interactions: see p. 215 and Appendix 1 (topiramate)Important Topiramate has been associated with acutemyopia with secondary angle-closure glaucoma, typicallyoccurring within 1 month of starting treatment. Choroidaleffusions resulting in anterior displacement of the lens andiris have also been reported. If raised intra-ocular pressureoccurs:. seek specialist ophthalmological advice;. use appropriate measures to reduce intra-ocular pressure;. stop topiramate as rapidly as feasibleHepatic impairment use with caution in moderate tosevere impairment—clearance may be reducedRenal impairment use with caution if estimatedglomerular filtration rate less than 60 mL/minute/1.73m 2 —reduced clearance and longer time to steady-stateplasma concentrationPregnancy see Pregnancy, p. 216Breast-feeding manufacturer advises avoid—presentin milk; see also Breast-feeding, p. 217

BNFC 2011–2012 4.8.1 Control of the epilepsies 227Side-effects nausea, diarrhoea, vomiting, constipation,dyspepsia, abdominal pain, dry mouth, tastedisturbance, gastritis, appetite changes, dyspnoea,impaired attention, cognitive impairment, movementdisorders, seizures, tremor, malaise, impaired coordination,speech disorder, drowsiness, dizziness, sleepdisturbance, anxiety, confusion, paraesthesia, aggression,mood changes, depression, agitation, irritability,nephrolithiasis, urinary disorders, anaemia, arthralgia,muscle spasm, myalgia, muscular weakness, visualdisturbances, nystagmus, tinnitus, epistaxis, alopecia,rash, pruritus; less commonly pancreatitis, flatulence,abdominal distension, gingival bleeding, salivation,halitosis, thirst, glossodynia, bradycardia, palpitation,hypotension, postural hypotension, flushing, alteredsense of smell, peripheral neuropathy, suicidal ideation,psychosis, panic attack, influenza-like symptoms,sexual dysfunction, urinary calculus, haematuria,blood disorders (including leucopenia, neutropenia,and thrombocytopenia), hypokalaemia, metabolicacidosis, dry eye, photophobia, blepharospasm,increased lacrimation, mydriasis, hearing loss,reduced sweating, skin discoloration; rarelyRaynaud’s syndrome, periorbital oedema, unilateralblindness, Stevens-Johnson syndrome, abnormal skinodour, calcinosis; very rarely angle-closure glaucoma;also reported hepatitis, hepatic failure, encephalopathy,hyperammonaemia, maculopathy, toxic epidermalnecrolysisLicensed use not licensed for use in children formigraine prophylaxisIndication and doseMonotherapy of generalised tonic-clonic seizuresor focal seizures with or without secondarygeneralisation. By mouthChild 6–18 years initially 0.5–1 mg/kg (max.25 mg) at night for 1 week then increased in stepsof 250–500 micrograms/kg (max. 25 mg) twicedaily at intervals of 1–2 weeks; initial target dose50 mg twice daily; max. 7.5 mg/kg (max. 250 mg)twice dailyAdjunctive treatment of generalised tonicclonicseizures or focal seizures with or withoutsecondary generalisation, adjunctive treatmentof seizures in Lennox-Gastaut syndrome. By mouthChild 2–18 years initially 1–3 mg/kg (max.25 mg) at night for 1 week then increased in stepsof 0.5–1.5 mg/kg (max. 25 mg) twice daily atintervals of 1–2 weeks; usual dose 2.5–4.5 mg/kgtwice daily; max. 7.5 mg/kg (max. 200 mg) twicedailyMigraine prophylaxis. By mouthChild 16–18 years initially 25 mg daily at night for1 week then increased in steps of 25 mg daily atintervals of 1 week; usual dose 50–100 mg daily in2 divided doses; max. 200 mg dailyNote If child cannot tolerate titration regimens recommendedabove then smaller steps or longer interval betweensteps may be usedTopiramate (Non-proprietary) TATablets, topiramate 25 mg, net price 60-tab pack =£6.17; 50 mg, 60-tab pack = £10.74; 100 mg, 60-tabpack = £12.52; 200 mg, 60-tab pack = £17.21. Label: 3,8, counselling, driving (see notes above)Capsules, topiramate 15 mg, net price 60-cap pack =£16.61; 25 mg, 60-cap pack = £24.91; 50 mg, 60-cappack = £40.93. Label: 3, 8, counselling, driving (seenotes above)Topamax c (Janssen) TATablets, f/c, topiramate 25 mg, net price 60-tab pack= £19.29; 50 mg (light yellow), 60-tab pack = £31.69;100 mg (yellow), 60-tab pack = £56.76; 200 mg (salmon),60-tab pack = £110.23. Label: 3, 8, counselling,driving (see notes above)Sprinkle capsules, topiramate 15 mg, net price 60-cap pack = £14.79; 25 mg, 60-cap pack = £22.18;50 mg, 60-cap pack = £36.45. Label: 3, 8, counselling,administration, driving (see notes above)Counselling Swallow whole or sprinkle contents of capsuleon soft food and swallow immediately without chewingValproateValproate (as either sodium valproate or valproic acid)is effective in controlling tonic-clonic seizures, particularlyin primary generalised epilepsy. It is a drug ofchoice in primary generalised epilepsy, generalisedabsences and myoclonic seizures, and can be tried inatypical absence, atonic, and tonic seizures. Valproateshould generally be avoided in children under 2 yearsespecially with other antiepileptics, but it may berequired in infants with continuing epileptic tendency.Sodium valproate has widespread metabolic effects, andmonitoring is essential (see Cautions below).Valproic acid (as semisodium valproate) is licensed inadults for acute mania associated with bipolar disorder.SODIUM VALPROATECautions see notes above; monitor liver functionbefore therapy and during first 6 months especially inchildren most at risk (see also below); measure fullblood count and ensure no undue potential forbleeding before starting and before surgery; systemiclupus erythematosus; false-positive urine tests forketones; avoid sudden withdrawal; consider vitamin Dsupplementation in patients that are immobilised forlong periods or who have inadequate sun exposure ordietary intake of calcium; interactions: see p. 215and Appendix 1 (valproate)Liver toxicity Liver dysfunction (including fatal hepatic failure)has occurred in association with valproate (especially inchildren under 3 years and in those with metabolic ordegenerative disorders, organic brain disease or severe seizuredisorders associated with mental retardation) usually infirst 6 months and usually involving multiple antiepileptictherapy. Raised liver enzymes during valproate treatment areusually transient but children should be reassessed clinicallyand liver function (including prothrombin time) monitoreduntil return to normal—discontinue if abnormally prolongedprothrombin time (particularly in association with otherrelevant abnormalities)Blood or hepatic disorders Children and their carers shouldbe told how to recognise signs of blood or liver disorders andadvised to seek immediate medical attention if symptomsdevelopPancreatitis Children and their carers should be told how torecognise signs and symptoms of pancreatitis and advised toseek immediate medical attention if symptoms such asabdominal pain, nausea, or vomiting develop; discontinue ifpancreatitis is diagnosed4 Central nervous system

228 4.8.1 Control of the epilepsies BNFC 2011–20124 Central nervous systemContra-indications family history of severe hepaticdysfunction; acute porphyria (section 9.8.2)Hepatic impairment avoid if possible—hepatotoxicityand hepatic failure may occasionally occur(usually in first 6 months); avoid in active liver disease;see also under CautionsRenal impairment reduce dose; adjust dosageaccording to free serum valproic acid concentrationPregnancy see Pregnancy, p. 216; neonatal bleeding(related to hypofibrinaemia) and neonatal hepatotoxicityalso reportedBreast-feeding amount too small to be harmful; seealso Breast-feeding, p. 217Side-effects nausea, gastric irritation, diarrhoea;weight gain; hyperammonaemia, thrombocytopenia;transient hair loss (regrowth may be curly); less frequentlyincreased alertness, aggression, hyperactivity,behavioural disturbances, ataxia, tremor, and vasculitis;rarely hepatic dysfunction (see under Cautions;withdraw treatment immediately if persistent vomitingand abdominal pain, anorexia, jaundice, oedema,malaise, drowsiness, or loss of seizure control),lethargy, drowsiness, confusion, stupor, hallucinations,blood disorders (including anaemia, leucopenia,and pancytopenia), hearing loss, and rash; very rarelypancreatitis (see under Cautions), peripheral oedema,increase in bleeding time, extrapyramidal symptoms,encephalopathy, coma, gynaecomastia, Fanconi’ssyndrome, hirsutism, enuresis, hyponatraemia, acne,toxic epidermal necrolysis, and Stevens-Johnsonsyndrome; suicidal ideation; reduced bone mineraldensity (see Cautions); also reported menstrual disturbancesIndication and doseAll forms of epilepsy. By mouth or by rectumNeonate initially 20 mg/kg once daily; usualmaintenance dose 10 mg/kg twice dailyChild 1 month–12 years initially 10–15 mg/kgdaily in 1–2 divided doses; usual maintenance dose25–30 mg/kg daily in 2 divided doses (up to60 mg/kg daily in 2 divided doses in infantilespasms; monitor clinical chemistry and haematologicalparameters if dose exceeds 40 mg/kg daily)Child 12–18 years initially 600 mg daily in 1–2divided doses increased gradually (in steps of 150–300 mg) every 3 days; usual maintenance dose 1–2 g daily in 2 divided doses; max. 2.5 g daily in 2divided doses. By intravenous administrationNote If switching from oral therapy to intravenous therapygive current oral daily dose by intravenous injectionor intermittent intravenous infusion in 2–4 divided doses,or by continuous intravenous infusionNeonate by intravenous injection 10 mg/kg twicedailyChild 1 month–12 years initially 10 mg/kg byintravenous injection, then 20–40 mg/kg daily bycontinuous intravenous infusion, or by intermittentintravenous infusion or intravenous injection in 2–4 divided dosesChild 12–18 years initially 10 mg/kg by intravenousinjection, then up to max. 2.5 g daily bycontinuous intravenous infusion, or by intermittentintravenous infusion or intravenous injection in 2–4 divided dosesAdministration for rectal administration, sodiumvalproate oral solution may be given rectally andretained for 15 minutes (may require dilution withwater to prevent rapid expulsion).For intravenous injection, may be diluted in Glucose5% or Sodium Chloride 0.9% and given over 3–5minutes.For intravenous infusion, dilute injection solution withGlucose 5% or Sodium Chloride 0.9%OralSodium Valproate (Non-proprietary) ATablets (crushable), scored, sodium valproate100 mg, net price 100 = £5.60. Label: 8, 21, counselling,pancreatitis, blood, or hepatic disorder symptoms(see above), driving (see notes above)Tablets, e/c, sodium valproate 200 mg, net price 100-tab pack = £4.83; 500 mg, 100-tab pack = £10.09.Label: 5, 8, 25, counselling, pancreatitis, blood, orhepatic disorder symptoms (see above), driving (seenotes above)Brands include Orlept cOral solution, sodium valproate 200 mg/5 mL, netprice 300 mL = £5.42. Label: 8, 21, counselling, pancreatitis,blood, or hepatic disorder symptoms (seeabove), driving (see notes above)Brands include Orlept c (sugar-free)Epilim c (Sanofi-Aventis) ATablets (crushable), scored, sodium valproate100 mg, net price 100 = £5.60. Label: 8, 21, counselling,pancreatitis, blood, or hepatic disorder symptoms(see above), driving (see notes above)Tablets, e/c, lilac, sodium valproate 200 mg, net price100 = £7.70; 500 mg, 100 = £19.25. Label: 5, 8, 25,counselling, pancreatitis, blood, or hepatic disordersymptoms (see above), driving (see notes above)Liquid, red, sugar-free, sodium valproate 200 mg/5 mL, net price 300-mL pack = £9.33. Label: 8, 21,counselling, pancreatitis, blood, or hepatic disordersymptoms (see above), driving (see notes above)Syrup, red, sodium valproate 200 mg/5 mL, net price300-mL pack = £7.78. Label: 8, 21, counselling, pancreatitis,blood, or hepatic disorder symptoms (seeabove), driving (see notes above)Note May be diluted, preferably in Syrup BP; use within 14daysModified releaseEpilim Chrono c (Sanofi-Aventis) ATablets, m/r, lilac, sodium valproate 200 mg (as sodiumvalproate and valproic acid), net price 100-tabpack = £11.65; 300 mg, 100-tab pack = £17.47;500 mg, 100-tab pack = £29.10. Label: 8, 21, 25,counselling, pancreatitis, blood, or hepatic disordersymptoms (see above), driving (see notes above)DoseChild body-weight over 20 kg as above, total daily dosegiven in 1–2 divided dosesEpilim Chronosphere c (Sanofi-Aventis) AGranules, m/r, sodium valproate 50 mg (as sodiumvalproate and valproic acid), net price 30-sachet pack= £30.00; 100 mg, 30-sachet pack = £30.00; 250 mg,30-sachet pack = £30.00; 500 mg, 30-sachet pack =£30.00; 750 mg, 30-sachet pack = £30.00; 1 g, 30-

BNFC 2011–2012 4.8.1 Control of the epilepsies 229sachet pack = £30.00. Label: 8, 21, 25, counselling,administration, pancreatitis, blood, or hepatic disordersymptoms (see above), driving (see notes above)DoseChild as above to the nearest whole 50-mg sachet; totaldaily dose given in 1–2 divided dosesCounselling Granules may be mixed with soft food or drinkthat is cold or at room temperature and swallowed immediatelywithout chewingEpisenta c (Beacon) ACapsules, enclosing m/r granules, sodium valproate150 mg, net price 100-cap pack = £7.00; 300 mg, 100-cap pack = £13.00. Label: 8, 21, 25, counselling,administration, pancreatitis, blood, or hepatic disordersymptoms (see above), driving (see notes above)DoseChild as above, total daily dose given in 1–2 divideddosesCounselling Contents of capsule may be mixed with coldfood or drink and swallowed immediately without chewingGranules, m/r, sodium valproate 500 mg, net price100-sachet pack = £21.00; 1 g, 100-sachet pack =£41.00. Label: 8, 21, 25, counselling, administration,pancreatitis, blood, or hepatic disorder symptoms (seeabove), driving (see notes above)DoseChild as above, total daily dose given in 1–2 divideddosesCounselling Granules may be mixed with cold food or drinkand swallowed immediately without chewingEpival c (Chanelle Medical) ATablets, m/r, scored, sodium valproate 300 mg, netprice 100-tab pack = £12.13; 500 mg 100-tab pack =£20.21. Label: 8, 21, 25, counselling, pancreatitis,blood, or hepatic disorder symptoms (see above),driving (see notes above)DoseChild body-weight over 20 kg as above, total daily dosegiven in 1–2 divided dosesCounselling Tablets may be halved but not crushed orchewedParenteralEpilim c Intravenous (Sanofi-Aventis) AInjection, powder for reconstitution, sodium valproate,net price 400-mg vial (with 4-mL amp waterfor injections) = £11.58Episenta c (Beacon) AInjection, sodium valproate 100 mg/mL, net price 3-mL amp = £7.00Valproic acidConvulex c (Pharmacia) ACapsules, e/c, valproic acid 150 mg, net price 100-cap pack = £3.68; 300 mg, 100-cap pack = £7.35;500 mg, 100-cap pack = £12.25. Label: 8, 21, 25,counselling, pancreatitis, blood, or hepatic disordersymptoms (see above), driving (see notes above)DoseChild as for sodium valproate, total daily dose given in 2–4 divided dosesEquivalence to Sodium valproate Manufacturer advises thatConvulex c has a 1:1 dose relationship with products containingsodium valproate, but nevertheless care is needed inmaking changesVigabatrinVigabatrin can be prescribed in combination with otherantiepileptic treatment for focal epilepsy with or withoutsecondary generalisation. It should not be prescribedunless all other appropriate drug combinations areineffective or have not been tolerated, and it shouldbe initiated and supervised by an appropriate specialist.Vigabatrin can be prescribed as monotherapy in themanagement of infantile spasms in West’s syndrome.About one-third of those treated with vigabatrin havesuffered visual field defects; counselling and carefulmonitoring for this side-effect are required (see alsoVisual Field Defects under Cautions below). Vigabatrinhas prominent behavioural side-effects in some children.VIGABATRINCautions closely monitor neurological function; avoidsudden withdrawal; history of psychosis, depressionor behavioural problems; absence seizures (may beexacerbated); interactions: see p. 215 and Appendix1 (vigabatrin)Visual field defects Vigabatrin is associated with visual fielddefects. The onset of symptoms varies from 1 month toseveral years after starting. In most cases, visual field defectshave persisted despite discontinuation, and further deteriorationafter discontinuation cannot be excluded. Productliterature advises visual field testing before treatment and at6-month intervals. Children and their carers should bewarned to report any new visual symptoms that develop andthose with symptoms should be referred for an urgentophthalmological opinion. Gradual withdrawal of vigabatrinshould be considered.Contra-indications visual field defectsRenal impairment consider reduced dose orincreased dose interval if estimated glomerular filtrationrate less than 60 mL/minute/1.73 m 2Pregnancy see Pregnancy, p. 216Breast-feeding present in milk—manufactureradvises avoid; see also Breast-feeding, p. 217Side-effects nausea, abdominal pain; oedema; drowsiness(rarely encephalopathic symptoms includingmarked sedation, stupor, and confusion with nonspecificslow wave EEG—reduce dose or withdraw),fatigue, excitation, agitation, dizziness, headache,nervousness, depression, aggression, irritability,paranoia, impaired concentration, impaired memory,tremor, paraesthesia, speech disorder, weight gain;visual field defects (see under Cautions), blurredvision, nystagmus, diplopia; less commonly ataxia,psychosis, mania, and rash; occasional increase inseizure frequency (especially if myoclonic); rarelysuicidal ideation and retinal disorders (including peripheralretinal neuropathy); very rarely hepatitis, opticneuritis and optic atrophy; also reported movementdisorders in infantile spasmsIndication and doseAdjunctive treatment of focal seizures with orwithout secondary generalisation not satisfactorilycontrolled with other antiepileptics. By mouthNeonate initially 15–20 mg/kg twice dailyincreased over 2–3 weeks to usual maintenancedose 30–40 mg/kg twice daily; max. 75 mg/kgtwice daily4 Central nervous system

230 4.8.1 Control of the epilepsies BNFC 2011–20124 Central nervous systemChild 1 month–2 years initially 15–20 mg/kgtwice daily increased over 2–3 weeks to usualmaintenance dose 30–40 mg/kg twice daily; max.75 mg/kg twice dailyChild 2–12 years initially 15–20 mg/kg (max.250 mg) twice daily increased over 2–3 weeks tousual maintenance dose 30–40 mg/kg (max. 1.5 g)twice dailyChild 12–18 years initially 250 mg twice dailyincreased over 2–3 weeks to usual maintenancedose 1–1.5 g twice dailyAdministration Tablets may be crushed and dispersed inliquid. By rectumChild 1 month–18 years dose as for oral therapy,see aboveAdministration dissolve contents of sachet in smallamount of water and administer rectallyInfantile spasms as monotherapy. By mouthNeonate initially 15–25 mg/kg twice dailyadjusted according to response over 7 days tousual maintenance dose 40–50 mg/kg twice daily;max. 75 mg/kg twice dailyChild 1 month–2 years initially 15–25 mg/kgtwice daily adjusted according to response over 7days to usual maintenance dose 40–50 mg/kgtwice daily; max. 75 mg/kg twice dailySabril c (Sanofi-Aventis) ATablets, f/c, scored, vigabatrin 500 mg, net price 100-tab pack = £30.84. Label: 3, 8, counselling, driving (seenotes above)Powder, sugar-free, vigabatrin 500 mg/sachet. Netprice 50-sachet pack = £17.08. Label: 3, 8, 13, counselling,driving (see notes above)Note The contents of a sachet should be dissolved in wateror a soft drink immediately before takingBenzodiazepinesClobazam may be used as adjunctive therapy in thetreatment of epilepsy. Clonazepam is occasionally usedin tonic-clonic or focal seizures, but its sedative sideeffectsmay be prominent. The effectiveness of clobazamand clonazepam may decrease significantly afterweeks or months of continuous therapy.Nitrazepam is used for treating infantile spasms.Hepatic impairment Benzodiazepines can precipitatecoma if used in hepatic impairment. Start with smallerinitial doses or reduce dose; avoid in severe impairment.Renal impairment Children with renal impairmenthave increased cerebral sensitivity to benzodiazepines;start with small doses in severe impairment.Pregnancy There is a risk of neonatal withdrawalsymptoms when benzodiazepines are used duringpregnancy. Avoid regular use and use only if there is aclear indication such as seizure control. High dosesadministered during late pregnancy or labour maycause neonatal hypothermia, hypotonia, and respiratorydepression.Breast-feeding Benzodiazepines are present in milk,and should be avoided if possible during breast-feeding.CLOBAZAMCautions see Diazepam, section 4.8.2Contra-indications see Diazepam, section 4.8.2Hepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see Diazepam, section 4.8.2Licensed use not licensed for use in children under 3yearsIndication and doseAdjunctive therapy for epilepsy, monotherapyunder specialist supervision for catamenial(menstruation) seizures (usually for 7–10 dayseach month, just before and during menstruation),cluster seizures. By mouthChild 1 month–12 years initially 125 micrograms/kgtwice daily increased every 5 days tousual maintenance dose of 250 micrograms/kgtwice daily; max. 500 micrograms/kg twice daily,not exceeding 15 mg twice dailyChild 12–18 years initially 10 mg twice dailyincreased every 5 days to usual maintenance doseof 10–15 mg twice daily; max. 30 mg twice daily1Clobazam (Non-proprietary) KDTablets, clobazam 10 mg. Net price 30-tab pack =£4.68. Label: 2 or 19, 8, counselling, driving (see notesabove)Brands include Frisium c DTablets, clobazam 5 mg available on a named patientbasis1. D except for epilepsy and endorsed ‘SLS’Extemporaneous formulations available seeExtemporaneous Preparations, p. 6CLONAZEPAMCautions see notes above; respiratory disease; spinalor cerebellar ataxia; myasthenia gravis (avoid ifunstable); history of alcohol or drug abuse, depressionor suicidal ideation; debilitated patients; avoid suddenwithdrawal; acute porphyria (section 9.8.2); interactions:see p. 215 and Appendix 1 (anxiolytics andhypnotics)Driving Drowsiness may affect performance of skilled tasks(e.g. driving); effects of alcohol enhancedContra-indications respiratory depression; acutepulmonary insufficiency; sleep apnoea syndrome;marked neuromuscular respiratory weakness includingunstable myasthenia gravisHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects drowsiness, fatigue, dizziness, musclehypotonia, coordination disturbances; also poor concentration,restlessness, confusion, amnesia, dependence,and withdrawal; salivary or bronchial hypersecretionin infants and small children; rarely gastrointestinalsymptoms, respiratory depression, head-

BNFC 2011–2012 4.8.2 Drugs used in status epilepticus 231ache, paradoxical effects including aggression andanxiety, sexual dysfunction, urinary incontinence,urticaria, pruritus, reversible hair loss, skin pigmentationchanges; dysarthria, and visual disturbances onlong-term treatment; blood disorders reported; overdosage:see Emergency Treatment of Poisoning, p. 30Indication and doseAll forms of epilepsy. By mouthChild 1 month–1 year initially 250 micrograms atnight for 4 nights, increased over 2–4 weeks tousual maintenance dose of 0.5–1 mg at night (maybe given in 3 divided doses if necessary)Child 1–5 years initially 250 micrograms at nightfor 4 nights, increased over 2–4 weeks to usualmaintenance of 1–3 mg at night (may be given in 3divided doses if necessary)Child 5–12 years initially 500 micrograms at nightfor 4 nights, increased over 2–4 weeks to usualmaintenance dose of 3–6 mg at night (may begiven in 3 divided doses if necessary)Child 12–18 years initially 1 mg at night for 4nights, increased over 2–4 weeks to usual maintenancedose of 4–8 mg at night (may be given in3–4 divided doses if necessary)Note Clonazepam doses in BNFC may differ from those inproduct literatureAdministration for administration by mouth, injectionsolution may be given orallyClonazepam (Non-proprietary) KTablets, clonazepam 500 micrograms, net price 100-tab pack = £3.93; 2 mg, 100 tab-pack = £5.28. Label: 2,8, counselling, driving (see notes above)Rivotril c (Roche) KTablets, both scored, clonazepam 500 micrograms(beige), net price 100-tab pack = £3.69; 2 mg (white),100-tab pack = £4.93. Label: 2, 8, counselling, driving(see notes above)Injection, section 4.8.2Liquid, clonazepam 0.5 mg/5 mL; 2 mg/5 mL;2.5 mg/mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Extemporaneous formulations available seeExtemporaneous Preparations, p. 6NITRAZEPAMCautions avoid abrupt withdrawal; respiratory disease;acute porphyria (section 9.8.2); muscle weaknessand myasthenia gravis; interactions: Appendix 1(anxiolytics and hypnotics)Contra-indications respiratory depression, acutepulmonary insufficiency, sleep apnoea syndrome;marked neuromuscular respiratory weakness includingmyasthenia gravisHepatic impairment see notes aboveRenal impairment see notes aboveSide-effects drowsiness, confusion, ataxia; see alsounder Diazepam (section 4.8.2); overdosage: seeEmergency Treatment of Poisoning, p. 30Licensed use not licensed for use in childrenIndication and doseInfantile spasms. By mouthChild 1 month–2 years initially 125 micrograms/kg twice daily, adjusted according to response over2–3 weeks to 250 micrograms/kg twice daily; max.500 micrograms/kg (not exceeding 5 mg) twicedaily; total daily dose may alternatively be given in3 divided dosesNitrazepam (Non-proprietary) KOral suspension, nitrazepam 2.5 mg/5 mL, net price150 mL = £5.09. Label: 1, 8Brands include Somnite c DOther drugsAcetazolamide (section 11.6), a carbonic anhydraseinhibitor, has a specific role in treating epilepsy associatedwith menstruation. It can also be used in conjunctionwith other antiepileptics for refractory tonicclonic,absence, or focal seizures. It is occasionallyhelpful in atypical absence, atonic, and tonic seizures.Piracetam is used as adjunctive treatment for corticalmyoclonus.4.8.2 Drugs used in statusepilepticusConvulsive status epilepticus Immediate measuresto manage status epilepticus include positioning thechild to avoid injury, supporting respiration includingthe provision of oxygen, maintaining blood pressure,and the correction of any hypoglycaemia. Pyridoxine(section 9.6.2) should be administered if the status epilepticusis caused by pyridoxine deficiency.Seizures lasting longer than 5 minutes should be treatedurgently with intravenous lorazepam and repeatedonce after 10 minutes if seizures recur or fail to respond.Intravenous diazepam is effective but it carries a highrisk of venous thrombophlebitis (reduced by using anemulsion formulation of diazepam injection). Clonazepamcan also be used as an alternative.Where facilities for resuscitation are not immediatelyavailable, midazolam can be given into the buccalcavity, or diazepam can be administered as a rectalsolution; the buccal route may be more acceptable inchildren.ImportantIf, after initial treatment with benzodiazepines, seizuresrecur or fail to respond 20 minutes after onset,phenytoin sodium, fosphenytoin, or phenobarbitalsodium should be used; the paediatric intensive careunit should be contacted.If these measures fail to control seizures 40 minutesafter onset, anaesthesia with thiopental (section15.1.1) or midazolam (section 15.1.4) should beinstituted with full intensive care support.Phenytoin sodium can be given by slow intravenousinjection, followed by the maintenance dosage if appropriate;monitor ECG and blood pressure, and reducerate of administration if bradycardia or hypotension4 Central nervous system

232 4.8.2 Drugs used in status epilepticus BNFC 2011–20124 Central nervous systemoccurs. Intramuscular phenytoin should not be used(absorption is slow and erratic).Alternatively, fosphenytoin (a pro-drug of phenytoin)can be given more rapidly, and when given intravenouslycauses fewer injection-site reactions than phenytoin.Intravenous administration requires ECG monitoring.Although it can also be given intramuscularly,absorption is too slow by this route for treatment ofstatus epilepticus. Doses of fosphenytoin should beexpressed in terms of phenytoin sodium.Paraldehyde given rectally causes little respiratorydepression and is therefore useful where facilities forresuscitation are poor.For neonatal seizures, see p. 217.Non-convulsive status epilepticus The urgency totreat non-convulsive status epilepticus depends on theseverity of the child’s condition. If there is incompleteloss of awareness, oral antiepileptic therapy should berestarted or continued. Children who fail to respond tooral antiepileptic therapy or have complete lack ofawareness can be treated in the same way as convulsivestatus epilepticus, although anaesthesia is rarelyneeded.CLONAZEPAMCautions see Clonazepam, section 4.8.1; facilities forreversing respiratory depression with mechanicalventilation must be at hand (but see also notes above)Intravenous infusion Intravenous infusion of clonazepam ispotentially hazardous (especially if prolonged), calling forclose and constant observation and best carried out inspecialist centres with intensive care facilities. Prolongedinfusion may lead to accumulation and delay recoveryContra-indications see Clonazepam, section 4.8.1;avoid injections containing benzyl alcohol in neonates(see under preparations below)Hepatic impairment see Benzodiazepines, section4.8.1Renal impairment see Benzodiazepines, section 4.8.1Pregnancy see Benzodiazepines, section 4.8.1Breast-feeding see Benzodiazepines, section 4.8.1Side-effects see Clonazepam, section 4.8.1; hypotensionand apnoeaIndication and doseStatus epilepticus. By intravenous injection over at least 2 minutesNeonate 100 micrograms/kg repeated after 24hours if necessary (avoid unless there is no saferalternative)Child 1 month–12 years 50 micrograms/kg(max. 1 mg) repeated if necessaryChild 12–18 years 1 mg repeated if necessary. By intravenous infusionChild 1 month–12 years initially 50 micrograms/kg (max. 1 mg) by intravenous injection then byintravenous infusion 10 micrograms/kg/houradjusted according to response; max. 60 micrograms/kg/hourChild 12–18 years initially 1 mg by intravenousinjection then by intravenous infusion 10 micrograms/kg/houradjusted according to response;max. 60 micrograms/kg/hourOther forms of epilepsy section 4.8.1Administration for intravenous injection, dilute to aconcentration of 500 micrograms/mL with Water forInjectionsFor intravenous infusion, dilute to a concentration of12 micrograms/mL with Glucose 5% or SodiumChloride 0.9%; incompatible with bicarbonate;adsorbed on PVC—glass infusion apparatus preferred(if PVC apparatus used, complete infusion within 2hours)Rivotril c (Roche) KInjection, clonazepam 1 mg/mL in solvent, net price1-mL amp (with 1 mL water for injections) = 60pExcipients include benzyl alcohol (avoid in neonates unless there is nosafer alternative available, see Excipients, p. 2), ethanol, propylene glycolOral preparationsSection 4.8.1DIAZEPAMCautions respiratory disease, muscle weakness andmyasthenia gravis, history of drug or alcohol abuse,marked personality disorder; avoid prolonged use(and abrupt withdrawal thereafter); when given parenterally,close observation required until full recoveryfrom sedation; when given intravenously, facilitiesfor reversing respiratory depression with mechanicalventilation must be at hand (but see also notes above);porphyria (section 9.8.2); interactions: Appendix 1(anxiolytics and hypnotics)Skilled tasks Drowsiness may affect performance of skilledtasks (e.g. driving); effects of alcohol enhancedContra-indications respiratory depression; markedneuromuscular respiratory weakness includingunstable myasthenia gravis; acute pulmonary insufficiency;sleep apnoea syndrome; not for chronic psychosis;should not be used alone in depression or inanxiety with depression; avoid injections containingbenzyl alcohol in neonates (see under preparationsbelow)Hepatic impairment see Benzodiazepines, section4.8.1Renal impairment see Benzodiazepines, section 4.8.1Pregnancy see Benzodiazepines, section 4.8.1Breast-feeding see Benzodiazepines, section 4.8.1Side-effects drowsiness and lightheadedness the nextday; confusion and ataxia; amnesia; dependence;paradoxical increase in aggression (see also section4.1); muscle weakness; occasionally: headache,vertigo, hypotension, salivation changes, gastrointestinaldisturbances, visual disturbances, dysarthria,tremor, changes in libido, incontinence, urinaryretention; blood disorders and jaundice reported; skinreactions; on intravenous injection, pain, thrombophlebitis,and rarely apnoea; overdosage: see EmergencyTreatment of Poisoning, p. 30Licensed use Diazepam Rectubes c and StesolidRectal Tubes c not licensed for use in children under1 yearIndication and doseStatus epilepticus, febrile convulsions (section4.8.3), convulsions caused by poisoning. By intravenous injection over 3–5 minutesNeonate 300–400 micrograms/kg repeated onceafter 10 minutes if necessary

BNFC 2011–2012 4.8.2 Drugs used in status epilepticus 233Child 1 month–12 years 300–400 micrograms/kg (max. 10 mg) repeated once after 10 minutes ifnecessaryChild 12–18 years 10 mg repeated once after 10minutes if necessary. By rectum (as rectal solution)Neonate 1.25–2.5 mg repeated once after 10minutes if necessaryChild 1 month–2 years 5 mg repeated once after10 minutes if necessaryChild 2–12 years 5–10 mg repeated once after 10minutes if necessaryChild 12–18 years 10–20 mg repeated once after10 minutes if necessaryMuscle spasm section 10.2.2Diazepam (Non-proprietary) KInjection (solution), diazepam 5 mg/mL, net price 2-mL amp = 45pExcipients include benzyl alcohol (avoid in neonates, see Excipients,p. 2), ethanol, propylene glycolInjection (emulsion), diazepam 5 mg/mL (0.5%), netprice 2-mL amp = 91pBrands include Diazemuls cRectal tubes (= rectal solution), diazepam 2 mg/mL,net price 1.25-mL (2.5-mg) tube = 90p, 2.5-mL (5-mg)tube = £1.41; 4 mg/mL, 2.5-mL (10-mg) tube = £1.88Brands include Diazepam Rectubes c , Stesolid cOral preparationsSection 10.2.2FOSPHENYTOIN SODIUMNote Fosphenytoin is a pro-drug of phenytoinCautions see Phenytoin Sodium; resuscitation facilitiesmust be available; interactions: see p. 215 andAppendix 1 (phenytoin)Contra-indications see Phenytoin SodiumHepatic impairment consider 10–25% reduction indose or infusion rate (except initial dose for statusepilepticus)Renal impairment consider 10–25% reduction indose or infusion rate (except initial dose for statusepilepticus)Pregnancy see Phenytoin (section 4.8.1) andPregnancy, p. 216Breast-feeding see Phenytoin (section 4.8.1)Side-effects see Phenytoin Sodium; also dry mouth,taste disturbance, vasodilatation, asthenia, euphoria,incoordination, chills, visual disturbances, tinnitus,pruritus, ecchymosis; less commonly dysarthria,hypoaesthesia, increased or decreased reflexes, stupor,muscle weakness, pain, hypoacusis; also reportedextrapyramidal disorder, twitching, confusion, hyperglycaemiaImportant Intravenous infusion of fosphenytoin has beenassociated with severe cardiovascular reactions includingasystole, ventricular fibrillation, and cardiac arrest. Hypotension,bradycardia, and heart block have also beenreported. The following are recommended:. monitor heart rate, blood pressure, and respiratoryfunction for duration of infusion;. observe patient for at least 30 minutes after infusion;. if hypotension occurs, reduce infusion rate or discontinue;. reduce dose or infusion rate in renal or hepatic impairment.Indication and doseExpressed as phenytoin sodium equivalent (PE);fosphenytoin sodium 1.5 mg : phenytoin sodium1 mgStatus epilepticus. By intravenous infusion (at a rate of 2–3 mg(PE)/kg/minute, max. 150 mg(PE)/minute)Child 5–18 years initially 20 mg(PE)/kg, then (ata rate of 1–2 mg(PE)/kg/minute, max.100 mg(PE)/minute) 4–5 mg(PE)/kg; total dailydose may be given in 1–4 divided doses; adjustedaccording to response and trough plasma-phenytoinconcentrationProphylaxis or treatment of seizures associatedwith neurosurgery or head injury. By intravenous infusion (at a rate of 1–2 mg(PE)/kg/minute, max. 100 mg(PE)/minute)Child 5–18 years initially 10–15 mg(PE)/kg then4–5 mg(PE)/kg daily; total daily dose may be givenin 1–4 divided doses; adjusted according toresponse and trough plasma-phenytoin concentrationTemporary substitution for oral phenytoin. By intravenous infusion (at a rate of 1–2 mg(PE)/kg/minute, max. 100 mg (PE)/minute)Child 5–18 years same dose and dosing frequencyas oral phenytoin therapyNote Fosphenytoin sodium doses in BNFC may differ fromthose in product literatureNote Prescriptions for fosphenytoin sodium should statethe dose in terms of phenytoin sodium equivalent (PE)Administration for intermittent intravenous infusion,dilute to a concentration of 1.5–25 mg (PE)/mL withGlucose 5% or Sodium Chloride 0.9%Pro-Epanutin c (Pfizer) AInjection, fosphenytoin sodium 75 mg/mL (equivalentto phenytoin sodium 50 mg/mL), net price 10-mLvial = £40.00Electrolytes phosphate 3.7 micromol/mg fosphenytoin sodium (phosphate5.6 micromol/mg phenytoin sodium)LORAZEPAMCautions see Diazepam; facilities for reversing respiratorydepression with mechanical ventilation must beavailableContra-indications see DiazepamHepatic impairment see Benzodiazepines, section4.8.1Renal impairment see Benzodiazepines, section 4.8.1Pregnancy see Benzodiazepines, section 4.8.1Breast-feeding see Benzodiazepines, section 4.8.1Side-effects see Diazepam; hypotension and apnoeaLicensed use not licensed for use in febrile convulsionsor convulsions caused by poisoning4 Central nervous system

234 4.8.2 Drugs used in status epilepticus BNFC 2011–20124 Central nervous systemIndication and doseStatus epilepticus, febrile convulsions (section4.8.3), convulsions caused by poisoning. By slow intravenous injectionNeonate 100 micrograms/kg as a single dose,repeated once after 10 minutes if necessaryChild 1 month–12 years 100 micrograms/kg(max. 4 mg) as a single dose, repeated once after10 minutes if necessaryChild 12–18 years 4 mg as a single dose, repeatedonce after 10 minutes if necessaryPeri-operative useSection 15.1.4.1Administration for intravenous injection, dilute withan equal volume of Sodium Chloride 0.9% (for neonates,dilute injection solution to a concentration of100 micrograms/mL)PreparationsSection 15.1.4.1MIDAZOLAMCautions see Midazolam, section 15.1.4.1Contra-indications see Midazolam, section 15.1.4.1Hepatic impairment see Midazolam, section 15.1.4.1Renal impairment see Midazolam, section 15.1.4.1Pregnancy see Midazolam, section 15.1.4.1Breast-feeding see Midazolam, section 15.1.4.1Side-effects see Midazolam, section 15.1.4.1Licensed use injection not licensed for use in statusepilepticus or febrile convulsionsIndication and doseStatus epilepticus, febrile convulsions (section4.8.3). By buccal administrationNeonate 300 micrograms/kg, repeated once after10 minutes if necessaryChild 1–6 months 300 micrograms/kg (max.2.5 mg), repeated once after 10 minutes if necessaryChild 6 months–1 year 2.5 mg, repeated onceafter 10 minutes if necessaryChild 1–5 years 5 mg, repeated once after 10minutes if necessaryChild 5–10 years 7.5 mg, repeated once after 10minutes if necessaryChild 10–18 years 10 mg, repeated once after 10minutes if necessary. By intravenous administrationNeonate initially by intravenous injection 150–200 micrograms/kg followed by continuous intravenousinfusion of 60 micrograms/kg/hour(increased by 60 micrograms/kg/hour every 15minutes until seizure controlled); max. 300 micrograms/kg/hourChild 1 month–18 years initially by intravenousinjection 150–200 micrograms/kg followed bycontinuous intravenous infusion of 60 micrograms/kg/hour(increased by 60 micrograms/kg/hour every 15 minutes until seizure controlled);max. 300 micrograms/kg/hourAdministration for intravenous injection, dilute withGlucose 5% or Sodium Chloride 0.9%; rapid intravenousinjection (less than 2 minutes) may causeseizure-like myoclonus in preterm neonateFor buccal administration, injection solution may begiven buccallyNeonatal intensive care, dilute 15 mg/kg body-weightto a final volume of 50 mL with infusion fluid; anintravenous infusion rate of 0.1 mL/hour provides adose of 30 micrograms/kg/hourPreparationsSection 15.1.4PARALDEHYDECautions bronchopulmonary disease; interactions:Appendix 1 (paraldehyde)Contra-indications gastric disorders; rectal administrationin colitisHepatic impairment use with cautionPregnancy avoid unless essential—crosses placentaBreast-feeding avoid unless essential—present inmilkSide-effects rashLicensed use not licensed for use in children as anenemaIndication and doseStatus epilepticus. By rectum (doses expressed as undiluted paraldehyde)Neonate 0.4 mL/kg as a single doseChild 1 month–18 years 0.4 mL/kg (max. 10 mL)as a single doseAdministration for rectal administration, do notadminister paraldehyde undilutedParaldehyde (Non-proprietary) AEnema, 8–50%, available from ‘special-order’ manufacturersor specialist importing companies, seep. 809PHENOBARBITAL SODIUMPhenobarbitone sodiumCautions see Phenobarbital, section 4.8.1; interactions:see p. 215 and Appendix 1 (phenobarbital)Hepatic impairment see Phenobarbital, section 4.8.1Renal impairment see Phenobarbital, section 4.8.1Pregnancy see Pregnancy, p. 216Breast-feeding see Phenobarbital, section 4.8.1Side-effects see Phenobarbital, section 4.8.1Indication and doseStatus epilepticus. By slow intravenous injection (no faster than1 mg/kg/minute)Neonate initially 20 mg/kg then 2.5–5 mg/kgonce or twice dailyChild 1 month–12 years initially 20 mg/kg then2.5–5 mg/kg once or twice dailyChild 12–18 years initially 20 mg/kg (max. 1 g)then 300 mg twice daily

BNFC 2011–2012 4.8.3 Febrile convulsions 235Other forms of epilepsy section 4.8.1Note For therapeutic purposes phenobarbital and phenobarbitalsodium may be considered equivalent in effectAdministration for intravenous injection, dilute to aconcentration of 20 mg/mL with Water for InjectionsPhenobarbital (Non-proprietary) 3Injection, phenobarbital sodium 15 mg/mL, net price1-mL amp = £1.64; 30 mg/mL, 1-mL amp = £2.04;60 mg/mL, 1-mL amp = £2.14; 200 mg/mL, 1-mLamp = £2.00Excipients include propylene glycol (see Excipients, p. 2)Note Must be diluted before intravenous administration (seeAdministration)Oral preparationsSection 4.8.1PHENYTOIN SODIUMCautions see notes above; respiratory depression;hypotension and heart failure; resuscitation facilitiesmust be available; injection solutions alkaline (irritantto tissues); see also p. 224; interactions: see p. 215and Appendix 1 (phenytoin)Contra-indications sinus bradycardia, sino-atrialblock, and second- and third-degree heart block;Stokes-Adams syndrome; acute porphyria (section9.8.2)Hepatic impairment see Phenytoin, section 4.8.1Pregnancy see Phenytoin, section 4.8.1 andPregnancy, p. 216Breast-feeding see Phenytoin, section 4.8.1Side-effects intravenous injection may cause cardiovascularand CNS depression (particularly if injectiontoo rapid) with arrhythmias, hypotension, and cardiovascularcollapse; alterations in respiratory function(including respiratory arrest); also reported tonicseizures, purple glove syndrome; see also p. 224Indication and doseStatus epilepticus, acute symptomatic seizuresassociated with trauma or neurosurgery. By slow intravenous injection or infusion (withblood-pressure and ECG monitoring)Neonate initially 20 mg/kg as a loading dose then2.5–5 mg/kg twice dailyChild 1 month–12 years initially 20 mg/kg as aloading dose then 2.5–5 mg/kg twice dailyChild 12–18 years initially 20 mg/kg as a loadingdose then up to 100 mg 3–4 times dailyOther forms of epilepsy section 4.8.1Note Phenytoin sodium doses in BNFC may differ fromthose in product literatureAdministration before and after administration flushintravenous line with Sodium Chloride 0.9%.For intravenous injection, give into a large vein at ratenot exceeding 1 mg/kg/minute (max. 50 mg/minute).For intravenous infusion, dilute to a concentration notexceeding 10 mg/mL with Sodium Chloride 0.9% andgive into a large vein through an in-line filter (0.22–0.50 micron) at a rate not exceeding 1 mg/kg/minute(max. 50 mg/minute); complete administration within1 hour of preparationPhenytoin (Non-proprietary) AInjection, phenytoin sodium 50 mg/mL with propyleneglycol 40% and alcohol 10% in water for injections,net price 5-mL amp = £3.40Epanutin c Ready-Mixed Parenteral (Pfizer) AInjection, phenytoin sodium 50 mg/mL with propyleneglycol 40% and alcohol 10% in water for injections.Net price 5-mL amp = £4.88Oral preparationsSection 4.8.14.8.3 Febrile convulsionsBrief febrile convulsions need no specific treatment;antipyretic medication (e.g. paracetamol, section4.7.1) is commonly used to reduce fever and preventfurther convulsions but evidence to support this practiceis lacking. Prolonged febrile convulsions (those lasting 5minutes or longer), or recurrent febrile convulsionswithout recovery, must be treated actively (as for convulsivestatus epilepticus section 4.8.2).Long-term anticonvulsant prophylaxis for febrile convulsionsis rarely indicated.4.9 Drugs used in dystoniasand related disorders4.9.1 Dopaminergic drugs used in dystonias4.9.2 Antimuscarinic drugs used indystonias4.9.3 Drugs used in essential tremor,chorea, tics, and related disordersDystonias may result from conditions such as cerebralpalsy or may be related to a deficiency of the neurotransmitterdopamine as in Segawa syndrome.4.9.1 Dopaminergic drugs usedin dystoniasLevodopa, the amino-acid precursor of dopamine, actsby replenishing depleted striatal dopamine. It is givenwith an extracerebral dopa-decarboxylase inhibitor,which reduces the peripheral conversion of levodopato dopamine, thereby limiting side-effects such asnausea, vomiting, and cardiovascular effects; additionally,effective brain-dopamine concentrations can beachieved with lower doses of levodopa. The extracerebraldopa-decarboxylase inhibitor most commonlyused in children is carbidopa (in co-careldopa).Levodopa therapy should be initiated at a low dose andincreased in small steps; the final dose should be as lowas possible. Intervals between doses should be chosento suit the needs of the individual child.In severe dystonias related to cerebral palsy, improvementcan be expected within 2 weeks. Children withSegawa syndrome are particularly sensitive to levodopa;they may even become symptom free on small doses.Levodopa also has a role in treating metabolic disorderssuch as defects in tetrahydrobiopterin synthesis and4 Central nervous system

236 4.9.1 Dopaminergic drugs used in dystonias BNFC 2011–20124 Central nervous systemdihydrobiopterin reductase deficiency. For the use oftetrahydrobiopterin in metabolic disorders see section9.4.1.Children may experience nausea within 2 hours oftaking a dose; nausea and vomiting with co-careldopais rarely dose-limiting, but domperidone (section 4.6)can be useful in controlling these effects.In dystonic cerebral palsy, treatment with larger dosesof levodopa is associated with the development ofpotentially troublesome motor complications (includingresponse fluctuations and dyskinesias). Response fluctuationsare characterised by large variations in motorperformance, with normal function during the ‘on’ period,and weakness and restricted mobility during the‘off’ period.Sudden onset of sleepExcessive daytime sleepiness and sudden onset ofsleep can occur with co-careldopa.Children starting treatment with these drugs, andtheir carers, should be warned of the risk and of theneed to exercise caution when performing skilledtasks e.g. driving or operating machinery. Childrenwho have experienced excessive sedation or suddenonset of sleep should refrain from performing skilledtasks until these effects have stopped occurring.Management of excessive daytime sleepiness shouldfocus on the identification of an underlying cause,such as depression or concomitant medication. Children,and their carers, should be counselled onimproving sleep behaviour.Licensed use not licensed for use in childrenIndication and doseDopamine-sensitive dystonias including Segawasyndrome and dystonias related to cerebralpalsy. By mouth, expressed as levodopaChild 3 months–18 years initially 250 micrograms/kg2–3 times daily of a preparation containing1:4 carbidopa:levodopa, increased accordingto response every 2–3 days to max. 1 mg/kgthree times dailyTreatment of defects in tetrahydrobiopterinsynthesis and dihydrobiopterin reductasedeficiency. By mouth, expressed as levodopaNeonate initially 250–500 micrograms/kg 4 timesdaily of a preparation containing 1:4 carbidopa:-levodopa, increased according to response every4–5 days to maintenance dose of 2.5–3 mg/kg 4times daily; at higher doses consider preparationcontaining 1:10 carbidopa:levodopa; review regularly(every 3–6 months)Child 1 month–18 years initially 250–500 micrograms/kg4 times daily of a preparation containing1:4 carbidopa:levodopa, increased accordingto response every 4–5 days to maintenancedose of 2.5–3 mg/kg 4 times daily; at higher dosesconsider preparation containing 1:10 carbidopa:-levodopa; review regularly (every 3–6 months inearly childhood)CO-CARELDOPAA mixture of carbidopa and levodopa; the proportions areexpressed in the form x/y where x and y are the strengths inmilligrams of carbidopa and levodopa respectivelyCautions see also notes above; pulmonary disease,peptic ulceration, cardiovascular disease (includinghistory of myocardial infarction with residualarrhythmia), diabetes mellitus, osteomalacia, susceptibilityto angle-closure glaucoma, history of skinmelanoma (risk of activation), psychiatric illness(avoid if severe and discontinue if deterioration); warnchildren and carers about excessive drowsiness (seenotes above); in prolonged therapy, psychiatric,hepatic, haematological, renal, and cardiovascularsurveillance is advisable; warn patients to resumenormal activities gradually; avoid abrupt withdrawal;interactions: Appendix 1 (levodopa)Pregnancy use with caution—toxicity in animal studiesBreast-feeding may suppress lactation; present inmilk—avoidSide-effects see also notes above; anorexia, nauseaand vomiting, insomnia, agitation, postural hypotension(rarely labile hypertension), dizziness, tachycardia,arrhythmias, reddish discoloration of urine andother body fluids; rarely hypersensitivity; very rarelyangle-closure glaucoma; abnormal involuntarymovements and psychiatric symptoms which includehypomania and psychosis may be dose-limiting;depression, drowsiness, headache, flushing, sweating,gastro-intestinal bleeding, peripheral neuropathy,taste disturbance, pruritus, rash, and liver enzymechanges also reported; syndrome resembling neurolepticmalignant syndrome reported on withdrawalCo-careldopa (Non-proprietary) ATablets, co-careldopa 10/100 (carbidopa 10 mg(anhydrous), levodopa 100 mg), net price 100-tabpack = £7.30. Label: 14, counselling, skilled tasks, seenotes aboveTablets, co-careldopa 25/100 (carbidopa 25 mg(anhydrous), levodopa 100 mg), net price 100-tabpack = £24.45. Label: 14, counselling, skilled tasks, seenotes aboveTablets, co-careldopa 25/250 (carbidopa 25 mg(anhydrous), levodopa 250 mg), net price 100-tabpack = £34.58. Label: 14, counselling, skilled tasks, seenotes aboveSinemet c (MSD) ASinemet-62.5 c tablets, yellow, scored, co-careldopa12.5/50 (carbidopa 12.5 mg (anhydrous), levodopa50 mg), net price 90-tab pack = £6.28. Label: 14,counselling, skilled tasks, see notes aboveNote 2 tablets Sinemet-62.5 c : 1 tablet Sinemet Plus c ;Sinemet-62.5 c previously known as Sinemet LS cSinemet-110 c tablets, blue, scored, co-careldopa10/100 (carbidopa 10 mg (anhydrous), levodopa100 mg), net price 90-tab pack = £6.57. Label: 14,counselling, skilled tasks, see notes aboveSinemet-Plus c tablets, yellow, scored, co-careldopa25/100 (carbidopa 25 mg (anhydrous), levodopa100 mg), net price 90-tab pack = £9.66. Label: 14,counselling, skilled tasks, see notes aboveSinemet-275 c tablets, blue, scored, co-careldopa25/250 (carbidopa 25 mg (anhydrous), levodopa250 mg), net price 90-tab pack = £13.72. Label: 14,counselling, skilled tasks, see notes above

BNFC 2011–2012 4.9.2 Antimuscarinic drugs used in dystonias 2374.9.2 Antimuscarinic drugsused in dystoniasThe antimuscarinic drugs procyclidine and trihexyphenidylreduce the symptoms of dystonias, includingthose induced by antipsychotic drugs; there is no justificationfor giving them routinely in the absence ofdystonic symptoms. Tardive dyskinesia is not improvedby antimuscarinic drugs and may be made worse.There are no important differences between the antimuscarinicdrugs, but some children tolerate one betterthan another.Procyclidine can be given parenterally and is effectiveemergency treatment for acute drug-induced dystonicreactions.Cautions Antimuscarinics should be used with cautionin cardiovascular disease, hypertension, psychotic disorders,pyrexia, and in those susceptible to angle-closureglaucoma. Antimuscarinics should not be withdrawnabruptly in children taking long-term treatment.Antimuscarinics are liable to abuse. Interactions:Appendix 1 (Antimuscarinics).Skilled tasks Antimuscarinics can affect performanceof skilled tasks (e.g. driving).Contra-indications Antimuscarinics should beavoided in gastro-intestinal obstruction and myastheniagravis.Hepatic and renal impairment Procyclidine andtrihexyphenidyl should be used with caution in childrenwith hepatic or renal impairment.Side-effects Side-effects of antimuscarinics includeconstipation, dry mouth, nausea, vomiting, tachycardia,dizziness, confusion, euphoria, hallucinations, impairedmemory, anxiety, restlessness, urinary retention, blurredvision, and rash. Angle-closure glaucoma occurs veryrarely.PROCYCLIDINE HYDROCHLORIDECautions see notes above; interactions: Appendix 1(antimuscarinics)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy use only if potential benefit outweighs riskBreast-feeding no information availableSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseDystonias. By mouthChild 7–12 years 1.25 mg 3 times dailyChild 12–18 years 2.5 mg 3 times dailyAcute dystonia. By intramuscular or intravenous injectionChild under 2 years 0.5–2 mg as a single doseChild 2–10 years 2–5 mg as a single doseChild 10–18 years 5–10 mg (occasionally morethan 10 mg)Note Usually effective in 5–10 minutes but may need 30minutes for reliefProcyclidine (Non-proprietary) ATablets, procyclidine hydrochloride 5 mg, net price28-tab pack = £2.77. Counselling, drivingArpicolin c (Rosemont) ASyrup, sugar-free, procyclidine hydrochloride 2.5 mg/5 mL, net price 150 mL = £4.22; 5 mg/5 mL, 150 mLpack = £7.54. Counselling, drivingKemadrin c (Aspen) ATablets, scored, procyclidine hydrochloride 5 mg, netprice 100-tab pack = £4.72. Counselling, drivingKemadrin c (Auden Mckenzie) AInjection, procyclidine hydrochloride 5 mg/mL, netprice 2-mL amp = £1.49TRIHEXYPHENIDYLHYDROCHLORIDE(Benzhexol hydrochloride)Cautions see notes above; interactions: Appendix 1(antimuscarinics)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy use only if potential benefit outweighs riskBreast-feeding avoidSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseDystonia. By mouthChild 3 months–18 years initially 1–2 mg daily in1–2 divided doses, increased every 3–7 days by1 mg daily; adjusted according to response andside-effects; max. 2 mg/kg dailyTrihexyphenidyl (Non-proprietary) ATablets, trihexyphenidyl hydrochloride 2 mg, netprice 84-tab pack = £19.60; 5 mg, 84-tab pack =£16.79, 100-tab pack = £15.60. Counselling, before orafter food, drivingBroflex c (Alliance) ASyrup, pink, black currant, trihexyphenidyl hydrochloride5 mg/5 mL, net price 200 mL = £7.44.Counselling, driving4.9.3 Drugs used in essentialtremor, chorea, tics, andrelated disordersHaloperidol can improve motor tics and symptoms ofTourette syndrome and related choreas (see section4.2.1). Other treatments for Tourette syndrome includepimozide (p. 176) [unlicensed indication] (important:ECG monitoring required) and sulpiride (p. 176) [unlicensedindication].Propranolol or another beta-adrenoceptor blockingdrug (section 2.4) may be useful in treating essential4 Central nervous system

238 4.10 Drugs used in substance dependence BNFC 2011–20124 Central nervous systemtremor or tremor associated with anxiety or thyrotoxicosis.BOTULINUM TOXIN TYPE ACautions neurological disorders (can lead to increasedsensitivity and exaggerated muscle weakness);excessive weakness or atrophy in target muscle; historyof dysphagia or aspiration; chronic respiratorydisorderContra-indications generalised disorders of muscleactivity (e.g. myasthenia gravis); infection at injectionsitePregnancy low risk of systemic absorption but avoidunless essentialBreast-feeding low risk of systemic absorption butavoid unless essentialSide-effects increased electrophysiologic jitter insome distant muscles; misplaced injections mayparalyse nearby muscle groups and excessive dosesmay paralyse distant muscles; influenza-like symptoms,rarely arrhythmias, myocardial infarction, seizures,hypersensitivity reactions including rash, pruritusand anaphylaxis, antibody formation (substantialdeterioration in response); very rarely exaggeratedmuscle weakness, dysphagia, and aspiration (seekmedical attention if swallowing, speech, or respiratorydisorder)Specific side-effects in paediatric cerebral palsy Drowsiness,paraesthesia, urinary incontinence, myalgiaIndication and doseIn children over 2 years for dynamic equinus footdeformity caused by spasticity in ambulant paediatriccerebral palsy for dose consult product literature(important: information specific to each individualpreparation and not interchangeable)Botox c (Allergan) AInjection, powder for reconstitution, botulinum toxintype A complex, net price 50-unit vial = £77.50; 100-unit vial = £138.20; 200-unit vial = £276.40Dysport c (Ipsen) AInjection, powder for reconstitution, botulinum typeA toxin-haemagglutinin complex, net price 300-unitvial = £92.40; 500-unit vial = £154.004.10 Drugs used in substancedependenceThis section includes drugs used in the treatment ofneonatal abstinence syndrome and cigarette smoking.Treatment of alcohol or opioid dependence in childrenrequires specialist management. The UK health departmentshave produced guidance on the treatment of drugmisuse in the UK. Drug Misuse and Dependence: UKGuidelines on Clinical Management (2007) is availableatwww.nta.nhs.uk/uploads/clinical_guidelines_2007.pdf.Neonatal abstinence syndrome Neonatal abstinencesyndrome occurs at birth as a result of intrauterineexposure to opioids or high-dose benzodiazepines.Treatment is usually initiated if:. feeding becomes a problem and tube feeding isrequired;. there is profuse vomiting or watery diarrhoea;. the baby remains very unsettled after two consecutivefeeds despite gentle swaddling and the use of apacifier.Treatment involves weaning the baby from the drug onwhich it is dependent. Morphine or methadone (section4.7.2) can be used in babies of mothers who havebeen taking opioids. Morphine is widely used becausethe dose can be easily adjusted, but methadone mayprovide smoother control of symptoms. Weaning babiesfrom opioids usually takes 7–10 days.Weaning babies from benzodiazepines that have a longhalf-life is difficult to manage; chlorpromazine (section4.2.1) may be used in these situations but excessivesedation may occur. For babies who are dependent onbarbiturates, phenobarbital (section 4.8.1) may be tried,although it does not control gastro-intestinal symptoms.4.10.1 Alcohol dependenceClassification not used in BNF for Children.4.10.2 Nicotine dependenceSmoking cessation interventions are a cost-effectiveway of reducing ill health and prolonging life. Smokersshould be advised to stop and offered help with followupwhen appropriate. If possible, smokers should haveaccess to smoking cessation services for behaviouralsupport.Therapy to aid smoking cessation is chosen accordingto the smoker’s likely compliance, availability of counsellingand support, previous experience of smokingcessationaids, contra-indications and adverse effects ofthe preparations, and the smoker’s preferences. Nicotinereplacement therapy is an effective aid to smokingcessation. The use of nicotine replacement preparationsin an individual who is already accustomed to nicotineintroduces few new risks and it is widely accepted thatthere are no circumstances in which it is safer to smokethan to use nicotine replacement therapy.Some individuals benefit from having more than onetype of nicotine replacement therapy prescribed, suchas a combination of transdermal and oral preparations.Concomitant medication Cigarette smokingincreases the metabolism of some medicines by stimulatingthe hepatic enzyme CYP1A2. When smoking isdiscontinued, the dose of these drugs, in particulartheophylline p. 142 and some antipsychotics (includingclozapine p. 178, olanzapine p. 179, chlorpromazinep. 174, and haloperidol p. 174), may need to be reduced.Regular monitoring for adverse effects is advised.

BNFC 2011–2012 4.10.2 Nicotine dependence 239Nicotine replacement therapyNicotine replacement therapy can be used in place ofcigarettes after abrupt cessation of smoking, or alternativelyto reduce the amount of cigarettes used inadvance of making a quit attempt. Nicotine replacementtherapy can also be used to minimise passive smoking,and to treat cravings and reduce compensatory smokingafter enforced abstinence in smoke-free environments.Smokers who find it difficult to achieve abstinenceshould consult a healthcare professional for advice.Choice Nicotine patches are a prolonged-release formulationand are applied for 16 hours (with the patchremoved overnight) or for 24 hours. If the individualexperiences strong cravings for cigarettes on waking, a24-hour patch may be more suitable. Immediate-releasenicotine preparations (gum, lozenges, sublingual tablets,inhalator, nasal spray, and oral spray) are used wheneverthe urge to smoke occurs.The choice of nicotine replacement preparationdepends largely on patient preference, and should takeinto account what preparations, if any, have been triedbefore. Patients with a high level of nicotine dependence,or who have failed with nicotine replacementtherapy previously, may benefit from using a combinationof an immediate-release preparation and patches toachieve abstinence.All preparations are licensed for children over 12 years(with the exception of Nicotinell c lozenges which arelicensed for children under 18 years only whenrecommended by a doctor).Cautions Most warnings for nicotine replacementtherapy also apply to continued cigarette smoking, butthe risk of continued smoking outweighs any risks ofusing nicotine preparations. Nicotine replacement therapyshould be used with caution in haemodynamicallyunstable patients hospitalised with severe arrhythmias,myocardial infarction, or cerebrovascular accident, andin patients with phaeochromocytoma or uncontrolledhyperthyroidism. Care is also needed in individuals withdiabetes mellitus—blood-glucose concentration shouldbe monitored closely when initiating treatment.Specific cautions for individual preparations are usuallyrelated to the local effect of nicotine. Oral preparationsshould be used with caution in patients with oesophagitis,gastritis, or peptic ulcers because swallowednicotine can aggravate these conditions. The gum mayalso stick to and damage dentures. Acidic beverages,such as coffee or fruit juice, may decrease the absorptionof nicotine through the buccal mucosa and shouldbe avoided for 15 minutes before the use of oral nicotinereplacement therapy. Care should be taken with theinhalation cartridges in patients with obstructive lungdisease, chronic throat disease, or bronchospastic disease.The nasal spray can cause worsening of bronchialasthma. Patches should not be placed on broken skinand should be used with caution in patients with skindisorders.Hepatic impairment Nicotine replacement therapyshould be used with caution in moderate to severehepatic impairment.Renal impairment Nicotine replacement therapyshould be used with caution in severe renal impairment.Pregnancy The use of nicotine replacement therapy inpregnancy is preferable to the continuation of smoking,but should be used only if smoking cessation withoutnicotine replacement fails. Intermittent therapy is preferableto patches but avoid liquorice-flavoured nicotineproducts. Patches are useful however, if the youngwoman is experiencing pregnancy-related nausea andvomiting. If patches are used, they should be removedbefore bed.Breast-feeding Nicotine is present in milk; however,the amount to which the infant is exposed is small andless hazardous than second-hand smoke. Intermittenttherapy is preferred.Side-effects Some systemic effects occur on initiationof therapy, particularly if the individual is using highstrengthpreparations; however, the individual may confuseside-effects of the nicotine-replacement preparationwith nicotine withdrawal symptoms. Commonsymptoms of nicotine withdrawal include malaise, headache,dizziness, sleep disturbance, coughing, influenzalikesymptoms, depression, irritability, increased appetite,weight gain, restlessness, anxiety, drowsiness, aphthousulcers, decreased heart rate, and impaired concentration.Mild topical reactions at the beginning of treatment arecommon because of the irritant effect of nicotine. Oralpreparations and inhalation cartridges can cause irritationof the throat, gum, lozenges, and oral spray cancause increased salivation, and patches can cause minorskin irritation. The nasal spray commonly causescoughing, nasal irritation, epistaxis, sneezing, andwatery eyes; the oral spray can cause watery eyesand blurred vision.Gastro-intestinal disturbances are common and may becaused by swallowed nicotine. Nausea, vomiting, dyspepsia,and hiccup occur most frequently. Ulcerativestomatitis has also been reported. Dry mouth is acommon side-effect of lozenges, patches, oral spray,and sublingual tablets. Lozenges cause diarrhoea, constipation,dysphagia, oesophagitis, gastritis, mouthulcers, bloating, flatulence, and less commonly, tastedisturbance, thirst, gingival bleeding, and halitosis. Theoral spray may also cause abdominal pain, flatulence,and taste disturbance.Palpitations may occur with nicotine replacement therapyand rarely patches and oral spray can causearrhythmia. Patches, lozenges, and oral spray cancause chest pain.Paraesthesia is a common side-effect of oral spray.Abnormal dreams can occur with patches; removal ofthe patch before bed may help. Lozenges and oral spraymay cause rash and hot flushes. Sweating and myalgiacan occur with patches and oral spray; the patches canalso cause arthralgia.Nicotine medicated chewing gum Individuals whosmoke fewer than 20 cigarettes each day should use onepiece of 2-mg strength gum when the urge to smokeoccurs; individuals who smoke more than 20 cigaretteseach day or who require more than 15 pieces of 2-mgstrength gum each day should use the 4-mg strength.Individuals should not exceed 15 pieces of 4-mgstrength gum daily. If attempting smoking cessation,treatment should continue for 3 months before reducingthe dose.4 Central nervous system

240 4.10.2 Nicotine dependence BNFC 2011–20124 Central nervous systemAdministration Chew the gum until the taste becomesstrong, then rest it between the cheek and gum; whenthe taste starts to fade, repeat this process. One piece ofgum lasts for approximately 30 minutes.Nicotine inhalation cartridge The cartridges can beused when the urge to smoke occurs or to preventcravings, up to a maximum of 12 cartridges daily.Administration Insert the cartridge into the device anddraw in air through the mouthpiece. The amount ofnicotine from 1 puff of the cartridge is less than thatfrom a cigarette, therefore it is necessary to inhale moreoften than when smoking a cigarette. A single cartridgelasts for approximately 20 minutes of intense use.Nicotine lozenge One lozenge should be used every1–2 hours when the urge to smoke occurs. Individualswho smoke less than 20 cigarettes each day shouldusually use the lower-strength lozenges; individualswho smoke more than 20 cigarettes each day andthose who fail to stop smoking with the low-strengthlozenges should use the higher-strength lozenges. Individualsshould not exceed 15 lozenges daily. If attemptingsmoking cessation, treatment should continue for 6–12 weeks before attempting a reduction in dose.Administration Slowly allow each lozenge to dissolvein the mouth; periodically move the lozenge from oneside of the mouth to the other. Lozenges last for 10–30minutes, depending on their size.Nicotine sublingual tablets Individuals who smokefewer than 20 cigarettes each day should initially use 1tablet each hour, increased to 2 tablets each hour ifnecessary; individuals who smoke more than 20 cigaretteseach day should use 2 tablets each hour. Individualsshould not exceed 40 tablets daily. If attemptingsmoking cessation, treatment should continue for up to3 months before reducing the dose.Administration Each tablet should be placed under thetongue and allowed to dissolve.Nicotine oral spray Individuals can use 1–2 sprays inthe mouth when the urge to smoke occurs. Individualsshould not exceed 2 sprays per episode (up to 4 spraysevery hour), and a maximum of 64 sprays daily.Administration The oral spray should be released intothe mouth, holding the spray as close to the mouth aspossible and avoiding the lips. The individual should notinhale while spraying and avoid swallowing for a fewseconds after use.Note If using the oral spray for the first time, or if unit not usedfor 2 or more days, prime the unit before administrationNicotine nasal spray Individuals can use 1 spray ineach nostril when the urge to smoke occurs, up to twiceevery hour for 16 hours daily (maximum 64 spraysdaily). If attempting smoking cessation, treatmentshould continue for 8 weeks before reducing the dose.Administration Initially 1 spray should be used in bothnostrils but when withdrawing from therapy, the dosecan be gradually reduced to 1 spray in 1 nostril.Nicotine transdermal patches As a general guidefor smoking cessation, individuals who smoke morethan 10 cigarettes daily should apply a high-strengthpatch daily for 6–8 weeks, followed by the mediumstrength patch for 2 weeks, and then the low-strengthpatch for the final 2 weeks; individuals who smoke fewerthan 10 cigarettes daily can usually start with themedium-strength patch for 6–8 weeks, followed by thelow-strength patch for 2–4 weeks. A slower titrationschedule can be used in patients who are not ready toquit but want to reduce cigarette consumption before aquit attempt.If abstinence is not achieved, or if withdrawal symptomsare experienced, the strength of the patch used shouldbe maintained or increased until the patient is stabilised.Individuals using the high-strength patch who experienceexcessive side-effects, that do not resolve within afew days, should change to a medium-strength patch forthe remainder of the initial period and then use the lowstrength patch for 2–4 weeks.Administration Patches should be applied on waking todry, non-hairy skin on the hip, trunk, or upper arm andheld in position for 10–20 seconds to ensure adhesion;place next patch on a different area and avoid using thesame site for several days.NICOTINECautions see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseSee notes aboveNicorette c (McNeil)Tablets (sublingual) (Nicorette Microtab c ), nicotine(as a cyclodextrin complex) 2 mg, net price starterpack of 2 15-tablet discs with dispenser = £4.46;pack of 100 = £12.12. Label: 26, counselling,administration, see notes aboveNote Also available as NicAssist cExcipients lemon flavour includes aspartame (section 9.4.1)Chewing gum, sugar-free, nicotine (as resin) 2 mg, netprice pack of 30 = £3.41, pack of 105 = £9.37, pack of210 = £14.82; 4 mg, pack of 30 = £3.99, pack of 105 =£11.48, pack of 210 = £18.24. Counselling, administration,see notes aboveNote Available in mint, freshfruit, freshmint, and icy whiteflavours (icy white flavour not available for pack size of 210pieces). Also available as NicAssist cMint lozenge, sugar-free, nicotine (as bitartrate) 2 mg,net price pack of 24 = £2.55, pack of 96 = £8.29.Label: 24, counselling, administration, see notesabovePatches, self-adhesive, beige, nicotine, ‘5 mg’ patch(releasing approx. 5 mg/16 hours), net price 7 = £9.07;‘10 mg’ patch (releasing approx. 10 mg/16 hours), 7 =£9.07; ‘15 mg’ patch (releasing approx. 15 mg/16hours), 2 = £2.85, 7 = £9.07. Counselling, administration,see notes aboveNote Also available as NicAssist cInvisi patches, self-adhesive, beige, nicotine, ‘10 mg’patch (releasing approx. 10 mg/16 hours), net price 7= £9.97; ‘15 mg’ patch (releasing approx. 15 mg/16hours), 7 = £9.97; ‘25 mg’ patch (releasing approx.25 mg/16 hours), 7 = £9.97. Counselling, administration,see notes aboveOral spray (Nicorette Quickmist c mouthspray),nicotine 1 mg/metered dose, net price 150-dose pack

BNFC 2011–2012 4.10.2 Nicotine dependence 241= £11.48, 2 150-dose pack = £18.50. Counselling,administration, see notes aboveNote Contains < 100 mg ethanol per doseNasal spray, nicotine 500 micrograms/meteredspray, net price 200-spray unit = £13.40. Counselling,administration, see notes aboveNote Also available as NicAssist cInhalator (nicotine-impregnated plug for use in inhalatormouthpiece), nicotine 10 mg/cartridge, net price6-cartridge (starter) pack = £4.46, 42-cartridge (refill)pack = £14.01. Counselling, administration, see notesaboveNote Also available as NicAssist c4.11 Drugs for dementiaClassification not used in BNF for Children.Nicotinell c (Novartis Consumer Health)Chewing gum, sugar-free, nicotine (as polacrilincomplex) 2 mg, net price pack of 12 = £1.71, pack of24 = £3.01, pack of 96 = £8.26, pack of 204 = £14.23;4 mg, pack of 12 = £1.70, pack of 24 = £3.30, pack of96 = £10.26. Counselling, administration, see notesaboveNote Also available in fruit, liquorice, and mint flavoursMint lozenge, sugar-free, nicotine (as bitartrate) 1 mg,net price pack of 12 = £1.71, pack of 36 = £4.27, packof 96 = £9.12; 2 mg, pack of 12 = £1.99, pack of 36 =£4.95, pack of 96 = £10.60. Label: 24, counselling,administration, see notes aboveExcipients include aspartame (section 9.4.1)TTS Patches, self-adhesive, all yellowish-ochre, nicotine,‘10’ patch (releasing approx. 7 mg/24 hours), netprice 7 = £9.12; ‘20’ patch (releasing approx. 14 mg/24 hours), net price 2 = £2.57, 7 = £9.40; ‘30’ patch(releasing approx. 21 mg/24 hours), net price 2 =£2.85, 7 = £9.97, 21 = £24.51. Counselling, administration,see notes aboveNiQuitin c (GSK Consumer Healthcare)Chewing gum, sugar-free, mint-flavour, nicotine 2 mg(white), net price pack of 12 = £1.71, pack of 24 =£2.85, pack of 96 = £8.55; 4 mg (yellow), pack of 12 =£1.71, pack of 24 = £2.85, pack of 96 = £8.55. Counselling,administration, see notes aboveLozenges, sugar-free, nicotine (as resinate) 1.5 mg(cherry- and mint-flavoured), net price pack of 20 =£3.18, pack of 60 = £8.93; nicotine (as polacrilex) 2 mg(mint-flavoured), pack of 36 = £5.12, pack of 72 =£9.97; nicotine (as resinate) 4 mg (mint-flavoured),pack of 20 = £3.18, pack of 60 = £8.93, nicotine (aspolacrilex) 4 mg (mint-flavoured) pack of 36 = £5.12,pack of 72 = £9.97. Label: 24, counselling, administration,see notes aboveExcipients include aspartame (section 9.4.1); contains 0.65 mmol Na + /lozengeNote Nicotine (as polacrilex) also available as Niquitin c Prequitlozenges. Nicotine (as resinate) available as Niquitin cMinis lozengesPatches, self-adhesive, pink/beige, nicotine ‘7 mg’patch (releasing approx. 7 mg/24 hours), net price 7 =£9.97; ‘14 mg’ patch (releasing approx. 14 mg/24hours), 7 = £9.97; ‘21 mg’ patch (releasing approx.21 mg/24 hours), 7 = £9.97, 14 = £18.79. Counselling,administration, see notes aboveNote Also available as a clear patch4 Central nervous system4.10.3 Opioid dependenceClassification not used in BNF for Children.

242 BNFC 2011–20125 Infections5 Infections5.1 Antibacterial drugs 2435.1.1 Penicillins 2575.1.1.1 Benzylpenicillin and phenoxymethylpenicillin2575.1.1.2 Penicillinase-resistant penicillins2595.1.1.3 Broad-spectrum penicillins 2605.1.1.4 Antipseudomonal penicillins 2645.1.1.5 Mecillinams 2655.1.2 Cephalosporins, carbapenems,and other beta-lactams 2665.1.2.1 Cephalosporins 2665.1.2.2 Carbapenems 2725.1.2.3 Other beta-lactam antibiotics 2735.1.3 Tetracyclines 2745.1.4 Aminoglycosides 2765.1.5 Macrolides 2805.1.6 Clindamycin 2835.1.7 Some other antibacterials 2845.1.8 Sulfonamides and trimethoprim 2895.1.9 Antituberculosis drugs 2905.1.10 Antileprotic drugs 2955.1.11 Metronidazole 2955.1.12 Quinolones 2975.1.13 Urinary-tract infections 2995.2 Antifungal drugs 3005.2.1 Triazole antifungals 3015.2.2 Imidazole antifungals 3055.2.3 Polyene antifungals 3055.2.4 Echinocandin antifungals 3065.2.5 Other antifungals 3085.3 Antiviral drugs 3095.3.1 HIV infection 3095.3.2 Herpesvirus infections 3215.3.2.1 Herpes simplex and varicella–zoster infection 3215.3.2.2 Cytomegalovirus infection 3245.3.3 Viral hepatitis 3255.3.4 Influenza 3265.3.5 Respiratory syncytial virus 3275.4 Antiprotozoal drugs 3295.4.1 Antimalarials 3295.4.2 Amoebicides 3395.4.3 Trichomonacides 3405.4.4 Antigiardial drugs 3405.4.5 Leishmaniacides 3405.4.6 Trypanocides 3415.4.7 Drugs for toxoplasmosis 3415.4.8 Drugs for pneumocystis pneumonia3425.5 Anthelmintics 3445.5.1 Drugs for threadworms 3445.5.2 Ascaricides 3455.5.3 Drugs for tapeworm infections 3455.5.4 Drugs for hookworms 3465.5.5 Schistosomicides 3465.5.6 Filaricides 3465.5.7 Drugs for cutaneous larvamigrans 3465.5.8 Drugs for strongyloidiasis 347This chapter includes advice on the drug managementof the following:anthrax, p. 297bacterial infections: table 1, summary of antibacterialtreatment, p. 244bacterial infections: table 2, summary of antibacterialprophylaxis, p. 254Lyme disease, p. 261MRSA infections, p. 259oral infections, p. 244 and p. 251

BNFC 2011–2012 5.1 Antibacterial drugs 243Notifiable diseasesDoctors must notify the Proper Officer of the localauthority (usually the consultant in communicabledisease control) when attending a patient suspectedof suffering from any of the diseases listed below; aform is available from the Proper Officer.AnthraxMumpsBotulismParatyphoid feverBrucellosisPlagueCholeraPoliomyelitis, acuteDiarrhoea (infectious bloody) RabiesDiphtheriaRubellaEncephalitis, acuteSARSFood poisoningScarlet feverHaemolytic uraemic syndrome SmallpoxHaemorrhagic fever (viral) Streptococcal diseaseHepatitis, viral(Group A, invasive)Legionnaires’ diseaseTetanusLeprosyTuberculosisMalariaTyphoid feverMeaslesTyphusMeningitisWhooping coughMeningococcal septicaemiaYellow feverNote It is good practice for doctors to also inform the consultantin communicable disease control of instances of otherinfections (e.g. psittacosis) where there could be a public healthrisk.5.1 Antibacterial drugs5.1.1 Penicillins5.1.2 Cephalosporins, carbapenems, andother beta-lactams5.1.3 Tetracyclines5.1.4 Aminoglycosides5.1.5 Macrolides5.1.6 Clindamycin5.1.7 Some other antibacterials5.1.8 Sulfonamides and trimethoprim5.1.9 Antituberculosis drugs5.1.10 Antileprotic drugs5.1.11 Metronidazole5.1.12 Quinolones5.1.13 Urinary-tract infectionsChoice of a suitable drug Before selecting an antibacterialthe clinician must first consider two factors—the child and the known or likely causative organism.Factors related to the child which must be consideredinclude history of allergy, renal and hepatic function,susceptibility to infection (i.e. whether immunocompromised),ability to tolerate drugs by mouth, severity ofillness, ethnic origin, age and, if an adolescent female,whether pregnant, breast-feeding or taking an oral contraceptive.The known or likely organism and its antibacterialsensitivity, in association with the above factors, willsuggest one or more antibacterials, the final choicedepending on the microbiological, pharmacological,and toxicological properties.The principles involved in selection of an antibacterialmust allow for a number of variables including age,changing renal and hepatic function, increasing bacterialresistance, and new information on side-effects.Duration of therapy, dosage, and route of administrationdepend on site, type and severity of infection andresponse.Antibacterial policies Local policies often limit theantibacterials that may be used to achieve reasonableeconomy consistent with adequate cover, and to reducethe development of resistant organisms. A policy mayindicate a range of drugs for general use, and permitother drugs only on the advice of the microbiologist orpaediatric infectious diseases specialist.Before starting therapy The following principlesshould be considered before starting:. Viral infections should not be treated with antibacterials.However, antibacterials may be indicated fortreatment of secondary bacterial infection (e.g. bacterialpneumonia secondary to influenza);. Samples should be taken for culture and sensitivitytesting whenever possible; ‘blind’ antibacterial prescribingfor unexplained pyrexia usually leads tofurther difficulty in establishing the diagnosis;. Knowledge of prevalent organisms and their currentsensitivity is of great help in choosing anantibacterial before bacteriological confirmation isavailable. Generally, narrow-spectrum antibacterialsare preferred to broad-spectrum antibacterialsunless there is a clear clinical indication(e.g. life-threatening sepsis);. The dose of an antibacterial varies according to anumber of factors including age, weight, hepaticfunction, renal function, and severity of infection.The prescribing of the so-called ‘standard’ dose inserious infections may result in failure of treatmentor even death of the patient; therefore it is importantto prescribe a dose appropriate to the condition.An inadequate dose may also increase thelikelihood of antibacterial resistance. On the otherhand, for an antibacterial with a narrow marginbetween the toxic and therapeutic dose (e.g. anaminoglycoside) it is also important to avoid anexcessive dose and the concentration of the drugin the plasma may need to be monitored;. The route of administration of an antibacterial oftendepends on the severity of the infection. Life-threateninginfections often require intravenous therapy.Antibacterials that are well absorbed may be givenby mouth even for some serious infections. Par-5 Infections

244 5.1 Antibacterial drugs BNFC 2011–2012enteral administration is also appropriate when theoral route cannot be used (e.g. because of vomiting)or if absorption is inadequate (e.g. in neonates andyoung children). Whenever possible painful intramuscularinjections should be avoided in children;. Duration of therapy depends on the nature of theinfection and the response to treatment. Coursesshould not be unduly prolonged because theyencourage resistance, they may lead to side-effectsand they are costly. However, in certain infectionssuch as tuberculosis or osteomyelitis it may benecessary to treat for prolonged periods.changed, preferably on the basis of bacteriologicalinvestigation. Failure to respond may also suggest anincorrect diagnosis, lack of essential additional measures(such as drainage), poor host resistance, or poorpatient compliance.Combination of a penicillin (or erythromycin) withmetronidazole may sometimes be helpful for the treatmentof severe or resistant oral infections.See also Penicillins (section 5.1.1), Cephalosporins(section 5.1.2.1), Tetracyclines (section 5.1.3), Macrolides(section 5.1.5), Clindamycin (section 5.1.6),Metronidazole (section 5.1.11), Fusidic acid (section13.10.1.2).5 InfectionsOral bacterial infections Antibacterial drugs shouldonly be prescribed for the treatment of oral infections onthe basis of defined need. They may be used in conjunctionwith (but not as an alternative to) other appropriatemeasures, such as providing drainage or extractinga tooth.The ‘blind’ prescribing of an antibacterial for unexplainedpyrexia, cervical lymphadenopathy, or facialswelling can lead to difficulty in establishing the diagnosis.A sample should always be taken for bacteriologyin the case of severe oral infection.Oral infections which may require antibacterial treatmentinclude acute periapical or periodontal abscess,cellulitis, acutely created oral-antral communication(and acute sinusitis), severe pericoronitis, localisedosteitis, acute necrotising ulcerative gingivitis, anddestructive forms of chronic periodontal disease. Mostof these infections are readily resolved by the earlyestablishment of drainage and removal of the cause(typically an infected necrotic pulp). Antibacterialsmay be required if treatment has to be delayed, inimmunocompromised patients, or in those with conditionssuch as diabetes. Certain rarer infections includingbacterial sialadenitis, osteomyelitis, actinomycosis, andinfections involving fascial spaces such as Ludwig’sangina, require antibiotics and specialist hospital care.Antibacterial drugs may also be useful after dentalsurgery in some cases of spreading infection. Infectionmay spread to involve local lymph nodes, to fascialspaces (where it can cause airway obstruction), or intothe bloodstream (where it can lead to cavernous sinusthrombosis and other serious complications). Extensionof an infection can also lead to maxillary sinusitis;osteomyelitis is a complication, which usually ariseswhen host resistance is reduced.If the oral infection fails to respond to antibacterialtreatment within 48 hours the antibacterial should beSuperinfection In general, broad-spectrum antibacterialdrugs such as the cephalosporins are morelikely to be associated with adverse reactions related tothe selection of resistant organisms e.g. fungal infectionsor antibiotic-associated colitis (pseudomembranouscolitis); other problems associated with superinfectioninclude vaginitis and pruritus ani.Therapy Suggested treatment is shown in Table 1.When the pathogen has been isolated treatment may bechanged to a more appropriate antibacterial if necessary.If no bacterium is cultured the antibacterial can becontinued or stopped on clinical grounds. Infections forwhich prophylaxis is useful are listed in table 2.Switching from parenteral to oral treatment Theongoing parenteral administration of an antibacterialshould be reviewed regularly. In older children it maybe possible to switch to an oral antibacterial; in neonatesand infants this should be done more cautiouslybecause of the relatively high incidence of bacteraemiaand the possibility of variable oral absorption.Prophylaxis Infections for which antibacterial prophylaxisis useful are listed in Table 2. In most situations,only a short course of prophylactic antibacterial isneeded. Longer-term antibacterial prophylaxis is appropriatein specific indications such as vesico-uretericrefluxTable 1. Summary of antibacterial therapyIf treating a patient suspected of suffering from a notifiable disease, the consultant in communicable diseasecontrol should be informed (see p. 243)Gastro-intestinal systemGastro-enteritisFrequently self-limiting and may not be bacterial.Antibacterial not usually indicated

BNFC 2011–2012 5.1 Antibacterial drugs 245Campylobacter enteritisFrequently self-limiting; treat if immunocompromised or if severe infection.Clarithromycin 1Alternative, ciprofloxacinSalmonella (non-typhoid)Treat invasive or severe infection. Do not treat less severe infection unless there is a risk of developing invasiveinfection (e.g. immunocompromised children, those with haemoglobinopathy, or children under 6 months of age).Ciprofloxacin or cefotaximeShigellosisAntibacterial not indicated for mild cases.Azithromycin or ciprofloxacinAlternatives if micro-organism sensitive, amoxicillin or trimethoprimTyphoid feverInfections from Middle-East, South Asia, and South-East Asia may be multiple-antibacterial-resistant and sensitivityshould be tested.Cefotaxime 2Azithromycin may be an alternative in mild or moderate disease caused by multiple-antibacterial-resistantmicro-organismsAlternative, ciprofloxacin or chloramphenicolStrains with decreased sensitivity to ciprofloxacin being isolatedClostridium difficile infectionOral metronidazoleSuggested duration of treatment 10–14 daysFor third or subsequent episode of infection, for severe infection, for infection not respondingto metronidazole, or in children intolerant of metronidazole, oral vancomycinSuggested duration of treatment 10–14 daysFor infection not responding to vancomycin, or for life-threatening infection, or in patientswith ileus, oral vancomycin + i/v metronidazoleSuggested duration of treatment 10–14 days5 InfectionsNecrotising enterocolitis in neonatesBenzylpenicillin + gentamicin + metronidazole or amoxicillin 3 + gentamicin + metronidazoleor amoxicillin 3 + cefotaxime + metronidazolePeritonitisA cephalosporin + metronidazole or amoxicillin + gentamicin + metronidazole or piperacillinwith tazobactam alonePeritonitis: peritoneal dialysis-associatedVancomycin 4 + ceftazidime added to dialysis fluid or vancomycin added to dialysis fluid +ciprofloxacin by mouthSuggested duration of treatment 14 days or longer1. Where clarithromycin is suggested azithromycin or erythromycin may be used2. Where cefotaxime is suggested ceftriaxone may be used3. Where amoxicillin is suggested ampicillin may be used4. Where vancomycin is suggested teicoplanin may be used

246 5.1 Antibacterial drugs BNFC 2011–2012Cardiovascular systemEndocarditis: initial ‘blind’ therapyFlucloxacillin (or benzylpenicillin if symptoms less severe) + gentamicinIf cardiac prostheses present, or if penicillin-allergic, or if meticillin-resistant Staphylococcusaureus suspected, vancomycin + rifampicin + gentamicinEndocarditis caused by staphylococciFlucloxacillinAdd rifampicin for at least 2 weeks in prosthetic valve endocarditis.Suggested duration of treatment at least 4 weeks (at least 6 weeks for prosthetic valve endocarditis)If penicillin-allergic or if meticillin-resistant Staphylococcus aureus, vancomycin + rifampicinSuggested duration of treatment at least 4 weeks (at least 6 weeks for prosthetic valve endocarditis)Native-valve endocarditis caused by fully-sensitive streptococci (e.g. viridans streptococci)BenzylpenicillinSuggested duration of treatment 4 weeksAlternative if a large vegetation, intracardial abscess, or infected emboli are absent, benzylpenicillin+ gentamicinSuggested duration of treatment 2 weeksIf penicillin-allergic, vancomycinSuggested duration of treatment 4 weeks5 InfectionsNative-valve endocarditis caused by less-sensitive streptococciBenzylpenicillin + gentamicinSuggested duration of treatment 4–6 weeks (stop gentamicin after 2 weeks for micro-organisms moderatelysensitive to penicillin)If aminoglycoside cannot be used and if streptococci moderately sensitive to penicillin,benzylpenicillinSuggested duration of treatment 4 weeksIf penicillin-allergic or highly penicillin-resistant, vancomycin 1 + gentamicinSuggested duration of treatment 4–6 weeks (stop gentamicin after 2 weeks for micro-organisms moderatelysensitive to penicillin)Prosthetic valve endocarditis caused by streptococciBenzylpenicillin + gentamicinSuggested duration of treatment at least 6 weeks (stop gentamicin after 2 weeks if micro-organisms fullysensitive to penicillin)If penicillin-allergic or highly penicillin-resistant, vancomycin 1 + gentamicinSuggested duration of treatment at least 6 weeks (stop gentamicin after 2 weeks if micro-organisms fullysensitive to penicillin)Endocarditis caused by enterococci (e.g. Enterococcus faecalis)Amoxicillin 2 + gentamicinIf gentamicin-resistant, substitute gentamicin with streptomycin.Suggested duration of treatment at least 4 weeks (at least 6 weeks for prosthetic valve endocarditis)If penicillin-allergic or penicillin-resistant, vancomycin 1 + gentamicinIf gentamicin-resistant, substitute gentamicin with streptomycin.Suggested duration of treatment at least 4 weeks (at least 6 weeks for prosthetic valve endocarditis)Endocarditis caused by haemophilus, actinobacillus, cardiobacterium, eikenella, and kingellaspecies (‘HACEK’ micro-organisms)Amoxicillin 2 + gentamicinSuggested duration of treatment 4 weeks (6 weeks for prosthetic valve endocarditis); stop gentamicin after2 weeksIf amoxicillin-resistant, ceftriaxone + gentamicinSuggested duration of treatment 4 weeks (6 weeks for prosthetic valve endocarditis); stop gentamicin after2 weeks1. Where vancomycin is suggested teicoplanin may be used2. Where amoxicillin is suggested ampicillin may be used

BNFC 2011–2012 5.1 Antibacterial drugs 247Respiratory systemHaemophilus influenzae epiglottitisCefotaxime 1If history of immediate hypersensitivity reaction to penicillin or to cephalosporins, chloramphenicolPneumonia: uncomplicated community-acquiredNeonate and child under 6 months, treat as for severe community-acquired pneumonia ofunknown aetiologyChild 6 months–18 years, oral amoxicillin 2Pneumococci with decreased penicillin sensitivity being isolated, but not yet common in UK.If staphylococci suspected (e.g. in influenza or measles), add flucloxacillin.Suggested duration of treatment 7 days (14–21 days for infections caused by staphylococci)Child 6 months–18 years, if penicillin-allergic or if atypical pathogens suspected, oralclarithromycin 3Suggested duration of treatment 7 days (14–21 days for infections caused by staphylococci)Pneumonia: severe community-acquired of unknown aetiologyNeonate, benzylpenicillin + gentamicinChild 1 month–18 years, co-amoxiclav or cefuroximeSuggested duration of treatment 7–10 days (may extend treatment to 14–21 days in some cases e.g. ifstaphylococci or Gram-negative enteric bacilli suspected)Child 1 month–18 years, if atypical pathogens such as mycoplasma (more common inchildren over 5 years) or chlamydia suspected, or if penicillin-allergic, clarithromycin 3Suggested duration of treatment 7–10 days (may extend treatment to 14–21 days in some cases e.g. ifstaphylococci or Gram-negative enteric bacilli suspected)Pneumonia possibly caused by atypical pathogensClarithromycin 3Suggested duration of treatment 14 daysAlternative for chlamydial or mycoplasma infections in children over 12 years, doxycyclineSuggested duration of treatment 14 daysPneumonia: hospital-acquiredEarly-onset infection (less than 5 days after admission to hospital), treat as for severecommunity-acquired pneumonia of unknown aetiology; if life-threatening infection, or ifrecent history of antibacterial treatment, or if resistant organisms suspected, treat as for lateonsethospital-acquired pneumoniaLate-onset infection (more than 5 days after admission to hospital), an antipseudomonalpenicillin (e.g. piperacillin with tazobactam) or another antipseudomonal beta-lactamIf meticillin-resistant Staphylococcus aureus suspected, add vancomycin.If severe illness caused by Pseudomonas aeruginosa, add an aminoglycoside.Suggested duration of treatment 7 days (longer if Pseudomonas aeruginosa confirmed)5 InfectionsCystic fibrosisStaphylococcal lung infection in cystic fibrosisFlucloxacillinIf child already taking flucloxacillin prophylaxis or if severe exacerbation, add sodium fusidate orrifampicin; use flucloxacillin at treatment doseIf penicillin-allergic and if micro-organism sensitive, clarithromycin 3Alternative if penicillin-allergic, clindamycinHaemophilus influenzae lung infection in cystic fibrosisAmoxicillin or a broad-spectrum cephalosporinIn severe exacerbation use a third-generation cephalosporin (e.g. cefotaxime)Pseudomonal lung infection in cystic fibrosisCiprofloxacin + nebulised colistimethate sodiumFor severe exacerbation, an antipseudomonal beta-lactam antibacterial + parenteral tobramycin1. Where cefotaxime is suggested ceftriaxone may be used2. Where amoxicillin is suggested ampicillin may be used3. Where clarithromycin is suggested azithromycin or erythromycin may be used

248 5.1 Antibacterial drugs BNFC 2011–2012Central nervous systemMeningitis: initial empirical therapy. Transfer patient to hospital urgently.. If meningococcal disease (meningitis with non-blanching rash or meningococcal septicaemia) suspected,benzylpenicillin (see p. 258 for dose) should be given before transfer to hospital, so long as this does not delaythe transfer. If a patient with suspected bacterial meningitis without non-blanching rash cannot be transferred tohospital urgently, benzylpenicillin (see p. 258 for dose) should be given before the transfer. Cefotaxime (section5.1.2) may be an alternative in penicillin allergy; chloramphenicol (section 5.1.7) may be used if history ofimmediate hypersensitivity reaction to penicillins or to cephalosporins.. In hospital, consider adjunctive treatment with dexamethasone (section 6.3.2), preferably starting before or withfirst dose of antibacterial, but no later than 12 hours after starting antibacterial; avoid dexamethasone in septicshock, meningococcal septicaemia, or if immunocompromised, or in meningitis following surgery.. In hospital, if aetiology unknown:Neonate and child 1–3 months, cefotaxime 1 + amoxicillin 2Consider adding vancomycin if prolonged or multiple use of other antibacterials in the last 3 months, or iftravelled, in the last 3 months, to areas outside the UK with highly penicillin- and cephalosporin-resistantpneumococciSuggested duration of treatment at least 14 daysChild 3 months–18 years, cefotaxime 1Consider adding vancomycin if prolonged or multiple use of other antibacterials in the last 3 months, or iftravelled, in the last 3 months, to areas outside the UK with highly penicillin- and cephalosporin-resistantpneumococciSuggested duration of treatment at least 10 days5 InfectionsMeningitis caused by group B streptococcusBenzylpenicillin + gentamicin or cefotaxime 1 aloneSuggested duration of treatment at least 14 daysMeningitis caused by meningococciBenzylpenicillin or cefotaxime 1Suggested duration of treatment 7 days.To eliminate nasopharyngeal carriage in patients treated with benzylpenicillin or cefotaxime see Table 2,section 5.1If history of immediate hypersensitivity reaction to penicillin or to cephalosporins, chloramphenicolSuggested duration of treatment 7 days.To eliminate nasopharyngeal carriage see Table 2, section 5.1Meningitis caused by pneumococciCefotaxime 1Consider adjunctive treatment with dexamethasone (section 6.3.2), preferably starting before or with firstdose of antibacterial, but no later than 12 hours after starting antibacterial (may reduce penetration ofvancomycin into cerebrospinal fluid).If micro-organism penicillin-sensitive, replace cefotaxime with benzylpenicillin.If micro-organism highly penicillin- and cephalosporin-resistant, add vancomycin and if necessary rifampicin.Suggested duration of antibacterial treatment 14 daysMeningitis caused by Haemophilus influenzaeCefotaxime 1Consider adjunctive treatment with dexamethasone (section 6.3.2), preferably starting before or with firstdose of antibacterial, but no later than 12 hours after starting antibacterial.Suggested duration of antibacterial treatment 10 days.For H. influenzae type b give rifampicin for 4 days before hospital discharge (see Table 2, section 5.1)If history of immediate hypersensitivity reaction to penicillin or to cephalosporins, or if microorganismresistant to cefotaxime, chloramphenicolConsider adjunctive treatment with dexamethasone (section 6.3.2), preferably starting before or with firstdose of antibacterial, but no later than 12 hours after starting antibacterial.Suggested duration of antibacterial treatment 10 days.For H. influenzae type b give rifampicin for 4 days before hospital discharge (see Table 2, section 5.1)Meningitis caused by ListeriaAmoxicillin 2 + gentamicinSuggested duration of treatment 21 days.Consider stopping gentamicin after 7 daysIf history of immediate hypersensitivity reaction to penicillin, co-trimoxazoleSuggested duration of treatment 21 days1. Where cefotaxime is suggested ceftriaxone may be used2. Where amoxicillin is suggested ampicillin may be used

BNFC 2011–2012 5.1 Antibacterial drugs 249Urinary tractUrinary-tract infectionChild under 3 months of age, i/v amoxicillin 1 + gentamicin or i/v cephalosporin aloneChild over 3 months of age with uncomplicated lower urinary-tract infection, trimethoprim ornitrofurantoinSuggested duration of treatment 3 days.Re-assess child if unwell 24–48 hours after initial assessmentChild over 3 months of age, alternative for uncomplicated lower urinary-tract infection,amoxicillin 1 or oral cephalosporin (e.g. cefalexin)Use amoxicillin only if micro-organism sensitive.Suggested duration of treatment 3 days.Re-assess child if unwell 24–48 hours after initial assessmentChild over 3 months of age with acute pyelonephritis, a cephalosporin or co-amoxiclavSuggested duration of treatment 7–10 daysGenital systemNeonatal congenital syphilisBenzylpenicillinAlso consider treating neonates with suspected congenital syphilis whose mothers were treated inadequatelyfor syphilis, or whose mothers were treated for syphilis in the 4 weeks before delivery, or whosemothers were treated with non-penicillin antibacterials for syphilis.Suggested duration of treatment 10 daysSyphilisContact tracing recommended.Child under 12 years, benzylpenicillin or procaine benzylpenicillin [unlicensed]Suggested duration of treatment 10 daysChild 12–18 years, early syphilis (infection of less than 2 years), benzathine benzylpenicillin[unlicensed]Suggested duration of treatment single-dose (repeat dose after 7 days for females in the third trimester ofpregnancy)Child 12–18 years, alternatives for early syphilis, doxycycline or erythromycinSuggested duration of treatment 14 daysChild 12–18 years, late latent syphilis (asymptomatic infection of more than 2 years),benzathine benzylpenicillin [unlicensed]Suggested duration of treatment once weekly for 2 weeksChild 12–18 years, alternative for late latent syphilis, doxycyclineSuggested duration of treatment 28 daysChild 12–18 years who is an asymptomatic contact of a patient with infectious syphilis,doxycyclineSuggested duration of treatment 14 daysGonorrhoea: uncomplicatedContact tracing recommended. Consider chlamydia co-infection. Choice of antibacterial depends on locality whereinfection acquired.Child under 12 years, ceftriaxoneSuggested duration of treatment single-doseChild 12–18 years, cefiximeSuggested duration of treatment single-doseChild 12–18 years, alternative if micro-organism sensitive, ciprofloxacinSuggested duration of treatment single-doseChild 12–18 years with pharyngeal infection, ceftriaxoneSuggested duration of treatment single-dose1. Where amoxicillin is suggested ampicillin may be used5 Infections

250 5.1 Antibacterial drugs BNFC 2011–2012Uncomplicated genital chlamydial infection, non-gonococcal urethritis and non-specificgenital infectionContact tracing recommended.Child under 12 years, erythromycinSuggested duration of treatment 14 daysChild 12–18 years, azithromycin or doxycyclineSuggested duration of treatment azithromycin as a single dose or doxycycline for 7 daysChild 12–18 years, alternative, erythromycinSuggested duration of treatment 14 daysPelvic inflammatory diseaseContact tracing recommendedChild 2–12 years, erythromycin + metronidazole + i/m ceftriaxoneSuggested duration of treatment 14 days (use i/m ceftriaxone as a single dose)Child 12–18 years, doxycycline + metronidazole + i/m ceftriaxoneIf severely ill, seek specialist advice.Suggested duration of treatment 14 days (use i/m ceftriaxone as a single dose)5 InfectionsBloodSepticaemiaNeonate less than 48 hours old, benzylpenicillin + gentamicin or amoxicillin 1 + cefotaximeNeonate more than 48 hours old, flucloxacillin + gentamicin or amoxicillin 1 + cefotaximeChild 1 month–18 years with community-acquired septicaemia, aminoglycoside +amoxicillin 1 or cefotaxime 2 aloneIf pseudomonas suspected, use a broad-spectrum antipseudomonal beta-lactam antibacterial.If anaerobic infection suspected, add metronidazole.If Gram-positive infection suspected, add flucloxacillin or vancomycin 3 .Child 1 month–18 years with hospital-acquired septicaemia, a broad-spectrum antipseudomonalbeta-lactam antibacterial (e.g. piperacillin with tazobactam, ticarcillin with clavulanicacid, imipenem with cilastatin, or meropenem)If pseudomonas suspected, or if multiple-resistant organisms suspected, or if severe sepsis, add aminoglycoside.If meticillin-resistant Staphylococcus aureus suspected, add vancomycin 3 .If anaerobic infection suspected, add metronidazole to a broad-spectrum cephalosporinSepticaemia related to vascular catheterVancomycin 3If Gram-negative sepsis suspected, especially in the immunocompromised, add a broad-spectrum antipseudomonalbeta-lactam.Consider removing vascular catheter, particularly if infection caused by Staphylococcus aureus, pseudomonas,or candidaMeningococcal septicaemiaIf meningococcal disease suspected, a single dose of benzylpenicillin (see p. 258 for dose) should be given beforeurgent transfer to hospital, so long as this does not delay the transfer; cefotaxime (section 5.1.2) may be analternative in penicillin allergy; chloramphenicol may be used if history of immediate hypersensitivity reaction topenicillin or to cephalosporins.Benzylpenicillin or cefotaxime 2To eliminate nasopharyngeal carriage in patients treated with benzylpenicillin or cefotaxime see Table 2,section 5.1If history of immediate hypersensitivity reaction to penicillin or to cephalosporins, chloramphenicolTo eliminate nasopharyngeal carriage see Table 2, section 5.11. Where amoxicillin is suggested ampicillin may be used2. Where cefotaxime is suggested ceftriaxone may be used3. Where vancomycin is suggested teicoplanin may be used

BNFC 2011–2012 5.1 Antibacterial drugs 251Musculoskeletal systemOsteomyelitisSeek specialist advice if chronic infection or prostheses present.FlucloxacillinConsider adding fusidic acid or rifampicin for initial 2 weeks.Suggested duration of treatment 6 weeks for acute infectionIf penicillin-allergic, clindamycinConsider adding fusidic acid or rifampicin for initial 2 weeks.Suggested duration of treatment 6 weeks for acute infectionIf meticillin-resistant Staphylococcus aureus suspected, vancomycin 1Consider adding fusidic acid or rifampicin for initial 2 weeks.Suggested duration of treatment 6 weeks for acute infectionSeptic arthritisSeek specialist advice if prostheses present.FlucloxacillinSuggested duration of treatment 4–6 weeks (longer if infection complicated)If penicillin-allergic, clindamycinSuggested duration of treatment 4–6 weeks (longer if infection complicated)If meticillin-resistant Staphylococcus aureus suspected, vancomycin 1Suggested duration of treatment 4–6 weeks (longer if infection complicated)If gonococcal arthritis or Gram-negative infection suspected, cefotaxime 2Suggested duration of treatment 4–6 weeks (longer if infection complicated; treat gonococcal infection for2 weeks)EyePurulent conjunctivitisNeonate, chloramphenicol or neomycin eye dropsSee also section 11.3.1Child 1 month–18 years, chloramphenicol eye-dropsSee also section 11.3.15 InfectionsCongenital chlamydial conjunctivitisErythromycin (by mouth)Suggested duration of treatment 14 daysCongenital gonococcal conjunctivitisCefotaxime 2Suggested duration of treatment single-doseEar, nose, and oropharynxPericoronitisAntibacterial required only in presence of systemic features of infection, or of trismus, or persistent swelling despitelocal treatment.MetronidazoleSuggested duration of treatment 3 days or until symptoms resolveAlternative, amoxicillinSuggested duration of treatment 3 days or until symptoms resolve1. Where vancomycin is suggested teicoplanin may be used2. Where cefotaxime is suggested ceftriaxone may be used

5 Infections252 5.1 Antibacterial drugs BNFC 2011–2012Gingivitis: acute necrotising ulcerativeAntibacterial required only if systemic features of infection.MetronidazoleSuggested duration of treatment 3 days or until symptoms resolveAlternative, amoxicillinSuggested duration of treatment 3 days or until symptoms resolvePeriapical or periodontal abscessAntibacterial required only in severe disease with cellulitis or if systemic features of infection.AmoxicillinSuggested duration of treatment 5 daysAlternative, metronidazoleSuggested duration of treatment 5 daysPeriodontitisAntibacterial used as an adjunct to debridement in severe disease or disease unresponsive to local treatment alone.MetronidazoleAlternative in child over 12 years, doxycyclineThroat infectionsMost throat infections are caused by viruses and many do not require antibacterial therapy. Consider antibacterial, ifhistory of valvular heart disease, if marked systemic upset, if peritonsillar cellulitis or abscess, or if at increased riskfrom acute infection (e.g. in immunosuppression, cystic fibrosis); prescribe antibacterial for beta-haemolyticstreptococcal pharyngitis.PhenoxymethylpenicillinIn severe infection, initial parenteral therapy with benzylpenicillin, then oral therapy with phenoxymethylpenicillinor amoxicillin 1 . Avoid amoxicillin if possibility of glandular fever, see section 5.1.1.3.Suggested duration of treatment 10 daysIf penicillin-allergic, clarithromycin 2Suggested duration of treatment 10 daysSinusitisAntibacterial should usually be used only for persistent symptoms and purulent discharge lasting at least 7 days or ifsevere symptoms. Also, consider antibacterial for those at high risk of serious complications (e.g. in immunosuppression,cystic fibrosis).Amoxicillin 1 or clarithromycin 2Suggested duration of treatment 7 days.Consider oral co-amoxiclav if no improvement after 48 hours.In severe infection, initial parenteral therapy with co-amoxiclav or cefuroxime may be requiredOtitis externaConsider systemic antibacterial if spreading cellulitis or child systemically unwell.For topical preparations see section 12.1.1.FlucloxacillinIf penicillin-allergic, clarithromycin 2If pseudomonas suspected, ciprofloxacin (or an aminoglycoside)Otitis mediaMany infections caused by viruses. Most uncomplicated cases resolve without antibacterial treatment. In childrenwithout systemic features, antibacterial treatment may be started after 72 hours if no improvement. Consider earliertreatment if deterioration, if systemically unwell, if at high risk of serious complications (e.g. in immunosuppression,cystic fibrosis), if mastoiditis present, or in children under 2 years of age with bilateral otitis media.Amoxicillin 1Consider co-amoxiclav if no improvement after 48 hours.In severe infection, initial parenteral therapy with co-amoxiclav or cefuroxime.Suggested duration of treatment 5 days (longer if severely ill)If penicillin-allergic, clarithromycin 2Suggested duration of treatment 5 days (longer if severely ill)1. Where amoxicillin is suggested ampicillin may be used2. Where clarithromycin is suggested azithromycin or erythromycin may be used

BNFC 2011–2012 5.1 Antibacterial drugs 253SkinImpetigo: small areas of skin infectedSeek local microbiology advice before using topical treatment in hospital.Topical fusidic acidSuggested duration of treatment 7 days is usually adequate (max. 10 days)Alternative if meticillin-resistant Staphylococcus aureus, topical mupirocinSuggested duration of treatment 7 days is usually adequate (max. 10 days)Impetigo: widespread infectionOral flucloxacillinIf streptococci suspected in severe infection, add phenoxymethylpenicillin.Suggested duration of treatment 7 daysIf penicillin-allergic, oral clarithromycin 1Suggested duration of treatment 7 daysErysipelasPhenoxymethylpenicillin or benzylpenicillinIf staphylococci suspected, replace phenoxymethylpenicillin or benzylpenicillin with flucloxacillin.Suggested duration of treatment at least 7 daysIf penicillin-allergic, clindamycin or clarithromycin 1Suggested duration of treatment at least 7 daysCellulitis: mild or moderateFlucloxacillinIf streptococcal infection confirmed, replace flucloxacillin with phenoxymethylpenicillin or benzylpenicillin.If Gram-negative bacteria or anaerobes suspected (e.g. facial infection, orbital infection, or infection causedby animal or human bites), use broad-spectrum antibacterialsIf penicillin-allergic, clindamycin or clarithromycin 1If Gram-negative bacteria or anaerobes suspected, use broad-spectrum antibacterialsCellulitis: severeBenzylpenicillin + flucloxacillinIf oral treatment required, replace benzylpenicillin with phenoxymethylpenicillin.If streptococcal infection confirmed, discontinue flucloxacillin.If Gram-negative bacteria or anaerobes suspected, use broad-spectrum antibacterialsIf penicillin-allergic, clindamycin or clarithromycin 1If Gram-negative bacteria or anaerobes suspected, use broad-spectrum antibacterialsStaphylococcal scalded skin syndromeFlucloxacillinSuggested duration of treatment 7–10 daysIf penicillin-allergic, clarithromycinSuggested duration of treatment 7–10 daysAnimal and human bitesCleanse wound thoroughly. For tetanus-prone wound, give human tetanus immunoglobulin (with a tetanuscontainingvaccine if necessary, according to immunisation history and risk of infection), see under TetanusVaccines, section 14.4. Consider rabies prophylaxis (section 14.4) for bites from animals in endemic countries;assess risk of blood-borne viruses.Co-amoxiclavIf penicillin-allergic, clindamycinAcneSee section 13.6.Paronychia or ‘septic spots’ in neonateFlucloxacillinIf systemically unwell, add an aminoglycosideSurgical wound infectionFlucloxacillin or co-amoxiclav1. Where clarithromycin is suggested azithromycin or erythromycin may be used5 Infections

254 5.1 Antibacterial drugs BNFC 2011–20125 InfectionsTable 2. Summary of antibacterialprophylaxisPrevention of recurrence of rheumatic feverPhenoxymethylpenicillin by mouthChild 1 month–6 years 125 mg twice dailyChild 6–18 years 250 mg twice dailyorErythromycin by mouthChild 1 month–2 years 125 mg twice dailyChild 2–18 years 250 mg twice dailyPrevention of secondary case of invasivegroup A streptococcal infection 1Phenoxymethylpenicillin by mouthNeonate 12.5 mg/kg (max. 62.5 mg) every 6 hours for10 daysChild 1 month–1 year 62.5 mg every 6 hours for 10daysChild 1–6 years 125 mg every 6 hours for 10 daysChild 6–12 years 250 mg every 6 hours for 10 daysChild 12–18 years 250–500 mg every 6 hours for 10daysIf child penicillin allergic,either erythromycin by mouthChild 1 month–2 years 125 mg every 6 hours for 10daysChild 2–8 years 250 mg every 6 hours for 10 daysChild 8–18 years 250–500 mg every 6 hours for 10 daysor azithromycin by mouth [unlicensed indication]Child 6 months–12 years 12 mg/kg (max. 500 mg)once daily for 5 daysChild 12–18 years 500 mg once daily for 5 daysPrevention of secondary case ofmeningococcal meningitis 2Ciprofloxacin by mouth [unlicensed indication]Child 1 month–5 years 125 mg as a single doseChild 5–12 years 250 mg as a single doseChild 12–18 years 500 mg as a single doseor1. For details of those who should receive chemoprophylaxiscontact a consultant in communicable disease control (or aconsultant in infectious diseases or the local HealthProtection Agency Laboratory)2. For details of those who should receive chemoprophylaxiscontact a consultant in communicable disease control (or aconsultant in infectious diseases or the local HealthProtection Agency laboratory). Unless there has beendirect exposure of the mouth or nose to infectious dropletsfrom a patient with meningococcal disease who hasreceived less than 24 hours of antibacterial treatment,healthcare workers do not generally require chemoprophylaxisRifampicin by mouthNeonate 5 mg/kg every 12 hours for 2 daysChild 1 month–1 year 5 mg/kg every 12 hours for 2daysChild 1–12 years 10 mg/kg (max. 600 mg) every 12hours for 2 daysChild 12–18 years 600 mg every 12 hours for 2 daysorCeftriaxone by intramuscular injection [unlicensed indication]Child 1 month–12 years 125 mg as a single doseChild 12–18 years 250 mg as a single dosePrevention of secondary case ofHaemophilus influenzae type b disease 2Rifampicin by mouthChild 1–3 months 10 mg/kg once daily for 4 daysChild 3 months–12 years 20 mg/kg (max. 600 mg)once daily for 4 daysChild 12–18 years 600 mg once daily for 4 daysPrevention of secondary case of diphtheriain non-immune patientErythromycin 3 by mouthChild 1 month–2 years 125 mg every 6 hours for 7 daysChild 2–8 years 250 mg every 6 hours for 7 daysChild 8–18 years 500 mg every 6 hours for 7 daysTreat for further 10 days if nasopharyngeal swabs positiveafter first 7 days’ treatment. For immunisation again diphtheriasee section 14.4Prevention of pertussisClarithromycin 4 by mouthNeonate 7.5 mg/kg twice daily for 7 daysChild 1 month–12 yearsBody-weight under 8 kg 7.5 mg/kg twice daily for 7daysBody-weight 8–11 kg 62.5 mg twice daily for 7 daysBody-weight 12–19 kg 125 mg twice daily for 7 daysBody-weight 20–29 kg 187.5 mg twice daily for 7 daysBody-weight 30–40 kg 250 mg twice daily for 7 daysChild 12–18 years 500 mg twice daily for 7 daysWithin 3 weeks of onset of cough in the index case, giveantibacterial prophylaxis to vulnerable close contacts and toother close contacts who are in contact with vulnerable individuals.Vulnerable contacts include neonates, unimmunised orpartially immunised children under 10 years of age, females inthe last month of pregnancy, the immunocompromised, orthose with chronic illness (e.g. asthma, congenital heart disease).For immunisation against pertussis see section 14.43. Where erythromycin is suggested another macrolide (e.g.azithromycin or clarithromycin) may be used4. Where clarithromycin is suggested azithromycin or erythromycinmay be used

BNFC 2011–2012 5.1 Antibacterial drugs 255Prevention of pneumococcal infection inasplenia or in patients with sickle-celldiseasePhenoxymethylpenicillin by mouthChild under 1 year 62.5 mg twice dailyChild 1–5 years 125 mg twice dailyChild 5–18 years 250 mg twice dailyIf cover also needed for H. influenzae in child giveamoxicillin insteadChild 1 month–5 years 125 mg twice dailyChild 5–12 years 250 mg twice dailyChild 12–18 years 500 mg twice dailyIf penicillin-allergic, erythromycin by mouthChild 1 month–2 years 125 mg twice dailyChild 2–8 years 250 mg twice dailyChild 8–18 years 500 mg twice dailyNote Antibacterial prophylaxis is not fully reliable; for vaccinesin asplenia see p. 602. Antibacterial prophylaxis may be discontinuedin children over 5 years of age with sickle-celldisease who have received pneumococcal immunisationPrevention of Staphylococcus aureus lunginfection in cystic fibrosisPrimary prevention, flucloxacillin by mouthNeonate 125 mg every 12 hoursChild 1 month–3 years 125 mg every 12 hoursSecondary prevention, flucloxacillin by mouthChild 1 month–18 years 50 mg/kg (max. 1 g) every 12hoursPrevention of tuberculosis in susceptibleclose contacts or those who have becometuberculin positive 1Isoniazid for 6 monthsNeonate 10 mg/kg dailyChild 1 month –12 years 10 mg/kg daily (max. 300 mgdaily)Child 12–18 years 300 mg dailyor isoniazid + rifampicin for 3 monthsChild 1 month–12 years isoniazid 10 mg/kg daily(max. 300 mg daily) + rifampicin 10 mg/kg daily (max.450 mg daily if body-weight less than 50 kg; max.600 mg daily if body-weight over 50 kg)Child 12–18 years isoniazid 300 mg daily + rifampicin600 mg daily (rifampicin 450 mg daily if body-weightless than 50 kg)or (if isoniazid-resistant tuberculosis) rifampicin for 6monthsChild 1 month–12 years 10 mg/kg daily (max. 450 mgdaily if body-weight less than 50 kg; max. 600 mg daily ifbody-weight over 50 kg)Child 12–18 years 600 mg daily (450 mg daily if bodyweightless than 50 kg)1. For details of those who should receive chemoprophylaxiscontact the lead clinician for local tuberculosis services (ora consultant in communicable disease control). See alsosection 5.1.9, for advice on immunocompromised patientsand on prevention of tuberculosisPrevention of urinary-tract infectionTrimethoprim by mouthNeonate 2 mg/kg at nightChild 1 month–12 years 2 mg/kg (max. 100 mg) atnightorChild 6 weeks–6 months 12.5 mg at nightChild 6 months–6 years 25 mg at nightChild 6–12 years 50 mg at nightChild 12–18 years 100 mg at nightor nitrofurantoin by mouthChild 3 months–12 years 1 mg/kg at nightChild 12–18 years 50–100 mg at nightAntibacterial prophylaxis can be considered for recurrent infection,significant urinary-tract anomalies, or significant kidneydamage. See also section 5.1.13Prevention of gas-gangrene in high lowerlimbamputations or following major traumai/v benzylpenicillinChild 1 month–12 years 25 mg/kg (max. 600 mg)every 6 hours for 5 daysChild 12–18 years 300–600 mg every 6 hours for 5 daysor if penicillin-allergic i/v or oral metronidazoleChild 1 month–12 years 7.5 mg/kg (max. 500 mg)every 8 hours for 5 daysChild 12–18 years 400–500 mg every 8 hours for 5 daysPrevention of infection in gastro-intestinalproceduresOperations on stomach or oesophagus 2Single dose 3 of i/v gentamicin or i/v cefuroxime or i/vco-amoxiclavAdd i/v teicoplanin 4 if high risk of meticillin-resistant StaphylococcusaureusOpen biliary surgery 2Single dose 3 of i/v cefuroxime + i/v metronidazole 5 ori/v gentamicin + i/v metronidazole 5 or i/v co-amoxiclavaloneAdd i/v teicoplanin 4 if high risk of meticillin-resistant Staphylococcusaureus2. Intravenous antibacterial prophylaxis should be given up to30 minutes before the procedure3. Additional intra-operative or postoperative doses of antibacterialmay be given for prolonged procedures or if thereis major blood loss4. Where teicoplanin is suggested vancomycin may be used5. Metronidazole may alternatively be given by suppositorybut to allow adequate absorption, it should be given 2hours before surgery5 Infections

256 5.1 Antibacterial drugs BNFC 2011–20125 InfectionsResections of colon and rectum, and resections ininflammatory bowel disease, and appendicectomy 1Single dose 2 of i/v gentamicin + i/v metronidazole 3 ori/v cefuroxime + i/v metronidazole 3 or i/v co-amoxiclavaloneAdd i/v teicoplanin 4 if high risk of meticillin-resistant StaphylococcusaureusEndoscopic retrograde cholangiopancreatography 1Single dose of i/v gentamicin or oral or i/v ciprofloxacinProphylaxis recommended if pancreatic pseudocyst, immunocompromised,history of liver transplantation, or risk ofincomplete biliary drainage. For biliary complications followingliver transplantation, add i/v amoxicillin or i/vvancomycinPercutaneous endoscopic gastrostomy orjejunostomy 1Single dose of i/v co-amoxiclav or i/v cefuroximeUse single dose of i/v teicoplanin 4 if history of allergy topenicillins or cephalosporins, or if high risk of meticillinresistantStaphylococcus aureusPrevention of infection in orthopaedicsurgeryClosed fractures 1Single dose 2 of i/v cefuroxime or i/v flucloxacillinIf history of allergy to penicillins or to cephalosporins or ifhigh risk of meticillin-resistant Staphylococcus aureus, usesingle dose 2 of i/v teicoplanin 4Open fracturesi/v co-amoxiclav alone or i/v cefuroxime + i/v metronidazole(or i/v clindamycin alone if history of allergy topenicillins or to cephalosporins)Add i/v teicoplanin 4 if high risk of meticillin-resistant Staphylococcusaureus. Start prophylaxis within 3 hours ofinjury and continue until soft tissue closure (max. 72 hours).At first debridement also use a single dose of i/v cefuroxime+ i/v metronidazole + i/v gentamicin or i/v co-amoxiclav +i/v gentamicin (or i/v clindamycin + i/v gentamicin ifhistory of allergy to penicillins or to cephalosporins).At time of skeletal stabilisation and definitive soft tissueclosure 1 use a single dose of i/v gentamicin and i/vteicoplanin 4Prevention of infection in obstetric surgeryTermination of pregnancySingle dose 2 of oral metronidazoleIf genital chlamydial infection cannot be ruled out, givedoxycycline (section 5.1.3) postoperativelyPrevention of endocarditisNICE GuidanceAntimicrobial prophylaxis against infectiveendocarditis in children and adultsundergoing interventional procedures(March 2008)Antibacterial prophylaxis and chlorhexidinemouthwash are not recommended for the preventionof endocarditis in patients undergoing dentalprocedures.Antibacterial prophylaxis is not recommended forthe prevention of endocarditis in patients undergoingprocedures of the:. upper and lower respiratory tract (including ear,nose, and throat procedures and bronchoscopy);. genito-urinary tract (including urological,gynaecological, and obstetric procedures);. upper and lower gastro-intestinal tract.While these procedures can cause bacteraemia,there is no clear association with the developmentof infective endocarditis. Prophylaxis may exposepatients to the adverse effects of antimicrobialswhen the evidence of benefit has not been proven.Any infection in patients at risk of endocarditis 5should be investigated promptly and treated appropriatelyto reduce the risk of endocarditis.If patients at risk of endocarditis 5 are undergoing agastro-intestinal or genito-urinary tract procedure ata site where infection is suspected, they shouldreceive appropriate antibacterial therapy thatincludes cover against organisms that cause endocarditis.Patients at risk of endocarditis 5 should be:. advised to maintain good oral hygiene;. told how to recognise signs of infective endocarditis,and advised when to seek expertadvice.Dermatological proceduresAdvice of a Working Party of the British Society forAntimicrobial Chemotherapy is that patients whoundergo dermatological procedures 6 do not requireantibacterial prophylaxis against endocarditis.1. Intravenous antibacterial prophylaxis should be given up to30 minutes before the procedure2. Additional intra-operative or postoperative doses of antibacterialmay be given for prolonged procedures or if thereis major blood loss3. Metronidazole may alternatively be given by suppositorybut to allow adequate absorption, it should be given 2hours before surgery4. Where teicoplanin is suggested vancomycin may be used5. Patients at risk of endocarditis include those with valvereplacement, acquired valvular heart disease with stenosisor regurgitation, structural congenital heart disease (includingsurgically corrected or palliated structural conditions,but excluding isolated atrial septal defect, fullyrepaired ventricular septal defect, fully repaired patentductus arteriosus, and closure devices considered to beendothelialised), hypertrophic cardiomyopathy, or a previousepisode of infective endocarditis6. The British Association of Dermatologists Therapy Guidelinesand Audit Subcommittee advise that such dermatologicalprocedures include skin biopsies and excision ofmoles or of malignant lesions

BNFC 2011–2012 5.1.1 Penicillins 257Joint prostheses and dental treatmentJoint prostheses and dental treatmentAdvice of a Working Party of the British Society forAntimicrobial Chemotherapy is that patients withprosthetic joint implants (including total hip replacements)do not require antibacterial prophylaxis fordental treatment. The Working Party considers thatit is unacceptable to expose patients to the adverseeffects of antibacterials when there is no evidencethat such prophylaxis is of any benefit, but that thosewho develop any intercurrent infection requireprompt treatment with antibacterials to which theinfecting organisms are sensitive.The Working Party has commented that joint infectionshave rarely been shown to follow dental proceduresand are even more rarely caused by oralstreptococci.Immunosuppression and indwellingintraperitoneal cathetersImmunosuppression and indwelling intraperitonealcathetersAdvice of a Working Party of the British Society forAntimicrobial Chemotherapy is that patients whoare immunosuppressed (including transplantpatients) and patients with indwelling intraperitonealcatheters do not require antibacterial prophylaxis fordental treatment provided there is no other indicationfor prophylaxis.The Working Party has commented that there is littleevidence that dental treatment is followed by infectionin immunosuppressed and immunodeficientpatients nor is there evidence that dental treatmentis followed by infection in patients with indwellingintraperitoneal catheters.Hypersensitivity reactions The most importantside-effect of the penicillins is hypersensitivity whichcauses rashes and anaphylaxis and can be fatal. Allergicreactions to penicillins occur in 1–10% of exposedindividuals; anaphylactic reactions occur in fewer than0.05% of treated patients. Individuals with a history ofanaphylaxis, urticaria, or rash immediately after penicillinadministration are at risk of immediate hypersensitivityto a penicillin; these individuals should not receivea penicillin. Children who are allergic to one penicillinwill be allergic to all because the hypersensitivity isrelated to the basic penicillin structure. As patientswith a history of immediate hypersensitivity to penicillinsmay also react to the cephalosporins and other betalactamantibiotics, they should not receive these antibiotics;aztreonam may be less likely to cause hypersensitivityin penicillin-sensitive patients and can beused with caution. If a penicillin (or another beta-lactamantibiotic) is essential in a child with immediate hypersensitivityto penicillin then specialist advice should besought on hypersensitivity testing or using a beta-lactamantibiotic with a different structure to the penicillinthat caused the hypersensitivity (see also p. 266).Individuals with a history of a minor rash (i.e. nonconfluent,non-pruritic rash restricted to a small areaof the body) or a rash that occurs more than 72 hoursafter penicillin administration are probably not allergicto penicillin and in these individuals a penicillin shouldnot be withheld unnecessarily for serious infections; thepossibility of an allergic reaction should, however, beborne in mind. Other beta-lactam antibiotics (includingcephalosporins) can be used in these patients.Other side effects A rare but serious toxic effect ofthe penicillins is encephalopathy due to cerebral irritation.This may result from excessively high doses or inpatients with severe renal failure. The penicillins shouldnot be given by intrathecal injection because they cancause encephalopathy which may be fatal.Another problem relating to high doses of penicillin, ornormal doses given to patients with renal failure, is theaccumulation of electrolyte since most injectable penicillinscontain either sodium or potassium.Diarrhoea frequently occurs during oral penicillin therapy.It is most common with broad-spectrum penicillins,which can also cause antibiotic-associated colitis.5 Infections5.1.1 Penicillins5.1.1.1 Benzylpenicillin andphenoxymethylpenicillin5.1.1.2 Penicillinase-resistant penicillins5.1.1.3 Broad-spectrum penicillins5.1.1.4 Antipseudomonal penicillins5.1.1.5 MecillinamsThe penicillins are bactericidal and act by interferingwith bacterial cell wall synthesis. They diffuse well intobody tissues and fluids, but penetration into the cerebrospinalfluid is poor except when the meninges areinflamed. They are excreted in the urine in therapeuticconcentrations.5.1.1.1 Benzylpenicillin andphenoxymethylpenicillinBenzylpenicillin (Penicillin G) remains an importantand useful antibiotic but is inactivated by bacterialbeta-lactamases. It is effective for many streptococcal(including pneumococcal), gonococcal, and meningococcalinfections and also for anthrax (section 5.1.12),diphtheria, gas-gangrene, leptospirosis, and treatment ofLyme disease (section 5.1.1.3) in children. It is also usedin combination with gentamicin for the empirical treatmentof sepsis in neonates less than 48 hours old.Pneumococci, meningococci, and gonococci whichhave decreased sensitivity to penicillin have been isolated;benzylpenicillin is no longer the drug of firstchoice for pneumococcal meningitis. Althoughbenzylpenicillin is effective in the treatment of tetanus,metronidazole (section 5.1.11) is preferred. Benzylpenicillinis inactivated by gastric acid and absorption fromthe gastro-intestinal tract is low; therefore it must begiven by injection.Benzathine benzylpenicillin or procaine benzylpenicillinis used in the treatment of syphilis (see Table 1section 5.1); both are available from ‘special-order’manufacturers or specialist importing companies, seep. 809.

258 5.1.1 Penicillins BNFC 2011–20125 InfectionsPhenoxymethylpenicillin (Penicillin V) has a similarantibacterial spectrum to benzylpenicillin, but is lessactive. It is gastric acid-stable, so is suitable for oraladministration. It should not be used for serious infectionsbecause absorption can be unpredictable andplasma concentrations variable. It is indicated principallyfor respiratory-tract infections in children, forstreptococcal tonsillitis, and for continuing treatmentafter one or more injections of benzylpenicillin whenclinical response has begun. It should not be used formeningococcal or gonococcal infections. Phenoxymethylpenicillinis used for prophylaxis against streptococcalinfections following rheumatic fever and againstpneumococcal infections following splenectomy or insickle cell disease.Oral infections Phenoxymethylpenicillin is effectivefor dentoalveolar abscess.BENZYLPENICILLIN SODIUM(Penicillin G)Cautions history of allergy; false-positive urinary glucose(if tested for reducing substances); interactions:Appendix 1 (penicillins)Contra-indications penicillin hypersensitivityRenal impairment neurotoxicity—high doses maycause convulsions. Estimated glomerular filtrationrate 10–50 mL/minute/1.73 m 2 , use normal doseevery 8–12 hours; estimated glomerular filtration rateless than 10 mL/minute/1.73 m 2 use normal doseevery 12 hoursPregnancy not known to be harmfulBreast-feeding trace amounts in milk—not known tobe harmful, but be alert for hypersensitivity in infantSide-effects hypersensitivity reactions including urticaria,fever, joint pains, rashes, angioedema, anaphylaxis,serum sickness-like reactions; rarely CNS toxicityincluding convulsions (especially with high dosesor in severe renal impairment), interstitial nephritis,haemolytic anaemia, leucopenia, thrombocytopeniaand coagulation disorders; also reported diarrhoea(including antibiotic-associated colitis)Indication and doseMild to moderate susceptible infections(including throat infections, otitis media,pneumonia, cellulitis, neonatal sepsis, Table 1,section 5.1). By intramuscular injection or by slow intravenousinjection or infusion (intravenous routerecommended in neonates and infants)Neonate under 7 days 25 mg/kg every 12 hours;dose doubled in severe infectionNeonate 7–28 days 25 mg/kg every 8 hours;dose doubled in severe infectionChild 1 month–18 years 25 mg/kg every 6 hours;increased to 50 mg/kg every 4–6 hours (max. 2.4 gevery 4 hours) in severe infectionEndocarditis (combined with another antibacterialif necessary, see Table 1, section 5.1). By slow intravenous injection or infusionChild 1 month–18 years 25 mg/kg every 4 hours,increased if necessary to 50 mg/kg (max. 2.4 g)every 4 hoursMeningitis, meningococcal disease. By slow intravenous injection or infusionNeonate 75 mg/kg every 8 hoursChild 1 month–18 years 50 mg/kg every 4–6hours (max. 2.4 g every 4 hours)Important. If meningococcal disease (meningitis withnon-blanching rash or meningococcal septicaemia) issuspected, a single dose of benzylpenicillin should begiven before transferring the child to hospital urgently, solong as this does not delay the transfer. If a child withsuspected bacterial meningitis without non-blanchingrash cannot be transferred to hospital urgently, a singledose of benzylpenicillin should be given before the transfer.Suitable doses of benzylpenicillin by intravenousinjection (or by intramuscular injection) are: Infantunder 1 year 300 mg; Child 1–9 years 600 mg, 10 yearsand over 1.2 g. In penicillin allergy, cefotaxime (section5.1.2) may be an alternative; chloramphenicol (section5.1.7) may be used if there is a history of anaphylaxis topenicillinsProven or suspected neonatal group B streptococcusinfection. By slow intravenous injection or infusionNeonate under 7 days 50 mg/kg every 12 hoursNeonate 7–28 days 50 mg/kg every 8 hoursProphylaxis in limb amputation Table 2, section5.1Administration Intravenous route recommended inneonates and infants. For intravenous infusion, dilutewith Glucose 5% or Sodium Chloride 0.9%; give over15–30 minutes. Longer administration time is particularlyimportant when using doses of 50 mg/kg (orgreater) to avoid CNS toxicitySafe practiceIntrathecal injection of benzylpenicillin is not recommendedCrystapen c (Genus) AInjection, powder for reconstitution, benzylpenicillinsodium (unbuffered), net price 600-mg vial = 95p, 2-vial ‘GP pack’ = £2.64; 1.2-g vial = £1.89Electrolytes Na + 1.68 mmol/600-mg vial; 3.36 mmol/1.2-g vialPHENOXYMETHYLPENICILLIN(Penicillin V)Cautions see under Benzylpenicillin; interactions:Appendix 1 (penicillins)Contra-indications see under BenzylpenicillinPregnancy not known to be harmfulBreast-feeding trace amounts in milk—not known tobe harmful, but be alert for hypersensitivity in infantSide-effects see under BenzylpenicillinIndication and doseSusceptible infections including oral infections,tonsillitis, otitis media, erysipelas,cellulitis. By mouthChild 1 month–1 year 62.5 mg 4 times daily;increased up to 12.5 mg/kg 4 times daily in severeinfectionChild 1–6 years 125 mg 4 times daily; increasedup to 12.5 mg/kg 4 times daily in severe infection

BNFC 2011–2012 5.1.1 Penicillins 259Child 6–12 years 250 mg 4 times daily; increasedup to 12.5 mg/kg 4 times daily in severe infectionChild 12–18 years 500 mg 4 times daily;increased in severe infection up to 1 g 4 times dailyPrevention of pneumococcal infection inasplenia or sickle cell disease, see Table 2, section5.1Prevention of recurrence of rheumatic fever, seeTable 2, section 5.1Prevention of group A streptococcal infection,see Table 2, section 5.1Phenoxymethylpenicillin (Non-proprietary) ATablets, phenoxymethylpenicillin (as potassium salt)250 mg, net price 28-tab pack = £1.27. Label: 9, 23Dental prescribing on NHS PhenoxymethylpenicillinTablets may be prescribedOral solution, phenoxymethylpenicillin (as potassiumsalt) for reconstitution with water, net price 125 mg/5 mL, 100 mL = £1.90; 250 mg/5 mL, 100 mL = £2.59.Label: 9, 23Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionDental prescribing on NHS Phenoxymethylpenicillin OralSolution may be prescribed5.1.1.2 Penicillinase-resistantpenicillinsMost staphylococci are now resistant to benzylpenicillinbecause they produce penicillinases. Flucloxacillin,however, is not inactivated by these enzymes and isthus effective in infections caused by penicillin-resistantstaphylococci, which is the main indication for its use.Flucloxacillin is acid-stable and can, therefore, be givenby mouth as well as by injection.Flucloxacillin is well absorbed from the gut. For awarning on hepatic disorders see under Flucloxacillin.MRSA Infection from Staphylococcus aureus strainsresistant to meticillin [now discontinued] (meticillinresistantStaph. aureus, MRSA) and to flucloxacillincan be difficult to manage. Treatment is guided by thesensitivity of the infecting strain.Rifampicin (section 5.1.9) or sodium fusidate (section5.1.7) should not be used alone because resistance maydevelop rapidly. Clindamycin alone or a combination ofrifampicin and sodium fusidate can be used for skin andsoft-tissue infections caused by MRSA; a tetracycline isan alternative in children over 12 years of age. A glycopeptide(e.g. vancomycin, section 5.1.7) can be used forsevere skin and soft-tissue infections associated withMRSA. A combination of a glycopeptide and sodiumfusidate or a glycopeptide and rifampicin can be consideredfor skin and soft-tissue infections that havefailed to respond to a single antibacterial. Linezolid(section 5.1.7) should be reserved for skin and softtissueinfections that have not responded to other antibacterialsor for children who cannot tolerate otherantibacterials.A glycopeptide can be used for pneumonia associatedwith MRSA. Linezolid should be reserved for hospitalacquiredpneumonia that has not responded to otherantibacterials or for children who cannot tolerate otherantibacterials.Trimethoprim or nitrofurantoin can be used forurinary-tract infections caused by MRSA; a tetracyclineis an alternative in children over 12 years of age. Aglycopeptide can be used for urinary-tract infectionsthat are severe or resistant to other antibacterials.A glycopeptide can be used for septicaemia associatedwith MRSA.For the management of endocarditis, osteomyelitis, orseptic arthritis associated with MRSA, see Table 1,section 5.1.Prophylaxis with vancomycin or teicoplanin (alone or incombination with another antibacterial active againstother pathogens) is appropriate for patients undergoingsurgery if:. there is a history of MRSA colonisation or infectionwithout documented eradication;. there is a risk that the patient’s MRSA carriage hasrecurred;. the patient comes from an area with a high prevalenceof MRSA.It is important that hospitals have infection controlguidelines to minimise MRSA transmission, includingpolicies on isolation and treatment of MRSA carriersand on hand hygiene. For eradication of nasal carriageof MRSA, see section 12.2.3.FLUCLOXACILLINCautions see under Benzylpenicillin (section 5.1.1.1);risk of kernicterus in jaundiced neonates when highdoses given parenterally; interactions: Appendix 1(penicillins)Hepatic disordersCholestatic jaundice and hepatitis may occur veryrarely, up to two months after treatment with flucloxacillinhas been stopped. Administration for more than2 weeks and increasing age are risk factors. Healthcareprofessionals are reminded that:. flucloxacillin should not be used in patients with a historyof hepatic dysfunction associated with flucloxacillin;. flucloxacillin should be used with caution in patients withhepatic impairment;. careful enquiry should be made about hypersensitivityreactions to beta-lactam antibacterials.Contra-indications see under Benzylpenicillin (section5.1.1.1)Hepatic impairment see Cautions and Hepatic DisordersaboveRenal impairment use normal dose every 8 hours ifestimated glomerular filtration rate less than 10 mL/minute/1.73 m 2Pregnancy not known to be harmfulBreast-feeding trace amounts in milk—not known tobe harmful but be alert for hypersensitivity in infantSide-effects see under Benzylpenicillin (section5.1.1.1); also gastro-intestinal disturbances; veryrarely hepatitis and cholestatic jaundice reported (seealso Hepatic Disorders above)5 Infections

260 5.1.1 Penicillins BNFC 2011–20125 InfectionsIndication and doseInfections due to beta-lactamase-producingstaphylococci including otitis externa; adjunctin pneumonia, impetigo, cellulitis. By mouthNeonate under 7 days 25 mg/kg twice dailyNeonate 7–21 days 25 mg/kg 3 times dailyNeonate 21–28 days 25 mg/kg 4 times dailyChild 1 month–2 years 62.5–125 mg 4 times dailyChild 2–10 years 125–250 mg 4 times dailyChild 10–18 years 250–500 mg 4 times daily. By intramuscular injectionChild 1 month–18 years 12.5–25 mg/kg every 6hours (max. 500 mg every 6 hours). By slow intravenous injection or by intravenousinfusionNeonate under 7 days 25 mg/kg every 12 hours;may be doubled in severe infectionNeonate 7–21 days 25 mg/kg every 8 hours; maybe doubled in severe infectionNeonate 21–28 days 25 mg/kg every 6 hours;may be doubled in severe infectionChild 1 month–18 years 12.5–25 mg/kg every 6hours (max. 1 g every 6 hours); may be doubled insevere infectionOsteomyelitis (Table 1, section 5.1), cerebralabscess, staphylococcal meningitis. By slow intravenous injection or by intravenousinfusionNeonate under 7 days 50–100 mg/kg every 12hoursNeonate 7–21 days 50–100 mg/kg every 8 hoursNeonate 21–28 days 50–100 mg/kg every 6hoursChild 1 month–18 years 50 mg/kg (max. 2 g)every 6 hoursEndocarditis (Table 1, section 5.1). By slow intravenous injection or by intravenousinfusionChild 1 month–18 years 50 mg/kg (max. 2 g)every 6 hoursPrevention of staphylococcal lung infection incystic fibrosisTable 2, section 5.1Staphylococcal lung infection in cystic fibrosis. By mouthChild 1 month–18 years 25 mg/kg (max. 1 g) 4times daily; total daily dose may alternatively begiven in 3 divided doses. By slow intravenous injection or by intravenousinfusionChild 1 month–18 years 50 mg/kg (max. 2 g)every 6 hoursAdministration for intermittent intravenous infusion,dilute reconstituted solution in Glucose 5% or SodiumChloride 0.9% and give over 30–60 minutesFlucloxacillin (Non-proprietary) ACapsules, flucloxacillin (as sodium salt) 250 mg, netprice 28 = £2.07; 500 mg, 28 = £3.21. Label: 9, 23Brands include Floxapen c , Fluclomix c , Ladropen cOral solution (= elixir or syrup), flucloxacillin (assodium salt) for reconstitution with water, 125 mg/5 mL, net price 100 mL = £4.41; 250 mg/5 mL,100 mL = £31.28. Label: 9, 23Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionInjection, powder for reconstitution, flucloxacillin (assodium salt). Net price 250-mg vial = £1.23; 500-mgvial = £2.45; 1-g vial = £4.905.1.1.3 Broad-spectrum penicillinsAmpicillin is active against certain Gram-positive andGram-negative organisms but is inactivated by penicillinasesincluding those produced by Staphylococcusaureus and by common Gram-negative bacilli such asEscherichia coli. Ampicillin is also active against Listeriaspp. and enterococci. Almost all staphylococci,approx. 60% of E. coli strains and approx. 20% ofHaemophilus influenzae strains are now resistant. Thelikelihood of resistance should therefore be consideredbefore using ampicillin for the ‘blind’ treatment of infections;in particular, it should not be used for hospitalpatients without checking sensitivity.Ampicillin can be given by mouth, but less than half thedose is absorbed and absorption is further decreased bythe presence of food in the gut. Ampicillin is wellexcreted in the bile and urine.Amoxicillin is a derivative of ampicillin and has asimilar antibacterial spectrum. It is better absorbedthan ampicillin when given by mouth, producing higherplasma and tissue concentrations; unlike ampicillin,absorption is not affected by the presence of food inthe stomach.Amoxicillin or ampicillin are principally indicated for thetreatment of community-acquired pneumonia and middleear infections, both of which may be due to Streptococcuspneumoniae and H. influenzae, and for urinarytractinfections (section 5.1.13). They are also used inthe treatment of endocarditis and listerial meningitis.Amoxicillin may also be used for the treatment of Lymedisease [not licensed], see below.Maculopapular rashes occur commonly with ampicillin(and amoxicillin) but are not usually related to truepenicillin allergy. They often occur in children withglandular fever; broad-spectrum penicillins should nottherefore be used for ‘blind’ treatment of a sore throat.The risk of rash is also increased in children with acuteor chronic lymphocytic leukaemia or in cytomegalovirusinfection.Co-amoxiclav consists of amoxicillin with the betalactamaseinhibitor clavulanic acid. Clavulanic acid itselfhas no significant antibacterial activity but, by inactivatingbeta-lactamases, it makes the combination activeagainst beta-lactamase-producing bacteria that areresistant to amoxicillin. These include resistant strains

BNFC 2011–2012 5.1.1 Penicillins 261of Staph. aureus, E. coli, and H. influenzae, as well asmany Bacteroides and Klebsiella spp. Co-amoxiclavshould be reserved for infections likely, or known, tobe caused by amoxicillin-resistant beta-lactamase-producingstrains.A combination of ampicillin with flucloxacillin (as cofluampicil)is available to treat infections involvingeither streptococci or staphylococci (e.g. cellulitis).Lyme disease Lyme disease should generally betreated by those experienced in its management. Amoxicillin[unlicensed indication], cefuroxime axetil ordoxycycline are the antibacterials of choice for earlyLyme disease or Lyme arthritis but doxycycline shouldonly be used in children over 12 years of age. If theseantibacterials are contra-indicated, a macrolide (e.g.clarithromycin) can be used for early Lyme disease.Intravenous administration of ceftriaxone, cefotaxime(section 5.1.2.1), or benzylpenicillin (p. 258) is recommendedfor Lyme disease associated with cardiac orneurological complications. The duration of treatment isusually 2–4 weeks; Lyme arthritis may require furthertreatment.Oral infections Amoxicillin or ampicillin are as effectiveas phenoxymethylpenicillin (section 5.1.1.1) butthey are better absorbed; however, they may encourageemergence of resistant organisms.Like phenoxymethylpenicillin, amoxicillin and ampicillinare ineffective against bacteria that producebeta-lactamases. Co-amoxiclav is active against betalactamase-producingbacteria that are resistant toamoxicillin. Co-amoxiclav may be used for severedental infection with spreading cellulitis or dental infectionnot responding to first-line antibacterial treatment.AMOXICILLIN(Amoxycillin)Cautions see under Ampicillin; maintain adequatehydration with high doses (particularly during parenteraltherapy); interactions: Appendix 1 (penicillins)Contra-indications see under AmpicillinRenal impairment risk of crystalluria with high doses(particularly during parenteral therapy). Reduce dosein severe impairment; rashes more commonPregnancy not known to be harmfulBreast-feeding trace amounts in milk—not known tobe harmful but be alert for hypersensitivity in infantSide-effects see under AmpicillinIndication and doseSusceptible infections including urinary-tractinfections, sinusitis, uncomplicated community-acquiredpneumonia, oral infections (Table1, section 5.1), Lyme disease (see notesabove), salmonellosis. By mouthNeonate 7–28 days 30 mg/kg (max. 62.5 mg) 3times daily; dose doubled in severe infectionChild 1 month–1 year 62.5 mg 3 times daily; dosedoubled in severe infection, community-acquiredpneumonia, salmonellosis, or Lyme diseaseChild 1–5 years 125 mg 3 times daily; dosedoubled in severe infection, community-acquiredpneumonia, salmonellosis, or Lyme diseaseChild 5–18 years 250 mg 3 times daily; dosedoubled in severe infection, community-acquiredpneumonia, salmonellosis, or Lyme disease. By intravenous injection or infusionNeonate under 7 days 30 mg/kg every 12 hours;dose doubled in severe infection, communityacquiredpneumonia, or salmonellosisNeonate 7–28 days 30 mg/kg every 8 hours;dose doubled in severe infection, communityacquiredpneumonia, or salmonellosisChild 1 month–18 years 20–30 mg/kg (max.500 mg) every 8 hours; dose doubled in severeinfection (max. 4 g daily)Otitis media (but see Table 1, section 5.1). By mouthChild 1 month–18 years 40 mg/kg daily in 3divided doses (max. 1.5 g daily in 3 divided doses)Listerial meningitis (in combination withanother antibacterial, Table 1, section 5.1),group B streptococcal infection, enterococcalendocarditis (in combination with another antibiotic). By intravenous infusionNeonate under 7 days 50 mg/kg every 12 hours;dose may be doubled in meningitisNeonate 7–28 days 50 mg/kg every 8 hours;dose may be doubled in meningitisChild 1 month–18 years 50 mg/kg every 4–6hours (max. 2 g every 4 hours)Cystic fibrosis (treatment of asymptomatic H.influenzae carriage or mild exacerbations). By mouthChild 1 month–1 year 125 mg 3 times dailyChild 1–7 years 250 mg 3 times dailyChild 7–18 years 500 mg 3 times dailyHelicobacter pylori eradication section 1.3Note Amoxicillin doses in BNFC may differ from those inproduct literatureAdministration Displacement value may be significantwhen reconstituting injection, consult localguidelines. Dilute intravenous injection to a concentrationof 50 mg/mL (100 mg/mL for neonates). Maybe further diluted with Glucose 5% or Glucose 10% orSodium chloride 0.9% or 0.45% for intravenous infusion.Give intravenous infusion over 30 minutes whenusing doses over 30 mg/kgAmoxicillin (Non-proprietary) ACapsules, amoxicillin (as trihydrate) 250 mg, net price21 = £1.07; 500 mg, 21 = £1.31. Label: 9Brands include Amix c , Amoram c , Amoxident c , Galenamox c ,Rimoxallin cDental prescribing on NHS Amoxicillin Capsules may beprescribedOral suspension, amoxicillin (as trihydrate) forreconstitution with water, 125 mg/5 mL, net price5 Infections

262 5.1.1 Penicillins BNFC 2011–20125 Infections100 mL = £1.22; 250 mg/5 mL, 100 mL = £1.39.Label: 9Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionBrands include Amoram c , Galenamox c , Rimoxallin cDental prescribing on NHS Amoxicillin Oral Suspensionmay be prescribedInjection, powder for reconstitution, amoxicillin (assodium salt), net price 250-mg vial = 32p; 500-mg vial= 66p; 1-g vial = £1.16Amoxil c (GSK) ACapsules, both maroon/gold, amoxicillin (as trihydrate),250 mg, net price 21-cap pack = £3.45; 500 mg,21-cap pack = £6.91. Label: 9Paediatric suspension, amoxicillin 125 mg (as trihydrate)/1.25mL when reconstituted with water, netprice 20 mL (peach- strawberry- and lemon-flavoured)= £3.25. Label: 9, counselling, use of pipetteExcipients include sucrose 600 mg/1.25 mLInjection, powder for reconstitution, amoxicillin (assodium salt), net price 500-mg vial = 56p; 1-g vial =£1.12Electrolytes Na + 3.3 mmol/gAMPICILLINCautions history of allergy; erythematous rashescommon in glandular fever (see notes above);increased risk of erythematous rashes in cytomegalovirusinfection, and acute or chronic lymphocyticleukaemia (see notes above); interactions:Appendix 1 (penicillins)Contra-indications penicillin hypersensitivityRenal impairment if estimated glomerular filtrationrate less than 10 mL/minute/1.73 m 2 reduce dose orfrequency—rashes more commonPregnancy not known to be harmfulBreast-feeding trace amounts in milk—not known tobe harmful but be alert for hypersensitivity in infantSide-effects nausea, vomiting, diarrhoea; rashes (discontinuetreatment); rarely, antibiotic-associated colitis;see also under Benzylpenicillin (section 5.1.1.1)Indication and doseSusceptible infections including urinary-tractinfections, otitis media, sinusitis, uncomplicatedcommunity-acquired pneumonia, oralinfections (Table 1, section 5.1), salmonellosis. By mouthNeonate under 7 days 30 mg/kg (max. 62.5 mg)twice daily; dose doubled in severe infectionNeonate 7–21 days 30 mg/kg (max. 62.5 mg) 3times daily; dose doubled in severe infectionNeonate 21–28 days 30 mg/kg (max. 62.5 mg) 4times daily; dose doubled in severe infectionChild 1 month–1 year 62.5 mg 4 times daily; dosedoubled in severe infection, community-acquiredpneumonia, or salmonellosisChild 1–5 years 125 mg 4 times daily; dosedoubled in severe infection, community-acquiredpneumonia, or salmonellosisChild 5–12 years 250 mg 4 times daily; dosedoubled in severe infection, community-acquiredpneumonia, or salmonellosisChild 12–18 years 250–500 mg 4 times daily;dose doubled in severe infection. By intravenous injection or infusionNeonate under 7 days 30 mg/kg every 12 hours;dose doubled in severe infection, communityacquiredpneumonia, or salmonellosisNeonate 7–21 days 30 mg/kg every 8 hours;dose doubled in severe infection, communityacquiredpneumonia, or salmonellosisNeonate 21–28 days 30 mg/kg every 6 hours;dose doubled in severe infection, communityacquiredpneumonia, or salmonellosisChild 1 month–18 years 25 mg/kg (max. 500 mg)every 6 hours; dose doubled in severe infectionListerial meningitis, group B streptococcalinfection, enterococcal endocarditis (in combinationwith another antibacterial, see Table 1, section5.1). By intravenous infusionNeonate under 7 days 50 mg/kg every 12 hours;dose doubled in meningitisNeonate 7–21 days 50 mg/kg every 8 hours;dose doubled in meningitisNeonate 21–28 days 50 mg/kg every 6 hours;dose doubled in meningitisChild 1 month–18 years 50 mg/kg every 4–6hours (max. 2 g every 4 hours)Administration Oral: administer at least 30 minutesbefore foodInjection: displacement value may be significant whenreconstituting injection, consult local guidelines.Dilute intravenous injection to a concentration of 50–100 mg/mL. May be further diluted with glucose 5%or 10% or sodium chloride 0.9% or 0.45% for infusion.Give over 30 minutes when using doses of greaterthan 50 mg/kg to avoid CNS toxicity including convulsions.Ampicillin (Non-proprietary) ACapsules, ampicillin 250 mg, net price 28 = £7.18;500 mg, 28 = £32.93. Label: 9, 23Brands include Rimacillin cDental prescribing on NHS Ampicillin Capsules may beprescribedOral suspension, ampicillin 125 mg/5 mL whenreconstituted with water, net price 100 mL = £9.23;250 mg/5 mL, 100 mL = £14.17. Label: 9, 23Brands include Rimacillin cDental prescribing on NHS Ampicillin Oral Suspension maybe prescribedInjection, powder for reconstitution, ampicillin (assodium salt), net price 500-mg vial = £7.83Penbritin c (Chemidex) ACapsules, both grey/red, ampicillin (as trihydrate)250 mg, net price 28-cap pack = £2.10; 500 mg, 28-cappack = £5.28. Label: 9, 23Syrup, apricot- caramel- and peppermint-flavoured,ampicillin (as trihydrate) for reconstitution with water,125 mg/5 mL, net price 100 mL = £3.78; 250 mg/5 mL, 100 mL = £7.39. Label: 9, 23Excipients include sucrose 3.6 g/5 mL

BNFC 2011–2012 5.1.1 Penicillins 263With flucloxacillinCo-fluampicil (Non-proprietary) ACapsules, co-fluampicil 250/250 (flucloxacillin250 mg as sodium salt, ampicillin 250 mg as trihydrate),net price 28-cap pack = £14.73. Label: 9, 22Brands include Flu-Amp cSyrup, co-fluampicil 125/125 (flucloxacillin 125 mgas magnesium salt, ampicillin 125 mg as trihydrate)/5 mL when reconstituted with water, net price 100 mL= £4.99. Label: 9, 22Magnapen c (Wockhardt) AInjection 500 mg, powder for reconstitution, co-fluampicil250/250 (flucloxacillin 250 mg as sodium salt,ampicillin 250 mg as sodium salt), net price per vial =£1.33Electrolytes Na + 1.3 mmol/vialCO-AMOXICLAVA mixture of amoxicillin (as the trihydrate or as thesodium salt) and clavulanic acid (as potassium clavulanate);the proportions are expressed in the formx/y where x and y are the strengths in milligrams ofamoxicillin and clavulanic acid respectivelyCautions see under Ampicillin and notes above;maintain adequate hydration with high doses (particularlyduring parenteral therapy); interactions:Appendix 1 (penicillins)Cholestatic jaundice Cholestatic jaundice can occur eitherduring or shortly after the use of co-amoxiclav. An epidemiologicalstudy has shown that the risk of acute livertoxicity was about 6 times greater with co-amoxiclav thanwith amoxicillin; these reactions have only rarely beenreported in children. Jaundice is usually self-limiting andvery rarely fatal. The duration of treatment should beappropriate to the indication and should not usually exceed14 daysContra-indications penicillin hypersensitivity, historyof co-amoxiclav-associated or penicillin-associatedjaundice or hepatic dysfunctionHepatic impairment monitor liver function in liverdisease. See also Cholestatic Jaundice aboveRenal impairment risk of crystalluria with high doses(particularly during parenteral therapy).Co-amoxiclav 125/31 suspension, 250/62 suspension,250/125 tablets, or 500/125 tablets: use normaldose every 12 hours if estimated glomerular filtrationrate 10–30 mL/minute/1.73 m 2 . Use the normal doserecommended for mild or moderate infections every12 hours if estimated glomerular filtration rate lessthan 10 mL/minute/1.73 m 2 .Co-amoxiclav 400/57 suspension: avoid if estimatedglomerular filtration rate less than 30 mL/minute/1.73 m 2 .Co-amoxiclav injection: use normal initial dose andthen use half normal dose every 12 hours if estimatedglomerular filtration rate 10–30 mL/minute/1.73 m 2 ;use normal initial dose and then use half normal doseevery 24 hours if estimated glomerular filtration rateless than 10 mL/minute/1.73 m 2Pregnancy not known to be harmfulBreast-feeding trace amounts present in milk—notknown to be harmful but be alert for hypersensitivityin the infantSide-effects see under Ampicillin; hepatitis, cholestaticjaundice (see above); Stevens-Johnsonsyndrome, toxic epidermal necrolysis, exfoliativedermatitis, vasculitis reported; rarely prolongation ofbleeding time, dizziness, headache, convulsions (particularlywith high doses or in renal impairment);superficial staining of teeth with suspension, phlebitisat injection siteIndication and doseInfections due to beta-lactamase-producingstrains (where amoxicillin alone not appropriate)including respiratory-tract infections, boneand joint infections, genito-urinary and abdominalinfections, cellulitis, animal bites. By mouth, expressed as co-amoxiclav (see alsounder Twice Daily Oral Preparations below)Neonate 0.25 mL/kg of 125/31 suspension 3times dailyChild 1 month–1 year 0.25 mL/kg of 125/31suspension 3 times daily; dose doubled in severeinfectionChild 1–6 years 5 mL of 125/31 suspension 3times daily or 0.25 mL/kg of 125/31 suspension 3times daily; dose doubled in severe infectionChild 6–12 years 5 mL of 250/62 suspension 3times daily or 0.15 mL/kg of 250/62 suspension 3times daily; dose doubled in severe infectionChild 12–18 years one 250/125 strength tablet 3times daily; increased in severe infections to one500/125 strength tablet 3 times daily. By intravenous injection over 3–4 minutes orby intravenous infusion, expressed as coamoxiclavNeonate 30 mg/kg every 12 hoursChild 1–3 months 30 mg/kg every 12 hoursChild 3 months–18 years 30 mg/kg (max. 1.2 g)every 8 hoursSevere dental infection with spreading cellulitisor dental infection not responding to first-lineantibacterial, see notes above. By mouth, expressed as co-amoxiclavChild 12–18 years one 250/125 strength tabletevery 8 hours for 5 daysAdministration for intermittent intravenous infusiondilute reconstituted solution to a concentration of10 mg/mL with Sodium Chloride 0.9%; give over 30–40 minutesCo-amoxiclav (Non-proprietary) ATablets, co-amoxiclav 250/125 (amoxicillin 250 mgas trihydrate, clavulanic acid 125 mg as potassiumsalt), net price 21-tab pack = £2.63. Label: 9Dental prescribing on NHS Co-amoxiclav 250/125 Tabletsmay be prescribedTablets, co-amoxiclav 500/125 (amoxicillin 500 mgas trihydrate, clavulanic acid 125 mg as potassiumsalt), net price 21-tab pack = £4.38. Label: 9Oral suspension, co-amoxiclav 125/31 (amoxicillin125 mg as trihydrate, clavulanic acid 31.25 mg aspotassium salt)/5 mL when reconstituted with water,net price 100 mL = £2.49. Label: 9Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionDental prescribing on NHS Co-amoxiclav 125/31 Suspensionmay be prescribed5 Infections

264 5.1.1 Penicillins BNFC 2011–20125 InfectionsOral suspension, co-amoxiclav 250/62 (amoxicillin250 mg as trihydrate, clavulanic acid 62.5 mg aspotassium salt)/5 mL when reconstituted with water,net price 100 mL = £6.29. Label: 9Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionDental prescribing on NHS Co-amoxiclav 250/62 Suspensionmay be prescribedInjection 500/100, powder for reconstitution, coamoxiclav500/100 (amoxicillin 500 mg as sodiumsalt, clavulanic acid 100 mg as potassium salt), netprice per vial = £1.21Injection 1000/200, powder for reconstitution, coamoxiclav1000/200 (amoxicillin 1 g as sodium salt,clavulanic acid 200 mg as potassium salt), net priceper vial = £2.63Augmentin c (GSK) ATablets 375 mg, f/c, co-amoxiclav 250/125 (amoxicillin250 mg as trihydrate, clavulanic acid 125 mg aspotassium salt), net price 21-tab pack = £4.19. Label: 9Tablets 625 mg, f/c, co-amoxiclav 500/125 (amoxicillin500 mg as trihydrate, clavulanic acid 125 mg aspotassium salt). Net price 21-tab pack = £8.00.Label: 9Suspension ‘125/31 SF’, sugar-free, co-amoxiclav125/31 (amoxicillin 125 mg as trihydrate, clavulanicacid 31.25 mg as potassium salt)/5 mL when reconstitutedwith water. Net price 100 mL (raspberry- andorange-flavoured) = £4.08. Label: 9Excipients include aspartame 12.5 mg/5 mL (section 9.4.1)Suspension ‘250/62 SF’, sugar-free, co-amoxiclav250/62 (amoxicillin 250 mg as trihydrate, clavulanicacid 62.5 mg as potassium salt)/5 mL when reconstitutedwith water. Net price 100 mL (raspberry- andorange-flavoured) = £5.74. Label: 9Excipients include aspartame 12.5 mg/5 mL (section 9.4.1)Injection 600 mg, powder for reconstitution, coamoxiclav500/100 (amoxicillin 500 mg as sodiumsalt, clavulanic acid 100 mg as potassium salt). Netprice per vial = £1.31Electrolytes Na + 1.35 mmol, K + 0.5 mmol/600-mg vialInjection 1.2 g, powder for reconstitution, co-amoxiclav1000/200 (amoxicillin 1 g as sodium salt, clavulanicacid 200 mg as potassium salt). Net price per vial= £2.61Electrolytes Na + 2.7 mmol, K + 1 mmol/1.2-g vialTwice daily oral preparationsCo-amoxiclav (Non-proprietary) ASuspension ‘400/57’, co-amoxiclav 400/57 (amoxicillin400 mg as trihydrate, clavulanic acid 57 mg aspotassium salt)/5 mL when reconstituted with water.Net price 35 mL = £4.13, 70 mL = £5.79. Label: 9Excipients may include aspartame (section 9.4.1)Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionBrands include Augmentin-Duo cDoseChild 2 months–2 years 0.15 mL/kg twice daily,doubled in severe infectionChild 2–6 years (13–21 kg) 2.5 mL twice daily, doubledin severe infectionChild 7–12 years (22–40 kg) 5 mL twice daily, doubledin severe infections5.1.1.4 Antipseudomonal penicillinsPiperacillin, a ureidopenicillin, is only available in combinationwith the beta-lactamase inhibitor tazobactam.Ticarcillin, a carboxypenicillin, is only available incombination with the beta-lactamase inhibitor clavulanicacid (section 5.1.1.3). Both preparations have abroad spectrum of activity against a range of Grampositiveand Gram-negative bacteria, and anaerobes.Piperacillin with tazobactam has activity against awider range of Gram-negative organisms than ticarcillinwith clavulanic acid and it is more active againstPseudomonas aeruginosa. These antibacterials arenot active against MRSA.These antipseudomonal penicillins are used in the treatmentof septicaemia, peritonitis, hospital-acquiredpneumonia, complicated urinary-tract infections, andskin and soft-tissue infections. They may be used forthe empirical treatment of septicaemia in immunocompromisedchildren but otherwise should generally bereserved for serious infections resistant to other antibacterials.For severe pseudomonas infections (especiallyin neutropenia or endocarditis) these antipseudomonalpenicillins can be given with an aminoglycoside(e.g. gentamicin, section 5.1.4) since they have a synergisticeffect.Piperacillin with tazobactam is used in cystic fibrosis forthe treatment of Ps. aeruginosa colonisation whenciprofloxacin and nebulised colistimethate sodiumhave been ineffective; it can also be used in infectiveexacerbations, when it is combined with an aminoglycoside.Owing to the sodium content of many of these antibiotics,high doses may lead to hypernatraemia.PIPERACILLIN WITH TAZOBACTAMCautions see under Benzylpenicillin (section 5.1.1.1);interactions: Appendix 1 (penicillins)Contra-indications see under Benzylpenicillin (section5.1.1.1)Renal impairment dose expressed as a combinationof piperacillin and tazobactam (both as sodium salts).Child under 12 years 90 mg/kg (max. 4.5 g) every 8hours if estimated glomerular filtration rate 20–40 mL/minute/1.73 m 2 ; 90 mg/kg (max. 4.5 g) every12 hours if estimated glomerular filtration rate lessthan 20 mL/minute/1.73 m 2 . Child 12–18 years max.4.5 g every 8 hours if estimated glomerular filtrationrate 20–80 mL/minute/1.73 m 2 ; max. 4.5 g every 12hours if estimated glomerular filtration rate less than20 mL/minute/1.73 m 2Pregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding present in milk—manufactureradvises use only if potential benefit outweighs riskSide-effects see under Benzylpenicillin (section5.1.1.1); also nausea, vomiting, diarrhoea; less commonlystomatitis, dyspepsia, constipation, jaundice,hypotension, headache, insomnia, and injection-sitereactions; rarely abdominal pain, hepatitis, oedema,fatigue and eosinophilia; very rarely hypoglycaemia,hypokalaemia, pancytopenia, Stevens-Johnsonsyndrome, and toxic epidermal necrolysisLicensed use not licensed for use in children under12 years (except for children with neutropenia andcomplicated appendicitis)

BNFC 2011–2012 5.1.1 Penicillins 265Indication and doseNote Expressed as a combination of piperacillin andtazobactam (both as sodium salts) in a ratio of 8:1Lower respiratory tract, urinary-tract, intraabdominaland skin infections, and bacterialsepticaemia. By intravenous injection over 3–5 minutes orby intravenous infusionNeonate 90 mg/kg every 8 hoursChild 1 month–12 years 90 mg/kg every 6–8hours; (max 4.5 g every 6 hours)Child 12–18 years 2.25–4.5 g every 6–8 hours,usually 4.5 g every 8 hoursInfections in children with neutropenia in combinationwith an aminoglycoside. By intravenous injection over 3–5 minutes orby intravenous infusionChild 1 month–18 years 90 mg/kg (max. 4.5 g)every 6 hoursComplicated appendicitis. By intravenous injection over 3–5 minutes orby intravenous infusionChild 2–12 years 112.5 mg/kg (max. 4.5 g) every8 hours for 5–14 daysAdministration displacement value may be significantwhen reconstituting injection, consult local guidelines.For intravenous infusion, dilute reconstitutedsolution to a concentration of 15–90 mg/mL withGlucose 5% or Sodium Chloride 0.9%; give over 20–30 minutesPiperacillin with tazobactam (Non-proprietary) AInjection 2.25 g, powder for reconstitution, piperacillin2 g (as sodium salt), tazobactam 250 mg (assodium salt), net price 2.25-g vial = £7.16Injection 4.5 g, powder for reconstitution, piperacillin4 g (as sodium salt), tazobactam 500 mg (as sodiumsalt), net price 4.5-g vial = £14.21Tazocin c (Wyeth) AInjection 2.25 g, powder for reconstitution, piperacillin2 g (as sodium salt), tazobactam 250 mg (assodium salt), net price 2.25-g vial = £7.65Electrolytes Na + 5.58 mmol/2.25-g vialInjection 4.5 g, powder for reconstitution, piperacillin4 g (as sodium salt), tazobactam 500 mg (as sodiumsalt), net price 4.5-g vial = £15.17Electrolytes Na + 11.16 mmol/4.5-g vialTICARCILLIN WITH CLAVULANICACIDCautions see under Benzylpenicillin (section 5.1.1.1);interactions: Appendix 1 (penicillins)Cholestatic Jaundice For a warning on cholestatic jaundicepossibly associated with clavulanic acid, see under CoamoxiclavContra-indications see under Benzylpenicillin (section5.1.1.1)Hepatic impairment manufacturer advises caution insevere impairment; also cholestatic jaundice, seeunder Co-amoxiclavRenal impairment Neonate reduce dose ifestimated glomerular filtration rate less than60 mL/minute/1.73 m 2 . Child 1 month–18 years usenormal dose every 8 hours if estimated glomerularfiltration rate 30–60 mL/minute/1.73 m 2 ; use halfnormal dose every 8 hours if estimated glomerularfiltration rate 10–30 mL/minute/1.73 m 2 ; use halfnormal dose every 12 hours if estimated glomerularfiltration rate less than 10 mL/minute/1.73 m 2Pregnancy not known to be harmfulBreast-feeding trace amounts present in milk—notknown to be harmful, but be alert for hypersensitivityin the infantSide-effects see under Benzylpenicillin (section5.1.1.1); also nausea, vomiting, coagulation disorders,haemorrhagic cystitis (more frequent in children),injection-site reactions, Stevens-Johnson syndrome,toxic epidermal necrolysis, hypokalaemia, eosinophiliaIndication and doseNote Expressed as a combination of ticarcillin (as sodiumsalt) and clavulanic acid (as potassium salt) in a ratio of15:1Infections due to Pseudomonas and Proteusspp. see notes above. By intravenous infusionPreterm neonate body-weight under 2 kg80 mg/kg every 12 hoursPreterm neonate body-weight over 2 kg andneonate 80 mg/kg every 8 hours, increased toevery 6 hours in more severe infectionsChild 1 month–18 years and body-weightunder 40 kg 80 mg/kg every 8 hours, increased toevery 6 hours in more severe infectionsChild under 18 years and body-weight over40 kg 3.2 g every 6–8 hours, increased to every 4hours in more severe infectionsAdministration Displacement value may be important,consult local guidelines. For intermittent infusion,dilute reconstituted solution further to a concentrationof 16–32 mg/mL with glucose 5%; infuseover 30–40 minutes.Timentin c (GSK) AInjection 3.2 g, powder for reconstitution, ticarcillin3 g (as sodium salt), clavulanic acid 200 mg (aspotassium salt). Net price per vial = £5.33Electrolytes Na + 16 mmol, K + 1 mmol /3.2-g vial5.1.1.5 MecillinamsPivmecillinam has significant activity against manyGram-negative bacteria including Escherichia coli, klebsiella,enterobacter, and salmonellae. It is not activeagainst Pseudomonas aeruginosa or enterococci.Pivmecillinam is hydrolysed to mecillinam, which isthe active drug.PIVMECILLINAM HYDROCHLORIDECautions see under Benzylpenicillin (section 5.1.1.1);also liver and renal function tests required in longtermuse; avoid in acute porphyria (section 9.8.2);interactions: Appendix 1 (penicillins)Contra-indications see under Benzylpenicillin (section5.1.1.1); also carnitine deficiency, oesophageal5 Infections

266 5.1.2 Cephalosporins, carbapenems, and other beta-lactams BNFC 2011–20125 Infectionsstrictures, gastro-intestinal obstruction, infants under3 monthsPregnancy not known to be harmful, but manufactureradvises avoidBreast-feeding trace amounts in milkSide-effects see under Benzylpenicillin (section5.1.1.1); nausea, vomiting, dyspepsia; also reducedserum and total body carnitine (especially with longtermor repeated use)Licensed use not licensed for use in children under 3monthsIndication and doseAcute uncomplicated cystitis. By mouthChild body-weight over 40 kg initially 400 mgthen 200 mg every 8 hours for 3 daysChronic or recurrent bacteriuriaChild body-weight over 40 kg 400 mg every 6–8hoursUrinary-tract infectionsChild body-weight under 40 kg 5–10 mg/kgevery 6 hours; total daily dose may alternatively begiven in 3 divided dosesSalmonellosis not recommended therefore no dosestatedCounselling Tablets should be swallowed whole with plentyof fluid during meals while sitting or standingSelexid c (LEO) ATablets, f/c, pivmecillinam hydrochloride 200 mg, netprice 10-tab pack = £4.50. Label: 9, 21, 27, counselling,posture (see Dose above)5.1.2 Cephalosporins,carbapenems, and otherbeta-lactamsAntibiotics in this section include the cephalosporins,such as cefotaxime, ceftazidime, cefuroxime, cefalexinand cefradine, the monobactam, aztreonam, and thecarbapenems, imipenem (a thienamycin derivative),meropenem, and ertapenem.5.1.2.1 CephalosporinsThe cephalosporins are broad-spectrum antibacterialswhich are used for the treatment of septicaemia, pneumonia,meningitis, biliary-tract infections, peritonitis,and urinary-tract infections. The pharmacology of thecephalosporins is similar to that of the penicillins, excretionbeing principally renal. Cephalosporins penetratethe cerebrospinal fluid poorly unless the meninges areinflamed; cefotaxime and ceftriaxone are suitable cephalosporinsfor infections of the CNS (e.g meningitis).The principal side-effect of the cephalosporins is hypersensitivityand about 0.5–6.5% of penicillin-sensitivepatients will also be allergic to the cephalosporins.Patients with a history of immediate hypersensitivityto penicillin should not receive a cephalosporin. If acephalosporin is essential in these patients because asuitable alternative antibacterial is not available, thencefixime, cefotaxime, ceftazidime, ceftriaxone, or cefuroximecan be used with caution; cefaclor, cefadroxil,cefalexin, and cefradine should be avoided.Antibiotic-associated colitis may occur with the use ofbroad-spectrum cephalosporins, particularly secondandthird-generation cephalosporins.Cefuroxime is a ‘second generation’ cephalosporin thatis less susceptible than the earlier cephalosporins toinactivation by beta-lactamases. It is, therefore, activeagainst certain bacteria that are resistant to the otherdrugs and has greater activity against Haemophilusinfluenzae.Cefotaxime, ceftazidime and ceftriaxone are ‘thirdgeneration’ cephalosporins with greater activity thanthe ‘second generation’ cephalosporins against certainGram-negative bacteria. However, they are less activethan cefuroxime against Gram-positive bacteria, mostnotably Staphylococcus aureus. Their broad antibacterialspectrum may encourage superinfection withresistant bacteria or fungi.Ceftazidime has good activity against pseudomonas. Itis also active against other Gram-negative bacteria.Ceftriaxone has a longer half-life and therefore needs tobe given only once daily. Indications include seriousinfections such as septicaemia, pneumonia, andmeningitis. The calcium salt of ceftriaxone forms aprecipitate in the gall bladder which may rarely causesymptoms but these usually resolve when the antibacterialis stopped. In neonates, ceftriaxone may displacebilirubin from plasma-albumin and should beavoided in neonates with unconjugated hyperbilirubinaemia,hypoalbuminaemia, acidosis or impaired bilirubinbinding.Orally active cephalosporins The orally active ‘firstgeneration’ cephalosporins, cefalexin, cefradine, andcefadroxil and the ‘second generation’ cephalosporin,cefaclor, have a similar antimicrobial spectrum. Theyare useful for urinary-tract infections which do notrespond to other drugs or which occur in pregnancy,respiratory-tract infections, otitis media, sinusitis, andskin and soft-tissue infections. Cefaclor has good activityagainst H. influenzae, but it is associated withprotracted skin reactions especially in children. Cefadroxilhas a long duration of action and can be giventwice daily; it has poor activity against H. influenzae.Cefuroxime axetil, an ester of the ‘second generation’cephalosporin cefuroxime, has the same antibacterialspectrum as the parent compound; it is poorly absorbedand needs to be given with food to maximise absorption.Cefixime and cefpodoxime proxetil are orally active‘third generation’ cephalosporins. Cefixime has a longerduration of action than the other cephalosporins that areactive by mouth. It is only licensed for acute infections.Cefpodoxime proxetil is more active than the other oralcephalosporins against respiratory bacterial pathogensand it is licensed for upper and lower respiratory-tractinfections.For treatment of Lyme disease, see section 5.1.1.3.Oral infections The cephalosporins offer little advantageover the penicillins in dental infections, often beingless active against anaerobes. Infections due to oralstreptococci (often termed viridans streptococci)

BNFC 2011–2012 5.1.2 Cephalosporins, carbapenems, and other beta-lactams 267which become resistant to penicillin are usually alsoresistant to cephalosporins. This is of importance in thecase of children who have had rheumatic fever and areon long-term penicillin therapy. Cefalexin and cefradinehave been used in the treatment of oral infections.Suspension, cefaclor (as monohydrate) for reconstitutionwith water, 125 mg/5 mL, net price 100 mL =£8.33; 250 mg/5 mL, 100 mL = £6.97. Label: 9Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionBrands include Keftid cCEFACLORCautions sensitivity to beta-lactam antibacterials(avoid if history of immediate hypersensitivity reaction,see also notes above and p. 257); false positiveurinary glucose (if tested for reducing substances) andfalse positive Coombs’ test; interactions: Appendix 1(cephalosporins)Contra-indications cephalosporin hypersensitivityRenal impairment no dosage adjustment required,manufacturer advises cautionPregnancy not known to be harmfulBreast-feeding present in milk in low concentration,considered compatible with breast-feedingSide-effects diarrhoea (rarely antibiotic-associatedcolitis), nausea and vomiting, abdominal discomfort,headache; allergic reactions including rashes, pruritus,urticaria, serum sickness-like reactions with rashes,fever and arthralgia, and anaphylaxis; Stevens-Johnsonsyndrome, toxic epidermal necrolysis reported;disturbances in liver enzymes, transient hepatitis andcholestatic jaundice; other side-effects reportedinclude eosinophilia and blood disorders (includingthrombocytopenia, leucopenia, agranulocytosis,aplastic anaemia and haemolytic anaemia); reversibleinterstitial nephritis, hyperactivity, nervousness, sleepdisturbances, hallucinations, confusion, hypertonia,and dizzinessIndication and doseInfections due to sensitive Gram-positive andGram-negative bacteria but see notes above. By mouthChild 1 month–12 years 20 mg/kg daily in 3divided doses, doubled for severe infection (usualmax. 1 g daily)orChild 1 month–1 year 62.5 mg 3 times daily; dosedoubled for severe infectionsChild 1–5 years 125 mg 3 times daily; dosedoubled for severe infectionsChild 5–12 years 250 mg 3 times daily; dosedoubled for severe infectionsChild 12–18 years 250 mg 3 times daily; dosedoubled for severe infections (max. 4 g daily)Asymptomatic carriage of Haemophilus influenzaeor mild exacerbations in cystic fibrosis. By mouthChild 1 month–1 year 125 mg every 8 hoursChild 1–7 years 250 mg 3 times dailyChild 7–18 years 500 mg 3 times dailyCefaclor (Non-proprietary) ACapsules, cefaclor (as monohydrate) 250 mg, netprice 21-cap pack = £5.09; 500 mg, 50-cap pack =£31.99. Label: 9Brands include Keftid cDistaclor c (Flynn) ACapsules, cefaclor (as monohydrate) 500 mg (violet/grey), net price 21-cap pack = £18.19. Label: 9Suspension, both pink, cefaclor (as monohydrate) forreconstitution with water, 125 mg/5 mL, net price100 mL = £4.13; 250 mg/5 mL, 100 mL = £8.26.Label: 9Distaclor MR c (Flynn) ATablets, m/r, both blue, cefaclor (as monohydrate)375 mg. Net price 14-tab pack = £8.31. Label: 9, 21, 25DoseSusceptible infectionsChild 12–18 years 375 mg every 12 hours with food,dose doubled for pneumoniaLower urinary-tract infectionsChild 12–18 years 375 mg every 12 hours with foodCEFADROXILCautions see under Cefaclor; interactions: Appendix1 (cephalosporins)Contra-indications see under CefaclorRenal impairment reduce dose if estimated glomerularfiltration rate less than 50 mL/minute/1.73 m 2Pregnancy not known to be harmfulBreast-feeding present in milk in low concentrationsSide-effects see under CefaclorIndication and doseInfections due to sensitive Gram-positive andGram-negative bacteria but see notes above. By mouthChild 6–18 yearsBody-weight under 40 kg 500 mg twice daily;Body-weight over 40 kg 0.5–1 g twice daily (1 gonce daily for skin, soft-tissue and uncomplicatedurinary-tract infections)Cefadroxil (Non-proprietary) ACapsules, cefadroxil (as monohydrate) 500 mg, netprice 20-cap pack = £4.83. Label: 9CEFALEXIN(Cephalexin)Cautions see under Cefaclor; interactions: Appendix1 (cephalosporins)Contra-indications see under CefaclorRenal impairment reduce dose in moderate impairmentPregnancy not known to be harmfulBreast-feeding present in milk in low concentrations,considered compatible with breast-feedingSide-effects see under Cefaclor5 Infections

268 5.1.2 Cephalosporins, carbapenems, and other beta-lactams BNFC 2011–20125 InfectionsIndication and doseInfections due to sensitive Gram-positive andGram-negative bacteria but see notes above. By mouthNeonate under 7 days 25 mg/kg (max. 125 mg)twice dailyNeonate 7–21 days 25 mg/kg (max. 125 mg) 3times dailyNeonate 21–28 days 25 mg/kg (max. 125 mg) 4times dailyChild 1 month–12 years 12.5 mg/kg twice daily;dose doubled in severe infection; max. 25 mg/kg 4times daily (max. 1 g 4 times daily)orChild 1 month–1 year 125 mg twice dailyChild 1–5 years 125 mg 3 times dailyChild 5–12 years 250 mg 3 times dailyChild 12–18 years 500 mg 2–3 times daily,increased to 1–1.5 g 3–4 times daily for severeinfectionProphylaxis of recurrent urinary-tract infection. By mouthChild 1 month–18 years 12.5 mg/kg at night(max. 125 mg at night)Cefalexin (Non-proprietary) ACapsules, cefalexin 250 mg, net price 28-cap pack =£1.66; 500 mg, 21-cap pack = £2.09. Label: 9Dental prescribing on NHS Cefalexin Capsules may beprescribedTablets, cefalexin 250 mg, net price 28-tab pack =£1.94; 500 mg, 21-tab pack = £2.39. Label: 9Dental prescribing on NHS Cefalexin Tablets may be prescribedOral suspension, cefalexin for reconstitution withwater, 125 mg/5 mL, net price 100 mL = £1.75;250 mg/5 mL, 100 mL = £2.15. Label: 9Dental prescribing on NHS Cefalexin Oral Suspension maybe prescribedCeporex c (Co-Pharma) ACapsules, both caramel/grey, cefalexin 250 mg, netprice 28-cap pack = £4.02; 500 mg, 28-cap pack =£7.85. Label: 9Tablets, all pink, f/c, cefalexin 250 mg, net price 28-tab pack = £4.02; 500 mg, 28-tab pack = £7.85.Label: 9Syrup, all orange, cefalexin for reconstitution withwater, 125 mg/5 mL, net price 100 mL = £1.43;250 mg/5 mL, 100 mL = £2.87; 500 mg/5 mL, 100 mL= £5.57. Label: 9Keflex c (Flynn) ACapsules, cefalexin 250 mg (green/white), net price28-cap pack = £1.46; 500 mg (pale green/dark green),21-cap pack = £1.98. Label: 9Tablets, both peach, cefalexin 250 mg, net price 28-tab pack = £1.60; 500 mg (scored), 21-tab pack =£2.08. Label: 9Suspension, cefalexin for reconstitution with water,125 mg/5 mL, net price 100 mL = 84p; 250 mg/5 mL,100 mL = £1.40. Label: 9CEFIXIMECautions see under Cefaclor; interactions: Appendix1 (cephalosporins)Contra-indications see under CefaclorRenal impairment reduce dose if estimated glomerularfiltration rate less than 20 mL/minute/1.73 m 2Pregnancy not known to be harmfulBreast-feeding manufacturer advises avoid—noinformation availableSide-effects see under CefaclorIndication and doseAcute infections due to sensitive Gram-positiveand Gram-negative bacteria, but see notesabove. By mouthChild 6 months–1 year 75 mg dailyChild 1–5 years 100 mg dailyChild 5–10 years 200 mg dailyChild 10–18 years 200–400 mg daily or 100–200 mg twice dailyUncomplicated gonorrhoea [unlicensed indication,see also Table 1, section 5.1]. By mouthChild 12–18 years 400 mg as a single doseSuprax c (Sanofi-Aventis) ATablets, f/c, scored, cefixime 200 mg. Net price 7-tabpack = £13.23. Label: 9Paediatric oral suspension, cefixime 100 mg/5 mLwhen reconstituted with water, net price 50 mL (withdouble-ended spoon for measuring 3.75 mL or 5 mLsince dilution not recommended) = £10.53, 100 mL =£18.91. Label: 9CEFOTAXIMECautions see under Cefaclor; interactions: Appendix1 (cephalosporins)Contra-indications see under CefaclorRenal impairment usual initial dose, then use halfnormal dose if estimated glomerular filtration rate lessthan 5 mL/minute/1.73 m 2Pregnancy not known to be harmfulBreast-feeding present in milk in low concentration,considered compatible with breast-feedingSide-effects see under Cefaclor; rarely arrhythmiasfollowing rapid injection reportedIndication and doseInfections due to sensitive Gram-positive andGram-negative bacteria, surgical prophylaxis,Haemophilus epiglottitis and meningitis (Table1, section 5.1) see also notes above. By intramuscular or by intravenous injection orintravenous infusionNeonate under 7 days 25 mg/kg every 12 hours;dose doubled in severe infection and meningitisNeonate 7–21 days 25 mg/kg every 8 hours;dose doubled in severe infection and meningitisNeonate 21–28 days 25 mg/kg every 6–8 hours;dose doubled in severe infection and meningitis

BNFC 2011–2012 5.1.2 Cephalosporins, carbapenems, and other beta-lactams 269Child 1 month–18 years 50 mg/kg every 8–12hours; increase to every 6 hours in very severeinfections and meningitis (max. 12 g daily)Important. If meningococcal disease (meningitis withnon-blanching rash or meningococcal septicaemia) issuspected, and the child cannot be given benzylpenicillin(e.g. because of an allergy), a single dose of cefotaximecan be given (if available) before urgent transfer tohospital, so long as this does not delay the transfer. If achild with suspected bacterial meningitis without nonblanchingrash cannot be transferred to hospital urgentlyand cannot be given benzylpenicillin, a single dose ofcefotaxime can be given before transfer. Suitable doses ofcefotaxime by intravenous injection (or by intramuscularinjection) are Child under 12 years 50 mg/kg; Child over12 years 1 g; chloramphenicol (section 5.1.7) may beused if there is a history of anaphylaxis to penicillins orcephalosporinsCongenital gonococcal conjunctivitis. By intramuscular injectionNeonate 100 mg/kg (max. 1 g) as a single doseUncomplicated gonorrhoea. By intramuscular or by intravenous injection orintravenous infusionChild 12–18 years 500 mg as a single doseSevere exacerbations of Haemophilus influenzaeinfection in cystic fibrosis. By intravenous injection or intravenous infusionChild 1 month–18 years 50 mg/kg every 6–8hours (max. 12 g daily)Administration Displacement value may be significant,consult local guidelines. For intermittent intravenousinfusion dilute in glucose 5% or sodiumchloride 0.9%; administer over 20–60 minutes;incompatible with alkaline solutionsCefotaxime (Non-proprietary) AInjection, powder for reconstitution, cefotaxime (assodium salt), net price 500-mg vial = £2.14; 1-g vial =£4.31; 2-g vial = £8.57CEFPODOXIMECautions see under Cefaclor; interactions: Appendix1 (cephalosporins)Contra-indications see under CefaclorRenal impairment increase dose interval to every 24hours if estimated glomerular filtration rate 10–40 mL/minute/1.73 m 2 . Increase dose interval toevery 48 hours if estimated glomerular filtration rateless than 10 mL/minute/1.73 m 2Pregnancy not known to be harmfulBreast-feeding present in milk in low concentrationSide-effects see under CefaclorIndication and doseUpper respiratory-tract infections (but inpharyngitis and tonsillitis reserved for infectionswhich are recurrent, chronic, or resistantto other antibacterials), lower respiratory-tractinfections (including bronchitis and pneumonia),skin and soft tissue infections,uncomplicated urinary-tract infections. By mouthChild 15 days–6 months 4 mg/kg twice dailyChild 6 months–2 years 40 mg twice dailyChild 3–8 years 80 mg twice dailyChild 9–12 years 100 mg twice dailyChild 12–18 years 100 mg twice daily (increasedto 200 mg twice daily in sinusitis, skin and softtissue infections, uncomplicated upper urinarytract infections and if necessary in lower respiratorytract infections)Orelox c (Sanofi-Aventis) ATablets, f/c, cefpodoxime 100 mg (as proxetil), netprice 10-tab pack = £9.78. Label: 5, 9, 21Oral suspension, cefpodoxime (as proxetil) forreconstitution with water, 40 mg/5 mL, net price100 mL = £11.50. Label: 5, 9, 21Excipients include aspartame (section 9.4.1)CEFRADINE(Cephradine)Cautions see under Cefaclor; interactions: Appendix1 (cephalosporins)Contra-indications see under CefaclorRenal impairment reduce dose if estimated glomerularfiltration rate less than 20 mL/minute/1.73 m 2Pregnancy not known to be harmfulBreast-feeding present in milk in low concentrationsSide-effects see under CefaclorLicensed use not licensed for use in children forprevention of Staphylococcus aureus lung infectionin cystic fibrosisIndication and doseInfections due to sensitive Gram-positive andGram-negative bacteria but see notes above. By mouthChild 7–12 years 12.5–25 mg/kg twice daily(total daily dose may alternatively be given in 3–4divided doses)Child 12–18 years 0.5–1 g twice daily or 250–500 mg 4 times daily; up to 1 g 4 times daily insevere infectionsPrevention of Staphylococcus aureus lunginfection in cystic fibrosis. By mouthChild 7–18 years 2 g twice dailyCefradine (Non-proprietary) ACapsules, cefradine 250 mg, net price 20-cap pack =£2.86; 500 mg, 20-cap pack = £4.50. Label: 9Brands include Nicef cDental prescribing on NHS Cefradine Capsules may beprescribedCEFTAZIDIMECautions see under Cefaclor; interactions: Appendix1 (cephalosporins)Contra-indications see under CefaclorRenal impairment reduce dose if estimated glomerularfiltration rate less than 50 mL/minute/1.73 m 2Pregnancy not known to be harmful5 Infections

270 5.1.2 Cephalosporins, carbapenems, and other beta-lactams BNFC 2011–20125 InfectionsBreast-feeding present in milk in low concentration,considered compatible with breast-feedingSide-effects see under CefaclorLicensed use nebulised route unlicensedIndication and doseInfections due to sensitive Gram-positive andGram-negative bacteria but see notes above. By intravenous injection or infusionNeonate under 7 days 25 mg/kg every 24 hours;dose doubled in severe infection and meningitisNeonate 7–21 days 25 mg/kg every 12 hours;dose doubled in severe infection and meningitisNeonate 21–28 days 25 mg/kg every 8 hours;dose doubled in severe infection and meningitisChild 1 month–18 years 25 mg/kg every 8 hours;dose doubled in severe infection, febrile neutropeniaand meningitis (max. 6 g daily)Pseudomonal lung infection in cystic fibrosis. By intravenous injection or infusion or by deepintramuscular injectionChild 1 month–18 years 50 mg/kg every 8 hours(max. 9 g daily)Chronic Burkholderia cepacia infection in cysticfibrosis. By inhalation of nebulised solutionChild 1 month–18 years 1 g twice dailyAdministration For parenteral administration, intravenousroute recommended in children. Displacementvalue may be significant, consult local guidelines.For intermittent intravenous infusion dilutereconstituted solution further to a concentration ofnot more than 40 mg/mL in Glucose 5% or Glucose10% or Sodium chloride 0.9%; give over 20–30 minutesFor nebulisation, dissolve dose in 3 mL of water forinjectionCeftazidime (Non-proprietary) AInjection, powder for reconstitution, ceftazidime (aspentahydrate), with sodium carbonate, net price 1-gvial = £8.50; 2-g vial = £17.90Fortum c (GSK) AInjection, powder for reconstitution, ceftazidime (aspentahydrate), with sodium carbonate, net price 500-mg vial = £4.40, 1-g vial = £8.79, 2-g vial = £17.59, 3-gvial = £25.76Electrolytes Na + 2.3 mmol/gKefadim c (Flynn) AInjection, powder for reconstitution, ceftazidime (aspentahydrate), with sodium carbonate, net price 1-gvial = £7.92; 2-g vial = £15.84Electrolytes Na + 2.3 mmol/gCEFTRIAXONECautions see under Cefaclor; neonates; may displacebilirubin from serum albumin, administer over 60minutes in neonates (see also Contra-indications);treatment longer than 14 days, renal failure, dehydration—riskof ceftriaxone precipitation in gallbladder; interactions: Appendix 1 (cephalosporins)Contra-indications see under Cefaclor; neonates lessthan 41 weeks postmenstrual age; neonates over 41weeks postmenstrual age with jaundice, hypoalbuminaemia,or acidosis; concomitant treatment withintravenous calcium (including total parenteral nutritioncontaining calcium) in neonates over 41 weekspostmenstrual age—risk of precipitation in urine andlungsHepatic impairment if hepatic impairment is accompaniedby severe renal impairment, reduce dose andmonitor plasma concentrationRenal impairment max. 50 mg/kg daily (max. 2 gdaily) in severe renal impairment; also monitorplasma concentration if hepatic impairment accompaniedby severe renal impairmentPregnancy not known to be harmfulBreast-feeding present in milk in low concentration,considered compatible with breast-feedingSide-effects see under Cefaclor; calcium ceftriaxoneprecipitates in urine (particularly in very young,dehydrated or those who are immobilised) or in gallbladder—consider discontinuation if symptomatic;rarely prolongation of prothrombin time, pancreatitisLicensed use not licensed for congenital gonococcalconjunctivitis or early syphilis; not licensed for usein children under 12 years of age for uncomplicatedgonorrhoea or pelvic inflammatory diseaseIndication and doseInfections due to sensitive Gram-positive andGram-negative bacteria. By intravenous infusion over 60 minutesNeonate 20–50 mg/kg once daily. By deep intramuscular injection, or by intravenousinjection over 2–4 minutes, or byintravenous infusionChild 1 month–12 yearsBody-weight under 50 kg 50 mg/kg once daily;up to 80 mg/kg daily in severe infections andmeningitis; doses of 50 mg/kg and over by intravenousinfusion onlyBody-weight 50 kg and over dose as for child 12–18 yearsChild 12–18 years 1 g daily; 2–4 g daily in severeinfections and meningitis; intramuscular dosesover 1 g divided between more than one site; singleintravenous doses above 1 g by intravenous infusiononlyCongenital gonococcal conjunctivitis. By intravenous infusion over 60 minutes or bydeep intramuscular injectionNeonate 25–50 mg/kg (max.125 mg) as a singledoseUncomplicated gonorrhoea, pelvic inflammatorydisease (Table 1, section 5.1). By deep intramuscular injectionChild under 12 yearsBody-weight under 45 kg 125 mg as a single doseBody-weight over 45 kg 250 mg as a single doseChild 12–18 years 250 mg as a single dose

BNFC 2011–2012 5.1.2 Cephalosporins, carbapenems, and other beta-lactams 271Early syphilis. By deep intramuscular injectionChild 12–18 years 500 mg daily for 10 daysSurgical prophylaxis. By deep intramuscular injection or by intravenousinjection over at least 2–4 minutes, or(for colorectal surgery) by intravenous infusionChild 12–18 years 1 g up to 30 minutes before theprocedure; colorectal surgery, 2 g up to 30 minutesbefore the procedure; intramuscular doses over 1 gdivided between more than one siteProphylaxis of meningococcal meningitis Table2, section 5.1Administration Displacement value may be significant,consult local guidelines. For intravenous infusion,dilute reconstituted solution with Glucose 5% or10% or Sodium Chloride 0.9%; give over at least 30minutes (60 minutes in neonates). Not to be givensimultaneously with parenteral nutrition or infusionfluids containing calcium, even by different infusionlines; may be infused sequentially with infusion fluidscontaining calcium if flush with sodium chloride 0.9%between infusions or give infusions by different infusionlines at different sites; see also Contra-indicationsaboveFor intramuscular injection ceftriaxone may be mixedwith 1% Lidocaine Hydrochloride Injection to reducepain at intramuscular injection site; final concentration250–350 mg/mL.Ceftriaxone (Non-proprietary) AInjection, powder for reconstitution, ceftriaxone (assodium salt), net price 1-g vial = £10.17; 2-g vial =£20.36Rocephin c (Roche) AInjection, powder for reconstitution, ceftriaxone (assodium salt), net price 250-mg vial = £2.40; 1-g vial =£9.58; 2-g vial = £19.18Electrolytes Na + 3.6 mmol /gCEFUROXIMECautions see under Cefaclor; interactions: Appendix1 (cephalosporins)Contra-indications see under CefaclorRenal impairment reduce parenteral dose if estimatedglomerular filtration rate less than 20 mL/minute/1.73 m 2Pregnancy not known to be harmfulBreast-feeding present in milk in low concentrationSide-effects see under CefaclorLicensed use not licensed for treatment of Lymedisease in children under 12 yearsIndication and doseInfections due to sensitive Gram-positive andGram-negative bacteria. By mouth (as cefuroxime axetil)Child 3 months–2 years 10 mg/kg (max. 125 mg)twice dailyChild 2–12 years 15 mg/kg (max. 250 mg) twicedailyChild 12–18 years 250 mg twice daily; dosedoubled in severe lower respiratory-tract infections,or if pneumonia suspected; dose reduced to125 mg twice daily in lower urinary-tract infection. By intravenous injection or infusion or byintramuscular injectionNeonate under 7 days 25 mg/kg every 12 hours;dose doubled in severe infection, intravenousroute onlyNeonate 7–21 days 25 mg/kg every 8 hours;dose doubled in severe infection, intravenousroute onlyNeonate 21–28 days 25 mg/kg every 6 hours;dose doubled in severe infection, intravenousroute onlyChild 1 month–18 years 20 mg/kg (max. 750 mg)every 8 hours; increase to 50–60 mg/kg (max.1.5 g) every 6–8 hours in severe infection andcystic fibrosisLyme disease (see also section 5.1.1.3). By mouthChild 3 months–12 years 15 mg/kg (max.500 mg) twice daily for 14–21 days (for 28 days inLyme arthritis)Child 12–18 years 500 mg twice daily for 14–21days (for 28 days in Lyme arthritis)Surgical prophylaxis. By intravenous injectionChild 1 month–18 years 50 mg/kg (max. 1.5 g)up to 30 minutes before the procedure; up to 3further doses of 30 mg/kg (max. 750 mg) may begiven by intramuscular or intravenous injectionevery 8 hours for high-risk proceduresAdministration Single doses over 750 mg should beadministered by the intravenous route only.Displacement value may be significant when reconstitutinginjection, consult local guidelines. For intermittentintravenous infusion, dilute reconstitutedsolution further in glucose 5% or sodium chloride0.9%; give over 30 minutes.Cefuroxime (Non-proprietary) ATablets, cefuroxime (as axetil) 250 mg, net price 14-tab pack = £10.39. Label: 9, 21, 25Injection, powder for reconstitution, cefuroxime (assodium salt), net price 750-mg vial = £2.52; 1.5-g vial= £5.05Zinacef c (GSK) AInjection, powder for reconstitution, cefuroxime (assodium salt). Net price 250-mg vial = 94p; 750-mg vial= £2.34; 1.5-g vial = £4.70Electrolytes Na + 1.8 mmol/750-mg vialZinnat c (GSK) ATablets, both f/c, cefuroxime (as axetil) 125 mg, netprice 14-tab pack = £4.56; 250 mg, 14-tab pack =£9.11. Label: 9, 21, 25Suspension, cefuroxime (as axetil) 125 mg/5 mLwhen reconstituted with water, net price 70 mL (tuttifrutti-flavoured)= £5.20. Label: 9, 21Excipients include aspartame (section 9.4.1), sucrose 3.1 g/5 mL5 Infections

272 5.1.2 Cephalosporins, carbapenems, and other beta-lactams BNFC 2011–20125 Infections5.1.2.2 CarbapenemsThe carbapenems are beta-lactam antibacterials with abroad-spectrum of activity which includes many Grampositiveand Gram-negative bacteria, and anaerobes;imipenem and meropenem have good activity againstPseudomonas aeruginosa. The carbapenems are notactive against meticillin-resistant Staphylococcus aureusand Enterococcus faecium.Imipenem and meropenem are used for the treatment ofsevere hospital-acquired infections and polymicrobialinfections caused by multiple-antibacterial resistantorganisms (including septicaemia, hospital-acquiredpneumonia, intra-abdominal infections, skin and softtissueinfections, and complicated urinary-tract infections).Ertapenem is licensed for treating abdominal andgynaecological infections and for community-acquiredpneumonia, but it is not active against atypical respiratorypathogens and it has limited activity against penicillin-resistantpneumococci. Unlike the other carbapenems,ertapenem is not active against Pseudomonas oragainst Acinetobacter spp.Imipenem is partially inactivated in the kidney by enzymaticactivity and is therefore administered in combinationwith cilastatin, a specific enzyme inhibitor, whichblocks its renal metabolism. Meropenem and ertapenemare stable to the renal enzyme which inactivates imipenemand therefore can be given without cilastatin.Side-effects of imipenem with cilastatin are similar tothose of other beta-lactam antibiotics; neurotoxicity hasbeen observed at very high dosage, in renal failure, or inpatients with CNS disease. Meropenem has less seizureinducingpotential and can be used to treat centralnervous system infection. Ertapenem has been associatedwith seizures uncommonly.ERTAPENEMCautions hypersensitivity to beta-lactam antibacterials(avoid if history of immediate hypersensitivityreaction, see also p. 257); renal impairment, CNSdisorders—risk of seizures; interactions: Appendix 1(ertapenem)Renal impairment risk of seizures; avoid if estimatedglomerular filtration rate less than 30 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid unless potentialbenefit outweighs riskBreast-feeding present in milk—manufactureradvises avoidSide-effects diarrhoea, nausea, vomiting, headache,injection-site reactions, rash (also reported witheosinophilia and systemic symptoms), pruritus, raisedplatelet count; less commonly dry mouth, taste disturbances,dyspepsia, abdominal pain, anorexia, constipation,melaena, antibiotic-associated colitis,bradycardia, hypotension, chest pain, oedema, pharyngealdiscomfort, dyspnoea, dizziness, sleep disturbances,confusion, asthenia, seizures, raised glucose,petechiae; rarely dysphagia, cholecystitis, liver disorder(including jaundice), arrhythmia, increase in bloodpressure, syncope, nasal congestion, cough, wheezing,anxiety, depression, agitation, tremor, pelvicperitonitis, renal impairment, muscle cramp, scleraldisorder, blood disorders (including neutropenia,thrombocytopenia, haemorrhage), hypoglycaemia,electrolyte disturbances; also reported hallucinations,dyskinesiaIndication and doseAbdominal infections, acute gynaecologicalinfections, community-acquired pneumonia. By intravenous infusionChild 3 months–13 years 15 mg/kg every 12hours (max. 1 g daily)Child 13–18 years 1 g once dailyAdministration reconstitute 1 g with 10 mL Water forInjections or Sodium Chloride 0.9%; for intermittentintravenous infusion, dilute requisite dose in SodiumChloride 0.9% to a final concentration not exceeding20 mg/mL; incompatible with glucose solutionsInvanz c (MSD) AIntravenous infusion, powder for reconstitution,ertapenem (as sodium salt), net price 1-g vial = £31.65Electrolytes Na + 6 mmol/1-g vialIMIPENEM WITH CILASTATINCautions CNS disorders (e.g. epilepsy); hypersensitivityto beta-lactam antibacterials (avoid if history ofimmediate hypersensitivity reaction, see also p. 257);interactions: Appendix 1 (imipenem with cilastatin)Renal impairment reduce dose if estimated glomerularfiltration rate less than 70 mL/minute/1.73 m 2 ;risk of CNS side-effectsPregnancy manufacturer advises avoid unless potentialbenefit outweighs risk (toxicity in animal studies)Breast-feeding present in milk but unlikely to beabsorbed (however, manufacturer advises avoid)Side-effects nausea, vomiting, diarrhoea (antibioticassociatedcolitis reported), taste disturbances, toothor tongue discoloration, hearing loss; blood disorders,positive Coombs’ test; allergic reactions (with rash,pruritus, urticaria, Stevens-Johnson syndrome, fever,anaphylactic reactions, rarely toxic epidermal necrolysis,exfoliative dermatitis); myoclonic activity, convulsions,confusion and mental disturbances reported;slight increases in liver enzymes and bilirubinreported, rarely hepatitis; increases in serum creatinineand blood urea; red coloration of urine in childrenreported; local reactions: erythema, pain andinduration, and thrombophlebitisLicensed use not licensed for use in children under 3months; not licensed for use in children with renalimpairmentIndication and doseAerobic and anaerobic Gram-positive andGram-negative infections, hospital-acquiredsepticaemia Table 1, section 5.1; not indicated forCNS infections. By intravenous infusionexpressed in terms of imipenemNeonate under 7 days 20 mg/kg every 12 hoursNeonate 7–21 days 20 mg/kg every 8 hoursNeonate 21–28 days 20 mg/kg every 6 hoursChild 1–3 months 20 mg/kg every 6 hours

BNFC 2011–2012 5.1.2 Cephalosporins, carbapenems, and other beta-lactams 273Child 3 months–18 yearsBody-weight under 40 kg 15 mg/kg (max.500 mg) every 6 hoursBody-weight over 40 kg 250–500 mg every 6hours; less sensitive organisms up to 12.5 mg/kg(max. 1 g) every 6 hours; total daily dose mayalternatively be given in 3 divided dosesCystic fibrosis. By intravenous infusionChild 1 month–18 yearsBody-weight under 40 kg 22.5 mg/kg every 6hoursBody-weight over 40 kg 1 g every 6–8 hoursAdministration for intermittent intravenous infusiondilute to a concentration of 5 mg (as imipenem)/mL insodium chloride 0.9% or sodium chloride and glucose;give up to 500 mg over 20–30 minutes; give 1 g over40–60 minutesPrimaxin c (MSD) AIntravenous infusion, powder for reconstitution,imipenem (as monohydrate) 500 mg with cilastatin (assodium salt) 500 mg, net price per vial = £12.00Electrolytes Na + 1.72 mmol/vialMEROPENEMCautions hypersensitivity to beta-lactam antibacterials(avoid if history of immediate hypersensitivityreaction, see also p. 257); interactions: Appendix 1(meropenem)Hepatic impairment monitor liver functionRenal impairment use normal dose every 12 hours ifestimated glomerular filtration rate 26–50 mL/minute/1.73m 2 ; use half normal dose every 12 hours ifestimated glomerular filtration rate 10–25 mL/minute/1.73m 2 ; use half normal dose every 24 hours ifestimated glomerular filtration rate less than 10 mL/minute/1.73 m 2Pregnancy manufacturer advises use only if potentialbenefit outweighs risk—no information availableBreast-feeding unlikely to be absorbed (but manufactureradvises avoid unless potential benefit outweighsrisk)Side-effects nausea, vomiting, diarrhoea (antibioticassociatedcolitis reported), abdominal pain, disturbancesin liver function tests, headache, thrombocythaemia,rash, pruritus; less commonly paraesthesia,eosinophilia, thrombocytopenia, leucopenia;rarely convulsions; also reported haemolytic anaemia,positive Coombs’ test, Stevens-Johnson syndrome,toxic epidermal necrolysisLicensed use not licensed for use in children under 3monthsIndication and doseAerobic and anaerobic Gram-positive andGram-negative infections (see notes above),hospital-acquired septicaemia Table 1, section5.1. By intravenous injection over 5 minutes or byintravenous infusionNeonate under 7 days 20 mg/kg every 12 hours,dose doubled in severe infectionNeonate 7–28 days 20 mg/kg every 8 hours;dose doubled in severe infectionChild 1 month–12 yearsBody-weight under 50 kg 10–20 mg/kg every 8hoursBody-weight over 50 kg dose as for child 12–18yearsChild 12–18 years 0.5–1 g every 8 hoursMeningitis. By intravenous infusionNeonate under 7 days 40 mg/kg every 12 hoursNeonate 7–28 days 40 mg/kg every 8 hoursChild 1 month–12 yearsBody-weight under 50 kg 40 mg/kg every 8hoursBody-weight over 50 kg dose as for child 12–18yearsChild 12–18 years 2 g every 8 hoursExacerbations of chronic lower respiratory-tractinfections in cystic fibrosis. By intravenous infusionChild 1 month–12 yearsBody-weight under 50 kg 40 mg/kg every 8hoursBody-weight over 50 kg dose as for child 12–18yearsChild 12–18 years 2 g every 8 hoursAdministration displacement value may be significantwhen reconstituting injection, consult local guidelines.For intravenous infusion, dilute reconstitutedsolution further to a concentration of 1–20 mg/mL inGlucose 5% or Sodium Chloride 0.9%; give over 15–30 minutesMeronem c (AstraZeneca) AInjection, powder for reconstitution, meropenem (astrihydrate), net price 500-mg vial = £8.60; 1-g vial =£17.19Electrolytes Na + 3.9 mmol/g5.1.2.3 Other beta-lactam antibioticsAztreonam is a monocyclic beta-lactam (‘monobactam’)antibiotic with an antibacterial spectrum limitedto Gram-negative aerobic bacteria including Pseudomonasaeruginosa, Neisseria meningitidis, and Haemophilusinfluenzae; it should not be used alone for ‘blind’treatment since it is not active against Gram-positiveorganisms. Aztreonam is also effective against Neisseriagonorrhoeae (but not against concurrent chlamydialinfection). Side-effects are similar to those of the otherbeta-lactams although aztreonam may be less likely tocause hypersensitivity in penicillin-sensitive patients.AZTREONAMCautions hypersensitivity to beta-lactam antibiotics;interactions: Appendix 1 (aztreonam)Contra-indications aztreonam hypersensitivityHepatic impairment use with caution and monitorliver functionRenal impairment usual initial dose, then half normaldose if estimated glomerular filtration rate 10–30 mL/5 Infections

274 5.1.3 Tetracyclines BNFC 2011–20125 Infectionsminute/1.73 m 2 ; usual initial dose, then one-quarternormal dose if estimated glomerular filtration rate lessthan 10 mL/minute/1.73 m 2Pregnancy no information available—manufactureradvises avoidBreast-feeding amount in milk probably too small tobe harmfulSide-effects nausea, vomiting, diarrhoea, abdominalcramps; mouth ulcers, altered taste; jaundice andhepatitis; flushing; hypersensitivity reactions; blooddisorders (including thrombocytopenia and neutropenia);rashes, injection-site reactions; rarely hypotension,seizures, asthenia, confusion, dizziness,headache, halitosis, and breast tenderness; very rarelyantibiotic-associated colitis, gastro-intestinal bleeding,and toxic epidermal necrolysisLicensed use not licensed for use in children under 7daysIndication and doseGram-negative infections including Pseudomonasaeruginosa, Haemophilus influenzae,and Neisseria meningitidis. By intravenous injection over 3–5 minutes orby intravenous infusionNeonate under 7 days 30 mg/kg every 12 hoursNeonate 7–28 days 30 mg/kg every 6–8 hoursChild 1 month–2 years 30 mg/kg every 6–8hoursChild 2–12 years 30 mg/kg every 6–8 hoursincreased to 50 mg/kg every 6–8 hours in severeinfection and cystic fibrosis (max. 2 g every 6hours)Child 12–18 years 1 g every 8 hours or 2 g every12 hours; 2 g every 6–8 hours for severe infections(including systemic Ps. aeruginosa and lunginfections in cystic fibrosis)Administration Displacement value may be significant,consult local guidelines. For intermittent intravenousinfusion, dilute reconstituted solution furtherin Glucose 5% or Sodium chloride 0.9% to a concentrationof less than 20 mg/mL; to be given over20–60 minutesAzactam c (Squibb) AInjection, powder for reconstitution, aztreonam. Netprice 1-g vial = £9.40; 2-g vial = £18.825.1.3 TetracyclinesThe tetracyclines are broad-spectrum antibiotics whosevalue has decreased owing to increasing bacterial resistance.In children over 12 years of age they are useful forinfections caused by chlamydia (trachoma, psittacosis,salpingitis, urethritis, and lymphogranuloma venereum),rickettsia (including Q-fever), brucella (doxycycline witheither streptomycin or rifampicin), and the spirochaete,Borrelia burgdorferi (Lyme disease—see section5.1.1.3). They are also used in respiratory and genitalmycoplasma infections, in acne, in destructive (refractory)periodontal disease, in exacerbations of chronicrespiratory diseases (because of their activity againstHaemophilus influenzae), and for leptospirosis in penicillinhypersensitivity (as an alternative to erythromycin).Microbiologically, there is little to choose between thevarious tetracyclines, the only exception being minocyclinewhich has a broader spectrum; it is activeagainst Neisseria meningitidis and has been used formeningococcal prophylaxis but is no longer recommendedbecause of side-effects including dizzinessand vertigo (see Table 2, section 5.1 for current recommendations).Compared to other tetracyclines, minocyclineis associated with a greater risk of lupus-erythematosus-likesyndrome. Minocycline sometimes causesirreversible pigmentation.For the role of tetracyclines in the management ofmeticillin-resistant Staphylococcus aureus (MRSA)infections, see p. 259.Oral infections In children over 12 years of age,tetracyclines can be effective against oral anaerobesbut the development of resistance (especially by oralstreptococci) has reduced their usefulness for the treatmentof acute oral infections; they may still have a rolein the treatment of destructive (refractory) forms ofperiodontal disease. Doxycycline has a longer durationof action than tetracycline or oxytetracycline and needonly be given once daily; it is reported to be more activeagainst anaerobes than some other tetracyclines.For the use of doxycycline in the treatment of recurrentaphthous ulceration, oral herpes, or as an adjunct togingival scaling and root planing for periodontitis, seesection 12.3.1 and section 12.3.2.Cautions Tetracyclines may increase muscle weaknessin patients with myasthenia gravis, and exacerbate systemiclupus erythematosus. Antacids, and aluminium,calcium, iron, magnesium and zinc salts decrease theabsorption of tetracyclines; milk also reduces theabsorption of demeclocycline, oxytetracycline, andtetracycline. Other interactions: Appendix 1 (tetracyclines).Contra-indications Deposition of tetracyclines ingrowing bone and teeth (by binding to calcium) causesstaining and occasionally dental hypoplasia, and theyshould not be given to children under 12 years, or topregnant or breast-feeding women. However, doxycyclinemay be used in children for treatment and postexposureprophylaxis of anthrax when an alternativeantibacterial cannot be given [unlicensed indication].Tetracyclines should not be given to children withacute porphyria (section 9.8.2).Hepatic impairment Tetracyclines should be avoidedor used with caution in children with hepatic impairment.Tetracyclines should also be used with caution inthose receiving potentially hepatotoxic drugs.Renal impairment With the exception of doxycyclineand minocycline, the tetracyclines may exacerbaterenal failure and should not be given to children withrenal impairment.Pregnancy Tetracyclines should not be given topregnant women; effects on skeletal developmenthave been documented in the first trimester in animalstudies. Administration during the second or third trimestermay cause discoloration of the child’s teeth, andmaternal hepatotoxicity has been reported with largeparenteral doses.

BNFC 2011–2012 5.1.3 Tetracyclines 275Breast-feeding Tetracyclines should not be given towomen who are breast-feeding (although absorptionand therefore discoloration of teeth in the infant isprobably usually prevented by chelation with calciumin milk).Side-effects Side-effects of the tetracyclines includenausea, vomiting, diarrhoea (antibiotic-associated colitisreported occasionally), dysphagia, and oesophagealirritation. Other rare side-effects include hepatotoxicity,pancreatitis, blood disorders, photosensitivity (particularlywith demeclocycline), and hypersensitivity reactions(including rash, exfoliative dermatitis, Stevens-Johnson syndrome, urticaria, angioedema, anaphylaxis,pericarditis). Headache and visual disturbances mayindicate benign intracranial hypertension (discontinuetreatment); bulging fontanelles have been reported ininfants.TETRACYCLINECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes above; max. 1 g dailyin divided dosesRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also acute renal failure,skin discolorationIndication and doseSusceptible infections see notes above. By mouthChild 12–18 years 250 mg 4 times daily,increased in severe infections to 500 mg 3–4 timesdailyAcne section 13.6.2Non-gonococcal urethritis. By mouthChild 12–18 years 500 mg 4 times daily for 7–14days (21 days if failure or relapse after first course)Tetracycline (Non-proprietary) ATablets, coated, tetracycline hydrochloride 250 mg,net price 28-tab pack = £13.67. Label: 7, 9, 23,counselling, postureDental prescribing on NHS Tetracycline Tablets may beprescribedDEMECLOCYCLINE HYDROCHLORIDECautions see notes above, but photosensitivity morecommon (avoid exposure to sunlight or sun lamps)Contra-indications see notes aboveHepatic impairment see notes above; max. 1 g dailyin divided dosesRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also reversible nephrogenicdiabetes insipidus, acute renal failureIndication and doseSusceptible infections see notes above. By mouthChild 12–18 years 150 mg 4 times daily or300 mg twice dailyDemeclocycline hydrochloride (Non-proprietary) ACapsules, demeclocycline hydrochloride 150 mg, netprice 28-cap pack = £25.09. Label: 7, 9, 11, 23DOXYCYCLINECautions see notes above; alcohol dependence;photosensitivity reported (avoid exposure to sunlightor sun lamps)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment use with caution (avoid excessivedoses)Pregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also anorexia, drymouth, flushing, anxiety, and tinnitusLicensed use not licensed for use in children under12 yearsIndication and doseSusceptible infections see notes above. By mouthChild 12–18 years 200 mg on first day, then100 mg daily; severe infections (including refractoryurinary-tract infections) 200 mg dailyEarly syphilis. By mouthChild 12–18 years 100 mg twice daily for 14 daysLate latent syphilis. By mouthChild 12–18 years 100 mg twice daily for 28 daysUncomplicated genital chlamydia, non-gonococcalurethritis, pelvic inflammatory diseaseTable 1, section 5.1. By mouthChild 12–18 years 100 mg twice daily for 7 days(14 days in pelvic inflammatory disease)Lyme disease (see also section 5.1.1.3). By mouthChild 12–18 years 100 mg twice daily for 10–14days (for 28 days in Lyme arthritis)Anthrax (treatment or post-exposure prophylaxis)see also section 5.1.12. By mouthChild under 12 years (only if alternative antibacterialcannot be given) 2.5 mg/kg twice daily(max. 100 mg twice daily)Child 12–18 years 100 mg twice dailyAcne section 13.6.25 Infections

276 5.1.4 Aminoglycosides BNFC 2011–20125 InfectionsAdjunct to gingival scaling and root planing forperiodontitis section 12.3.1Counselling Capsules should be swallowed whole withplenty of fluid during meals while sitting or standingNote Doxycycline doses in BNF for Children may differ fromthose in product literatureDoxycycline (Non-proprietary) ACapsules, doxycycline (as hyclate) 50 mg, net price28-cap pack = £1.79; 100 mg, 8-cap pack = £1.16.Label: 6, 9, 11, 27, counselling, postureBrands include Doxylar cDental prescribing on NHS Doxycycline Capsules 100 mgmay be prescribedVibramycin-D c (Pfizer) ADispersible tablets, yellow, scored, doxycycline100 mg, net price 8-tab pack = £4.91. Label: 6, 9, 11,13Dental prescribing on NHS May be prescribed as DispersibleDoxycycline TabletsLYMECYCLINECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseSusceptible infections see notes above. By mouthChild 12–18 years 408 mg twice daily, increasedto 1.224–1.632 g daily in severe infectionsAcne. By mouthChild 12–18 years 408 mg daily for at least 8weeksTetralysal 300 c (Galderma) ACapsules, red/yellow, lymecycline 408 mg (= tetracycline300 mg). Net price 28-cap pack = £7.77, 56-cap pack = £14.97. Label: 6, 9MINOCYCLINE UCautions see notes above; if treatment continued forlonger than 6 months, monitor every 3 months forhepatotoxicity, pigmentation and for systemic lupuserythematosus—discontinue if these develop or ifpre-existing systemic lupus erythematosus worsensContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment use with caution (avoid excessivedoses)Pregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also dizziness andvertigo (more common in women); rarely anorexia,tinnitus, impaired hearing, hyperaesthesia, paraesthesia,acute renal failure, pigmentation (sometimesirreversible), and alopecia; very rarely systemic lupuserythematosus, discoloration of conjunctiva, tears,and sweatIndication and doseSusceptible infections see notes above. By mouthChild 12–18 years 100 mg twice dailyAcne section 13.6.2Counselling Tablets or capsules should be swallowed wholewith plenty of fluid while sitting or standingMinocycline (Non-proprietary) AUCapsules, minocycline (as hydrochloride) 50 mg, netprice 56-cap pack = £15.27; 100 mg, 28-cap pack =£13.09. Label: 6, 9, counselling, postureBrands include Aknemin cTablets, minocycline (as hydrochloride) 50 mg, netprice 28-tab pack = £4.93; 100 mg, 28-tab pack =£9.52. Label: 6, 9, counselling, postureModified releaseMinocycline m/r preparations AUCapsules, m/r, minocycline (as hydrochloride)100 mg, net price 56-cap pack = £20.08. Label: 6, 25Brands include Acnamino c MR, Minocin MR c , Sebomin MR cDoseAcne. By mouthChild 12–18 years 1 capsule dailyOXYTETRACYCLINECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseSusceptible infections see notes above. By mouthChild 12–18 years 250–500 mg 4 times dailyAcne section 13.6.2Oxytetracycline (Non-proprietary) ATablets, coated, oxytetracycline dihydrate 250 mg,net price 28-tab pack = £1.28. Label: 7, 9, 23Brands include Oxymycin cDental prescribing on NHS Oxtetracycline Tablets may beprescribed5.1.4 AminoglycosidesThese include amikacin, gentamicin, neomycin, streptomycin,and tobramycin. All are bactericidal and activeagainst some Gram-positive and many Gram-negativeorganisms. Amikacin, gentamicin, and tobramycin arealso active against Pseudomonas aeruginosa; streptomycinis active against Mycobacterium tuberculosis andis now almost entirely reserved for tuberculosis (section5.1.9).The aminoglycosides are not absorbed from the gut(although there is a risk of absorption in inflammatorybowel disease and liver failure) and must therefore begiven by injection for systemic infections.

BNFC 2011–2012 5.1.4 Aminoglycosides 277Most side-effects of this group of antibiotics are doserelated;therefore care must be taken with dosage andwhenever possible treatment should not exceed 7 days.The important side-effects are ototoxicity, and nephrotoxicity;they occur most commonly in children withrenal failure.Aminoglycosides may impair neuromuscular transmissionand should not be given to children with myastheniagravis; large doses given during surgery havebeen responsible for a transient myasthenic syndromein patients with normal neuromuscular function.Aminoglycosides should preferably not be given withpotentially ototoxic diuretics (e.g. furosemide); if concurrentuse is unavoidable, administration of the aminoglycosideand of the diuretic should be separated byas long a period as practicable.Renal impairment Excretion of aminoglycosides isprincipally via the kidney and accumulation occurs inrenal impairment. Ototoxicity and nephrotoxicity occurcommonly in patients with renal failure. If there isimpairment of renal function, the interval betweendoses must be increased; if the renal impairment issevere, the dose itself should be reduced as well.Serum-aminoglycoside concentrations must be monitoredin patients with renal impairment, see SerumConcentrations below; renal, auditory, and vestibularfunction should also be monitored. A once-daily, highdoseregimen of an aminoglycoside should be avoidedin children over 1 month of age with a creatinineclearance less than 20 mL/minute/1.73 m 2 .Once daily dosage Once daily administration ofaminoglycosides is more convenient, provides adequateserum concentrations, and has largely superseded multiple-dailydose regimens (given in 2–3 divided dosesduring the 24 hours). Local guidelines on dosage andserum concentrations should be consulted. A oncedaily,high-dose regimen of an aminoglycoside shouldbe avoided in children with endocarditis or burns ofmore than 20% of the total body surface area, or inchildren over 1 month of age with a creatinine clearanceof less than 20 mL/minute/1.73m 2 . The extended intervaldose regimen is used in neonates to reflect thechanges in renal function that occur with increasinggestational and postnatal age (see Neonates below).Serum concentrations Serum concentration monitoringavoids both excessive and subtherapeutic concentrationsthus preventing toxicity and ensuring efficacy.In children with normal renal function,aminoglycoside concentration should be measured initiallyafter 3 or 4 doses of a multiple daily dose regimen;children with renal impairment may require earlier andmore frequent measurement of aminoglycoside concentration.Blood samples should be taken just before the next doseis administered (‘trough’ concentration). If the pre-dose(‘trough’) concentration is high, the interval betweendoses must be increased. For multiple daily dose regimens,blood samples should also be taken approximately1 hour after intramuscular or intravenous administration(‘peak’ concentration). If the post-dose (‘peak’)concentration is high, the dose must be decreased.Serum-aminoglycoside concentration should be measuredin all children and must be determined in infants,in neonates, in obesity, and in cystic fibrosis, or if highdoses are being given, or if there is renal impairment.Cystic fibrosis A higher dose of parenteral aminoglycosideis often required in children with cystic fibrosisbecause renal clearance of the aminoglycoside isincreased. For the role of aminoglycosides in the treatmentof pseudomonal lung infections in cystic fibrosissee Table 1, section 5.1. Nebulised tobramycin is usedfor chronic pseudomonal lung infection in cystic fibrosis;however, resistance may develop, and some childrendo not respond to treatment.Endocarditis Gentamicin is used in combination withother antibiotics for the treatment of bacterial endocarditis(Table 1, section 5.1). Serum-gentamicin concentrationshould be determined twice each week (moreoften in renal impairment). Streptomycin may be usedas an alternative in gentamicin-resistant enterococcalendocarditis.Gentamicin is the aminoglycoside of choice in the UKand is used widely for the treatment of serious infections.It has a broad spectrum but is inactive againstanaerobes and has poor activity against haemolyticstreptococci and pneumococci. When used for the‘blind’ therapy of undiagnosed serious infections it isusually given in conjunction with a penicillin or metronidazole(or both). Gentamicin is used together withanother antibiotic for the treatment of endocarditis (seeabove and Table 1, section 5.1).Loading and maintenance doses may be calculated onthe basis of the patient’s weight and renal function (e.g.using a nomogram); adjustments are then made accordingto serum-gentamicin concentrations. High doses areoccasionally indicated for serious infections, especiallyin the neonate, children with cystic fibrosis or theimmunocompromised patient; whenever possible treatmentshould not exceed 7 days.Amikacin is more stable than gentamicin to enzymeinactivation. Amikacin is used in the treatment of seriousinfections caused by gentamicin-resistant Gramnegativebacilli.Tobramycin has similar activity to gentamicin. It isslightly more active against Ps. aeruginosa but showsless activity against certain other Gram-negative bacteria.Tobramycin may be administered by nebuliser for thetreatment of Ps. aeruginosa infection in cystic fibrosis(see Cystic Fibrosis, above).Neomycin is too toxic for parenteral administration andcan only be used for infections of the skin or mucousmembranes or to reduce the bacterial population of thecolon prior to bowel surgery or in hepatic failure. Oraladministration may lead to malabsorption. Smallamounts of neomycin may be absorbed from the gutin children with hepatic failure and, as these childrenmay also be uraemic, cumulation may occur with resultantototoxicity.Neonates As aminoglycosides are eliminated principallyvia the kidney, neonatal treatment must reflect thechanges in glomerular filtration that occur with increasinggestational and postnatal age. The extended intervaldose regimen is used in neonates, and serum-aminoglycosideconcentrations must be measured. In patients onsingle daily dose regimens it may become necessary toprolong the dose interval to more than 24 hours if thetrough concentration is high.5 Infections

278 5.1.4 Aminoglycosides BNFC 2011–20125 InfectionsPregnancy There is a risk of auditory or vestibularnerve damage when aminoglycosides are used in thesecond and third trimesters of pregnancy. The risk isgreatest with streptomycin (section 5.1.9). The risk isprobably very small with gentamicin and tobramycin,but their use should be avoided unless essential (if given,serum-aminoglycoside concentration monitoring isessential).GENTAMICINCautions neonates, infants (adjust dose and monitorrenal, auditory and vestibular function together withserum gentamicin concentrations); avoid prolongeduse; conditions characterised by muscular weakness;see also notes above; interactions: Appendix 1(aminoglycosides)Contra-indications myasthenia gravisRenal impairment see notes abovePregnancy see notes aboveSide-effects vestibular and auditory damage,nephrotoxicity; rarely, hypomagnesaemia on prolongedtherapy, antibiotic-associated colitis; alsoreported, nausea, vomiting, rash, blood disorders; seealso notes aboveLicensed use not licensed for nebulisationPharmacokinetics Extended interval dose regimenin neonates: pre-dose (‘trough’) concentrationshould be less than 2 mg/litreOnce daily dose regimen: pre-dose (‘trough’) concentrationshould be less than 1 mg/litreMultiple daily dose regimen: one hour (‘peak’)serum concentration should be 5–10 mg/litre (3–5 mg/litre for endocarditis, 8–12 mg/litre in cysticfibrosis); pre-dose (‘trough’) concentration shouldbe less than 2 mg/litre (less than 1 mg/litre forendocarditis)Intrathecal/intraventricular injection: cerebrospinalfluid concentration should not exceed 10 mg/litreIndication and doseTo avoid excessive dosage in obese children, use idealweight for height to calculate parenteral dose andmonitor serum-gentamicin concentration closelySepticaemia, meningitis and other CNS infections,biliary-tract infection, acute pyelonephritis,endocarditis (see notes above), pneumoniain hospital patients, adjunct in listerialmeningitis (Table 1, section 5.1). Once daily dose regimen (not for endocarditisor meningitis) by intravenous infusionChild 1 month–18 years initially 7 mg/kg, thenadjusted according to serum-gentamicin concentration. Multiple daily dose regimen by intramuscularor by slow intravenous injection over at least 3minutesChild 1 month–12 years 2.5 mg/kg every 8 hoursChild 12–18 years 2 mg/kg every 8 hoursPseudomonal lung infection in cystic fibrosis. Multiple daily dose regimen by slow intravenousinjection over at least 3 minutes or byintravenous infusionChild 1 month–18 years 3 mg/kg every 8 hoursBacterial ventriculitis and CNS infection (supplementto systemic therapy). By intrathecal or intraventricular injection,seek specialist adviceNeonate seek specialist adviceChild 1 month–18 years 1 mg daily (increased ifnecessary to 5 mg daily)Note only preservative-free, intrathecal preparationshould be usedEye section 11.3.1Ear section 12.1.1Note Local guidelines may varyAdministration for intravenous infusion, dilute inGlucose 5% or Sodium Chloride 0.9%; give over 30minutesFor nebulisation, dilute preservative-free preparationin 3 mL sodium chloride 0.9%. Administer after physiotherapyand bronchodilatorsFor intrathecal or intraventricular injection, use preservative-freeintrathecal preparations onlyNeonatal sepsis. Extended interval dose regimen by slow intravenousinjection or intravenous infusionNeonate less than 32 weeks postmenstrual age4–5 mg/kg every 36 hoursNeonate 32 weeks and over postmenstrual age4–5 mg/kg every 24 hours. Multiple daily dose regimen by slow intravenousinjectionNeonate less than 29 weeks postmenstrual age2.5 mg/kg every 24 hoursNeonate 29–35 weeks postmenstrual age2.5 mg/kg every 18 hoursNeonate over 35 weeks postmenstrual age2.5 mg/kg every 12 hoursGentamicin (Non-proprietary) AInjection, gentamicin (as sulphate), net price 40 mg/mL, 1-mL amp = £1.40, 2-mL amp = £1.54, 2-mL vial= £1.48Paediatric injection, gentamicin (as sulphate) 10 mg/mL, net price 2-mL vial = £1.80Intrathecal injection, gentamicin (as sulphate) 5 mg/mL, net price 1-mL amp = 74pIntravenous infusion, gentamicin (as sulphate) 1 mg/mL in sodium chloride intravenous infusion 0.9%, netprice 80-mL (80 mg) bottle = £1.95; 3 mg/mL, 80-mL(240 mg) bottle = £5.95, 120-mL (360 mg) bottle =£8.45Cidomycin c (Sanofi-Aventis) AInjection, gentamicin (as sulphate) 40 mg/mL. Netprice 2-mL amp or vial = £1.48

BNFC 2011–2012 5.1.4 Aminoglycosides 279Genticin c (Amdipharm) AInjection, gentamicin (as sulphate) 40 mg/mL. Netprice 2-mL amp = £1.40Isotonic Gentamicin Injection (Baxter) AIntravenous infusion, gentamicin (as sulphate)800 micrograms/mL in sodium chloride intravenousinfusion 0.9%. Net price 100-mL (80-mg) Viaflex cbag = £1.61Electrolytes Na + 15.4 mmol/100-mL bagAMIKACINCautions see under Gentamicin; interactions:Appendix 1 (aminoglycosides)Contra-indications see under GentamicinRenal impairment see notes abovePregnancy see notes aboveSide-effects see under GentamicinPharmacokinetics Multiple dose regimen: one-hour(‘peak’) serum concentration should not exceed30 mg/litre; pre-dose (‘trough’) concentrationshould be less than 10 mg/litreOnce daily dose regimen: pre-dose (‘trough’) concentrationshould be less than 5 mg/litreLicensed use dose for cystic fibrosis not licensedIndication and doseTo avoid excessive dosage in obese children, use idealweight for height to calculate dose and monitorserum-amikacin concentration closelyNeonatal sepsis. Extended interval dose regimen by slow intravenousinjection over 3–5 minutes or by intravenousinfusionNeonate 15 mg/kg every 24 hours. Multiple daily dose regimen by intramuscularor by slow intravenous injection or by infusionNeonate loading dose of 10 mg/kg then 7.5 mg/kg every 12 hoursSerious Gram-negative infections resistant togentamicin. By slow intravenous injection over 3–5 minutesChild 1 month–12 years 7.5 mg/kg every 12hoursChild 12–18 years 7.5 mg/kg every 12 hours,increased to 7.5 mg/kg every 8 hours in severeinfections, max. 500 mg every 8 hours for up to 10days (max. cumulative dose 15 g)Once daily dose regimen (not for endocarditisor meningitis). By intravenous injection or infusionChild 1 month–18 years initially 15 mg/kg, thenadjusted according to serum-amikacin concentrationPseudomonal lung infection in cystic fibrosis. Multiple daily dose regimen by slow intravenousinjection or infusionChild 1 month–18 years 10 mg/kg every 8 hours(max. 500 mg every 8 hours)Note Local dosage guidelines may varyAdministration for intravenous infusion, dilute withGlucose 5% or Sodium Chloride 0.9%; give over 30–60 minutesAmikacin (Non-proprietary) AInjection, amikacin (as sulphate) 250 mg/mL. Netprice 2-mL vial = £10.14Electrolytes Na + 0.56 mmol/500-mg vialAmikin c (Bristol-Myers Squibb) AInjection, amikacin (as sulphate) 50 mg/mL. Netprice 2-mL vial = £2.07Electrolytes Na + < 0.5 mmol/vialTOBRAMYCINCautions see under Gentamicin; interactions:Appendix 1 (aminoglycosides)Specific cautions for inhaled treatment Other inhaleddrugs should be administered before tobramycin; monitor forbronchospasm with initial dose, measure peak flow beforeand after nebulisation—if bronchospasm occurs, repeat testusing bronchodilator; monitor renal function before treatmentand then annually; severe haemoptysisContra-indications see under GentamicinRenal impairment see notes abovePregnancy see notes aboveSide-effects see under Gentamicin; on inhalation,mouth ulcers, taste disturbances, voice alteration,cough, bronchospasm (see Cautions)Pharmacokinetics Extended interval dose regimenin neonates: pre-dose (‘trough’) concentrationshould be less than 2 mg/litreOnce daily dose regimen: pre-dose (‘trough’) concentrationshould be less than 1 mg/litreMultiple daily dose regimen: one-hour (‘peak’)serum concentration should not exceed 10 mg/litre(8–12 mg/litre in cystic fibrosis); pre-dose (‘trough’)concentration should be less than 2 mg/litreIndication and doseTo avoid excessive dosage in obese children, use idealweight for height to calculate parenteral dose andmonitor serum-tobramycin concentration closelyNeonatal sepsis. Extended interval dose regimen by intravenousinjection over 3–5 minutes or by intravenousinfusionNeonate less than 32 weeks postmenstrual age4–5 mg/kg every 36 hoursNeonate 32 weeks and over postmenstrual age4–5 mg/kg every 24 hours. Multiple daily dose regimen by intramuscularinjection or by slow intravenous injection or byintravenous infusionNeonate under 7 days 2 mg/kg every 12 hoursNeonate 7–28 days 2–2.5 mg/kg every 8 hoursSepticaemia, meningitis and other CNS infections,biliary-tract infection, acute pyelonephritis,pneumonia in hospital patients. Multiple daily dose regimen by slow intravenousinjection over 3–5 minutesChild 1 month–12 years 2–2.5 mg/kg every 8hours5 Infections

280 5.1.5 Macrolides BNFC 2011–20125 InfectionsChild 12–18 years 1 mg/kg every 8 hours; insevere infections up to 5 mg/kg daily in divideddoses every 6–8 hours (reduced to 3 mg/kg dailyas soon as clinically indicated). Once daily dose regimen by intravenous infusionChild 1 month–18 years initially 7 mg/kg, thenadjusted according to serum-tobramycin concentrationPseudomonal lung infection in cystic fibrosis. Multiple daily dose regimen by slow intravenousinjection over 3–5 minutesChild 1 month–18 years 8–10 mg/kg/daily in 3divided doses. Once daily dose regimen by intravenous infusionover 30 minutesChild 1 month–18 years initially 10 mg/kg (max.660 mg), then adjusted according to serum-tobramycinconcentrationChronic pulmonary Pseudomonas aeruginosainfection in patients with cystic fibrosis. By inhalation of nebulised solutionChild 6–18 years 300 mg every 12 hours for 28days, subsequent courses repeated after 28-dayinterval without tobramycin nebuliser solutionNote Local dosage guidelines may varyAdministration for intravenous infusion, dilute withGlucose 5% or Sodium Chloride 0.9%; give over 20–60 minutesParenteralTobramycin (Non-proprietary) AInjection, tobramycin (as sulphate) 40 mg/mL, netprice 1-mL (40-mg) vial = £4.00, 2-mL (80-mg) vial =£4.16, 6-mL (240-mg) vial = £19.20InhalationBramitob c (Chiesi) ANebuliser solution, tobramycin 75 mg/mL, net price56 x 4-mL (300-mg) unit = £1187.00Tobi c (Novartis) ANebuliser solution, tobramycin 60 mg/mL, net price56 5-mL (300-mg) unit = £1187.205.1.5 MacrolidesErythromycin has an antibacterial spectrum that issimilar but not identical to that of penicillin; it is thusan alternative in penicillin-allergic patients.Indications for erythromycin include respiratory infections,whooping cough, legionnaires’ disease, andcampylobacter enteritis. It is active against many penicillin-resistantstaphylococci but some are now alsoresistant to erythromycin; it has poor activity againstHaemophilus influenzae. Erythromycin is also activeagainst chlamydia and mycoplasmas.Erythromycin causes nausea, vomiting, and diarrhoea insome children; in mild to moderate infections this canbe avoided by giving a lower dose or the total dose in 4divided doses but if a more serious infection, such asLegionella pneumonia, is suspected higher doses areneeded.Clarithromycin is an erythromycin derivative withslightly greater activity than the parent compound.Tissue concentrations are higher than with erythromycin.It is given twice daily.Azithromycin is a macrolide with slightly less activitythan erythromycin against Gram-positive bacteria butenhanced activity against some Gram-negative organismsincluding H. influenzae. Plasma concentrations arevery low but tissue concentrations are much higher. Ithas a long tissue half-life and once daily dosage isrecommended. Azithromycin is also used in the treatmentof trachoma [unlicensed indication] (section11.3.1).For the role of erythromycin, azithromycin, andclarithromycin in the treatment of Lyme disease, seesection 5.1.1.3.Spiramycin is also a macrolide (section 5.4.7).Oral infections Clarithromycin or erythromycin is analternative for oral infections in penicillin-allergicpatients or where a beta-lactamase producing organismis involved. However, many organisms are now resistantto macrolides or rapidly develop resistance; their useshould therefore be limited to short courses. Metronidazole(section 5.1.11) may be preferred as an alternativeto a penicillin.Cautions Macrolides should be used with caution inchildren with a predisposition to QT interval prolongation(including electrolyte disturbances and concomitantuse of drugs that prolong the QT interval).Side-effects Nausea, vomiting, abdominal discomfort,and diarrhoea are the most common side-effects of themacrolides, but they are mild and less frequent withazithromycin and clarithromycin than with erythromycin.Hepatotoxicity (including cholestatic jaundice)and rash occur less frequently. Other side-effectsreported rarely or very rarely include pancreatitis, antibiotic-associatedcolitis, QT interval prolongation,arrhythmias, generally reversible hearing loss (sometimeswith tinnitus) after large doses, Stevens-Johnsonsyndrome, and toxic epidermal necrolysis. Intravenousinfusion may cause local tenderness and phlebitis.AZITHROMYCINCautions see notes above; interactions: Appendix 1(macrolides)Hepatic impairment manufacturers advise avoid insevere liver disease—no information availableRenal impairment use with caution if estimatedglomerular filtration rate less than 10 mL/minute/1.73 m 2Pregnancy manufacturers advise use only if adequatealternatives not availableBreast-feeding present in milk; use only if no suitablealternativeSide-effects see notes above; also anorexia, dyspepsia,flatulence, syncope, dizziness, headache,drowsiness, convulsions, arthralgia, and disturbancesin taste and smell; rarely constipation, hypotension,insomnia, agitation, anxiety, asthenia, paraesthesia,hyperactivity, thrombocytopenia, haemolytic anae-

BNFC 2011–2012 5.1.5 Macrolides 281mia, insterstitial nephritis, acute renal failure, photosensitivity,tooth and tongue discolorationLicensed use not licensed for typhoid fever, Lymedisease, chronic Pseudomonas aeruginosa infectionin cystic fibrosis, or prophylaxis of group A streptococcalinfectionIndication and doseRespiratory-tract infections, otitis media, skinand soft-tissue infections. By mouthChild over 6 months 10 mg/kg once daily (max.500 mg once daily) for 3 daysorBody-weight 15–25 kg 200 mg once daily for 3daysBody-weight 26–35 kg 300 mg once daily for 3daysBody-weight 36–45 kg 400 mg once daily for 3daysBody-weight over 45 kg 500 mg once daily for 3daysInfection in cystic fibrosis. By mouthChild 6 months–18 years 10 mg/kg once daily(max. 500 mg once daily) for 3 days; courserepeated after 1 week, then repeat as necessaryChronic Pseudomonas aeruginosa infection incystic fibrosis. By mouthChild 6–18 yearsBody-weight 25–40 kg 250 mg 3 times a weekBody-weight over 40 kg 500 mg 3 times a weekUncomplicated genital chlamydial infectionsand non-gonococcal urethritis. By mouthChild 12–18 years 1 g as a single doseLyme disease (see also section 5.1.1.3), mild tomoderate typhoid due to multiple-antibacterialresistant organisms. By mouthChild 6 months–18 years 10 mg/kg once daily(max. 500 mg) for 7–10 days (for 7 days in typhoid)Prevention of group A streptococcal infectionTable 2, section 5.1Azithromycin (Non-proprietary) ACapsules, azithromycin (as dihydrate) 250 mg, netprice 4-cap pack = £9.82, 6-cap pack = £14.73.Label: 5, 9, 23Tablets, azithromycin (as monohydrate hemi-ethanolate)250 mg, net price 4-tab pack = £9.83; 500 mg,3-tab pack = £6.75. Label: 5, 9Note Azithromycin tablets can be sold to the public for thetreatment of confirmed, asymptomatic Chlamydia trachomatisgenital infection in those over 16 years of age, and forthe epidemiological treatment of their sexual partners, subjectto max. single dose of 1 g, max. daily dose 1 g, and a packsize of 1 gOral suspensio, azithromycin (as monohydrate)200 mg/5 mL when reconstituted with water, netprice 15-mL pack = £5.81, 30-mL pack = £11.04.Label: 5, 9Dental prescribing on NHS May be prescribed as AzithromycinOral Suspension 200 mg/5 mLZithromax c (Pfizer) ACapsules, azithromycin (as dihydrate) 250 mg, netprice 4-cap pack = £7.16, 6-cap pack = £10.74.Label: 5, 9, 23Oral suspension, cherry/banana-flavoured, azithromycin(as dihydrate) 200 mg/5 mL when reconstitutedwith water. Net price 15-mL pack = £4.06, 22.5-mL pack = £6.10, 30-mL pack = £11.04. Label: 5, 9CLARITHROMYCINCautions see notes above; interactions: Appendix 1(macrolides)Hepatic impairment hepatic dysfunction includingjaundice reportedRenal impairment use half normal dose if estimatedglomerular filtration rate less than 30 mL/minute/1.73 m 2 ; avoid Klaricid XL c if estimated glomerularfiltration rate less than 30 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid unless potentialbenefit outweighs riskBreast-feeding manufacturer advises avoid unlesspotential benefit outweighs risk—present in milkSide-effects see notes above; also dyspepsia, toothand tongue discoloration, smell and taste disturbances,stomatitis, glossitis, and headache; less commonlyarthralgia and myalgia; rarely tinnitus; veryrarely dizziness, insomnia, nightmares, anxiety, confusion,psychosis, paraesthesia, convulsions, hypoglycaemia,renal failure, interstitial nephritis, leucopenia,and thrombocytopeniaLicensed use tablets and intravenous infusion notlicensed for use in children under 12 yearsIndication and doseRespiratory-tract infections, mild to moderateskin and soft-tissue infections, otitis media(see also Table 1, section 5.1). By mouthNeonate 7.5 mg/kg twice dailyChild 1 month–12 yearsBody-weight under 8 kg 7.5 mg/kg twice dailyBody-weight 8–11 kg 62.5 mg twice dailyBody-weight 12–19 kg 125 mg twice dailyBody-weight 20–29 kg 187.5 mg twice dailyBody-weight 30–40 kg 250 mg twice dailyChild 12–18 years 250 mg twice daily for 7 days,increased if necessary in severe infections to500 mg every 12 hours for up to 14 days. By intravenous infusion into large proximalveinChild 1 month–12 years 7.5 mg/kg every 12hoursChild 12–18 years 500 mg every 12 hours5 Infections

282 5.1.5 Macrolides BNFC 2011–20125 InfectionsLyme disease (see also section 5.1.1.3). By mouthChild 1 month–12 years 7.5 mg/kg (max.500 mg) twice daily for 14–21 daysChild 12–18 years 500 mg twice daily for 14–21daysHelicobacter pylori eradication section 1.3Prevention of pertussis Table 2, section 5.1Administration for intermittent intravenous infusiondilute reconstituted solution further in Glucose 5% orSodium chloride 0.9% to a concentration of 2 mg/mL;give into large proximal vein over 60 minutesClarithromycin (Non-proprietary) ATablets, clarithromycin 250 mg, net price 14-tab pack= £3.17; 500 mg, 14-tab pack = £4.10. Label: 9Dental prescribing on NHS Clarithromycin Tablets may beprescribedOral suspension, clarithromycin for reconstitutionwith water 125 mg/5 mL, net price 70 mL = £6.82;250 mg/5 mL, 70 mL = £13.63. Label: 9Dental prescribing on NHS Clarithromycin Oral Suspensionmay be prescribedIntravenous infusion, powder for reconstitution,clarithromycin; net price 500-mg vial = £10.31Klaricid c (Abbott) ATablets, both yellow, f/c, clarithromycin 250 mg, netprice 14-tab pack = £6.30; 500 mg, 14-tab pack =£10.17, 20-tab pack = £14.54. Label: 9Paediatric suspension, clarithromycin for reconstitutionwith water 125 mg/5 mL, net price 70 mL =£4.73, 100 mL = £8.14; 250 mg/5 mL, 70 mL = £9.46.Label: 9Granules, clarithromycin 250 mg/sachet, net price14-sachet pack = £11.68. Label: 9, 13Intravenous infusion, powder for reconstitution,clarithromycin. Net price 500-mg vial = £9.45Electrolytes Na + < 0.5 mmol/500-mg vialKlaricid XL c (Abbott) ATablets, m/r, yellow, clarithromycin 500 mg, net price7-tab pack = £6.46, 14-tab pack = £12.71. Label: 9, 21,25Dose. By mouthChild 12–18 years 500 mg once daily (doubled in severeinfections) for 7–14 daysIndication and doseSusceptible infections in patients with penicillinhypersensitivity, oral infections (seenotes above), campylobacter enteritis, respiratory-tractinfections (including Legionellainfection), skin infections, chlamydial ophthalmia,prevention and treament of pertussis (seealso Table 2, section 5.1). By mouthNeonate 12.5 mg/kg every 6 hoursChild 1 month–2 years 125 mg 4 times daily;dose doubled in severe infectionsChild 2–8 years 250 mg 4 times daily; dosedoubled in severe infectionsChild 8–18 years 250–500 mg 4 times daily; dosedoubled in severe infectionsNote Total daily dose may be given in two divided doses. By intravenous infusionNeonate 10–12.5 mg/kg every 6 hoursChild 1 month–18 years 12.5 mg/kg (max. 1 g)every 6 hoursEarly syphilis. By mouthChild 12–18 years 500 mg 4 times daily for 14daysUncomplicated genital chlamydia, non-gonococcalurethritis, pelvic inflammatory disease(see also Table 1, section 5.1). By mouthChild 1 month–2 years 12.5 mg/kg 4 times dailyfor 14 daysChild 2–12 years 250 mg twice daily for 14 daysChild 12–18 years 500 mg twice daily for 14 daysLyme disease (see also section 5.1.1.3). By mouthChild 1 month–18 years 12.5 mg/kg (max.500 mg) 4 times daily for 14–21 daysProphylaxis against pneumococcal infectionTable 2, section 5.1Gastric stasis section 1.2ERYTHROMYCINCautions see notes above; neonate under 2 weeks (riskof hypertrophic pyloric stenosis); acute porphyria(section 9.8.2); interactions: Appendix 1 (macrolides)Hepatic impairment may cause idiosyncratichepatotoxicityRenal impairment reduce dose in severe renalimpairment (ototoxicity)Pregnancy not known to be harmfulBreast-feeding only small amounts in milk—notknown to be harmfulSide-effects see notes above; also myasthenia-likesyndromeAcne vulgaris section 13.6Diphtheria prophylaxis Table 2, section 5.1Prevention of group A streptococcal infectionTable 2, section 5.1Administration Dilute reconstituted solution furtherin glucose 5% (neutralised with Sodium bicarbonate)or sodium chloride 0.9% to a concentration of 1–5 mg/mL; give over 20–60 minutesConcentration of up to 10 mg/mL may be used influid-restriction if administered via a central venouscatheter

BNFC 2011–2012 5.1.6 Clindamycin 283Erythromycin (Non-proprietary) ACapsules, enclosing e/c microgranules, erythromycin250 mg, net price 28-cap pack = £15.00. Label: 5, 9, 25Brands include Tiloryth cTablets, e/c, erythromycin 250 mg, net price 28 =£1.54. Label: 5, 9, 25Dental prescribing on NHS Erythromycin Tablets e/c maybe prescribedErythromycin Ethyl Succinate (Non-proprietary) AOral suspension, erythromycin (as ethyl succinate)for reconstitution with water 125 mg/5 mL, net price100 mL = £1.99; 250 mg/5 mL, 100 mL = £2.64;500 mg/5 mL, 100 mL = £4.31. Label: 9Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionBrands include Primacine cDental prescribing on NHS Erythromycin Ethyl SuccinateOral Suspension may be prescribedErythromycin Lactobionate (Non-proprietary) AIntravenous infusion, powder for reconstitution,erythromycin (as lactobionate), net price 1-g vial =£9.98Erymax c (Cephalon) ACapsules, opaque orange/clear orange, enclosingorange and white e/c pellets, erythromycin 250 mg,net price 28-cap pack = £5.61, 112-cap pack = £22.44.Label: 5, 9, 25Erythrocin c (Amdipharm) ATablets, both f/c, erythromycin (as stearate), 250 mg,net price 100–tab pack = £18.20; 500 mg, 100–tabpack = £36.40. Label: 9Dental prescribing on NHS May be prescribed as ErythromycinStearate TabletsErythroped c (Amdipharm) ASuspension SF, sugar-free, banana-flavoured,erythromycin (as ethyl succinate) for reconstitutionwith water, 125 mg/5 mL (Suspension PI SF), netprice 140 mL = £3.06; 250 mg/5 mL, 140 mL = £5.95;500 mg/5 mL (Suspension SF Forte), 140 mL =£10.56. Label: 9Erythroped A c (Amdipharm) ATablets, yellow, f/c, erythromycin 500 mg (as ethylsuccinate). Net price 28-tab pack = £10.78. Label: 9Dental prescribing on NHS May be prescribed as ErythromycinEthyl Succinate Tablets5.1.6 ClindamycinClindamycin is active against Gram-positive cocci,including streptococci and penicillin-resistant staphylococci,and also against many anaerobes, especially Bacteroidesfragilis. It is well concentrated in bone andexcreted in bile and urine.Clindamycin is recommended for staphylococcal jointand bone infections such as osteomyelitis, and intraabdominalsepsis; it is an alternative to macrolides forerysipelas or cellulitis in penicillin-allergic patients. It isalso used in combination with other antibacterials forcellulitis in immunocompromised children. Clindamycincan also be used for infections associated with meticillin-resistantStaphylococcus aureus (MRSA) in boneand joint infections, and skin and soft-tissue infections.Clindamycin has been associated with antibiotic-associatedcolitis (section 1.5), which may be fatal. Althoughit can occur with most antibacterials, antibiotic-associatedcolitis occurs more frequently with clindamycin.Children should therefore discontinue treatment immediatelyif diarrhoea develops.Oral infections Clindamycin should not be usedroutinely for the treatment of oral infections because itmay be no more effective than penicillins against anaerobesand there may be cross-resistance with erythromycin-resistantbacteria. Clindamycin can be used forthe treatment of dentoalveolar abscess that has notresponded to penicillin or to metronidazole.CLINDAMYCINCautions discontinue immediately if diarrhoea or colitisdevelops; monitor liver and renal function iftreatment exceeds 10 days, and in neonates andinfants; avoid rapid intravenous administration; avoidin acute porphyria (section 9.8.2); interactions:Appendix 1 (clindamycin)Contra-indications diarrhoeal states; avoid injectionscontaining benzyl alcohol in neonates (see underpreparations below)Pregnancy not known to be harmfulBreast-feeding amount probably too small to beharmful; bloody diarrhoea reported in 1 infantSide-effects diarrhoea (discontinue treatment),abdominal discomfort, oesophagitis, oesophagealulcers, taste disturbances, nausea, vomiting, antibiotic-associatedcolitis; jaundice; leucopenia, eosinophilia,and thrombocytopenia reported; polyarthritisreported; rash, pruritus, urticaria, anaphylactoidreactions, Stevens-Johnson syndrome, toxic epidermalnecrolysis, exfoliative and vesiculobullousdermatitis reported; pain, induration, and abscessafter intramuscular injection; thrombophlebitis afterintravenous injectionIndication and doseStaphylococcal bone and joint infections, peritonitissee notes above. By mouthNeonate under 14 days 3–6 mg/kg 3 times dailyNeonate 14–28 days 3–6 mg/kg 4 times dailyChild 1 month–12 years 3–6 mg/kg 4 times daily(body-weight under 10 kg, minimum dose 37.5 mg3 times daily)Child 12–18 years 150–300 mg 4 times daily; insevere infections 450 mg 4 times daily. By deep intramuscular injection or by intravenousinfusionChild 1 month–12 years 3.75–6.25 mg/kg 4times daily; increased up to 10 mg/kg 4 times dailyin severe infections; total daily dose may alternativelybe given in 3 divided dosesChild 12–18 years 150–675 mg 4 times daily;total daily dose may alternatively be given in 2–3divided doses; in life-threatening infection up to1.2 g 4 times daily; single doses above 600 mg byintravenous infusion only; single doses by intravenousinfusion not to exceed 1.2 g5 Infections

284 5.1.7 Some other antibacterials BNFC 2011–20125 InfectionsStaphylococcal lung infection in cystic fibrosis. By mouthChild 1 month–18 years 5–7 mg/kg (max.600 mg) 4 times dailyTreatment of falciparum malaria, see p. 330Administration for intravenous infusion, dilute to aconcentration of not more than 18 mg/mL with Glucose5% or Sodium Chloride 0.9%; give over 10–60minutes at a max. rate of 20 mg/kg/hourClindamycin (Non-proprietary) ACapsules, clindamycin (as hydrochloride) 150 mg, netprice 24-cap pack = £11.75. Label: 9, 27, counselling,see above (diarrhoea)Dental prescribing on NHS Clindamycin Capsules may beprescribedLiquid, 75 mg/5 mL available from ‘special-order’manufacturers or specialist importing companies, seep. 809Dalacin C c (Pharmacia) ACapsules, clindamycin (as hydrochloride) 75 mg(green/white), net price 24-cap pack = £7.45; 150 mg,(white), 24-cap pack = £13.72. Label: 9, 27, counselling,see above (diarrhoea)Dental prescribing on NHS May be prescribed as ClindamycinCapsulesInjection, clindamycin (as phosphate) 150 mg/mL,net price 2-mL amp = £6.20; 4-mL amp = £12.35Excipients include benzyl alcohol (avoid in neonates, see Excipients,p. 2)5.1.7 Some other antibacterialsAntibacterials discussed in this section include chloramphenicol,fusidic acid, glycopeptide antibiotics(vancomycin and teicoplanin), linezolid, and the polymyxin,colistimethate sodium.ChloramphenicolChloramphenicol is a potent broad-spectrum antibiotic;however, it is associated with serious haematologicalside-effects when given systemically and should thereforebe reserved for the treatment of life-threateninginfections, particularly those caused by Haemophilusinfluenzae, and also for typhoid fever. Chloramphenicolis also used in cystic fibrosis for the treatment of respiratoryBurkholderia cepacia infection resistant to otherantibacterials.Grey baby syndrome may follow excessive doses inneonates with immature hepatic metabolism; monitoringof plasma concentrations is recommended.Chloramphenicol eye drops (section 11.3.1) and chloramphenicolear drops (section 12.1.1) are also available.CHLORAMPHENICOLCautions avoid repeated courses and prolongedtreatment; blood counts required before and periodicallyduring treatment; monitor plasma-chloramphenicolconcentration in neonates (see below);interactions: Appendix 1 (chloramphenicol)Contra-indications acute porphyria (section 9.8.2)Hepatic impairment avoid if possible—increased riskof bone-marrow depression; reduce dose and monitorplasma-chloramphenicol concentrationRenal impairment avoid in severe impairment unlessno alternative; dose-related depression of haematopoiesisPregnancy manufacturer advises avoid; neonatalgrey-baby syndrome if used in third trimesterBreast-feeding manufacturer advises avoid; useanother antibiotic; may cause bone-marrow toxicity ininfant; concentration in milk usually insufficient tocause ‘grey-baby syndrome’Side-effects blood disorders including reversible andirreversible aplastic anaemia (with reports of resultingleukaemia), peripheral neuritis, optic neuritis, headache,depression, urticaria, erythema multiforme,nausea, vomiting, diarrhoea, stomatitis, glossitis, drymouth; nocturnal haemoglobinuria reported; greysyndrome (abdominal distension, pallid cyanosis, circulatorycollapse) may follow excessive doses inneonates with immature hepatic metabolism (seePharmacokinetics below)Pharmacokinetics plasma concentration monitoringrequired in neonates and preferred in those under 4years of age, and in hepatic impairment; recommendedpeak plasma concentration (approx. 2hours after administration by mouth, intravenousinjection or infusion) 10–25 mg/litre; pre-dose(‘trough’) concentration should not exceed 15 mg/litreIndication and doseSee notes above. By intravenous injectionNeonate up to 14 days 12.5 mg/kg twice dailyNeonate 14–28 days 12.5 mg/kg 2–4 times dailyNote Check dosage carefully; overdosage can be fatal(see also pharmacokinetics above). By mouth or by intravenous injection or infusionChild 1 month–18 years 12.5 mg/kg every 6hours; dose may be doubled in severe infectionssuch as septicaemia, meningitis and epiglottitisproviding plasma-chloramphenicol concentrationsare measured and high doses reduced as soon asindicatedAdministration Displacement value may be significantfor injection, consult local guidelines. For intermittentintravenous infusion, dilute reconstitutedsolution further in glucose 5% or sodium chloride0.9%Chloramphenicol (Non-proprietary) ACapsules, chloramphenicol 250 mg. Net price 60 =£377.00Extemporaneous formulations available seeExtemporaneous Preparations, p. 6Kemicetine c (Pharmacia) AInjection, powder for reconstitution, chloramphenicol(as sodium succinate). Net price 1-g vial = £1.39Electrolytes Na + 3.14 mmol/gFusidic acidFusidic acid and its salts are narrow-spectrum antibiotics.The only indication for their use is in infections

BNFC 2011–2012 5.1.7 Some other antibacterials 285caused by penicillin-resistant staphylococci, especiallyosteomyelitis, as they are well concentrated in bone;they are also used for staphylococcal endocarditis. Asecond antistaphylococcal antibiotic is usually requiredto prevent emergence of resistance during treatment.SODIUM FUSIDATECautions monitor liver function with high doses or onprolonged therapy; elimination may be reduced inhepatic impairment or biliary disease or biliaryobstruction; interactions: Appendix 1 (fusidic acid)Hepatic impairment impaired biliary excretion, avoidor reduce dose; possibly increased risk of hepatotoxicity,monitor liver functionPregnancy not known to be harmful; manufactureradvises use only if potential benefit outweighs riskBreast-feeding present in milk; manufacturer advisescautionSide-effects nausea, vomiting, reversible jaundice,especially after high dosage or rapid infusion (withdrawtherapy if persistent); rarely hypersensitivityreactions, acute renal failure (usually with jaundice),blood disordersIndication and dosePenicillin-resistant staphylococcal infectionincluding osteomyelitis, staphylococcal endocarditisin combination with other antibacterialssee under Preparations, belowSodium fusidate (LEO) AIntravenous infusion, powder for reconstitution,sodium fusidate 500 mg (= fusidic acid 480 mg), withbuffer, net price per vial (with diluent) = £70.04Electrolytes Na + 3.1 mmol/vial when reconstituted with bufferDoseAs sodium fusidate. By intravenous infusionNeonate 10 mg/kg every 12 hoursChild 1 month–18 years 6–7 mg/kg (max. 500 mg)every 8 hoursAdministration reconstitute with buffer solution provided;further dilute to 1 mg/mL with Sodium chloride 0.9% or Glucose5% intravenous infusion (but see below); infuse over at least 6hours via a superficial vein or 2 hours via a central venous line;incompatible in solution of pH less than 7.4Fucidin c (LEO) ATablets, f/c, sodium fusidate 250 mg, net price 10-tabpack = £6.02. Label: 9DoseAs sodium fusidate. By mouthChild 12–18 years 500 mg every 8 hours, dose doubledfor severe infectionsSkin infection as sodium fusidate. By mouthChild 12–18 years 250 mg every 12 hours for 5–10 daysSuspension, off-white, banana- and orange-flavoured,fusidic acid 250 mg/5 mL, net price 50 mL =£6.73. Label: 9, 21DoseAs fusidic acid. By mouthNeonate 15 mg/kg 3 times dailyChild 1 month–1 year 15 mg/kg 3 times dailyChild 1–5 years 250 mg 3 times dailyChild 5–12 years 500 mg 3 times dailyChild 12–18 years 750 mg 3 times dailyNote Fusidic acid is incompletely absorbed and dosesrecommended for suspension are proportionately higherthan those for sodium fusidate tabletsVancomycin and teicoplaninThe glycopeptide antibiotics vancomycin and teicoplaninhave bactericidal activity against aerobic andanaerobic Gram-positive bacteria including multi-resistantStaphylococci. However, there are reports of Staphylococcusaureus with reduced susceptibility to glycopeptides.There are increasing reports ofglycopeptide-resistant Enterococci.Vancomycin is used by the intravenous route in theprophylaxis and treatment of serious infections causedby Gram-positive cocci. Vancomycin is principallyexcreted via the kidney and dose reduction is necessaryin renal impairment.Penetration in to cerebrospinal fluid is poor; vancomycinmay be administered by the intrathecal or intraventricularroute for treatment of meningitis [unlicensed].Vancomycin (added to dialysis fluid) is alsoused in the treatment of peritonitis associated withperitoneal dialysis [unlicensed route] (Table 1 section5.1).Vancomycin given by mouth for 10–14 days is effectivein the treatment of Clostridium difficile infection (seealso section 1.5); low doses are considered adequate(higher dose may be considered if the infection fails torespond or if it is life-threatening). Vancomycin shouldnot be given by mouth for systemic infections since it isnot significantly absorbed.Teicoplanin is similar to vancomycin but has a significantlylonger duration of action allowing once-dailyadministration. Plasma concentration monitoring isnot usually necessary, but may help optimise therapy.Unlike vancomycin, teicoplanin can be given by intramuscularas well as by intravenous injection; it is notgiven by mouth.VANCOMYCINCautions avoid rapid infusion (risk of anaphylactoidreactions, see Side-effects); rotate infusion sites; avoidif history of deafness; all patients require plasmavancomycinmeasurement (after 3 or 4 doses if renalfunction normal, earlier if renal impairment), bloodcounts, urinalysis, and renal function tests; monitorauditory function in renal impairment; teicoplaninsensitivity; systemic absorption may follow oraladministration especially in inflammatory bowel disordersor following multiple doses; interactions:Appendix 1 (vancomycin)Renal impairment reduce dose—monitor plasmavancomycinconcentration and renal function regularly;see also Cautions abovePregnancy manufacturer advises use only if potentialbenefit outweighs risk—plasma-vancomycin concentrationmonitoring essential to reduce risk of fetaltoxicityBreast-feeding present in milk—significant absorptionfollowing oral administration unlikely5 Infections

286 5.1.7 Some other antibacterials BNFC 2011–20125 InfectionsSide-effects after parenteral administration: nephrotoxicityincluding renal failure and interstitial nephritis;ototoxicity (discontinue if tinnitus occurs); blooddisorders including neutropenia (usually after 1 weekor high cumulative dose), rarely agranulocytosis andthrombocytopenia; nausea; chills, fever; eosinophilia,anaphylaxis, rashes (including exfoliative dermatitis,Stevens-Johnson syndrome, toxic epidermal necrolysis,and vasculitis); phlebitis (irritant to tissue); onrapid infusion, severe hypotension (including shockand cardiac arrest), wheezing, dyspnoea, urticaria,pruritus, flushing of the upper body (‘red man’syndrome), pain and muscle spasm of back and chestPharmacokinetics plasma concentration monitoringrequired; pre-dose (‘trough’) concentration shouldbe 10–15 mg/litre (15–20 mg/litre for less sensitivestrains of meticillin-resistant Staphylococcus aureus)Licensed use not licensed for intraventricular useIndication and doseInfections due to Gram-positive bacteriaincluding osteomyelitis, septicaemia and softtissueinfections see notes above. By intravenous infusionNeonate less than 29 weeks postmenstrual age15 mg/kg every 24 hours, adjusted according toplasma concentrationNeonate 29–35 weeks postmenstrual age15 mg/kg every 12 hours, adjusted according toplasma concentrationNeonate over 35 weeks postmenstrual age15 mg/kg every 8 hours, adjusted according toplasma concentrationChild 1 month–18 years 15 mg/kg every 8 hours(maximum daily dose 2 g), adjusted according toplasma concentrationClostridium difficile infection (see also notesabove). By mouthChild 1 month–5 years 5 mg/kg 4 times daily for10–14 days (increased up to 10 mg/kg 4 timesdaily if infection fails to respond or is life-threatening)Child 5–12 years 62.5 mg 4 times daily for 10–14days (increased up to 250 mg 4 times daily ifinfection fails to respond or is life-threatening)Child 12–18 years 125 mg 4 times daily for 10–14days (increased up to 500 mg 4 times daily ifinfection fails to respond or is life-threatening)CNS infection e.g. ventriculitis. By intraventricular administration, seek specialistadviceNeonate 10 mg once every 24 hoursChild 1 month–18 years 10 mg once every 24hoursNote for all children reduce to 5 mg daily if ventricularsize reduced or increase to 15–20 mg once daily ifventricular size increased. Adjust dose according to CSFconcentration after 3-4 days; aim for pre-dose (‘trough’)concentration less than 10 mg/litre. If CSF not drainingfreely reduce dose frequency to once every 2–3 daysPeritonitis associated with peritoneal dialysisAdd to each bag of dialysis fluid to achieve a concentrationof 20–25 mg/litreNote Vancomycin doses in BNF for Children may differ fromthose in product literatureAdministration Displacement value may be significant,consult product literature and local guidelines.For intermittent intravenous infusion, the reconstitutedpreparation should be further diluted in sodiumchloride 0.9% or glucose 5% to a concentration of upto 5 mg/mL; give over at least 60 minutes (rate not toexceed 10 mg/minute for doses over 500 mg); usecontinuous infusion only if intermittent not available(limited evidence); 10 mg/mL can be used if infusedvia a central venous line over at least 1 hourInjection may be given orally; flavouring syrups maybe added to the solution at the time of administration.Safe PracticeFor intraventricular administration, seek specialistadviceVancomycin (Non-proprietary) ACapsules, vancomycin (as hydrochloride) 125 mg, netprice 28-cap pack = £132.47; 250 mg, 28-cap pack =£132.47. Label: 9Injection, powder for reconstitution, vancomycin (ashydrochloride), for use as an infusion, net price 500-mg vial = £7.25; 1-g vial = £14.50Note Can be used to prepare solution for oral administrationVancocin c (Flynn) AMatrigel capsules, vancomycin (as hydrochloride)125 mg, net price 28-cap pack = £88.31. Label: 9Injection, powder for reconstitution, vancomycin (ashydrochloride), for use as an infusion, net price 500-mg vial = £8.05; 1-g vial = £16.11Note Can be used to prepare solution for oral administrationTEICOPLANINCautions vancomycin sensitivity; blood counts andliver and kidney function tests required—monitorrenal and auditory function on prolonged administrationduring renal impairment or if other nephrotoxicor neurotoxic drugs given; monitor plasmateicoplaninconcentration if severe sepsis or burns,deep-seated staphylococcal infection (including boneand joint infection), endocarditis, renal impairment,and in intravenous drug abusers; interactions:Appendix 1 (teicoplanin)Renal impairment reduce dose on day 4: use halfnormal dose if estimated glomerular filtration rate 40–60 mL/minute/1.73 m 2 and use one-third normaldose if estimated glomerular filtration rate less than40 mL/minute/1.73 m 2 ; see also Cautions abovePregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding no information availableSide-effects rash, pruritus; less commonly nausea,vomiting, diarrhoea, bronchospasm, dizziness, headache,fever, leucopenia, thrombocytopenia, eosinophilia,tinnitus, mild hearing loss, vestibular disorders,thrombophlebitis; also reported renal failure, exfoliativedermatitis, Stevens-Johnson syndrome, toxicepidermal necrolysisPharmacokinetics plasma-teicoplanin concentrationis not measured routinely because there is no

BNFC 2011–2012 5.1.7 Some other antibacterials 287clear relationship between plasma-teicoplanin concentrationand toxicity. However, the plasmateicoplaninconcentration can be used to optimisetreatment in some patients (see Cautions). Pre-dose(‘trough’) concentration should be greater than10 mg/litre (greater than 15–20 mg/litre in endocarditis)but less than 60 mg/litreIndication and dosePotentially serious Gram-positive infectionsincluding endocarditis, and serious infectionsdue to Staphylococcus aureus. By intravenous injection or intravenous infusionover 30 minutesNeonate initially 16 mg/kg for one dose followed24 hours later by 8 mg/kg once daily (intravenousinfusion only)Child 1 month–18 years initially 10 mg/kg (max.400 mg) every 12 hours for 3 doses, then 6 mg/kg(max. 400 mg) once daily; in severe infections(including burns, septicaemia, septic arthritis andosteomyelitis) initially 10 mg/kg every 12 hoursfor 3 doses then 10 mg/kg once daily; after first 3doses, subsequent doses can be given by intramuscularinjection if necessary although intravenousroute preferable for childrenAdministration For intermittent intravenous infusion,dilute reconstituted solution further in sodium chloride0.9% or glucose 5%; give over 30 minutes. Intermittentintravenous infusion preferred in neonatesTargocid c (Sanofi-Aventis) AInjection, powder for reconstitution, teicoplanin, netprice 200-mg vial (with diluent) = £3.57; 400-mg vial(with diluent) = £6.10Electrolytes Na + < 0.5 mmol/200- and 400-mg vialLinezolidLinezolid, an oxazolidinone antibacterial, is activeagainst Gram-positive bacteria including meticillinresistantStaphylococcus aureus (MRSA), and glycopeptide-resistantenterococci. Resistance to linezolidcan develop with prolonged treatment or if the dose isless than that recommended. Linezolid should bereserved for infections caused by Gram-positive bacteriawhen the organisms are resistant to other antibacterialsor when patients cannot tolerate other antibacterials.Linezolid is not active against common Gramnegativeorganisms; it must be given in combinationwith other antibacterials for mixed infections that alsoinvolve Gram-negative organisms. There is limitedinformation on use in children and expert advice shouldbe sought. A higher incidence of blood disorders andoptic neuropathy have been reported in patients receivinglinezolid for more than the maximum recommendedduration of 28 days.LINEZOLIDCautions monitor full blood count (including plateletcount) weekly (see also Blood Disorders below);unless close observation and blood-pressure monitoringpossible, avoid in uncontrolled hypertension,phaeochromocytoma, carcinoid tumour, thyrotoxicosis,bipolar depression, schizophrenia, or acute confusionalstates; interactions: Appendix 1 (MAOIs)Blood disordersHaematopoietic disorders (including thrombocytopenia,anaemia, leucopenia, and pancytopenia) havebeen reported in patients receiving linezolid. It isrecommended that full blood counts are monitoredweekly. Close monitoring is recommended in patientswho:. receive treatment for more than 10–14 days;. have pre-existing myelosuppression;. are receiving drugs that may have adverse effects onhaemoglobin, blood counts, or platelet function;. have severe renal impairment.If significant myelosuppression occurs, treatmentshould be stopped unless it is considered essential,in which case intensive monitoring of blood countsand appropriate management should be implemented.CHM advice (optic neuropathy)Severe optic neuropathy may occur rarely, particularlyif linezolid is used for longer than 28 days. The CHMrecommends that:. patients should be warned to report symptoms of visualimpairment (including blurred vision, visual field defect,changes in visual acuity and colour vision) immediately;. patients experiencing new visual symptoms (regardless oftreatment duration) should be evaluated promptly, andreferred to an ophthalmologist if necessary;. visual function should be monitored regularly if treatmentis required for longer than 28 days.Monoamine oxidase inhibition Linezolid is a reversible,non-selective monoamine oxidase inhibitor (MAOI). Patientsshould avoid consuming large amounts of tyramine-richfoods (such as mature cheese, yeast extracts, undistilledalcoholic beverages, and fermented soya bean products). Inaddition, linezolid should not be given with another MAOI orwithin 2 weeks of stopping another MAOI. Unless closeobservation and blood-pressure monitoring is possible, avoidin those receiving SSRIs, 5HT 1 agonists (‘triptans’), tricyclicantidepressants, sympathomimetics, dopaminergics, buspirone,pethidine and possibly other opioid analgesics. For otherinteractions see Appendix 1 (MAOIs)Contra-indications see Monoamine Oxidase InhibitionaboveHepatic impairment no dose adjustment necessarybut in severe hepatic impairment use only if potentialbenefit outweighs riskRenal impairment no dose adjustment necessary butmetabolites may accumulate if estimated glomerularfiltration rate less than 30 mL/minute/1.73 m 2 ; seealso Blood Disorders abovePregnancy manufacturer advises use only if potentialbenefit outweighs risk—no information availableBreast-feeding manufacturer advises avoid—presentin milk in animal studiesSide-effects diarrhoea (antibiotic-associated colitisreported), nausea, vomiting, taste disturbances,headache; less commonly thirst, dry mouth, glossitis,stomatitis, tongue discoloration, abdominal pain,dyspepsia, gastritis, constipation, pancreatitis, hypertension,fever, fatigue, dizziness, insomnia,hypoaesthesia, paraesthesia, tinnitus, polyuria, leucopenia,thrombocytopenia, eosinophilia, electrolytedisturbances, blurred vision, rash, pruritus, diaphoresis,injection-site reactions; rarely tachycardia, transientischaemic attacks, renal failure; also reportedtooth discoloration, convulsions, lactic acidosis, pancytopenia,anaemia, Stevens-Johnson syndrome,toxic epidermal necrolysis; peripheral and opticneuropathy reported on prolonged therapy (see alsoCHM Advice above)5 Infections

288 5.1.7 Some other antibacterials BNFC 2011–20125 InfectionsLicensed use not licensed for use in childrenIndication and dosePneumonia, complicated skin and soft-tissueinfections caused by Gram-positive bacteria(initiated under expert supervision). By mouth or by intravenous infusion over 30–120 minutesNeonate under 7 days 10 mg/kg every 12 hours,increase to every 8 hours if poor responseNeonate over 7 days 10 mg/kg every 8 hoursChild 1 month–12 years 10 mg/kg (max. 600 mg)every 8 hoursChild 12–18 years 600 mg every 12 hoursZyvox c (Pharmacia) TATablets, f/c, linezolid 600 mg, net price 10-tab pack =£445.00. Label: 9, 10, patient information leafletSuspension, yellow, linezolid 100 mg/5 mL whenreconstituted with water, net price 150 mL (orangeflavoured)= £222.50. Label: 9, 10 patient informationleafletExcipients include aspartame 20 mg/5 mL (section 9.4.1)Intravenous infusion, linezolid 2 mg/mL, net price300-mL Excel c bag = £44.50Excipients include Na + 5 mmol/300-mL bag, glucose 13.71 g/300-mLbagPolymyxinsThe polymyxin antibiotic, colistimethate sodium (colistinsulphomethate sodium), is active against Gramnegativeorganisms including Pseudomonas aeruginosa,Acinetobacter baumanii, and Klebsiella pneumoniae.It is not absorbed by mouth and is given byinjection for a systemic effect. Intravenous administrationof colistimethate sodium should be reserved forGram-negative infections resistant to other antibacterials;its major adverse effects are dose-related neurotoxicityand nephrotoxicity.Colistimethate sodium is also given by inhalation of anebulised solution as an adjunct to standard antibacterialtherapy in patients with cystic fibrosis.Both colistimethate sodium and polymyxin B areincluded in some preparations for topical application.COLISTIMETHATE SODIUM(Colistin sulphomethate sodium)Cautions acute porphyria (section 9.8.2); risk of bronchospasmon inhalation—may be prevented or treatedwith a selective beta 2 agonist; interactions:Appendix 1 (polymyxins)Contra-indications myasthenia gravisRenal impairment monitor plasma-colistimethatesodium concentration; reduce dose during parenteraltreatment–consult product literaturePregnancy avoid—possible risk of fetal toxicity especiallyin second and third trimestersBreast-feeding present in milk but poorly absorbedfrom gut; manufacturers advise avoid (or use only ifpotential benefit outweighs risk)Side-effectsSpecific side-effects for parenteral treatment neurotoxicityreported especially with excessive doses (includingapnoea, perioral and peripheral paraesthesia, vertigo, headache,muscle weakness; rarely vasomotor instability, slurredspeech, confusion, psychosis, visual disturbances), nephrotoxicity;rashSpecific side-effects for inhaled treatment sore throat,sore mouth, cough, bronchospasmPharmacokinetics see notes above; plasma concentrationmonitoring required in renal impairment;recommended ‘peak’ plasma-colistimethate sodiumconcentration (approx. 30 minutes after intravenousinjection or infusion) 10–15 mg/litre (125–200 units/mL)Indication and dosePseudomonas aeruginosa infection in cysticfibrosis. By slow intravenous injection into a totallyimplantable venous access device, or by intravenousinfusion (but see notes above)Child 1 month–18 yearsBody-weight under 60 kg 25 000 units/kg every8 hoursBody-weight over 60 kg 2 million units every 8hours. By inhalation of nebulised solutionChild 1 month–2 years 0.5–1 million units twicedaily; increased to 1 million units 3 times daily forsubsequent respiratory isolates of Ps. aeruginosaChild 2–18 years 1–2 million units twice daily;increased to 2 million units 3 times daily for subsequentrespiratory isolates of Ps. aeruginosaAdministration For intravenous infusion, dilute to aconcentration of 40 000 units/mL with SodiumChloride 0.9%; give over 30 minutesFor slow intravenous injection into a totally implantablevenous access device, dilute to a concentrationof 90 000 units/mL with Sodium Chloride 0.9% forchild under 12 years (200 000 units/mL for child over12 years)For nebulisation administer required dose in 2–4 mLof sodium chloride 0.9% (or water for injections).Colistimethate sodium must not be mixed withtobramycin as they are chemically unstable together;it may be mixed with gentamicin if used immediatelyColistimethate sodium (Non-proprietary) AInjection, powder for reconstitution, colistimethatesodium, net price 1 million-unit vial = £1.68Colomycin c (Forest) AInjection, powder for reconstitution, colistimethatesodium, net price 1 million-unit vial = £1.68; 2 millionunitvial = £3.09Electrolytes (before reconstitution) Na + < 0.5 mmol/1 million-unit and 2million-unit vialNote Colomycin c Injection (dissolved in physiologicalsaline) may be used for nebulisationPromixin c (Profile) APowder for nebuliser solution, colistimethate sodium,net price 1 million-unit vial = £4.60.Injection, powder for reconstitution, colistimethatesodium, net price 1 million unit-vial = £2.30Electrolytes (before reconstitution) Na + < 0.5 mmol/1 million-unit vial

BNFC 2011–2012 5.1.8 Sulfonamides and trimethoprim 2895.1.8 Sulfonamides andtrimethoprimThe importance of the sulfonamides has decreased as aresult of increasing bacterial resistance and their replacementby antibacterials which are generally moreactive and less toxic.Sulfamethoxazole and trimethoprim are used in combination(as co-trimoxazole) because of their synergisticactivity. However, co-trimoxazole is associated with rarebut serious side-effects e.g. Stevens-Johnson syndromeand blood dyscrasias, notably bone marrow depressionand agranulocytosis (see CSM recommendationsbelow). Co-trimoxazole should be avoided in childrenless than 6 weeks of age (except for treatment andprophylaxis of pneumocystis pneumonia) because ofthe risk of kernicterus. There is a risk of haemolyticanaemia if used in children with glucose-6-phosphatedehydrogenase (G6PD) deficiency (section 9.1.5).Restrictions on the use of co-trimoxazoleCo-trimoxazole should be limited to the role of drugof choice in Pneumocystis jirovecii (Pneumocystiscarinii) pneumonia; it is also indicated for toxoplasmosisand nocardiasis. It should now only beconsidered for use in acute exacerbations of chronicbronchitis and infections of the urinary tract whenthere is good bacteriological evidence of sensitivityto co-trimoxazole and good reason to prefer thiscombination to a single antibacterial; similarly itshould only be used in acute otitis media in childrenwhen there is good reason to prefer it.Trimethoprim can be used alone for urinary- and respiratory-tractinfections and for shigellosis and invasivesalmonella infections. Trimethoprim has side-effectssimilar to co-trimoxazole but they are less severe andoccur less frequently.For topical preparations of sulfonamides used in thetreatment of burns see section 13.10.1.1.CO-TRIMOXAZOLEA mixture of trimethoprim and sulfamethoxazole(sulphamethoxazole) in the proportions of 1 part to 5partsCautions maintain adequate fluid intake; avoid inblood disorders (unless under specialist supervision);monitor blood counts on prolonged treatment; discontinueimmediately if blood disorders or rashdevelop; predisposition to folate deficiency; asthma;G6PD deficiency (section 9.1.5); avoid in infants under6 weeks (except for treatment or prophylaxis ofpneumocystis pneumonia); interactions: Appendix 1(trimethoprim, sulfamethoxazole)Contra-indications acute porphyria (section 9.8.2)Hepatic impairment manufacturer advises avoid insevere liver diseaseRenal impairment use half normal dose if estimatedglomerular filtration rate 15–30 mL/minute/1.73 m 2 ;avoid if estimated glomerular filtration rate less than15 mL/minute/1.73 m 2 and if plasma-sulfamethoxazoleconcentration cannot be monitoredPregnancy teratogenic risk in first trimester (trimethoprima folate antagonist). Neonatal haemolysisand methaemoglobinaemia in third trimester; fear ofincreased risk of kernicterus in neonates appears tobe unfoundedBreast-feeding small risk of kernicterus in jaundicedinfants and of haemolysis in G6PD-deficient infants(due to sulfamethoxazole)Side-effects nausea, diarrhoea; headache, hyperkalaemia;rash (very rarely including Stevens-Johnsonsyndrome, toxic epidermal necrolysis, photosensitivity)—discontinueimmediately; less commonlyvomiting; very rarely glossitis, stomatitis, anorexia,liver damage (including jaundice and hepatic necrosis),pancreatitis, antibiotic-associated colitis, myocarditis,cough and shortness of breath, pulmonaryinfiltrates, aseptic meningitis, depression, convulsions,peripheral neuropathy, ataxia, tinnitus, vertigo, hallucinations,hypoglycaemia, blood disorders (includingleucopenia, thrombocytopenia, megaloblastic anaemia,eosinophilia), hyponatraemia, renal disordersincluding interstitial nephritis, arthralgia, myalgia,vasculitis, systemic lupus erythematosus, and uveitis;rhabdomyolysis reported in HIV-infected patientsPharmacokinetics plasma concentration monitoringmay be required with high doses or during moderateto severe renal impairment; seek expert adviceLicensed use not licensed for use in children under 6weeksIndication and doseTreatment of susceptible infections (but seenotes above) dose expressed as co-trimoxazole. By mouthChild 6 weeks–12 years 24 mg/kg twice dailyorChild 6 weeks–6 months 120 mg twice dailyChild 6 months–6 years 240 mg twice dailyChild 6–12 years 480 mg twice dailyChild 12–18 years 960 mg twice daily. By intravenous infusionChild 6 weeks–18 years 18 mg/kg every 12hours; increased in severe infection to 27 mg/kg(max. 1.44 g) every 12 hoursTreatment of Pneumocystis jirovecii (P. carinii)infections (undertaken where facilities forappropriate monitoring available—consultmicrobiologist and product literature). By mouth or by intravenous infusionChild 1 month–18 years 60 mg/kg every 12hours for 14–21 days; total daily dose may alternativelybe given in 3–4 divided dosesNote oral route preferredProphylaxis of Pneumocystis jirovecii (P. carinii)infections. By mouthChild 1 month–18 years 450 mg/m 2 (max960 mg) twice daily for three days of the week(either consecutively or on alternate days)Note dose regimens may vary, consult local guidelinesNote 480 mg of co-trimoxazole consists of sulfamethoxazole400 mg and trimethoprim 80 mgAdministration for intermittent intravenous infusionmay be further diluted in glucose 5% and 10% orsodium chloride 0.9%. Dilute contents of5 Infections

290 5.1.9 Antituberculosis drugs BNFC 2011–20125 Infections1 ampoule (5 mL) to 125 mL, 2 ampoules (10 mL) to250 mL or 3 ampoules (15 mL) to 500 mL; suggestedduration of infusion 60–90 minutes (but may beadjusted according to fluid requirements); if fluidrestriction necessary, 1 ampoule (5 mL) may bediluted with 75 mL glucose 5% and the required doseinfused over max. 60 minutes; check container forhaze or precipitant during administration. In severefluid restriction may be given undiluted via a centralvenous lineCo-trimoxazole (Non-proprietary) ATablets, co-trimoxazole 480 mg, net price 28-tab pack= £18.99; 960 mg, 100 = £23.46. Label: 9Brands include Fectrim c , Fectrim c FortePaediatric oral suspension, co-trimoxazole 240 mg/5 mL, net price 100 mL = £1.12. Label: 9Oral suspension, co-trimoxazole 480 mg/5 mL. Netprice 100 mL = £4.41. Label: 9Septrin c (Aspen) ATablets, co-trimoxazole 480 mg, net price 100-tabpack = £15.52. Label: 9Forte tablets, scored, co-trimoxazole 960 mg, netprice 100-tab pack = £23.46. Label: 9Adult suspension, co-trimoxazole 480 mg/5 mL, netprice 100 mL (vanilla-flavoured) = £4.41. Label: 9Paediatric suspension, sugar-free, co-trimoxazole240 mg/5 mL. Net price 100 mL (banana- and vanillaflavoured)= £2.45. Label: 9Intravenous infusion, co-trimoxazole 96 mg/mL. Tobe diluted before use. Net price 5-mL amp = £1.78Electrolytes Na + 1.7 mmol/5 mLExcipients include alcohol 13.2%, propylene glycol, sulphitesTRIMETHOPRIMCautions predisposition to folate deficiency; manufacturerrecommends blood counts on long-termtherapy (but evidence of practical value unsatisfactory);neonates (specialist supervision required); acuteporphyria (section 9.8.2); interactions: Appendix 1(trimethoprim)Blood disorders On long-term treatment, patients and theircarers should be told how to recognise signs of blooddisorders and advised to seek immediate medical attention ifsymptoms such as fever, sore throat, rash, mouth ulcers,purpura, bruising or bleeding developContra-indications blood dyscrasiasRenal impairment use half normal dose after 3 days ifestimated glomerular filtration rate 15–30 mL/minute/1.73m 2 ; use half normal dose if estimated glomerularfiltration rate less than 15 mL/minute/1.73 m 2(monitor plasma-trimethoprim concentration if estimatedglomerular filtration rate less than 10 mL/minute/1.73 m 2 )Pregnancy teratogenic risk in first trimester (folateantagonist); manufacturers advise avoidBreast-feeding present in milk—short-term use notknown to be harmfulSide-effects gastro-intestinal disturbances includingnausea and vomiting, pruritus, rashes, hyperkalaemia,depression of haematopoiesis; rarely erythema multiforme,toxic epidermal necrolysis, photosensitivityand other allergic reactions including angioedemaand anaphylaxis; aseptic meningitis reportedLicensed use not licensed for use in children under 6weeksIndication and doseUrinary-tract infections; respiratory-tractinfections. By mouthNeonate initially 3 mg/kg as a single dose then 1–2 mg/kg twice dailyChild 1 month–12 years 4 mg/kg (max. 200 mg)twice dailyorChild 6 weeks–6 months 25 mg twice dailyChild 6 months–6 years 50 mg twice dailyChild 6–12 years 100 mg twice dailyChild 12–18 years 200 mg twice dailyProphylaxis of urinary-tract infectionTable 2, section 5.1Pneumocystis pneumonia see p. 342Trimethoprim (Non-proprietary) ATablets, trimethoprim 100 mg, net price 28 = 94p;200 mg, 14-tab pack = 91p. Label: 9Brands include Trimopan cSuspension, trimethoprim 50 mg/5 mL, net price100 mL = £2.37. Label: 95.1.9 Antituberculosis drugsTuberculosis is treated in two phases—an initial phaseusing 4 drugs and a continuation phase using two drugsin fully sensitive cases. Treatment requires specialisedknowledge, particularly where the disease involvesresistant organisms or non-respiratory organs.The regimens given below are recommended for thetreatment of tuberculosis in the UK; variations occur inother countries. Either the unsupervised regimen or thesupervised regimen described below should be used; thetwo regimens should not be used concurrently. Compliancewith therapy is a major determinant of itssuccess. Treatment needs to be carefully monitored infamilies in whom concordance may be problematic.Initial phase The concurrent use of 4 drugs during theinitial phase is designed to reduce the bacterial populationas rapidly as possible and to prevent the emergenceof drug-resistant bacteria. The drugs are best given ascombination preparations, provided the respective doseof each drug is appropriate, unless the child is unable toswallow the tablets or one of the components cannot begiven because of resistance or intolerance. The treatmentof choice for the initial phase is the daily use ofisoniazid, rifampicin, pyrazinamide and ethambutol.However, care is needed in young children receivingethambutol because of the difficulty in testing eyesightand in obtaining reports of visual symptoms (see below).Treatment should be started without waiting for cultureresults if clinical features or histology results are consistentwith tuberculosis; treatment should be continuedeven if initial culture results are negative. The initialphase drugs should be continued for 2 months. Where apositive culture for M. tuberculosis has been obtained,but susceptibility results are not available after 2months, treatment with rifampicin, isoniazid, pyrazin-

BNFC 2011–2012 5.1.9 Antituberculosis drugs 291amide and ethambutol should be continued until fullsusceptibility is confirmed, even if this is for longer than2 months.Streptomycin is rarely used in the UK although it may beused in the initial phase of treatment if resistance toisoniazid has been established before therapy is commencedand ethambutol is contra-indicated.Continuation phase After the initial phase, treatmentis continued for a further 4 months with isoniazid andrifampicin (preferably given as a combination preparation).Longer treatment is necessary for meningitis,direct spinal cord involvement, and for resistant organismswhich may also require modification of the regimen.Unsupervised treatment The following regimenshould be used for those who are likely to take antituberculousdrugs reliably without supervision. Childrenand families who are unlikely to comply with dailyadministration of antituberculous drugs should be treatedwith the regimen described under Supervised Treatment.Recommended dosage for standard unsupervised 6-month treatmentIsoniazid (for 2-month initial and 4-month continuationphases)Child 1 month–18 years 10 mg/kg (max. 300 mg) once dailyRifampicin (for 2-month initial and 4–month continuationphase)Child 1 month–18 years 10 mg/kg once daily (max. 450 mgdaily if body-weight under 50 kg; max. 600 mg daily if bodyweight50 kg and over)Pyrazinamide (for 2-month initial phase only)Child 1 month–18 years 35 mg/kg once daily (max. 1.5 gdaily if body-weight under 50 kg; max. 2 g daily if bodyweight50 kg and over)Ethambutol (for 2-month initial phase only)Child 1 month–18 years 15 mg/kg once dailyNote In general, doses should be rounded up to facilitateadministration of suitable volumes of liquid or an appropriatestrength of tablet. The exception is ethambutol due to the riskof toxicity. Doses may also need to be recalculated to allow forweight gain in younger children.The fixed-dose combination preparations (Rifater c , Rifinah c )are unlicensed for use in children. Consideration may be givento use of these preparations in older children, provided therespective dose of each drug is appropriate for the weight of thechild.Pregnancy The standard regimen (above) may beused during pregnancy . Streptomycin should not begiven in pregnancy.Breast-feeding The standard regimen (above) may beused during breast-feeding.Neonates Congenital tuberculosis is acquired frommaternal extrapulmonary sites at birth, particularly thegenital tract; if infection is suspected, the baby willrequire treatment with isoniazid 10 mg/kg once daily,rifampicin 10 mg/kg once daily, pyrazinamide 35 mg/kgonce daily, and ethambutol 15 mg/kg once daily. Isoniazid,rifampicin, pyrazinamide, and ethambutol are usedfor 2 months during the initial phase of treatment. Afterthe initial phase, treatment is continued for a further 4months with isoniazid and rifampicin.Supervised treatment Drug administration needs tobe fully supervised (directly observed therapy, DOT) inchildren or families who cannot comply reliably with thetreatment regimen. These patients are given isoniazid,rifampicin, pyrazinamide and ethambutol (or streptomycin)3 times a week under supervision for the first 2months followed by isoniazid and rifampicin 3 times aweek for a further 4 months.Recommended dosage for intermittent supervised 6-month treatmentIsoniazid (for 2-month initial and 4-month continuationphases)Child 1 month–18 years, 15 mg/kg (max. 900 mg) 3 times aweekRifampicin (for 2-month initial and 4-month continuationphases)Child 1 month–18 years, 15 mg/kg (max. 900 mg) 3 times aweekPyrazinamide (for 2-month initial phase only)Child 1 month–18 years, 50 mg/kg 3 times a week (max. 2 g3 times a week if body-weight under 50 kg; max. 2.5 g 3 timesa week if body-weight 50 kg and over)Ethambutol (for 2-month initial phase only)Child 1 month–18 years, 30 mg/kg 3 times a weekNote In general, doses should be rounded up to facilitateadministration of suitable volumes of liquid or an appropriatestrength of tablet. The exception is ethambutol due to the riskof toxicity. Doses may also need to be recalculated to allow forweight gain in younger children.The fixed-dose combination preparations (Rifater c , Rifinah c )are unlicensed for use in children. Consideration may be givento use of these preparations in older children, provided therespective dose of each drug is appropriate for the weight of thechild.Immunocompromised patients Multi-resistantMycobacterium tuberculosis may be present in immunocompromisedchildren. The organism should alwaysbe cultured to confirm its type and drug sensitivity.Confirmed M. tuberculosis infection sensitive to firstlinedrugs should be treated with a standard 6-monthregimen; after completing treatment, children should beclosely monitored. The regimen may need to be modifiedif infection is caused by resistant organisms, andspecialist advice is needed.Specialist advice should be sought about tuberculosistreatment or chemoprophylaxis in a HIV-positive individual;care is required in choosing the regimen and inavoiding potentially serious interactions. Starting antiretroviraltreatment in the first 2 months of antituberculosistreatment increases the risk of immunereconstitution syndrome.Infection may also be caused by other mycobacteria e.g.M. avium complex in which case specialist advice onmanagement is needed.Corticosteroids A corticosteroid should be given (inaddition to antituberculosis therapy) for meningeal orpericardial tuberculosis.Prevention of tuberculosis Chemoprophylaxis maybe required in children who are close contacts of a caseof smear-positive pulmonary tuberculosis and who areseverely immunosuppressed (including congenitalimmunodeficiencies, cytotoxic or immunosuppressivetherapy) and in those who have evidence of latenttuberculosis and require treatment with immunosuppressants;expert advice should be sought.Chemoprophylaxis involves use of either isoniazid alonefor 6 months or of isoniazid and rifampicin for 3 months(see Table 2, section 5.1).5 Infections

292 5.1.9 Antituberculosis drugs BNFC 2011–20125 InfectionsFor prevention of tuberculosis in susceptible close contactsor those who have become tuberculin-positive, seeTable 2, section 5.1. For advice on immunisation againsttuberculosis and tuberculin testing, see section 14.4.Monitoring Since isoniazid, rifampicin and pyrazinamideare associated with liver toxicity, hepatic functionshould be checked before treatment with these drugs.Those with pre-existing liver disease should have frequentchecks particularly in the first 2 months. If there isno evidence of liver disease (and pre-treatment liverfunction is normal), further checks are only necessary ifthe patient develops fever, malaise, vomiting, jaundiceor unexplained deterioration during treatment. In viewof the need to comply fully with antituberculous treatmenton the one hand and to guard against serious liverdamage on the other, children and their carers should beinformed carefully how to recognise signs of liver disordersand advised to discontinue treatment and seekimmediate medical attention should symptoms of liverdisease occur.Renal function should be checked before treatment withantituberculous drugs and appropriate dosage adjustmentsmade. Streptomycin or ethambutol should preferablybe avoided in patients with renal impairment,but if used, the dose should be reduced and the plasmadrugconcentration monitored.Visual acuity should be tested before ethambutol isused (see below).Major causes of treatment failure are incorrect prescribingby the physician and inadequate complianceby the child or their carer. Monthly tabletcounts and urine examination (rifampicin impartsan orange-red coloration) may be useful indicatorsof compliance with treatment. Avoid both excessiveand inadequate dosage. Treatment should be supervisedby a specialist paediatrician.Isoniazid is cheap and highly effective. Like rifampicinit should always be included in any antituberculousregimen unless there is a specific contra-indication. Itsonly common side-effect is peripheral neuropathy whichis more likely to occur where there are pre-existing riskfactors such as diabetes, chronic renal failure, malnutritionand HIV infection. In these circumstances, and inbreast-fed infants treated with isoniazid, pyridoxine(section 9.6.2) should be given prophylactically fromthe start of treatment. Other side-effects such as hepatitis(important: see Monitoring above) and psychosis arerare.Rifampicin, a rifamycin, is a key component of anyantituberculous regimen. Like isoniazid it should alwaysbe included unless there is a specific contra-indication.During the first two months (‘initial phase’) of rifampicinadministration transient disturbance of liver functionwith elevated serum transaminases is common butgenerally does not require interruption of treatment.Occasionally more serious liver toxicity requires achange of treatment particularly in those with pre-existingliver disease (important: see Monitoring above).On intermittent treatment six toxicity syndromes havebeen recognised—influenza-like, abdominal, and respiratorysymptoms, shock, renal failure, and thrombocytopenicpurpura—and can occur in 20 to 30% ofpatients.Rifampicin induces hepatic enzymes which acceleratethe metabolism of several drugs including oestrogens,corticosteroids, phenytoin, sulfonylureas, and anticoagulants;interactions: Appendix 1 (rifamycins). Important:the effectiveness of hormonal contraceptives isreduced and alternative family planning advice shouldbe offered (section 7.3.1).Rifabutin is indicated in adults for prophylaxis againstM. avium complex infections in patients with a low CD4count; it is also licensed in adults for the treatment ofnon-tuberculous mycobacterial disease and pulmonarytuberculosis. There is limited experience in children. Aswith rifampicin it induces hepatic enzymes and theeffectiveness of hormonal contraceptives is reducedrequiring alternative family planning methods.Pyrazinamide is a bactericidal drug only active againstintracellular dividing forms of Mycobacterium tuberculosis;it exerts its main effect only in the first two orthree months. It is particularly useful in tuberculousmeningitis because of good meningeal penetration. Itis not active against M. bovis. Serious liver toxicity mayoccasionally occur (important: see Monitoring above).Ethambutol is included in a treatment regimen if isoniazidresistance is suspected; it can be omitted if therisk of resistance is low.Side-effects of ethambutol are largely confined to visualdisturbances in the form of loss of acuity, colour blindness,and restriction of visual fields. These toxic effectsare more common where excessive dosage is used or ifthe child’s renal function is impaired. The earliest featuresof ocular toxicity are subjective and children andtheir carers should be advised to discontinue therapyimmediately if deterioration in vision develops andpromptly seek further advice. Early discontinuation ofthe drug is almost always followed by recovery of eyesight.Those who cannot understand warnings aboutvisual side-effects should, if possible, be given an alternativedrug. In particular, ethambutol should be usedwith caution in children until they are at least 5 years oldand capable of reporting symptomatic visual changesaccurately.Where possible visual acuity should be tested by Snellenchart before treatment with ethambutol.Streptomycin is now rarely used in the UK except forresistant organisms. Plasma-drug concentration shouldbe measured in patients with impaired renal function inwhom streptomycin must be used with great care. Sideeffectsincrease after a cumulative dose of 100 g, whichshould only be exceeded in exceptional circumstances.Drug-resistant tuberculosis should be treated by a specialistpaediatrician with experience in such cases, andwhere appropriate facilities for infection-control exist.Second-line drugs available for infections caused byresistant organisms, or when first-line drugs cause unacceptableside-effects, include amikacin, capreomycin,cycloserine, newer macrolides (e.g. azithromycin andclarithromycin), quinolones (e.g. moxifloxacin) and protionamide(prothionamide; no longer on UK market).Availability of suitable formulations may limit choice inchildren.CYCLOSERINECautions monitor haematological, renal, and hepaticfunction; interactions: Appendix 1 (cycloserine)

BNFC 2011–2012 5.1.9 Antituberculosis drugs 293Contra-indications epilepsy, depression, severeanxiety, psychotic states, alcohol dependence, acuteporphyria (section 9.8.2)Renal impairment reduce dose and monitor bloodcycloserineconcentration; avoid in severe impairmentPregnancy manufacturer advises use only if potentialbenefit outweighs risk—crosses the placentaBreast-feeding present in milk—amount too small tobe harmfulSide-effects mainly neurological, including headache,dizziness, vertigo, drowsiness, tremor, convulsions,confusion, psychosis, depression (discontinue orreduce dose if symptoms of CNS toxicity); rashes,allergic dermatitis (discontinue or reduce dose);megaloblastic anaemia; changes in liver functiontests; heart failure at high doses reportedPharmacokinetics blood concentration should notexceed a peak concentration of 30 mg/litre (measured3–4 hours after the dose); penetrates CNSLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseTuberculosis resistant to first-line drugs, usedin combination with other drugs. By mouthChild 2–12 years initially 5 mg/kg (max. 250 mg)twice daily, adjusted according to blood concentrationand response up to 10 mg/kg (max.500 mg) twice dailyChild 12–18 years initially 250 mg twice daily for2 weeks adjusted according to blood concentrationand response to max. 500 mg twice dailyCycloserine (King) ACapsules, red/grey cycloserine 250 mg, net price100-cap pack = £333.80. Label: 2, 8ETHAMBUTOL HYDROCHLORIDECautions test visual acuity before treatment and warnpatients to report visual changes—see notes above;young children (see notes above)—routine ophthalmologicalmonitoring recommendedContra-indications optic neuritis, poor visionRenal impairment reduce dose; if creatinine clearanceless than 30 mL/minute/1.73 m 2 , monitorplasma-ethambutol concentration; risk of optic nervedamagePregnancy not known to be harmful; see also p. 291Breast-feeding amount too small to be harmful; seealso p. 291Side-effects optic neuritis, red/green colour blindness,peripheral neuritis, rarely rash, pruritus, urticaria,thrombocytopeniaPharmacokinetics ‘peak’ concentration (2–2.5 hoursafter dose) should be 2–6 mg/litre (7–22 micromol/litre); ‘trough’ (pre-dose) concentration should beless than 1 mg/litre (4 micromol/litre); for advice onlaboratory assay of ethambutol contact the PoisonsUnit at New Cross Hospital (Tel (020) 7771 5360)Indication and doseTuberculosis, used in combination with otherdrugs see notes aboveEthambutol (Non-proprietary) ATablets, ethambutol hydrochloride 100 mg, net price56-tab pack = £12.00; 400 mg, 56-tab pack = £44.18.Label: 8Extemporaneous formulations available seeExtemporaneous Preparations, p. 6ISONIAZIDCautions see Monitoring in notes above; also slowacetylator status (increased risk of side-effects); epilepsy;history of psychosis; alcohol dependence,malnutrition, diabetes mellitus, HIV infection (risk ofperipheral neuritis); acute porphyria (section 9.8.2);interactions: Appendix 1 (isoniazid)Hepatic disorders Children and their carers should be toldhow to recognise signs of liver disorder, and advised todiscontinue treatment and seek immediate medical attentionif symptoms such as persistent nausea, vomiting, malaise orjaundice developContra-indications drug-induced liver diseaseHepatic impairment use with caution; monitor liverfunction regularly and particularly frequently in thefirst 2 months; see also Hepatic Disorders aboveRenal impairment reduce dose if estimated glomerularfiltration rate less than 10 mL/minute/1.73 m 2 ;risk of peripheral neuropathyPregnancy not known to be harmful; see notes aboveBreast-feeding monitor infant for possible toxicity;theoretical risk of convulsions and neuropathy; prophylacticpyridoxine advisable in mother and infant;see also p. 291Side-effects nausea, vomiting, constipation, drymouth; peripheral neuritis with high doses (pyridoxineprophylaxis, see notes above), optic neuritis, convulsions,psychotic episodes, vertigo; hypersensitivityreactions including fever, Stevens-Johnson syndrome,purpura; blood disorders including agranulocytosis,haemolytic anaemia, aplastic anaemia; hepatitis;pancreatitis; interstitial pneumonitis; systemic lupuserythematosus-like syndrome, pellagra, hyperreflexia,difficulty with micturition, hyperglycaemia, andgynaecomastia reported; hearing loss and tinnitus (inchildren with end-stage renal impairment); when usedwith tyramine or histamine rich foods, tachycardia,palpitation, hypotension, flushing, headache, dizziness,and sweating also reportedIndication and doseTuberculosis, used in combination with otherdrugs see notes aboveIsoniazid (Non-proprietary) ATablets, isoniazid 50 mg, net price 56-tab pack =£11.10; 100 mg, 28-tab pack = £11.30. Label: 8, 22Injection, isoniazid 25 mg/mL, net price 2-mL amp =£11.04Extemporaneous formulations available seeExtemporaneous Preparations, p. 6PYRAZINAMIDECautions see Monitoring in notes above; also diabetes;interactions: Appendix 1 (pyrazinamide)Hepatic disorders Children and their carers should be toldhow to recognise signs of liver disorder, and advised todiscontinue treatment and seek immediate medical attentionif symptoms such as persistent nausea, vomiting, malaise orjaundice develop5 Infections

294 5.1.9 Antituberculosis drugs BNFC 2011–20125 InfectionsContra-indications acute porphyria (section 9.8.2)Hepatic impairment monitor hepatic function—idiosyncratichepatotoxicity more common; avoid insevere hepatic impairment; see also Hepatic DisordersabovePregnancy manufacturer advises use only if potentialbenefit outweighs risk; see also notes aboveBreast-feeding amount too small to be harmful; seealso p. 291Side-effects hepatotoxicity including fever, anorexia,hepatomegaly, splenomegaly, jaundice, liver failure;nausea, vomiting, dysuria, arthralgia, sideroblasticanaemia, thrombocytopenia, rash and occasionallyphotosensitivityLicensed use not licensedIndication and doseTuberculosis in combination with other drugssee notes abovePyrazinamide (Non-proprietary) ATablets, scored, pyrazinamide 500 mg. Label: 8Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Extemporaneous formulations available seeExtemporaneous Preparations, p. 6RIFABUTINCautions see under Rifampicin; acute porphyria (section9.8.2)Hepatic impairment reduce dose in severe impairmentRenal impairment use half normal dose if estimatedglomerular filtration rate less than 30 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid—no informationavailableBreast-feeding manufacturer advises avoid—noinformation availableSide-effects nausea, vomiting; leucopenia, thrombocytopenia,anaemia, rarely haemolysis; raised liverenzymes, jaundice, rarely hepatitis; uveitis followinghigh doses or administration with drugs which raiseplasma concentration—see also interactions:Appendix 1 (rifamycins); arthralgia, myalgia, influenza-likesyndrome, dyspnoea; also hypersensitivityreactions including fever, rash, eosinophilia, bronchospasm,shock; skin, urine, saliva and other bodysecretions coloured orange-red; asymptomaticcorneal opacities reported with long-term useLicensed use not licensed for use in childrenIndication and doseProphylaxis of Mycobacterium avium complexinfections in immunosuppressed patients withlow CD4 count (see product literature) Also seenotes above. By mouthChild 1–12 years 5 mg/kg (max. 300 mg) oncedailyChild 12–18 years 300 mg once dailyTreatment of non-tuberculous mycobacterialdisease, in combination with other drugs. By mouthChild 1month–12 years 5 mg/kg once daily forup to 6 months after cultures negativeChild 12–18 years 450–600 mg once daily for upto 6 months after cultures negativeTreatment of pulmonary tuberculosis, in combinationwith other drugs. By mouthChild 12–18years 150–450 mg once daily for atleast 6 monthsMycobutin c (Pharmacia) ACapsules, red-brown, rifabutin 150 mg. Net price 30-cap pack = £90.38. Label: 8, 14, counselling, lenses,see under RifampicinExtemporaneous formulations available seeExtemporaneous Preparations, p. 6RIFAMPICINCautions see Monitoring in notes above; also liverfunction tests and blood counts in hepatic disorders,and on prolonged therapy, see also below; acuteporphyria (section 9.8.2); important: effectiveness ofhormonal contraceptives is reduced and alternativefamily planning advice should be offered (see alsosection 7.3.1); discolours soft contact lenses; see alsonotes above; interactions: Appendix 1 (rifamycins)Note If treatment interrupted re-introduce with low dosageand increase gradually; discontinue permanently if seriousside-effects developHepatic disorders Children and their carers should be toldhow to recognise signs of liver disorder, and advised todiscontinue treatment and seek immediate medical attentionif symptoms such as persistent nausea, vomiting, malaise orjaundice developContra-indications jaundiceHepatic impairment impaired elimination; monitorliver function; avoid or do not exceed 8 mg/kg daily;see also Cautions aboveRenal impairment use with caution if dose above10 mg/kg dailyPregnancy manufacturers advise very high doses teratogenicin animal studies in first trimester; risk ofneonatal bleeding may be increased in third trimester;see also notes aboveBreast-feeding amount too small to be harmful; seealso p. 291Side-effects gastro-intestinal symptoms includinganorexia, nausea, vomiting, diarrhoea (antibioticassociatedcolitis reported); headache, drowsiness;those occurring mainly on intermittent therapyinclude influenza-like symptoms (with chills, fever,dizziness, bone pain), respiratory symptoms (includingshortness of breath), collapse and shock, haemolyticanaemia, disseminated intravascular coagulationand acute renal failure, thrombocytopenic purpura;alterations of liver function, jaundice; flushing, urticaria,and rashes; other side-effects reported includeoedema, psychoses, adrenal insufficiency, muscularweakness and myopathy, exfoliative dermatitis, toxicepidermal necrolysis, Stevens-Johnson syndrome,pemphigoid reactions, leucopenia, eosinophilia,menstrual disturbances; urine, saliva, and other body

BNFC 2011–2012 5.1.11 Metronidazole 295secretions coloured orange-red; thrombophlebitisreported if infusion used for prolonged periodLicensed use not licensed for use in children forpruritus due to cholestasisIndication and doseTuberculosis, in combination with other drugssee notes aboveProphylaxis of meningococcal meningitis andHaemophilus influenzae (type b) infection Table2, section 5.1Brucellosis, legionnaires disease, serious staphylococcalinfections, in combination withother antibacterials. By mouth or by intravenous infusionNeonates 5–10 mg/kg twice dailyChild 1 month–1 year 5–10 mg/kg twice dailyChild 1–18 years 10 mg/kg (max. 600 mg) twicedailyPruritus due to cholestasis. By mouthChild 1 month–18 years 5–10 mg/kg (max.600 mg) once dailyAdministration Displacement value may be significant,consult local reconstitution guidelines; reconstitutewith solvent provided. May be further dilutedwith glucose 5% or sodium chloride 0.9% to a finalconcentration of 1.2 mg/mL. Infuse over 2–3 hours.Rifampicin (Non-proprietary) ACapsules, rifampicin 150 mg, net price 100 = £20.82;300 mg, 100 = £46.21. Label: 8, 14, 22, counselling,see contact lenses aboveRifadin c (Sanofi-Aventis) ACapsules, rifampicin 150 mg (blue/red), net price100-cap pack = £18.32; 300 mg (red), 100-cap pack =£36.63. Label: 8, 14, 22, counselling, see contactlenses aboveSyrup, red, rifampicin 100 mg/5 mL (raspberry-flavoured).Net price 120 mL = £3.56. Label: 8, 14, 22,counselling, see contact lenses aboveExcipients include sucroseIntravenous infusion, powder for reconstitution, rifampicin.Net price 600-mg vial (with solvent) = £7.67Electrolytes Na + < 0.5 mmol/vialRimactane c (Sandoz) ACapsules, rifampicin 150 mg (red), net price 60-cappack = £11.35; 300 mg (red/brown), 60-cap pack =£22.69. Label: 8, 14, 22, counselling, see contactlenses aboveCombined preparationsSee notes aboveRifater c (Sanofi-Aventis) ATablets, pink, s/c, rifampicin 120 mg, isoniazid 50 mg,pyrazinamide 300 mg. Net price 100-tab pack =£21.95. Label: 8, 14, 22, counselling, see contactlenses aboveRifinah c 150/100 (Sanofi-Aventis) ATablets, pink, s/c, rifampicin 150 mg, isoniazid100 mg, net price 84-tab pack = £15.91. Label: 8, 14,22, counselling, see contact lenses aboveNote Some stock packaged as Rifinah 150 or Rifinah 100/150Rifinah c 300/150 (Sanofi-Aventis) ATablets, orange, s/c, rifampicin 300 mg, isoniazid150 mg, net price 56-tab pack = £21.02. Label: 8, 14,22, counselling, see contact lenses aboveNote Some stock packaged as Rifinah 300 or Rifinah 150/300STREPTOMYCINCautions see under Aminoglycosides, section 5.1.4;measure plasma-concentration in renal impairment;interactions: Appendix 1 (aminoglycosides)Contra-indications see under Aminoglycosides, section5.1.4Renal impairment see under Aminoglycosides, section5.1.4Pregnancy see under Aminoglycosides, section 5.1.4Side-effects see under Aminoglycosides, section5.1.4; also hypersensitivity reactions, paraesthesia ofmouthPharmacokinetics one-hour (‘peak’) concentrationshould be 15–40 mg/litre; pre-dose (‘trough’) concentrationshould be less than 5 mg/litre (less than1 mg/litre in renal impairment)Licensed use not licensed for use in childrenIndication and doseTuberculosis, resistant to other treatment, incombination with other drugs. By deep intramuscular injectionChild 1 month–18 years 15 mg/kg (max. 1 g)once dailyAdjunct to doxycycline in brucellosis, expertadvice essential. By deep intramuscular injectionChild 1 month–18 years 5–10 mg/kg every 6hours; total daily dose may alternatively be givenin 2–3 divided dosesStreptomycin Sulphate (Non-proprietary) AInjection, powder for reconstitution, streptomycin (assulphate), net price 1-g vial = £8.25Available as an unlicensed preparation from UCB Pharma5.1.10 Antileprotic drugsClassification not used in BNF for Children.5.1.11 MetronidazoleMetronidazole is an antimicrobial drug with high activityagainst anaerobic bacteria and protozoa. It is alsoused for surgical and gynaecological sepsis in which itsactivity against colonic anaerobes, especially Bacteroidesfragilis, is important. Metronidazole by mouthis effective for the treatment of Clostridium difficileinfection (see also section 1.5); it can be given by intravenousinfusion if oral treatment is inappropriate.5 Infections

296 5.1.11 Metronidazole BNFC 2011–20125 InfectionsMetronidazole is well absorbed orally and the intravenousroute is normally reserved for severe infections.Metronidazole by the rectal route is an effective alternativeto the intravenous route when oral administrationis not possible. Intravenous metronidazole is used forthe treatment of established cases of tetanus; diazepam(section 10.2.2) and tetanus immunoglobulin (section14.5.2) are also used.Topical metronidazole (section 13.10.1.2) reduces theodour produced by anaerobic bacteria in fungatingtumours; it is also used in the management of rosacea(section 13.6).Oral infections Metronidazole is an alternative to apenicillin for the treatment of many oral infectionswhere the patient is allergic to penicillin or the infectionis due to beta-lactamase-producing anaerobes (Table 1,section 5.1). It is the drug of first choice for the treatmentof acute necrotising ulcerative gingivitis (Vincent’sinfection) and pericoronitis; suitable alternatives areamoxicillin (section 5.1.1.3) and erythromycin (section5.1.5). For these purposes treatment with metronidazolefor 3 days is sufficient, but the duration of treatmentmay need to be longer in pericoronitis. Tinidazole islicensed for the treatment of acute ulcerative gingivitis.METRONIDAZOLECautions disulfiram-like reaction with alcohol, clinicaland laboratory monitoring advised if treatmentexceeds 10 days; interactions: Appendix 1 (metronidazole)Hepatic impairment in severe liver disease reducetotal daily dose to one-third, and give once daily; usewith caution in hepatic encephalopathyPregnancy manufacturer advises avoidance of highdoseregimens; use only if potential benefit outweighsriskBreast-feeding significant amount in milk; manufactureradvises avoid large single doses though otherwisecompatible; may give milk a bitter tasteSide-effects gastro-intestinal disturbances (includingnausea and vomiting), taste disturbances, furred tongue,oral mucositis, anorexia; very rarely hepatitis,jaundice, pancreatitis, drowsiness, dizziness, headache,ataxia, psychotic disorders, darkening of urine,thrombocytopenia, pancytopenia, myalgia, arthralgia,visual disturbances, rash, pruritus, and erythemamultiforme; on prolonged or intensive therapy peripheralneuropathy, transient epileptiform seizures,and leucopeniaIndication and doseProtozoal infections section 5.4.2Anaerobic infections (usually treated for 7 daysand for 10–14 days in Clostridium difficileinfection). By mouthChild 1–2 months 7.5 mg/kg every 12 hoursChild 2 months–12 years 7.5 mg/kg (max.400 mg) every 8 hoursChild 12–18 years 400 mg every 8 hours. By rectumChild 1 month–1 year 125 mg 3 times daily for 3days, then twice daily thereafterChild 1–5 years 250 mg 3 times daily for 3 days,then twice daily thereafterChild 5–10 years 500 mg 3 times daily, for 3 days,then twice daily thereafterChild 10–18 years 1 g 3 times daily for 3 days,then twice daily thereafter. By intravenous infusion over 20–30 minutesNeonate 7.5 mg/kg every 12 hoursChild 1–2 months 7.5 mg/kg every 12 hoursChild 2 months–18 years 7.5 mg/kg (max.500 mg) every 8 hoursPelvic inflammatory disease (see also Table 1,section 5.1). By mouthChild 12–18 years 400 mg twice daily for 14 daysAcute ulcerative gingivitis and other acutedental infections. By mouthChild 1–3 years 50 mg every 8 hoursChild 3–7 years 100 mg every 12 hoursChild 7–10 years 100 mg every 8 hoursChild 10–18 years 200–250 mg every 8 hoursHelicobacter pylori eradication section 1.3Surgical prophylaxis. By mouthChild 1 month–12 years 30 mg/kg (max. 500 mg)2 hours before the procedureChild 12–18 years 400–500 mg 2 hours beforethe procedure; up to 3 further doses of 400–500 mgmay be given every 8 hours for high-risk procedures. By intravenous infusionNeonate under 40 weeks postmenstrual age10 mg/kg up to 30 minutes before the procedureNeonate over 40 weeks postmenstrual age 20–30 mg/kg up to 30 minutes before the procedureChild 1 month–12 years 30 mg/kg (max. 500 mg)up to 30 minutes before the procedureChild 12–18 years 500 mg up to 30 minutesbefore the procedure; up to 3 further doses of500 mg may be given every 8 hours for high-riskprocedures. By rectumChild 5–10 years 500 mg 2 hours before surgery;up to 3 further doses of 500 mg may be given every8 hours for high-risk proceduresChild 10–18 years 1 g 2 hours before surgery; upto 3 further doses of 1 g may be given every 8hours for high-risk procedures

BNFC 2011–2012 5.1.12 Quinolones 297Metronidazole (Non-proprietary) ATablets, metronidazole 200 mg, net price 21-tab pack= £1.36; 400 mg, 21-tab pack = £1.35. Label: 4, 9, 21,25, 27Brands include Vaginyl cDental prescribing on NHS Metronidazole Tablets may beprescribedTablets, metronidazole 500 mg, net price 21-tab pack= £29.84. Label: 4, 9, 21, 25, 27Dental prescribing on NHS Metronidazole Tablets may beprescribedSuspension, metronidazole (as benzoate) 200 mg/5 mL. Net price 100 mL = £11.43. Label: 4, 9Brands include Norzol cDental prescribing on NHS Metronidazole Oral Suspensionmay be prescribedIntravenous infusion, metronidazole 5 mg/mL. Netprice 20-mL amp = £1.56, 100-mL container = £3.41Flagyl c (Winthrop) ATablets, both f/c, ivory, metronidazole 200 mg, netprice 21-tab pack = £4.49; 400 mg, 14-tab pack =£6.34. Label: 4, 9, 21, 25, 27Suppositories, metronidazole 500 mg, net price 10 =£15.18; 1 g, 10 = £23.06. Label: 4, 9Flagyl S c (Winthrop) ASuspension, orange- and lemon-flavoured, metronidazole(as benzoate) 200 mg/5 mL. Net price100 mL = £11.18. Label: 4, 9Metrolyl c (Sandoz) AIntravenous infusion, metronidazole 5 mg/mL, netprice 100-mL Steriflex c bag = £1.22Electrolytes Na + 14.53 mmol/100-mL bagSuppositories, metronidazole 500 mg, net price 10 =£12.34; 1 g, 10 = £18.34. Label: 4, 95.1.12 QuinolonesCiprofloxacin is active against both Gram-positive andGram-negative bacteria. It is particularly active againstGram-negative bacteria, including salmonella, shigella,campylobacter, neisseria, and pseudomonas. Ciprofloxacinhas only moderate activity against Gram-positivebacteria such as Streptococcus pneumoniae and Enterococcusfaecalis; it should not be used for pneumococcalpneumonia. It is active against chlamydia andsome mycobacteria. Most anaerobic organisms are notsusceptible. Ciprofloxacin is licensed in children over 1year of age for pseudomonal infections in cystic fibrosis,for complicated urinary-tract infections, and for treatmentand prophylaxis of inhalation anthrax. When thebenefits of treatment outweigh the risks, ciprofloxacin islicensed in children over 1 year of age for severe infectionsof the respiratory tract and of the gastro-intestinalsystem (including typhoid fever). It is also used in thetreatment of septicaemia caused by multi-resistantorganisms (usually hospital acquired) and gonorrhoea(although resistance is increasing). Ciprofloxacin is alsoused in the prophylaxis of meningococcal disease.Nalidixic acid may be used in uncomplicated urinarytractinfections that are resistant to other antibiotics.Many staphylococci are resistant to quinolones andtheir use should be avoided in MRSA infections.Ofloxacin eye drops are used in ophthalmic infections(section 11.3.1).There is much less experience of the other quinolones inchildren; expert advice should be sought.Anthrax Inhalation or gastro-intestinal anthraxshould be treated initially with either ciprofloxacin or,in children over 12 years, doxycycline [unlicensedindication] (section 5.1.3) combined with one or twoother antibacterials (such as amoxicillin, benzylpenicillin,chloramphenicol, clarithromycin, clindamycin,imipenem with cilastatin, rifampicin [unlicensed indication],and vancomycin). When the condition improvesand the sensitivity of the Bacillus anthracis strain isknown, treatment may be switched to a single antibacterial.Treatment should continue for 60 daysbecause germination may be delayed.Cutaneous anthrax should be treated with either ciprofloxacin[unlicensed indication] or doxycycline [unlicensedindication] (section 5.1.3) for 7 days. Treatmentmay be switched to amoxicillin (section 5.1.1.3) if theinfecting strain is susceptible. Treatment may need to beextended to 60 days if exposure is due to aerosol. Acombination of antibacterials for 14 days is recommendedfor cutaneous anthrax with systemic features,extensive oedema, or lesions of the head or neck.Ciprofloxacin or doxycycline may be given for postexposureprophylaxis. If exposure is confirmed, antibacterialprophylaxis should continue for 60 days. Antibacterialprophylaxis may be switched to amoxicillinafter 10–14 days if the strain of B. anthracis is susceptible.Vaccination against anthrax (section 14.4) mayallow the duration of antibacterial prophylaxis to beshortened.Cautions Quinolones should be used with caution inchildren with a history of epilepsy or conditions thatpredispose to seizures, in G6PD deficiency (section9.1.5), myasthenia gravis (risk of exacerbation). Exposureto excessive sunlight should be avoided (discontinueif photosensitivity occurs). The CSM has warnedthat quinolones may induce convulsions in patientswith or without a history of convulsions; taking NSAIDsat the same time may also induce them. Other interactions:Appendix 1 (quinolones).Quinolones cause arthropathy in the weight-bearingjoints of immature animals and are therefore generallynot recommended in children and growing adolescents.However, the significance of this effect in humans isuncertain and in some specific circumstances shorttermuse of a quinolone in children is justified. Nalidixicacid is used for resistant urinary-tract infections inchildren over 3 months of age.Tendon damageTendon damage (including rupture) has beenreported rarely in patients receiving quinolones.Tendon rupture may occur within 48 hours of startingtreatment; cases have also been reported severalmonths after stopping a quinolone. Healthcare professionalsare reminded that:. quinolones are contra-indicated in patients witha history of tendon disorders related to quinoloneuse;. the risk of tendon damage is increased by theconcomitant use of corticosteroids;. if tendinitis is suspected, the quinolone shouldbe discontinued immediately.5 Infections

298 5.1.12 Quinolones BNFC 2011–20125 InfectionsContra-indications Quinolone hypersensitivity.Pregnancy Quinolones should be avoided inpregnancy because they have been shown to causearthropathy in animal studies; safer alternatives areavailable.Side-effects Side-effects of the quinolones includenausea, vomiting, dyspepsia, abdominal pain, diarrhoea(rarely antibiotic-associated colitis), headache, dizziness,rash (very rarely Stevens-Johnson syndrome andtoxic epidermal necrolysis). Less frequent side-effectsinclude anorexia, sleep disturbances, asthenia, confusion,anxiety, depression, hallucinations, tremor, blooddisorders (including eosinophilia, leucopenia, thrombocytopenia),arthralgia, myalgia, disturbances in visionand taste. Other side-effects reported rarely or veryrarely include hepatic dysfunction (including jaundiceand hepatitis), hypotension, vasculitis, dyspnoea, convulsions,psychoses, paraesthesia, renal failure, interstitialnephritis, tendon inflammation and damage (seealso Tendon Damage above), photosensitivity, disturbancesin hearing and smell. The drug should be discontinuedif psychiatric, neurological or hypersensitivityreactions (including severe rash) occur.CIPROFLOXACINCautions see notes above; avoid excessive alkalinity ofurine and ensure adequate fluid intake (risk of crystalluria);interactions: Appendix 1 (quinolones)Skilled tasks May impair performance of skilled tasks (e.g.driving)Contra-indications see notes aboveRenal impairment reduce dose if estimated glomerularfiltration rate less than 30 mL/minute/1.73 m 2 —consult product literaturePregnancy see notes aboveBreast-feeding amount probably too small to beharmful but manufacturer advises avoidSide-effects see notes above; also flatulence, pain andphlebitis at injection site; rarely dysphagia, pancreatitis,chest pain, tachycardia, syncope, oedema, hotflushes, abnormal dreams, sweating, hyperglycaemia,and erythema nodosum; very rarely movement disorders,tinnitus, vasculitis, and tenosynovitisLicensed use licensed for use in children over 1 yearfor complicated urinary-tract infections, for pseudomonallower respiratory-tract infections in cysticfibrosis, for prophylaxis and treatment of inhalationalanthrax; licensed for use in children over 1year for other infections where the benefit is consideredto outweigh the potential risks; not licensedfor use in children for gastro-intestinal anthrax; notlicensed for use in children for prophylaxis ofmeningococcal meningitis; not licensed for use inchildren under 1 year of ageIndication and doseComplicated urinary-tract infections. By mouthNeonate 10 mg/kg twice dailyChild 1 month–18 years 10 mg/kg twice daily;dose doubled in severe infection (max. 750 mgtwice daily). By intravenous infusion over 60 minutesNeonate 6 mg/kg every 12 hoursChild 1 month–18 years 6 mg/kg every 8 hours;increased to 10 mg/kg every 8 hours in severeinfection (max. 400 mg every 8 hours)Severe respiratory-tract infections, gastrointestinalinfections; see notes above. By mouthNeonate 15 mg/kg twice dailyChild 1 month–18 years 20 mg/kg (max. 750 mg)twice daily. By intravenous infusion over 60 minutesNeonate 10 mg/kg every 12 hoursChild 1 month–18 years 10 mg/kg (max. 400 mg)every 8 hoursPseudomonal lower respiratory-tract infectionin cystic fibrosis. By mouthChild 1 month–18 years 20 mg/kg (max. 750 mg)twice daily. By intravenous infusion over 60 minutesChild 1 month–18 years 10 mg/kg (max. 400 mg)every 8 hoursGonorrhoea. By mouthChild 12–18 years 500 mg as a single doseAnthrax (treatment and post-exposure prophylaxis,see notes above). By mouthChild 1 month–18 years 15 mg/kg (max. 500 mg)twice daily. By intravenous infusion over 60 minutesChild 1 month–18 years 10 mg/kg (max. 400 mg)every 12 hoursEye infections section 11.3.1Prophylaxis of meningococcal meningitis Table2, section 5.1Ciprofloxacin (Non-proprietary) ATablets, ciprofloxacin (as hydrochloride) 100 mg, netprice 6-tab pack = £1.42; 250 mg, 10-tab pack = 96p,20-tab pack = £1.09; 500 mg, 10-tab pack = £1.06, 20-tab pack = £1.22; 750 mg, 10-tab pack = £6.15.Label: 7, 9, 25, counselling, drivingIntravenous infusion, ciprofloxacin (as lactate)2 mg/mL, net price 50-mL bottle = £8.00, 100-mLbottle = £15.00, 200-mL bottle = £22.00Ciproxin c (Bayer Schering) ATablets, all f/c, ciprofloxacin (as hydrochloride)250 mg (scored), net price 10-tab pack = £6.59;500 mg (scored), 10-tab pack = £12.49; 750 mg, 10-tabpack = £17.78. Label: 7, 9, 25, counselling, drivingSuspension, strawberry-flavoured, ciprofloxacin forreconstitution with diluent provided, 250 mg/5 mL,net price 100 mL = £16.83. Label: 7, 9, 25, counselling,driving

BNFC 2011–2012 5.1.13 Urinary-tract infections 299Intravenous infusion, ciprofloxacin (as lactate)2 mg/mL, in sodium chloride 0.9%, net price 50-mLbottle = £7.61, 100-mL bottle = £15.02, 200-mL bottle= £22.85Electrolytes Na + 15.4 mmol/100-mL bottleNALIDIXIC ACIDCautions see notes above; avoid in acute porphyria(section 9.8.2); false positive urinary glucose (if testedfor reducing substances); monitor blood counts, renaland liver function if treatment exceeds 2 weeks;interactions: Appendix 1 (quinolones)Contra-indications see notes aboveHepatic impairment manufacturer advises caution inliver diseaseRenal impairment use with caution; avoid if estimatedglomerular filtration rate less than 20 mL/minute/1.73 m 2Pregnancy see notes aboveBreast-feeding risk to infant very small but one caseof haemolytic anaemia reportedSide-effects see notes above; also reported toxicpsychosis, increased intracranial pressure, cranialnerve palsy, peripheral neuropathy, metabolic acidosisLicensed use not licensed for use in children under 3months of ageIndication and doseUrinary tract infection resistant to other antibiotics. By mouthChild 3 months–12 years 12.5 mg/kg 4 timesdaily for 7 days, reduced to 7.5 mg/kg 4 times dailyin prolonged therapy or 15 mg/kg twice daily forprophylaxisChild 12–18 years 900 mg 4 times daily for 7days, reduced in chronic infections to 600 mg 4times dailyNalidixic acid (Rosemont) ASuspension, pink, nalidixic acid 300 mg/5 mL, netprice 150 mL (raspberry- and strawberry-flavoured) =£12.50. Label: 9, 11Excipients include sucrose 450 mg/5 mL5.1.13 Urinary-tract infectionsUrinary-tract infection is more common in adolescentgirls than in boys; when it occurs in adolescent boysthere is frequently an underlying abnormality of therenal tract. Recurrent episodes of infection are an indicationfor radiological investigation especially in childrenin whom untreated pyelonephritis may lead topermanent kidney damage.Escherichia coli is the most common cause of urinarytractinfection; Staphylococcus saprophyticus is alsocommon in sexually active young women. Less commoncauses include Proteus and Klebsiella spp. Pseudomonasaeruginosa infections usually occur in the hospitalsetting and may be associated with functional oranatomical abnormalities of the renal tract. Staphylococcusepidermidis and Enterococcus faecalis infectionmay complicate catheterisation or instrumentation.A specimen of urine should be collected for cultureand sensitivity testing before starting antibacterialtherapy;. in children under 3 years of age;. in children with suspected upper urinary-tractinfection, complicated infection, or recurrentinfection;. if resistant organisms are suspected;. if urine dipstick testing gives a single positiveresult for leucocyte esterase or nitrite;. if clinical symptoms are not consistent withresults of dipstick testing;. in pregnant women.Treatment should not be delayed while waiting forresults. The antibacterial chosen should reflect currentlocal bacterial sensitivity to antibacterials.Urinary-tract infections in children require prompt antibacterialtreatment to minimise the risk of renal scarring.Uncomplicated ‘lower’ urinary-tract infections inchildren over 3 months of age can be treated withtrimethoprim, nitrofurantoin, a first generation cephalosporin,or amoxicillin for 3 days; children should bereassessed if they continue to be unwell 24–48 hoursafter the initial assessment.Acute pyelonephritis in children over 3 months of agecan be treated with a first generation cephalosporin orco-amoxiclav for 7–10 days. If the patient is severely ill,then the infection is best treated initially by intravenousinjection of a broad-spectrum antibacterial such as cefotaximeor co-amoxiclav; gentamicin is an alternative.Children under 3 months of age should be transferred tohospital and treated initially with intravenous antibacterialssuch as ampicillin with gentamicin, or cefotaximealone, until the infection responds; full doses of oralantibacterials are then given for a further period.Resistant infections Widespread bacterial resistanceto ampicillin, amoxicillin, and trimethoprim has beenreported. Alternatives for resistant organisms includeco-amoxiclav (amoxicillin with clavulanic acid), an oralcephalosporin, pivmecillinam, or a quinolone.Antibacterial prophylaxis Recurrent episodes ofinfection are an indication for imaging tests. Antibacterialprophylaxis with low doses of trimethoprimor nitrofurantoin may be considered for children withrecurrent infection, significant urinary-tract anomalies,or significant kidney damage. Nitrofurantoin is contraindicatedin children under 3 months of age because ofthe theoretical possibility of haemolytic anaemia.Pregnancy Urinary-tract infection in pregnancy maybe asymptomatic and requires prompt treatment toprevent progression to acute pyelonephritis. Penicillinsand cephalosporins are suitable for treating urinarytractinfection during pregnancy. Nitrofurantoin mayalso be used but it should be avoided at term. Sulfonamides,quinolones, and tetracyclines should be avoidedduring pregnancy; trimethoprim should also preferablybe avoided particularly in the first trimester.Renal impairment In renal failure antibacterialsnormally excreted by the kidney accumulate with resultanttoxicity unless the dose is reduced. This appliesespecially to the aminoglycosides which should be used5 Infections

300 5.2 Antifungal drugs BNFC 2011–20125 Infectionswith great caution; tetracyclines, methamine, and nitrofurantoinshould be avoided altogether.NITROFURANTOINCautions anaemia; diabetes mellitus; electrolyteimbalance; vitamin B and folate deficiency; pulmonarydisease; on long-term therapy, monitor liverfunction and monitor for pulmonary symptoms (discontinueif deterioration in lung function); susceptibilityto peripheral neuropathy; false positive urinaryglucose (if tested for reducing substances); urine maybe coloured yellow or brown; interactions: Appendix1 (nitrofurantoin)Contra-indications infants less than 3 months old,G6PD deficiency (section 9.1.5), acute porphyria(section 9.8.2)Hepatic impairment use with caution; cholestaticjaundice and chronic active hepatitis reportedRenal impairment avoid if estimated glomerular filtrationrate less than 60 mL/minute/1.73 m 2 ; risk ofperipheral neuropathy; ineffective because of inadequateurine concentrationsPregnancy avoid at term—may produce neonatalhaemolysisBreast-feeding avoid; only small amounts in milk butenough to produce haemolysis in G6PD-deficientinfants (section 9.1.5)Side-effects anorexia, nausea, vomiting, and diarrhoea;acute and chronic pulmonary reactions (pulmonaryfibrosis reported; possible association withlupus erythematosus-like syndrome); peripheralneuropathy; also reported, hypersensitivity reactions(including angioedema, anaphylaxis, sialadenitis,urticaria, rash and pruritus); rarely, cholestatic jaundice,hepatitis, exfoliative dermatitis, erythema multiforme,pancreatitis, arthralgia, blood disorders(including agranulocytosis, thrombocytopenia, andaplastic anaemia), benign intracranial hypertension,and transient alopeciaIndication and doseAcute uncomplicated urinary-tract infection. By mouthChild 3 months–12 years 750 micrograms/kg 4times daily for 3–7 daysChild 12–18 years 50 mg 4 times daily for 3–7days; increased to 100 mg 4 times daily in severechronic recurrent infectionsProphylaxis of urinary-tract infection (but seeCautions above)Table 2, section 5.1Nitrofurantoin (Non-proprietary) ATablets, nitrofurantoin 50 mg, net price 28-tab pack =£1.84; 100 mg, 28-tab pack = £4.43 Label: 9, 14, 21Oral suspension, nitrofurantoin 25 mg/5 mL, netprice 300 mL = £99.05. Label: 9, 14, 21Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionFuradantin c (Goldshield) ATablets, all yellow, scored, nitrofurantoin 50 mg, netprice 100-tab pack = £9.79; 100 mg, 100-tab pack =£18.11. Label: 9, 14, 21Macrodantin c (Goldshield) ACapsules, yellow/white, nitrofurantoin 50 mg (asmacrocrystals), net price 30-cap pack = £2.49; 100 mg(yellow/white), 30-cap pack = £4.81. Label: 9, 14, 21Modified releaseMacrobid c (Goldshield) ACapsules, m/r, blue/yellow, nitrofurantoin 100 mg(as nitrofurantoin macrocrystals and nitrofurantoinmonohydrate). Net price 14-cap pack = £4.89.Label: 9, 14, 21, 25DoseUncomplicated urinary-tract infectionChild 12–18 years 1 capsule twice daily with foodGenito-urinary surgical prophylaxisChild 12–18 years 1 capsule twice daily on day ofprocedure and for 3 days after5.2 Antifungal drugsTreatment of fungal infectionsThe systemic treatment of common fungal infections isoutlined below; specialist treatment is required in mostforms of systemic or disseminated fungal infections. Forlocal treatment of fungal infections, see section 7.2.2(genital), section 7.4.4 (bladder), section 11.3.2 (eye),section 12.1.1 (ear), section 12.3.2 (oropharynx), andsection 13.10.2 (skin).Aspergillosis Aspergillosis most commonly affectsthe respiratory tract but in severely immunocompromisedpatients, invasive forms can affect the heart,brain, and skin. Voriconazole (section 5.2.1) is thetreatment of choice for aspergillosis; liposomalamphotericin (section 5.2.3) is an alternative first-linetreatment when voriconazole cannot be used. Caspofungin(section 5.2.4) or itraconazole (section 5.2.1)can be used in patients who are refractory to, or intolerantof voriconazole and liposomal amphotericin. Itraconazoleis also used for the treatment of chronic pulmonaryaspergillosis or as an adjunct in the treatment ofallergic bronchopulmonary aspergillosis.Candidiasis Many superficial candidal infections,including infections of the skin (section 13.10.2), aretreated locally. Systemic antifungal treatment is requiredin widespread or intractable infection. Vaginal candidiasiscan be treated with locally acting antifungals(section 7.2.2); alternatively, fluconazole (section5.2.1) can be given by mouth.Oropharyngeal candidiasis generally responds to topicaltherapy (section 12.3.2). Fluconazole is given bymouth for unresponsive infections; it is reliablyabsorbed and is effective. Itraconazole (section 5.2.1)can be used for fluconazole-resistant infections. Topicaltherapy may not be adequate in immunocompromisedchildren and an oral triazole antifungal is preferred.For invasive or disseminated candidiasis, eitheramphotericin (section 5.2.3) by intravenous infusionor an echinocandin (section 5.2.4) can be used. Flu-

BNFC 2011–2012 5.2.1 Triazole antifungals 301conazole (section 5.2.1) is an alternative for Candidaalbicans infection in clinically stable children who havenot received an azole antifungal recently. Amphotericinshould be considered for the initial treatment of CNScandidiasis. Voriconazole (section 5.2.1) can be usedfor infections caused by fluconazole-resistant Candidaspp. when oral therapy is required, or in children intolerantof amphotericin or an echinocandin. In refractorycases, flucytosine (section 5.2.5) can be used withintravenous amphotericin.Cryptococcosis Cryptococcosis is uncommon butinfection in the immunocompromised, especially HIVpositivechildren, can be life-threatening; cryptococcalmeningitis is the most common form of fungal meningitis.The treatment of choice in cryptococcal meningitisis amphotericin (section 5.2.3) by intravenous infusionwith flucytosine (section 5.2.5) by intravenous infusionfor 2 weeks, followed by fluconazole (section 5.2.1) bymouth for 8 weeks or until cultures are negative. Incryptococcosis, fluconazole is sometimes given alone asan alternative in HIV-positive children with mild localisedinfection or in those who cannot tolerate amphotericin.Following successful treatment, fluconazole canbe used for prophylaxis against relapse until immunityrecovers.Histoplasmosis Histoplasmosis is rare in temperateclimates; it can be life-threatening, particularly in HIVinfectedchildren. Itraconazole (section 5.2.1) can beused for the treatment of immunocompetent childrenwith indolent non-meningeal infection, includingchronic pulmonary histoplasmosis. Amphotericin (section5.2.3) by intravenous infusion is preferred in childrenwith fulminant or severe infections. Followingsuccessful treatment, itraconazole can be used forprophylaxis against relapse until immunity recovers.Skin and nail infections Mild localised fungal infectionsof the skin (including tinea corporis, tinea cruris,and tinea pedis) respond to topical therapy (section13.10.2). Systemic therapy is appropriate if topical therapyfails, if many areas are affected, or if the site ofinfection is difficult to treat such as in infections of thenails (onychomycosis) and of the scalp (tinea capitis).Oral imidazole or triazole antifungals (particularly itraconazole)and terbinafine are used more frequentlythan griseofulvin because they have a broader spectrumof activity and require a shorter duration of treatment.Tinea capitis is treated systemically; additional topicalapplication of an antifungal (section 13.10.2) mayreduce transmission. Griseofulvin (section 5.2.5) isused for tinea capitis; it is effective against infectionscaused by Trichophyton tonsurans and Microsporumspp. Terbinafine (section 5.2.5) is used for tinea capitiscaused by T. tonsurans [unlicensed indication]; the roleof terbinafine in the management of Microsporum infectionsis uncertain. Fluconazole (section 5.2.1) or itraconazole(section 5.2.1) are alternatives in the treatmentof tinea capitis caused by T. tonsurans orMicrosporum spp. [both unlicensed indications].Pityriasis versicolor (section 13.10.2) may be treatedwith itraconazole (section 5.2.1) by mouth if topicaltherapy is ineffective; fluconazole (section 5.2.1) bymouth is an alternative. Oral terbinafine is not effectivefor pityriasis versicolor.Antifungal treatment may not be necessary in asymptomaticchildren with tinea infection of the nails. If treatmentis necessary, a systemic antifungal is more effectivethan topical therapy. Terbinafine (section 5.2.5) anditraconazole (section 5.2.1) have largely replacedgriseofulvin for the systemic treatment of onychomycosis,particularly of the toenail; they should beused under specialist advice. Although terbinafine isnot licensed for use in children, it is considered to bethe drug of choice for onychomycosis. Itraconazole canbe administered as intermittent ‘pulse’ therapy. For therole of topical antifungals in the treatment of onychomycosis,see section 13.10.2.Immunocompromised children Immunocompromisedchildren are at particular risk of fungal infectionsand may receive antifungal drugs prophylactically; oraltriazole antifungals are the drugs of choice for prophylaxis.Fluconazole (section 5.2.1) is more reliablyabsorbed than itraconazole (section 5.2.1), but fluconazoleis not effective against Aspergillus spp. Itraconazoleis preferred in patients at risk of invasive aspergillosis.Micafungin (section 5.2.4) can be used forprophylaxis of candidiasis in patients undergoing haematopoieticstem cell transplantation when fluconazoleor itraconazole cannot be used.Amphotericin (section 5.2.3) by intravenous infusion orcaspofungin (section 5.2.4) is used for the empiricaltreatment of serious fungal infections in immunocompromisedchildren; caspofungin is not effective againstfungal infections of the CNS.5.2.1 Triazole antifungalsFor the role of triazole antifungal drugs in the preventionand systemic treatment of fungal infections, see p. 300.Fluconazole is very well absorbed after oral administration.It also achieves good penetration into the cerebrospinalfluid to treat fungal meningitis. Fluconazole isexcreted largely unchanged in the urine and can be usedto treat candiduria.Itraconazole is active against a wide range of dermatophytes.There is limited information available on usein children. Itraconazole capsules require an acid environmentin the stomach for optimal absorption.Itraconazole has been associated with liver damage andshould be avoided or used with caution in children withliver disease; fluconazole is less frequently associatedwith hepatotoxicity.Voriconazole is a broad-spectrum antifungal drugwhich is licensed in adults for the treatment of lifethreateninginfections.FLUCONAZOLECautions concomitant use with hepatotoxic drugs,monitor liver function with high doses or extendedcourses—discontinue if signs or symptoms of hepaticdisease (risk of hepatic necrosis); susceptibility to QTinterval prolongation; interactions: Appendix 1(antifungals, triazole)Contra-indications acute porphyria (section 9.8.2)Hepatic impairment toxicity with related drugsRenal impairment usual initial dose then halve subsequentdoses if estimated glomerular filtration rateless than 50 mL/minute/1.73m 25 Infections

302 5.2.1 Triazole antifungals BNFC 2011–20125 InfectionsPregnancy manufacturer advises avoid—multiplecongenital abnormalities reported with long-termhigh dosesBreast-feeding present in milk but amount probablytoo small to be harmfulSide-effects nausea, abdominal discomfort, diarrhoea,flatulence, headache, rash (discontinue treatmentor monitor closely if infection invasive or systemic);less frequently dyspepsia, vomiting, tastedisturbance, hepatic disorders, angioedema, anaphylaxis,dizziness, seizures, alopecia, pruritus, toxic epidermalnecrolysis, Stevens-Johnson syndrome(severe cutaneous reactions more likely in AIDSpatients), hyperlipidaemia, leucopenia, thrombocytopenia,and hypokalaemia reportedLicensed use not licensed for tinea infections inchildren, or for vaginal candidiasis in girls under 16years, or for prevention of relapse of cryptococcalmeningitis after completion of primary therapy inchildren with AIDSIndication and doseMucosal candidiasis (except genital). By mouth or by intravenous infusionNeonate under 2 weeks 3–6 mg/kg on first daythen 3 mg/kg every 72 hoursNeonate 2–4 weeks 3–6 mg/kg on first day then3 mg/kg every 48 hoursChild 1 month–12 years 3–6 mg/kg on first daythen 3 mg/kg (max. 100 mg) daily for 7–14 days inoropharyngeal candidiasis (max. 14 days except inseverely immunocompromised patients); for 14–30days in other mucosal infections (e.g. oesophagitis,candiduria, non-invasive bronchopulmonaryinfections)Child 12–18 years 50 mg daily (100 mg daily inunusually difficult infections) given for 7–14 daysin oropharyngeal candidiasis (max. 14 days exceptin severely immunocompromised patients); for 14–30 days in other mucosal infections (e.g. oesophagitis,candiduria, non-invasive bronchopulmonaryinfections)Vaginal candidiasis (see also Recurrent VulvovaginalCandidiasis, section 7.2.2). By mouthChild under 16 years (post-puberty) a singledose of 150 mgChild 16–18 years a single dose of 150 mgCandidal balanitis. By mouthChild 16–18 years a single dose of 150 mgTinea pedis, corporis, cruris, pityriasis versicolor,and dermal candidiasis. By mouthChild 1 month–18 years 3 mg/kg (max. 50 mg)daily for 2–4 weeks (for up to 6 weeks in tineapedis); max. duration of treatment 6 weeksTinea capitis. By mouthChild 1–18 years 6 mg/kg (max. 300 mg) daily for2–4 weeksInvasive candidal infections (including candidaemiaand disseminated candidiasis) andcryptococcal infections (including meningitis). By mouth or by intravenous infusionNeonate under 2 weeks 6–12 mg/kg every 72hours, treatment continued according to response(at least 8 weeks for cryptococcal meningitis)Neonate 2–4 weeks 6–12 mg/kg every 48 hours,treatment continued according to response (atleast 8 weeks for cryptococcal meningitis)Child 1 month–18 years 6–12 mg/kg (max.800 mg) daily, treatment continued according toresponse (at least 8 weeks for cryptococcalmeningitis)Prevention of relapse of cryptococcal meningitisin HIV-infected patients after completion ofprimary therapy. By mouth or by intravenous infusionChild 1 month–18 years 6 mg/kg (max. 200 mg)dailyPrevention of fungal infections in immunocompromisedpatients. By mouth or by intravenous infusionNeonate under 2 weeks according to extent andduration of neutropenia, 3–12 mg/kg every 72hoursNeonate 2–4 weeks according to extent andduration of neutropenia, 3–12 mg/kg every 48hoursChild 1 month–18 years according to extent andduration of neutropenia, 3–12 mg/kg (max.400 mg) daily; 12 mg/kg (max. 400 mg) daily ifhigh risk of systemic infections e.g. following bonemarrowtransplantation; commence treatmentbefore anticipated onset of neutropenia and continuefor 7 days after neutrophil count in desirablerangeAdministration for intravenous infusion, give over10–30 minutes; do not exceed an infusion rate of 5–10 mL/minuteFluconazole (Non-proprietary) A1Capsules, fluconazole 50 mg, net price 7-cap pack =£1.14; 150 mg, single-capsule pack = 98p; 200 mg, 7-cap pack = £5.04. Label: 9, (50 and 200 mg)Dental prescribing on NHS Fluconazole Capsules 50 mgmay be prescribedIntravenous infusion, fluconazole 2 mg/mL, netprice 25-mL bottle = £7.31; 100-mL bottle = £29.27;100-mL infusion bag = £3.89; 50-mL infusion bag =£2.70Diflucan c (Pfizer) A1Capsules, fluconazole 50 mg (blue/white), net price7-cap pack = £16.61; 150 mg (blue), single-capsulepack = £7.12; 200 mg (purple/white), 7-cap pack =£66.42. Label: 9, (50 and 200 mg)Oral suspension, orange-flavoured, fluconazole forreconstitution with water, 50 mg/5 mL, net price1. Capsules can be sold to the public for vaginal candidiasisand associated candidal balanitis in those aged 16–18years, in a container or packaging containing not morethan 150 mg and labelled to show a max. dose of 150 mg

BNFC 2011–2012 5.2.1 Triazole antifungals 30335 mL = £16.61; 200 mg/5 mL, 35 mL = £66.42.Label: 9Dental prescribing on NHS May be prescribed as FluconazoleOral Suspension 50 mg/5 mLIntravenous infusion, fluconazole 2 mg/mL in sodiumchloride intravenous infusion 0.9%, net price 25-mL bottle = £7.32; 100-mL bottle = £29.28Electrolytes Na + 15 mmol/100-mL bottleITRACONAZOLECautions absorption reduced in AIDS and neutropenia(monitor plasma-itraconazole concentration andincrease dose if necessary); susceptibility to congestiveheart failure (see also Heart Failure, below);interactions: Appendix 1 (antifungals, triazole)Hepatotoxicity Potentially life-threatening hepatotoxicityreported very rarely—discontinue if signs of hepatitisdevelop. Avoid or use with caution if history of hepatotoxicitywith other drugs or in active liver disease. Monitor liverfunction if treatment continues for longer than one month, ifreceiving other hepatotoxic drugs, if history of hepatotoxicitywith other drugs, or in hepatic impairmentCounselling Children or their carers should be told how torecognise signs of liver disorder and advised to seek promptmedical attention if symptoms such as anorexia, nausea,vomiting, fatigue, abdominal pain or dark urine developHeart failureFollowing reports of heart failure, caution is advisedwhen prescribing itraconazole to patients at high riskof heart failure. Those at risk include:. patients receiving high doses and longer treatmentcourses;. those with cardiac disease;. patients receiving treatment with negative inotropic drugs,e.g. calcium channel blockers.Itraconazole should be avoided in patients with ventriculardysfunction or a history of heart failure unlessthe infection is serious.Contra-indications acute porphyria (section 9.8.2)Hepatic impairment use only if potential benefit outweighsrisk of hepatotoxicity (see Hepatotoxicityabove); dose reduction may be necessaryRenal impairment risk of congestive heart failure;bioavailability of oral formulations possibly reduced;use intravenous infusion with caution if estimatedglomerular filtration rate 30–80 mL/minute/1.73 m 2(monitor renal function); avoid intravenous infusion ifestimated glomerular filtration rate less than 30 mL/minute/1.73 m 2Pregnancy manufacturer advises use only in lifethreateningsituations (toxicity at high doses in animalstudies); ensure effective contraception duringtreatment and until the next menstrual period followingend of treatmentBreast-feeding small amounts present in milk—mayaccumulate; manufacturer advises avoidSide-effects nausea, abdominal pain, rash; less commonlyvomiting, dyspepsia, taste disturbances, flatulence,diarrhoea, constipation, oedema, headache,dizziness, paraesthesia (discontinue treatment ifneuropathy), menstrual disorder, and alopecia; rarelypancreatitis, hypoaesthesia, urinary frequency, leucopenia,visual disturbances, and tinnitus; also reported,heart failure (see Cautions above), hypertriglyceridaemia,hepatitis (see Hepatotoxicity above), erectiledysfunction, thrombocytopenia, hypokalaemia, myalgia,arthralgia, photosensitivity, toxic epidermalnecrolysis, and Stevens-Johnson Syndrome; withintravenous injection hypertension and hyperglycaemiaLicensed use Sporanox c capsules and Sporanox cPulse are not licensed for use in children under 12years; Sporanox c liquid and Sporanox c infusionare not licensed for use in children (age range notspecified by manufacturer)Indication and doseOropharyngeal candidiasis. By mouthChild 1 month–12 years 3–5 mg/kg once daily;max. 100 mg daily (200 mg daily in AIDS or neutropenia)for 15 daysChild 12–18 years 100 mg once daily (200 mgonce daily in AIDS or neutropenia) for 15 daysPityriasis versicolor. By mouthChild 1 month–12 years 3–5 mg/kg (max.200 mg) once daily for 7 daysChild 12–18 years 200 mg once daily for 7 daysTinea corporis and tinea cruris. By mouthChild 1 month–12 years 3–5 mg/kg (max.100 mg) once daily for 15 daysChild 12–18 years either 100 mg once daily for 15days or 200 mg once daily for 7 daysTinea pedis and tinea manuum. By mouthChild 1 month–12 years 3–5 mg/kg (max.100 mg) once daily for 30 daysChild 12–18 years either 100 mg once daily for 30days or 200 mg twice daily for 7 daysTinea capitis. By mouthChild 1–18 years 3–5 mg/kg (max. 200 mg) dailyfor 2–6 weeksOnychomycosis. By mouthChild 1–12 years course (‘pulse’) of 5 mg/kg(max. 200 mg) daily for 7 days; subsequent coursesrepeated after 21 day intervals; fingernails 2courses, toenails 3 coursesChild 12–18 years either 200 mg once daily for 3months or course (‘pulse’) of 200 mg twice daily for7 days, subsequent courses repeated after 21-dayintervals; fingernails 2 courses, toenails 3 coursesSystemic aspergillosis, candidiasis andcryptococcosis including cryptococcal meningitiswhere other antifungal drugs inappropriateor ineffective (limited information available). By mouthChild 1 month–18 years 5 mg/kg (max. 200 mg)once daily; increased in invasive or disseminateddisease and in cryptococcal meningitis to 5 mg/kg(max. 200 mg) twice daily5 Infections

304 5.2.1 Triazole antifungals BNFC 2011–20125 Infections. By intravenous infusionChild 1 month–18 years 2.5 mg/kg (max.200 mg) every 12 hours for 2 days, then 2.5 mg/kg(max. 200 mg) once daily for max. 12 daysHistoplasmosis. By mouthChild 1 month–18 years 5 mg/kg (max. 200 mg)1–2 times dailyMaintenance in HIV-infected patients to preventrelapse of underlying fungal infection andprophylaxis in neutropenia when standardtherapy inappropriate. By mouthChild 1 month–18 years 5 mg/kg (max. 200 mg)once daily, increased to 5 mg/kg (max. 200 mg)twice daily if low plasma-itraconazole concentration(see Cautions)Prophylaxis of deep fungal infections (whenstandard therapy inappropriate) in patientswith haematological malignancy or undergoingbone-marrow transplantation who are expectedto become neutropenic. By mouth (liquid preparation only)Child 1 month–18 years 2.5 mg/kg twice dailystarting before transplantation or before chemotherapy(taking care to avoid interaction withcytotoxic drugs) and continued until neutrophilcount recoversAdministration For intravenous infusion, dilute250 mg with 50 mL Sodium Chloride 0.9% and giverequisite dose through an in-line filter (0.2 micron)over 60 minutesItraconazole (Non-proprietary) ACapsules, enclosing coated beads, itraconazole100 mg, net price 15-cap pack = £7.21. Label: 5, 9, 21,25, counselling, hepatotoxicitySporanox c (Janssen) ACapsules, blue/pink, enclosing coated beads, itraconazole100 mg, net price 4-cap pack = £3.67; 15-cappack = £13.77; 28-cap pack (Sporanox c -Pulse) =£25.72; 60-cap pack = £55.10. Label: 5, 9, 21, 25,counselling, hepatotoxicityOral liquid, sugar-free, cherry-flavoured, itraconazole10 mg/mL, net price 150 mL (with 10-mL measuringcup) = £45.80. Label: 9, 23, counselling, administration,hepatotoxicityCounselling Do not take with food; swish around mouth andswallow, do not rinse afterwardsConcentrate for intravenous infusion, itraconazole10 mg/mL. For dilution before use. Net price 25-mLamp (with infusion bag and filter) = £62.58Excipients include propylene glycolVORICONAZOLECautions electrolyte disturbances, cardiomyopathy,bradycardia, symptomatic arrhythmias, history of QTinterval prolongation, concomitant use with otherdrugs that prolong QT interval; avoid exposure tosunlight; patients at risk of pancreatitis; monitor liverfunction before treatment and during treatment; haematologicalmalignancy (increased risk of hepaticreactions); monitor renal function; interactions:Appendix 1 (antifungals, triazole)Contra-indications acute porphyria (section 9.8.2)Hepatic impairment in mild to moderate hepaticcirrhosis use usual initial dose then halve subsequentdoses; no information available for severe hepaticcirrhosis—manufacturer advises use only if potentialbenefit outweighs riskRenal impairment intravenous vehicle may accumulateif estimated glomerular filtration rate less than50 mL/minute/1.73 m 2 —use intravenous infusiononly if potential benefit outweighs risk, and monitorrenal function; alternatively, use tablets or oral suspension(no dose adjustment required)Pregnancy toxicity in animal studies—manufactureradvises avoid unless potential benefit outweighs risk;effective contraception required during treatmentBreast-feeding manufacturer advises avoid—noinformation availableSide-effects nausea, vomiting, abdominal pain, diarrhoea,jaundice, oedema, hypotension, chest pain,respiratory distress syndrome, sinusitis, headache,dizziness, asthenia, anxiety, depression, confusion,agitation, hallucinations, paraesthesia, tremor, influenza-likesymptoms, hypoglycaemia, haematuria,blood disorders (including anaemia, thrombocytopenia,leucopenia, pancytopenia), acute renal failure,hypokalaemia, visual disturbances, (including alteredperception, blurred vision, and photophobia), rash,pruritus, photosensitivity, alopecia, cheilitis, injectionsitereactions; less commonly dyspepsia, duodenitis,cholecystitis, pancreatitis, hepatitis, constipation,arrhythmias (including QT interval prolongation),syncope, raised serum cholesterol, hypersensitivityreactions (including flushing), ataxia, nystagmus,hypoaesthesia, adrenocortical insufficiency, arthritis,blepharitis, optic neuritis, scleritis, glossitis, gingivitis,psoriasis, Stevens-Johnson syndrome; rarelypseudomembranous colitis, taste disturbances (morecommon with oral suspension), convulsions, insomnia,tinnitus, hearing disturbances, extrapyramidaleffects, hypertonia, hypothyroidism, hyperthyroidism,discoid lupus erythematosus, toxic epidermal necrolysis,pseudoporphyria, retinal haemorrhage, opticatrophy; also reported squamous cell carcinoma ofskin (particularly in presence of phototoxicity)Indication and doseInvasive aspergillosis; serious infectionscaused by Scedosporium spp., Fusarium spp.,or invasive fluconazole-resistant Candida spp.(including C. krusei). By mouthChild 2–12 years (oral suspension recommended)200 mg every 12 hoursChild 12–18 years, body-weight under 40 kg200 mg every 12 hours for 2 doses then 100 mgevery 12 hours, increased if necessary to 150 mgevery 12 hoursChild 12–18 years, body-weight over 40 kg400 mg every 12 hours for 2 doses then 200 mgevery 12 hours, increased if necessary to 300 mgevery 12 hours

BNFC 2011–2012 5.2.2 Imidazole antifungals 305. By intravenous infusionChild 2–12 years 7 mg/kg every 12 hours(reduced to 4 mg/kg every 12 hours if not tolerated)for max. 6 monthsChild 12–18 years 6 mg/kg every 12 hours for 2doses, then 4 mg/kg every 12 hours (reduced to3 mg/kg every 12 hours if not tolerated) for max. 6monthsAdministration For intravenous infusion, reconstituteeach 200 mg with 19 mL Water for Injections to producea 10 mg/mL solution; dilute dose to concentrationof 0.5–5 mg/mL with Glucose 5% or SodiumChloride 0.9% and give at a rate not exceeding 3 mg/kg/hourVfend c (Pfizer) ATablets, f/c, voriconazole 50 mg, net price 28-tabletpack = £275.68; 200 mg, 28-tab pack = £1102.74.Label: 9, 11, 23Oral suspension, voriconazole 200 mg/5 mL whenreconstituted with water, net price 75 mL (orangeflavoured)= £551.37. Label: 9, 11, 23Intravenous infusion, powder for reconstitution,voriconazole, net price 200-mg vial = £77.14Excipients include sulphobutylether beta cyclodextrin sodium (risk ofaccumulation in renal impairment)Electrolytes Na + 9.47 mmol/vial5.2.2 Imidazole antifungalsThe imidazole antifungals include clotrimazole, econazole,ketoconazole, and tioconazole. They are used forthe local treatment of vaginal candidiasis (section 7.2.2)and for dermatophyte infections (section 13.10.2).Ketoconazole is better absorbed by mouth than otherimidazoles. However, its use is restricted because it isassociated with fatal hepatotoxicity (see below).Miconazole (section 12.3.2) can be used locally for oralinfections; it is also effective in intestinal infections.Systemic absorption may follow use of miconazoleoral gel and may result in significant drug interactions.KETOCONAZOLE UCautions predisposition to adrenocortical insufficiency;interactions: Appendix 1 (antifungals, imidazole)Hepatotoxicity Potentially life-threatening hepatotoxicityreported very rarely; risk of hepatotoxicity greater if given forlonger than 10 days. Monitor liver function before treatment,then on weeks 2 and 4 of treatment, then every month. Avoidor use with caution if abnormal liver function tests (avoid inactive liver disease) or if history of hepatotoxicity with otherdrugs.Counselling Children and their carers should be told how torecognise signs of liver disorder and advised to seek promptmedical attention if symptoms such as anorexia, nausea,vomiting, fatigue, abdominal pain, jaundice, or dark urinedevelopContra-indications acute porphyria (section 9.8.2)Hepatic impairment avoid (see also Hepatotoxicityabove)Pregnancy manufacturer advises avoid unless potentialbenefit outweighs risk (teratogenicity in animalstudies)Breast-feeding manufacturer advises avoidSide-effects nausea, vomiting, abdominal pain; pruritus;less commonly diarrhoea, headache, dizziness,drowsiness, and rash; also reported fatal liver damage(see Hepatotoxicity above), dyspepsia, raised intracranialpressure, paraesthesia, adrenocortical insufficiency,erectile dysfunction, menstrual disorders,azoospermia (with high doses), gynaecomastia,thrombocytopenia, photophobia, photosensitivity,and alopeciaIndication and doseDermatophytoses and Malassezia folliculitiseither resistant to fluconazole, terbinafine, oritraconazole or in patients intolerant of theseantifungals; chronic mucocutaneous, cutaneous,and oropharyngeal candidiasis eitherresistant to fluconazole or itraconazole or inpatients intolerant of these antifungals. By mouthChild body-weight 15–30 kg 100 mg once dailyChild body-weight over 30 kg 200 mg once daily,increased if response inadequate to 400 mg oncedailyNote Treatment continued until symptoms have clearedand cultures negative, but see Cautions (max. duration oftreatment 4 weeks for Malassezia infection)Nizoral c (Janssen) AUTablets, scored, ketoconazole 200 mg. Net price 30-tab pack = £14.02. Label: 5, 9, 21, Counselling,hepatotoxicityExtemporaneous formulations available seeExtemporaneous Preparations, p. 65.2.3 Polyene antifungalsThe polyene antifungals include amphotericin and nystatin;neither drug is absorbed when given by mouth.Nystatin is used for oral, oropharyngeal, and perioralinfections by local application in the mouth (section12.3.2). Nystatin is also used for Candida albicansinfection of the skin (section 13.10.2)Amphotericin by intravenous infusion is used for thetreatment of systemic fungal infections and is activeagainst most fungi and yeasts. It is highly protein boundand penetrates poorly into body fluids and tissues.When given parenterally amphotericin is toxic andside-effects are common. Lipid formulations of amphotericin(Abelcet c and AmBisome c ) are significantly lesstoxic and are recommended when the conventionalformulation of amphotericin is contra-indicated becauseof toxicity, especially nephrotoxicity, or when responseto conventional amphotericin is inadequate; lipidformulations are more expensive. For the role ofamphotericin in the systemic treatment of fungalinfections, see p. 300.AMPHOTERICIN(Amphotericin B)Cautions when given parenterally, toxicity common(close supervision necessary and close observationrequired for at least 30 minutes after test dose; seeAnaphylaxis below); hepatic and renal function tests,blood counts and plasma electrolyte (includingplasma-potassium and magnesium concentration)monitoring required; corticosteroids (avoid except to5 Infections

306 5.2.4 Echinocandin antifungals BNFC 2011–20125 Infectionscontrol reactions); avoid rapid infusion (risk of arrhythmias);interactions: Appendix 1 (amphotericin)Anaphylaxis Anaphylaxis occurs rarely with any intravenousamphotericin product and a test dose is advisablebefore the first infusion in children over 1 month of age; thepatient should be carefully observed for at least 30 minutesafter the test dose. Prophylactic antipyretics or hydrocortisoneshould only be used in patients who have previouslyexperienced acute adverse reactions (in whom continuedtreatment with amphotericin is essential)Renal impairment use only if no alternative; nephrotoxicitymay be reduced with use of lipid formulationPregnancy not known to be harmful, but manufacturersadvise avoid unless potential benefit outweighsriskBreast-feeding no information availableSide-effects when given parenterally, anorexia,nausea and vomiting, diarrhoea, epigastric pain; febrilereactions, headache, muscle and joint pain;anaemia; disturbances in renal function (includinghypokalaemia and hypomagnesaemia) and renaltoxicity; also cardiovascular toxicity (includingarrhythmias, blood pressure changes), blood disorders,neurological disorders (including hearing loss,diplopia, convulsions, peripheral neuropathy,encephalopathy), abnormal liver function (discontinuetreatment), rash, anaphylactoid reactions (seeAnaphylaxis, above); pain and thrombophlebitis atinjection siteLicensed use intravenous conventional formulationamphotericin (Fungizone c ) is licensed for use inchildren (age range not specified by manufacturer);Ambisome c not licensed for use in children under 1monthIndication and doseSystemic fungal infections. By intravenous infusionSee preparationsNote Different preparations of intravenous amphotericinvary in their pharmacodynamics, pharmacokinetics,dosage, and administration; these preparations shouldnot be considered interchangeable. To avoid confusion,prescribers should specify the brand to be dispensed.Fungizone c (Squibb) AIntravenous infusion, powder for reconstitution,amphotericin (as sodium deoxycholate complex), netprice 50-mg vial = £3.88Electrolytes Na + < 0.5 mmol/vialDoseSystemic fungal infection. By intravenous infusionNeonate 1 mg/kg once daily, increased if necessary to1.5 mg/kg daily; after 7 days, may be reduced to 1–1.5 mg/kg on alternate daysChild 1 month–18 years initial test dose of 100 micrograms/kg(max. 1 mg) included as part of first dose of250 micrograms/kg daily; increased over 2–4 days, iftolerated, to 1 mg/kg daily; in severe infection max.1.5 mg/kg daily or on alternate daysNote prolonged treatment usually necessary; if interruptedfor longer than 7 days, recommence at250 micrograms/kg daily and increase graduallyAdministration For intravenous infusion, reconstitute each vialwith 10 mL Water for Injections and shake immediately to producea 5 mg/mL colloidal solution; dilute further in Glucose 5% toa concentration of 100 micrograms/mL (in fluid-restricted children,up to 400 micrograms/mL given via a central line); pH ofglucose solution must not be below 4.2 (check each container—consult product literature for details of buffer); infuse over 4–6hours, or if tolerated over a minimum of 2 hours (initial test dosegiven over 20–30 minutes); begin infusion immediately afterdilution and protect from light; incompatible with Sodium Chloridesolutions—flush existing intravenous line with Glucose 5% oruse separate line; an in-line filter (pore size no less than 1 micron)may be usedLipid formulationsAbelcet c (Cephalon) AIntravenous infusion, amphotericin 5 mg/mL as lipidcomplex with L-a-dimyristoylphosphatidylcholine andL-a-dimyristoylphosphatidylglycerol, net price 20-mLvial = £77.43 (hosp. only)Electrolytes Na + 3.12 mmol/vialDoseSevere invasive candidiasis; severe systemic fungalinfections in children not responding to conventionalamphotericin or to other antifungal drugs or wheretoxicity or renal impairment precludes conventionalamphotericin, including invasive aspergillosis,cryptococcal meningitis and disseminated cryptococcosisin children with HIV. By intravenous infusionChild 1 month–18 years initial test dose of 100 micrograms/kg(max. 1 mg) then 5 mg/kg once dailyAdministration for intravenous infusion, allow suspension toreach room temperature, shake gently to ensure no yellow settlement,withdraw requisite dose (using 17–19 gauge needle) intoone or more 20-mL syringes; replace needle on syringe with a 5-micron filter needle provided (fresh needle for each syringe) anddilute in Glucose 5% to a concentration of 2 mg/mL; preferablygive via an infusion pump at a rate of 2.5 mg/kg/hour (initial testdose given over 15 minutes); an in-line filter (pore size no less than15 micron) may be used; do not use sodium chloride or otherelectrolyte solutions—flush existing intravenous line with Glucose5% or use separate lineAmBisome c (Gilead) AIntravenous infusion, powder for reconstitution,amphotericin 50 mg encapsulated in liposomes, netprice 50-mg vial = £96.69Electrolytes Na + < 0.5 mmol/vialExcipients include sucrose 900 mg/vialDoseSevere systemic or deep mycoses where toxicity(particularly nephrotoxicity) precludes use of conventionalamphotericin; suspected or proven infectionin febrile neutropenic patients unresponsive tobroad-spectrum antibacterials. By intravenous infusionNeonate 1 mg/kg once daily; increased if necessary to3 mg/kg once daily; max. 5 mg/kg once dailyChild 1 month–18 years initial test dose 100 micrograms/kg(max. 1 mg) then 3 mg/kg once daily; max.5 mg/kg once dailyVisceral leishmaniasis see section 5.4.5 and productliteratureAdministration for intravenous infusion, reconstitute each vialwith 12 mL Water for Injections and shake vigorously to produce apreparation containing 4 mg/mL; withdraw requisite dose fromvial and introduce into Glucose 5% or 10% through the 5-micronfilter provided, to produce a final concentration of 0.2 –2 mg/mL;infuse over 30–60 minutes, or if non-anaphylactic infusion-relatedreactions occur infuse over 2 hours (initial test dose given over 10minutes); an in-line filter (pore size no less than 1 micron) may beused; incompatible with sodium chloride solutions—flush existingintravenous line with Glucose 5% or 10%, or use separate line5.2.4 Echinocandin antifungalsThe echinocandin antifungals include caspofungin andmicafungin. They are only active against Aspergillusspp. and Candida spp; however micafungin is not usedfor the treatment of aspergillosis. Echinocandins are not

BNFC 2011–2012 5.2.4 Echinocandin antifungals 307effective against fungal infections of the CNS. For therole of echinocandin antifungals in the prevention andsystemic treatment of fungal infections, see p. 300.CASPOFUNGINCautions interactions: Appendix 1 (caspofungin)Hepatic impairment usual initial dose, then use 70%of normal maintenance dose in moderate impairment;no information available for severe impairmentPregnancy manufacturer advises avoid unless essential—toxicityin animal studiesBreast-feeding present in milk in animal studies—manufacturer advises avoidSide-effects nausea, diarrhoea, vomiting; tachycardia,hypotension, flushing; dyspnoea; headache; hypokalaemia,hypomagnesaemia; arthralgia; rash, pruritus,sweating, injection-site reactions; less commonlyabdominal pain, dyspepsia, dysphagia, dry mouth,taste disturbances, anorexia, constipation, flatulence,cholestasis, hepatic dysfunction, ascites, palpitation,arrhythmia, chest pain, heart failure, thrombophlebitis,hypertension, bronchospasm, cough, dizziness,fatigue, paraesthesia, hypoaesthesia, sleep disturbances,tremor, anxiety, disorientation, hyperglycaemia,renal failure, hypocalcaemia, metabolic acidosis,anaemia, thrombocytopenia, leucopenia,myalgia, muscular weakness, blurred vision, anderythema multiforme; also reported, acute respiratorydistress syndrome, anaphylaxis, and hypercalcaemiaIndication and doseInvasive aspergillosis (see notes above); invasivecandidiasis (see notes above); empiricaltreatment of systemic fungal infections inpatients with neutropenia. By intravenous infusionNeonate 25 mg/m 2 once dailyChild 1 month–3 months 25 mg/m 2 once dailyChild 3 months–1 year 50 mg/m 2 once dailyChild 1–18 years 70 mg/m 2 (max. 70 mg) on firstday then 50 mg/m 2 (max. 70 mg) once daily;increased to 70 mg/m 2 (max. 70 mg) daily if lowerdose tolerated but inadequate responseAdministration for intravenous infusion, allow vial toreach room temperature; initially reconstitute 50 mgwith 10.5 mL Water for Injections to produce a5.2 mg/mL solution, or reconstitute 70 mg with10.5 mL Water for Injections to produce a 7.2 mg/mLsolution; mix gently to dissolve; dilute requisite doseto a final concentration not exceeding 500 micrograms/mLwith Sodium Chloride 0.9%; give over 60minutes; incompatible with glucose solutionsCancidas c (MSD) AIntravenous infusion, powder for reconstitution,caspofungin (as acetate), net price 50-mg vial =£327.67; 70-mg vial = £416.78MICAFUNGINCautions monitor renal function; interactions:Appendix 1 (micafungin)Hepatotoxicity Potentially life-threatening hepatotoxicityreported. Monitor liver function—discontinue if significantand persistent abnormalities in liver function tests develop.Use with caution in hepatic impairment (avoid if severe) or ifreceiving other hepatotoxic drugs. Risk of hepatic sideeffectsgreater in children under 1 year of ageHepatic impairment use with caution in mild tomoderate impairment; avoid in severe impairment;see also Hepatotoxicity aboveRenal impairment use with caution; deterioration inrenal functionPregnancy manufacturer advises avoid unless essential—toxicityin animal studiesBreast-feeding manufacturer advises use only ifpotential benefit outweighs risk—present in milk inanimal studiesSide-effects nausea, vomiting, diarrhoea, abdominalpain, hepatomegaly; blood pressure changes, tachycardia;headache, fever; hypokalaemia, hypomagnesaemia,hypocalcaemia, leucopenia, anaemia, thrombocytopenia,renal failure; rash, phlebitis; lesscommonly dyspepsia, constipation, hepatitis andcholestasis (see also Hepatotoxicity above), tastedisturbances, anorexia, palpitation, bradycardia,flushing, dyspnoea, sleep disturbances, anxiety, confusion,dizziness, tremor, pancytopenia, eosinophilia,hyponatraemia, hyperkalaemia, hypophosphataemia,hyperhidrosis, and pruritus; rarely haemolytic anaemiaIndication and doseInvasive candidiasis. By intravenous infusionNeonate 2 mg/kg once daily (increased to 4 mg/kg daily if inadequate response) for at least 14 daysChild 1 month–18 years, body-weight under40 kg 2 mg/kg once daily (increased to 4 mg/kgdaily if inadequate response) for at least 14 daysChild 1 month–18 years, body-weight over40 kg 100 mg once daily (increased to 200 mgdaily if inadequate response) for at least 14 daysOesophageal candidiasis. By intravenous infusionChild 16–18 years, body-weight under 40 kg3 mg/kg once dailyChild 16–18 years, body-weight over 40 kg150 mg once dailyProphylaxis of candidiasis in children undergoingbone-marrow transplantation or who areexpected to become neutropenic for over 10days. By intravenous infusionNeonate 1 mg/kg once daily; continue for at least7 days after neutrophil count in desirable rangeChild 1 month–18 years, body-weight under40 kg 1 mg/kg once daily; continue for at least 7days after neutrophil count in desirable rangeChild 1 month–18 years, body-weight over40 kg 50 mg once daily; continue for at least 7days after neutrophil count in desirable rangeAdministration for intravenous infusion reconstituteeach vial with 5 mL Glucose 5% or Sodium Chloride0.9%; gently rotate vial, without shaking, to dissolve;dilute requisite dose to a concentration of 0.5–2 mg/mL with Glucose 5% or Sodium Chloride 0.9%; protectinfusion from light; give over 60 minutes5 Infections

308 5.2.5 Other antifungals BNFC 2011–20125 InfectionsMycamine c (Astellas) TAIntravenous infusion, powder for reconstitution,micafungin (as sodium), net price 50-mg vial =£196.08; 100-mg vial = £341.005.2.5 Other antifungalsFlucytosine is used with amphotericin in a synergisticcombination. Bone marrow depression can occur whichlimits its use, particularly in children with AIDS; weeklyblood counts are necessary during prolonged therapy.Resistance to flucytosine can develop during therapyand sensitivity testing is essential before and duringtreatment. For the role of flucytosine in the treatmentof systemic candidiasis and cryptococcal meningitis, seep. 300.Griseofulvin is effective for widespread or intractabledermatophyte infections but has been superseded bynewer antifungals, particularly for nail infections.Griseofulvin is used in the treatment of tinea capitis. Itis the drug of choice for trichophyton infections inchildren, see p. 301. Duration of therapy is dependenton the site of the infection and may extend to a numberof months.Terbinafine is the drug of choice for fungal nail infectionsand is also used for ringworm infections whereoral treatment is considered appropriate (see p. 301.FLUCYTOSINECautions blood disorders; liver- and kidney-functiontests and blood counts required (weekly in blooddisorders); interactions: Appendix 1 (flucytosine)Renal impairment liver- and kidney-function testsand blood counts required weekly; use normal doseevery 12 hours if creatinine clearance 20–40 mL/minute; use normal dose every 24 hours if creatinineclearance 10–20 mL/minute; use initial normal dose ifcreatinine clearance less than 10 mL/minute and thenadjust dose according to plasma-flucytosine concentrationPregnancy teratogenic in animal studies; manufactureradvises use only if potential benefit outweighsriskBreast-feeding manufacturer advises avoidSide-effects nausea, vomiting, diarrhoea, rashes; lessfrequently cardiotoxicity, confusion, hallucinations,convulsions, headache, sedation, vertigo, alterationsin liver function tests (hepatitis and hepatic necrosisreported), and toxic epidermal necrolysis; blood disordersincluding thrombocytopenia, leucopenia, andaplastic anaemia reportedPharmacokinetics for plasma-concentration monitoringblood should be taken shortly before startingthe next infusion. Plasma concentration for optimumresponse 25–50 mg/litre (200–400 micromol/litre)—should not be allowed to exceed 80 mg/litre(620 micromol/litre)Licensed use tablets not licensedIndication and doseSystemic yeast and fungal infections, adjunctto amphotericin in severe systemic candidiasisand in other severe or long-standing infections. By intravenous infusion or by mouthNeonate 50 mg/kg every 12 hoursChild 1 month–18 years 50 mg/kg every 6 hours;extremely sensitive organisms, 25–37.5 mg/kgevery 6 hours may be sufficient; treatment continuedusually for not more than 7 daysCryptococcal meningitis (adjunct to amphotericin,see Cryptococcosis, p. 301). By intravenous infusion or by mouthNeonate 50 mg/kg every 12 hoursChild 1 month–18 years 25 mg/kg every 6 hoursfor 2 weeksAdministration for intravenous infusion, give over20–40 minutesAncotil c (Meda) AIntravenous infusion, flucytosine 10 mg/mL. Netprice 250-mL infusion bottle = £30.33 (hosp. only)Electrolytes Na + 34.5 mmol/250-mL bottleNote Flucytosine tablets may be available from ‘special-order’manufacturers or specialist importing companies, see p. 809Extemporaneous formulations available seeExtemporaneous Preparations, p. 6GRISEOFULVINCautions interactions: Appendix 1 (griseofulvin)Skilled tasks May impair performance of skilled tasks;effects of alcohol enhancedContra-indications systemic lupus erythematosus(risk of exacerbation); acute porphyria (section 9.8.2)Hepatic impairment avoid in severe liver diseasePregnancy avoid (fetotoxicity and teratogenicity inanimals); effective contraception required during andfor at least 1 month after administration to women(important: effectiveness of oral contraceptives maybe reduced, additional contraceptive precautions e.g.barrier method, required); also males should avoidfathering a child during and for at least 6 months aftertreatmentBreast-feeding avoid—no information availableSide-effects nausea, vomiting, diarrhoea, headache;also reported, abdominal pain, dyspepsia, hepatotoxicity,glossitis, taste disturbances, sleep disturbances,dizziness, fatigue, confusion, agitation,depression, impaired co-ordination and hearing, peripheralneuropathy, menstrual disturbances, renalfailure, leucopenia, systemic lupus erythematosus,rash (including rarely erythema multiforme, toxicepidermal necrolysis), and photosensitivityLicensed use tablets licensed for use in children (agerange not specified by manufacturer); suspensionnot licensedIndication and doseDermatophyte infections where topical therapyhas failed or is inappropriate. By mouthChild 1 month–12 years 10 mg/kg (max. 500 mg)once daily or in divided doses; in severe infectiondose may be doubled, reducing when responseoccursChild 12–18 years 500 mg once daily or individed doses; in severe infection dose may bedoubled, reducing when response occurs

BNFC 2011–2012 5.3 Antiviral drugs 309Tinea capitis caused by Trichophyton tonsurans. By mouthChild 1 month–12 years 15–20 mg/kg (max. 1 g)once daily or in divided dosesChild 12–18 years 1 g once daily or in divideddosesGriseofulvin (Non-proprietary) ATablets, griseofulvin 125 mg, net price 100 = £34.86;500 mg, 100 = £90.34. Label: 9, 21, counselling, skilledtasksFulsovin c (Kappin) AOral suspension, griseofulvin 125 mg/5 mL, netprice 100 mL (peppermint-flavoured) = £59.90.Label: 9, 21, counselling, skilled tasksTERBINAFINECautions psoriasis (risk of exacerbation); autoimmmunedisease (risk of lupus-erythematosus-like effect)interactions: Appendix 1 (terbinafine)Hepatic impairment manufacturer advises avoid—elimination reducedRenal impairment use half normal dose if estimatedglomerular filtration rate less than 50 mL/minute/1.73 m 2 and no suitable alternative availablePregnancy manufacturer advises use only if benefitoutweighs risk—no information availableBreast-feeding avoid—present in milkSide-effects abdominal discomfort, anorexia, nausea,diarrhoea; headache; rash and urticaria occasionallywith arthralgia or myalgia; less commonly taste disturbance;rarely liver toxicity (including jaundice,cholestasis and hepatitis)—discontinue treatment,angioedema, dizziness, malaise, paraesthesia,hypoaesthesia, photosensitivity, serious skin reactions(including Stevens-Johnson syndrome and toxic epidermalnecrolysis)—discontinue treatment if progressiveskin rash; very rarely psychiatric disturbances,blood disorders (including incidence ofleucopenia higher and thrombocytopenia), lupuserythematosus-like effect, and exacerbation of psoriasisLicensed use not licensed for use in childrenIndication and doseDermatophyte infections of the nails, ringworminfections (including tinea pedis, cruris, corporis,and capitis) where oral therapy appropriate(due to site, severity or extent). By mouthChild over 1 year; body-weight 10–20 kg62.5 mg once dailyChild body-weight 20–40 kg 125 mg once dailyChild body-weight over 40 kg 250 mg once dailyNote treatment usually for 4 weeks in tinea capitis, 2–6weeks in tinea pedis, 2–4 weeks in tinea cruris, 4 weeks intinea corporis, 6 weeks–3 months in nail infections(occasionally longer in toenail infections)Fungal skin infections section 13.10.2Terbinafine (Non-proprietary) ATablets, terbinafine (as hydrochloride) 250 mg, netprice 14-tab pack = £2.33, 28-tab pack = £3.02.Label: 9Lamisil c (Novartis) ATablets, off-white, scored, terbinafine (as hydrochloride)250 mg, net price 14-tab pack = £21.30, 28-tab pack = £41.09. Label: 95.3 Antiviral drugs5.3.1 HIV infection5.3.2 Herpesvirus infections5.3.3 Viral hepatitis5.3.4 Influenza5.3.5 Respiratory syncytial virusThe majority of virus infections resolve spontaneouslyin immunocompetent subjects. A number of specifictreatments for viral infections are available, particularlyfor the immunocompromised. This section includesnotes on herpes simplex and varicella-zoster, humanimmunodeficiency virus, cytomegalovirus, respiratorysyncytial virus, viral hepatitis and influenza.5.3.1 HIV infectionThere is no cure for infection caused by the humanimmunodeficiency virus (HIV) but a number of drugsslow or halt disease progression. Drugs for HIV infection(antiretrovirals) may be associated with seriousside-effects. Although antiretrovirals increase life expectancyconsiderably and decrease the risk of complicationsassociated with premature ageing, mortality andmorbidity remain slightly higher than in uninfectedindividuals.The natural progression of HIV disease is different inchildren compared to adults; drug treatment shouldonly be undertaken by specialists within a formal paediatricHIV clinical network. Guidelines and dose regimensare under constant review and for this reasonsome dose recommendations have not been included inBNF for Children.Further information on the management of childrenwith HIV can be obtained from the Children’s HIVAssociation (CHIVA) www.chiva.org.uk; and furtherinformation on antiretroviral use and toxicity can beobtained from the Paediatric European Network forTreatment of AIDS (PENTA) websitewww.pentatrials.org.Principles of treatment Treatment is aimed atsuppressing viral replication for as long as possible; itshould be started before the immune system is irreversiblydamaged. The need for early drug treatmentshould, however, be balanced against the risk of toxicity.Commitment to treatment and strict adherence overmany years are required; the regimen chosen shouldtake into account convenience and the child’s toleranceof treatment. The development of drug resistance isreduced by using a combination of drugs; such combinationsshould have synergistic or additive activity whileensuring that their toxicity is not additive. It is recommendedthat viral sensitivity to antiretroviral drugs is5 Infections

310 5.3.1 HIV infection BNFC 2011–20125 Infectionsestablished before starting treatment or before switchingdrugs if the infection is not responding.Initiation of treatment Treatment is started in allHIV infected children under 1 year of age regardless ofclinical and immunological parameters. In children over1 year of age, treatment is based on the child’s age, CD4cell count, viral load, and symptoms. The choice ofantiviral treatment for children should take into accountthe method and frequency of administration, risk ofside-effects, compatibility of drugs with food, palatability,and the appropriateness of the formulation. Initiatingtreatment with a combination of drugs (‘highly activeantiretroviral therapy’ which includes 2 nucleosidereverse transcriptase inhibitors with either a nonnucleosidereverse transcriptase inhibitor or a boostedprotease inhibitor) is recommended. Abacavir and lamivudineare the nucleoside reverse transcriptase inhibitorsof choice for initial therapy; however, zidovudineand lamivudine are used in children who are positive forthe HLA-B*5701 allele. Nevirapine is the preferred nonnucleosidereverse transcriptase inhibitor in childrenunder 3 years of age, but efavirenz is preferred inolder children. Lopinavir with ritonavir is the preferredboosted protease inhibitor for initial therapy. Themetabolism of many antiretrovirals varies in youngchildren; it may therefore be necessary to adjust thedose according to the plasma-drug concentration. Childrenwho require treatment for both HIV and chronichepatitis B should receive antivirals that are activeagainst both diseases (section 5.3.3).Switching therapy Deterioration of the condition(including clinical, virological changes, and CD4 cellchanges) may require a complete change of therapy.The choice of an alternative regimen depends on factorssuch as the response to previous treatment, tolerance,and the possibility of cross-resistance.Pregnancy Treatment of HIV infection in pregnancyaims to reduce the risk of toxicity to the fetus (althoughthe teratogenic potential of most antiretroviral drugs isunknown), to minimise the viral load and disease progressionin the mother, and to prevent transmission ofinfection to the neonate. All treatment options requirecareful assessment by a specialist. Zidovudine monotherapyreduces transmission of infection to the neonate.However, combination antiretroviral therapy maximisesthe chance of preventing transmission andrepresents optimal therapy for the mother. Combinationantiretroviral therapy may be associated with a greaterrisk of preterm delivery. Local protocols and nationalguidelines (www.bhiva.org) should be consulted forrecommendations on treatment during pregnancy andthe perinatal period.Breast-feeding Breast-feeding by HIV-positivemothers may cause HIV infection in the infant andshould be avoided.Post-exposure prophylaxis Children exposed toHIV infection through needlestick injury or by anotherroute should be sent immediately to an accident andemergency department for post-exposure prophylaxis[unlicensed indication]. Antiretrovirals for prophylaxisare chosen on the basis of efficacy and potential fortoxicity. Recommendations have been developed by theChildren’s HIV Association, www.chiva.org.uk.Drugs used for HIV infection Zidovudine, a nucleosidereverse transcriptase inhibitor (or ‘nucleoside analogue’),was the first anti-HIV drug to be introduced.Other nucleoside reverse transcriptase inhibitorsinclude abacavir, didanosine, emtricitabine, lamivudine,stavudine, and tenofovir. There are concernsabout renal toxicity and effects on bone mineralisationwhen tenofovir is used in prepubertal children.The protease inhibitors include atazanavir, darunavir,fosamprenavir (a pro-drug of amprenavir), indinavir,lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.Indinavir is no longer recommended because it isassociated with nephrolithiasis. Ritonavir in low dosesboosts the activity of atazanavir, darunavir, fosamprenavir,lopinavir, saquinavir, and tipranavir increasing thepersistence of plasma concentrations of these drugs; atsuch a low dose, ritonavir has no intrinsic antiviralactivity. A combination of lopinavir with low-dose ritonaviris available for use in children. The protease inhibitorsare metabolised by cytochrome P450 enzymesystems and therefore have a significant potential fordrug interactions. Protease inhibitors are associatedwith lipodystrophy and metabolic effects (see below).The non-nucleoside reverse transcriptase inhibitors efavirenz,etravirine, and nevirapine are active againstthe subtype HIV-1 but not HIV-2, a subtype that is rarein the UK. These drugs may interact with a number ofdrugs metabolised in the liver. Nevirapine is associatedwith a high incidence of rash (including Stevens-Johnsonsyndrome) and rarely fatal hepatitis. Rash is alsoassociated with efavirenz and etravirine but it is usuallymilder. Psychiatric or CNS disturbances are commonwith efavirenz. CNS disturbances are often self-limitingand can be reduced by taking the dose at bedtime(especially in the first 2–4 weeks of treatment). Efavirenzhas also been associated with an increased plasmacholesterol concentration. Etravirine is used in regimenscontaining a boosted protease inhibitor for HIV infectionresistant to other non-nucleoside reverse transcriptaseinhibitors and protease inhibitors.Enfuvirtide, which inhibits the fusion of HIV to the hostcell, is licensed for managing infection that has failed torespond to a regimen of other antiretroviral drugs.Enfuvirtide should be combined with other potentiallyactive antiretroviral drugs; it is given by subcutaneousinjection.Maraviroc is an antagonist of the CCR5 chemokinereceptor. It is used in patients exclusively infectedwith CCR5–tropic HIV.Raltegravir is an inhibitor of HIV integrase. It is used forthe treatment of HIV infection resistant to multipleantiretrovirals.Immune reconstitution syndrome Improvement inimmune function as a result of antiretroviral treatmentmay provoke a marked inflammatory reaction againstresidual opportunistic organisms.Lipodystrophy syndrome Metabolic effects associatedwith antiretroviral treatment include fat redistribution,insulin resistance, and dyslipidaemia; collectivelythese have been termed lipodystrophysyndrome. Children should be encouraged to lead ahealthy lifestyle that reduces their long-term cardiovascularrisk. Plasma lipids and blood glucose should bemeasured before starting antiretroviral therapy, after 3–6 months of treatment, and then at least annually. Insu-

BNFC 2011–2012 5.3.1 HIV infection 311lin resistance and hyperglycaemia occur only rarely inchildren.Fat redistribution (with loss of subcutaneous fat,increased abdominal fat, ‘buffalo hump’ and breastenlargement) is associated with regimens containingprotease inhibitors and nucleoside reverse transcriptaseinhibitors. Stavudine, and to a lesser extent zidovudine,are associated with a higher risk of lipoatrophy andshould be used only if alternative regimens are notsuitable.Dyslipidaemia is associated with antiretroviral treatment,particularly with protease inhibitors; in children,hypercholesterolaemia appears to be more commonthan hypertriglyceridaemia. Protease inhibitors andsome nucleoside reverse transciptase inhibitors areassociated with insulin resistance and hyperglycaemia,but they occur rarely in children. Of the protease inhibitors,atazanavir and darunavir are less likely to causedyslipidaemia, while saquinavir and atazanavir are lesslikely to impair glucose tolerance.Osteonecrosis Osteonecrosis has been reported inchildren with advanced HIV disease or following longtermexposure to combination antiretroviral therapy.Nucleoside reverse transcriptaseinhibitorsCautionsLactic acidosis Life-threatening lactic acidosis associatedwith hepatomegaly and hepatic steatosis hasbeen reported with nucleoside reverse transcriptaseinhibitors. They should be used with caution in childrenwith hepatomegaly, hepatitis (especially hepatitis Ctreated with interferon alfa and ribavirin), liver-enzymeabnormalities and with other risk factors for liver diseaseand hepatic steatosis. Treatment with the nucleosidereverse transcriptase inhibitor should be discontinuedin case of symptomatic hyperlactataemia, lacticacidosis, progressive hepatomegaly or rapid deteriorationof liver function. Stavudine, especially with didanosine,is associated with a higher risk of lactic acidosisand should be used only if alternative regimens are notsuitable.Hepatic impairment Nucleoside reverse transcriptaseinhibitors should be used with caution in childrenwith hepatic impairment (greater risk of hepatic sideeffects,see also Lactic Acidosis above). However, somenucleoside reverse transcriptase inhibitors are used inchildren who also have chronic hepatitis B.Pregnancy See p. 310Breast-feeding See p. 310Side-effects Side-effects of the nucleoside reversetranscriptase inhibitors include gastro-intestinal disturbances(such as nausea, vomiting, abdominal pain,flatulence and diarrhoea), anorexia, pancreatitis, liverdamage (see also Lactic Acidosis, above), dyspnoea,cough, headache, insomnia, dizziness, fatigue, blooddisorders (including anaemia, neutropenia, and thrombocytopenia),myalgia, arthralgia, rash, urticaria, andfever. See notes above for Lipodystrophy Syndrome(p. 310) and Osteonecrosis (above).ABACAVIRCautions see notes above; also test for HLA-B*5701allele before treatment (or if re-starting treatment andHLA-B*5701 status not known)—increased risk ofhypersensitivity reaction in presence of HLA-B*5701allele; interactions: Appendix 1 (abacavir)Hypersensitivity reactions Life-threatening hypersensitivityreactions reported—characterised by fever or rash andpossibly nausea, vomiting, diarrhoea, abdominal pain, dyspnoea,cough, lethargy, malaise, headache, and myalgia; lessfrequently mouth ulceration, oedema, hypotension, sorethroat, acute respiratory distress syndrome, anaphylaxis,paraesthesia, arthralgia, conjunctivitis, lymphadenopathy,lymphocytopenia and renal failure; rarely myolysis; laboratoryabnormalities may include raised liver function tests(see Lactic Acidosis above) and creatine kinase; symptomsusually appear in the first 6 weeks, but may occur at anytime; monitor for symptoms every 2 weeks for 2 months;discontinue immediately if any symptom of hypersensitivitydevelops and do not rechallenge (risk of more severehypersensitivity reaction); discontinue if hypersensitivitycannot be ruled out, even when other diagnoses possible—ifrechallenge necessary it must be carried out in hospitalsetting; if abacavir is stopped for any reason other thanhypersensitivity, exclude hypersensitivity reaction as thecause and rechallenge only if medical assistance is readilyavailable; care needed with concomitant use of drugs whichcause skin toxicityCounselling Children and carers should be told the importanceof regular dosing (intermittent therapy may increasethe risk of sensitisation), how to recognise signs of hypersensitivity,and advised to seek immediate medical attentionif symptoms develop or before re-starting treatment; childrenor their carers should be advised to keep Alert Cardwith them at all timesHepatic impairment see notes above; also avoid inmoderate impairment unless essential; avoid in severeimpairmentRenal impairment manufacturer advises avoid inend-stage renal disease; avoid Kivexa c or Trizivir c ifestimated glomerular filtration rate less than 50 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid (toxicity inanimal studies); see also Pregnancy, p. 310Breast-feeding see p. 310Side-effects see notes above; also hypersensitivityreactions (see above); very rarely Stevens-Johnsonsyndrome and toxic epidermal necrolysis; rash andgastro-intestinal disturbances more common in childrenLicensed use Trizivir c not licensed for use inchildrenIndication and doseHIV infection in combination with other antiretroviraldrugs. By mouthChild 3 months–12 years 8 mg/kg (max. 300 mg)twice daily or 16 mg/kg (max. 600 mg) once dailyorBody-weight 14–21 kg 150 mg twice daily or300 mg once dailyBody-weight 21–30 kg 150 mg in the morningand 300 mg in the evening or 450 mg once dailyBody-weight over 30 kg 300 mg twice daily or600 mg once dailyChild 12–18 years 300 mg twice daily or 600 mgonce daily5 Infections

312 5.3.1 HIV infection BNFC 2011–2012Ziagen c (ViiV) ATablets, yellow, f/c, scored, abacavir (as sulphate)300 mg, net price 60-tab pack = £208.95. Counselling,hypersensitivity reactionsOral solution, sugar-free, banana and strawberryflavoured, abacavir (as sulphate) 20 mg/mL, net price240-mL = £55.72. Counselling, hypersensitivity reactionsExcipients include propylene glycolWith lamivudineFor cautions, contra-indications and side-effects seeunder individual drugsKivexa c (ViiV) ATablets, orange, f/c, abacavir (as sulphate) 600 mg,lamivudine 300 mg, net price 30-tab pack = £352.25.Counselling, hypersensitivity reactionsDoseHIV infection in combination with other antiretroviraldrugs. By mouthChild 12–18 years and body-weight over 40 kg 1tablet once dailySide-effects see notes above; also pancreatitis (lesscommon in children, see also under Cautions), liverfailure, anaphylactic reactions, peripheral neuropathy(switch to another antiretroviral if peripheral neuropathydevelops), diabetes mellitus, hypoglycaemia,acute renal failure, rhabdomyolysis, dry eyes, retinaland optic nerve changes, dry mouth, parotid glandenlargement, sialadenitis, alopecia, hyperuricaemia(suspend if raised significantly)Licensed use tablets not licensed for use in childrenunder 3 months; EC capsules not licensed for use inchildren under 6 yearsIndication and doseHIV infection in combination with other antiretroviraldrugs. By mouthNeonate 14–28 days 50–100 mg/m 2 twice dailyChild 1–8 months 50–100 mg/m 2 twice dailyChild 8 months–18 years 180–240 mg/m 2 oncedaily; usual dose 200 mg/m 2 once daily; max.400 mg daily5 InfectionsWith lamivudine and zidovudineNote use only if child is stabilised (for 6–8 weeks) on theindividual components in the same proportions. For cautions,contra-indications and side-effects see under individualdrugsTrizivir c (ViiV) ATablets, blue-green, f/c, abacavir (as sulphate)300 mg, lamivudine 150 mg, zidovudine 300 mg, netprice 60-tab pack = £509.06. Counselling, hypersensitivityreactionsDoseHIV infection. By mouthChild body-weight over 30 kg 1 tablet twice dailyDIDANOSINE(ddI, DDI)Cautions see notes above; also history of pancreatitis(preferably avoid, otherwise extreme caution, see alsobelow); peripheral neuropathy or hyperuricaemia (seeunder Side-effects); ophthalmological examination(including visual acuity, colour vision, and dilatedfundus examination) recommended annually or ifvisual changes occur; interactions: Appendix 1(didanosine)Pancreatitis If symptoms of pancreatitis develop or if serumlipase is raised and pancreatitis is confirmed, discontinuetreatment. Whenever possible avoid concomitant treatmentwith other drugs known to cause pancreatic toxicity (e.g.intravenous pentamidine isetionate); monitor closely if concomitanttherapy unavoidable. Since significant elevations oftriglycerides cause pancreatitis monitor closely if triglycerideselevatedHepatic impairment see notes aboveRenal impairment reduce dose if estimated glomerularfiltration rate less than 60 mL/minute/1.73 m 2 ;consult product literaturePregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding see p. 310Videx c (Bristol-Myers Squibb) ATablets, with calcium and magnesium antacids,didanosine 25 mg, net price 60-tab pack = £25.06.Label: 23, counselling, administration, see belowExcipients include aspartame equivalent to phenylalanine 36.5 mg pertablet (section 9.4.1)Note Antacids in formulation may affect absorption of otherdrugs—see interactions: Appendix 1 (antacids)Administration to ensure sufficient antacid, each dose to betaken as at least 2 tablets (child under 1 year 1 tablet) chewedthoroughly, crushed or dispersed in water; clear apple juice maybe added for flavouring; tablets to be taken 2 hours after lopinavirwith ritonavir capsules and oral solution or atazanavir with ritonavirVidex c EC capsules, enclosing e/c granules, didanosine125 mg, net price 30-cap pack = £48.18;200 mg, 30-cap pack = £77.09; 250 mg, 30-cap pack =£96.37; 400 mg, 30-cap pack = £154.19. Label: 25,counselling, administration, see belowAdministration capsules should be swallowed whole and taken atleast 2 hours before or 2 hours after foodEMTRICITABINE(FTC)Cautions see notes above; also on discontinuation,monitor patients with hepatitis B (risk of exacerbationof hepatitis); interactions: Appendix 1 (emtricitabine)Hepatic impairment see notes above and CautionsaboveRenal impairment reduce dose or increase dosageinterval if estimated glomerular filtration rate lessthan 50 mL/minute/1.73 m 2 ; consult product literaturePregnancy manufacturer advises use only if essential—noinformation availableBreast-feeding see p. 310Side-effects see notes above; also abnormal dreams,pruritus, and hyperpigmentationIndication and doseSee preparations

BNFC 2011–2012 5.3.1 HIV infection 313Emtriva c (Gilead) ACapsules, white/blue, emtricitabine 200 mg, net price30-cap pack = £163.50DoseHIV infection in combination with other antiretroviraldrugs. By mouthChild body-weight over 33 kg 200 mg once dailyOral solution, orange, emtricitabine 10 mg/mL, netprice 170-mL pack (candy-flavoured) = £46.50Electrolytes Na + 460 micromol/mLDoseHIV infection in combination with other antiretroviraldrugs. By mouthChild 4 months–18 yearsBody-weight under 33 kg 6 mg/kg once dailyBody-weight over 33 kg 240 mg once dailyNote 240 mg oral solution : 200 mg capsule; where appropriatethe capsule may be used instead of the oral solutionWith tenofovirSee under TenofovirWith efavirenz and tenofovirSee under TenofovirLAMIVUDINE(3TC)Cautions see notes above; interactions: Appendix 1(lamivudine)Chronic hepatitis B Recurrent hepatitis in patients withchronic hepatitis B may occur on discontinuation of lamivudine.When treating chronic hepatitis B with lamivudine,monitor liver function tests every 3 months, and viral andserological markers of hepatitis B every 3–6 months, morefrequently in patients with advanced liver disease or followingtransplantation (monitoring to continue for at least 1 yearafter discontinuation)Hepatic impairment see notes above and CautionsaboveRenal impairment reduce dose if estimated glomerularfiltration rate less than 50 mL/minute/1.73 m 2 ;consult product literaturePregnancy see p. 310Breast-feeding can be used with caution in womeninfected with chronic hepatitis B alone, providingadequate measures are taken to prevent hepatitis Binfection in infants; for women infected with HIV, seep. 310Side-effects see notes above; also peripheral neuropathy,muscle disorders including rhabdomyolysis,nasal symptoms, alopeciaLicensed use Epivir c not licensed for use in childrenunder 3 months; Zeffix c not licensed for use inchildrenIndication and doseSee preparationsEpivir c (ViiV) ATablets, f/c, lamivudine 150 mg (scored, white), netprice 60-tab pack = £143.32; 300 mg (grey), 30-tabpack = £157.51Oral solution, banana- and strawberry-flavoured,lamivudine 50 mg/5 mL, net price 240-mL pack =£39.01Excipients include sucrose 1 g/5 mLDoseHIV infection in combination with other antiretroviraldrugs. By mouthChild 1–3 months 4 mg/kg twice dailyChild 3 months–12 years 4 mg/kg (max. 150 mg) twicedaily or 8 mg/kg (max. 300 mg) once dailyorBody-weight 14–21 kg 75 mg twice daily or 150 mgonce dailyBody-weight 21–30 kg 75 mg in the morning and150 mg in the evening or 225 mg once dailyBody-weight over 30 kg 150 mg twice daily or 300 mgonce dailyChild 12–18 years 150 mg twice daily or 300 mg oncedailyZeffix c (ViiV) ATablets, brown, f/c, lamivudine 100 mg, net price 28-tab pack = £78.09DoseChronic hepatitis B infection either with compensatedliver disease (with evidence of viral replicationand histology of active liver inflammation or fibrosis)when first-line treatments cannot be used, or (incombination with another antiviral drug withoutcross-resistance to lamivudine) with decompensatedliver disease. By mouthChild 2–12 years 3 mg/kg (max. 100 mg) once dailyChild 12–18 years 100 mg once dailyNote Children receiving lamivudine for concomitant HIVinfection should continue to receive lamivudine in a doseappropriate for HIV infectionWith abacavirSee under AbacavirWith zidovudineSee under ZidovudineWith abacavir and zidovudineSee under AbacavirSTAVUDINE(d4T)Cautions see notes above; also history of peripheralneuropathy, excessive alcohol intake, concomitantuse of isoniazid—risk of peripheral neuropathy (seeunder Side-effects); history of pancreatitis or concomitantuse with other drugs associated with pancreatitis;interactions: Appendix 1 (stavudine)Hepatic impairment see notes aboveRenal impairment risk of peripheral neuropathy;reduce dose to 50% if estimated glomerular filtrationrate 25–50 mL/minute/1.73 m 2 ; reduce dose to 25%if estimated glomerular filtration rate less than 25 mL/minute/1.73 m 2Pregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding see p. 3105 Infections

314 5.3.1 HIV infection BNFC 2011–20125 InfectionsSide-effects see notes above; also peripheral neuropathy(switch to another antiretroviral if peripheralneuropathy develops), abnormal dreams, cognitivedysfunction, drowsiness, depression, pruritus; lesscommonly anxiety, gynaecomastiaLicensed use capsules not licensed for use in childrenunder 3 monthsIndication and doseHIV infection in combination with other antiretroviraldrugs when no suitable alternativeavailable and when prescribed for shortestperiod possible. By mouthChild 1 month–18 yearsBody-weight under 30 kg 1 mg/kg twice daily,preferably at least 1 hour before foodBody-weight 30–60 kg 30 mg twice daily, preferablyat least 1 hour before foodBody-weight over 60 kg 40 mg twice daily, preferablyat least 1 hour before foodZerit c (Bristol-Myers Squibb) ACapsules, stavudine 20 mg (brown), net price 56-cappack = £139.46; 30 mg (light orange/dark orange), 56-cap pack = £146.25; 40 mg (dark orange), 56-cap pack= £150.66 (all hosp. only)Oral solution, cherry-flavoured, stavudine for reconstitutionwith water, 1 mg/mL, net price 200 mL =£22.94TENOFOVIR DISOPROXILCautions see notes above; also test renal function andserum phosphate before treatment, then every 4weeks (more frequently if at increased risk of renalimpairment) for 1 year and then every 3 months,interrupt treatment if renal function deteriorates orserum phosphate decreases; concomitant or recentuse of nephrotoxic drugs; on discontinuation, monitorpatients with hepatitis B (risk of exacerbation ofhepatitis); interactions: Appendix 1 (tenofovir)Hepatic impairment see notes above and CautionsaboveRenal impairment increase dose interval if estimatedglomerular filtration rate less than 50 mL/minute/1.73 m 2 ; avoid Atripla c if estimated glomerularfiltration rate less than 50 mL/minute/1.73 m 2 ; avoidTruvada c if estimated glomerular filtration rate lessthan 30 mL/minute/1.73 m 2Pregnancy manufacturer advises use only if potentialbenefit outweighs risk—no information availableBreast-feeding see p. 310Side-effects see notes above; also hypophosphataemia;rarely renal failure, proximal renal tubulopathy,nephrogenic diabetes insipidus; also reported reducedbone densityLicensed use not licensed for use in childrenIndication and doseHIV infection in combination with other antiretroviraldrugsFor dose, consult Guidelines (see notes above)Viread c (Gilead) TATablets, f/c, blue, tenofovir disoproxil (as fumarate)245 mg, net price 30-tab pack = £255.00. Label: 21,counselling, administrationCounselling Children with swallowing difficulties may dispersetablet in half a glass of water, orange juice, or grapejuice (but bitter taste)With emtricitabineFor cautions, contra-indications, and side-effectssee under individual drugsTruvada c (Gilead) ATablets, blue, f/c, tenofovir disoproxil (as fumarate)245 mg, emtricitabine 200 mg, net price 30-tab pack =£418.50. Label: 21, Counselling, administrationChildren with swallowing difficulties may disperse tablet inhalf a glass of water, orange juice, or grape juice (but bittertaste)With efavirenz and emtricitabineFor cautions, contra-indications, and side-effectssee under individual drugsAtripla c (Gilead) ATablets, pink, f/c, efavirenz 600 mg, emtricitabine200 mg, tenofovir disoproxil (as fumarate) 245 mg, netprice 30-tab pack = £626.90. Label: 23, 25ZIDOVUDINE(Azidothymidine, AZT)Note The abbreviation AZT which is sometimes used forzidovudine has also been used for another drugCautions see notes above; also haematological toxicityparticularly with high dose and advanced disease—monitorfull blood count after 4 weeks oftreatment, then every 3 months; vitamin B 12 deficiency(increased risk of neutropenia); if anaemia ormyelosuppression occur, reduce dose or interrupttreatment according to product literature, or considerother treatment; interactions: Appendix 1 (zidovudine)Contra-indications abnormally low neutrophil countor haemoglobin concentration (consult product literature);neonates with hyperbilirubinaemia requiringtreatment other than phototherapy, or with raisedtransaminase (consult product literature); acute porphyria(section 9.8.2)Hepatic impairment see notes above; also accumulationmay occurRenal impairment reduce dose if estimated glomerularfiltration rate less than 10 mL/minute/1.73 m 2 ;consult product literaturePregnancy limited information available; manufactureradvises use only if clearly indicated; see alsop. 310Breast-feeding see p. 310Side-effects see notes above; also anaemia (mayrequire transfusion), taste disturbance, chest pain,influenza-like symptoms, paraesthesia, neuropathy,convulsions, dizziness, drowsiness, anxiety, depression,loss of mental acuity, myopathy, gynaecomastia,urinary frequency, sweating, pruritus, pigmentation ofnails, skin and oral mucosa

BNFC 2011–2012 5.3.1 HIV infection 315Indication and doseHIV infection in combination with other antiretroviraldrugs. By mouthChild 1 month–18 years 180 mg/m 2 (max.300 mg) twice dailyorBody-weight 4–9 kg 12 mg/kg twice dailyBody-weight 9–30 kg 9 mg/kg twice dailyBody-weight over 30 kg 250–300 mg twice dailyorBody-weight 8–14 kg 100 mg twice dailyBody-weight 14–21 kg 100 mg in the morningand 200 mg in the eveningBody-weight 21–28 kg 200 mg twice dailyBody-weight 28–30 kg 200–250 mg twice daily. By intravenous infusion over 1 hour in childrentemporarily unable to take zidovudine bymouthChild 3 months–12 years 60–80 mg/m 2 every 6hours (approximating to 9–12 mg/kg twice dailyby mouth) usually for not more than 2 weeksChild 12–18 years 0.8–1 mg/kg every 4 hours(approximating to 1.2–1.5 mg/kg every 4 hours bymouth) usually for not more than 2 weeksPrevention of maternal-fetal HIV transmissionseek specialist advice (combination therapy preferred)Administration for intermittent intravenous infusion,dilute to a concentration of 2 mg/mL or 4 mg/mLwith Glucose 5% and give over 1 hour.For administration by mouth, Combivir c tablets maybe crushed and mixed with semi-solid food or liquidjust before administrationZidovudine (Non-proprietary) ACapsules, zidovudine 100 mg, net price 60-cap pack= £50.17; 250 mg, 60-cap pack = £125.44Retrovir c (ViiV) ACapsules, zidovudine 100 mg (white/blue band), netprice 100-cap pack = £104.54; 250 mg (blue/white/dark blue band), 40-cap pack = £104.54Oral solution, sugar-free, strawberry-flavoured,zidovudine 50 mg/5 mL, net price 200-mL pack with10-mL oral syringe = £20.91Injection, zidovudine 10 mg/mL. For dilution and useas an intravenous infusion. Net price 20-mL vial =£10.50With lamivudineFor cautions, contra-indications, and side-effectssee under individual drugsCombivir c (ViiV) ATablets, f/c, zidovudine 300 mg, lamivudine 150 mg,net price 60-tab pack = £300.12DoseHIV infection in combination with other antiretrovirals. By mouthChild body-weight 14–21 kg half a tablet twice dailyChild body-weight 21–30 kg half a tablet in the morningand one tablet in the eveningChild body-weight over 30 kg one tablet twice dailyWith abacavir and lamivudineSee under AbacavirProtease inhibitorsCautionsProtease inhibitors should be used withcaution in diabetes (see also Lipodystrophy Syndrome,p. 310). Caution is also needed in children with haemophiliawho may be at increased risk of bleeding.Contra-indications Protease inhibitors should not begiven to patients with acute porphyria (but see section9.8.2).Hepatic impairment Protease inhibitors should beused with caution in children with chronic hepatitis B orC (increased risk of hepatic side-effects).Pregnancy See p. 310Breast-feeding See p. 310Side-effects Side-effects of the protease inhibitorsinclude gastro-intestinal disturbances (including diarrhoea,nausea, vomiting, abdominal pain, flatulence),anorexia, hepatic dysfunction, pancreatitis; blood disordersincluding anaemia, neutropenia, and thrombocytopenia;sleep disturbances, fatigue, headache, dizziness,paraesthesia, myalgia, myositis, rhabdomyolysis;taste disturbances; rash, pruritus, Stevens-Johnsonsyndrome, hypersensitivity reactions including anaphylaxis;see also Lipodystrophy Syndrome (p. 310) andOsteonecrosis (p. 311).ATAZANAVIRCautions see notes above; concomitant use with drugsthat prolong PR interval; cardiac conduction disorders;predisposition to QT interval prolongation(including electrolyte disturbances, concomitant useof drugs that prolong QT interval); interactions:Appendix 1 (atazanavir)Contra-indications see notes aboveHepatic impairment see notes above; also use withcaution in mild impairment; avoid in moderate tosevere impairmentPregnancy manufacturer advises use only if potentialbenefit outweighs risk; theoretical risk of hyperbilirubinaemiain neonate if used at termBreast-feeding see p. 310Side-effects see notes above; also AV block; lesscommonly mouth ulcers, dry mouth, hypertension,syncope, chest pain, dyspnoea, peripheral neuropathy,abnormal dreams, amnesia, disorientation, depression,anxiety, weight changes, increased appetite,gynaecomastia, nephrolithiasis, urinary frequency,haematuria, proteinuria, arthralgia, and alopecia;rarely hepatosplenomegaly, oedema, palpitation, andabnormal gait; also reported cholelithiasis, cholecystitis,and torsade de pointes5 Infections

316 5.3.1 HIV infection BNFC 2011–20125 InfectionsIndication and doseHIV infection in combination with other antiretroviraldrugs. By mouthWith low-dose ritonavirChild 6–18 yearsBody-weight 15–20 kg 150 mg once dailyBody-weight 20–40 kg 200 mg once dailyBody-weight over 40 kg 300 mg once dailyReyataz c (Bristol-Myers Squibb) TACapsules, atazanavir (as sulphate) 150 mg (dark blue/light blue), net price 60-cap pack = £303.38; 200 mg(dark blue), 60-cap pack = £303.38; 300 mg (red/blue), 30-cap pack = £303.38. Label: 5, 21DARUNAVIRCautions see notes above; also sulfonamide sensitivity;monitor liver function before and during treatment;interactions: Appendix 1 (daruanvir)Rash Mild to moderate rash occurs commonly, usuallywithin the first 4 weeks of therapy and resolves withoutstopping treatment. Severe skin rash (including Stevens-Johnson syndrome and toxic epidermal necrolysis) occursless frequently and may be accompanied by fever, malaise,arthralgia, myalgia, oral lesions, conjunctivitis, hepatitis, oreosinophilia; treatment should be stopped if severe rashdevelopsContra-indications see notes aboveHepatic impairment see notes above; also manufactureradvises caution in mild to moderate impairment;avoid in severe impairment—no information availablePregnancy manufacturer advises use only if potentialbenefit outweighs risk—no information availableBreast-feeding see p. 310Side-effects see notes above; also haematemesis,myocardial infarction, chest pain, QT interval prolongation,syncope, bradycardia, tachycardia, palpitation,hypertension, flushing, peripheral oedema,dyspnoea, cough, peripheral neuropathy, anxiety,confusion, memory impairment, depression, abnormaldreams, convulsions, increased appetite, weightchanges, pyrexia, hypothyroidism, osteoporosis,gynaecomastia, erectile dysfunction, reduced libido,dysuria, polyuria, nephrolithiasis, renal failure, arthralgia,visual disturbances, dry eyes, conjunctivalhyperaemia, rhinorrhoea, throat irritation, dry mouth,stomatitis, nail discoloration, acne, seborrhoeicdermatitis, eczema, increased sweating, and alopeciaIndication and doseIn combination with other antiretroviral drugs,for HIV infection resistant to other proteaseinhibitors in children previously treated withantiretrovirals. By mouthWith low-dose ritonavirChild 6–18 yearsBody-weight 20–30 kg 375 mg twice dailyBody-weight 30–40 kg 450 mg twice dailyBody-weight over 40 kg 600 mg twice dailyPrezista c (Janssen) TATablets, f/c, darunavir (as ethanolate) 75 mg (white),net price 480-tab pack = £446.70; 150 mg (white),240-tab pack = £446.70; 400 mg (light orange), 60-tabpack = £297.80; 600 mg (orange), 60-tab pack =£446.70. Label: 21FOSAMPRENAVIRNote Fosamprenavir is a pro-drug of amprenavirCautions see notes above; interactions: Appendix 1(fosamprenavir)Rash Rash may occur, usually in the second week of therapy;discontinue permanently if severe rash with systemic orallergic symptoms or, mucosal involvement; if rash mild ormoderate, may continue without interruption—usuallyresolves within 2 weeks and may respond to antihistaminesContra-indications see notes aboveHepatic impairment see notes above; also manufactureradvises caution in mild impairment; reduce dosein moderate to severe impairmentPregnancy toxicity in animal studies; manufactureradvises use only if potential benefit outweighs riskBreast-feeding see p. 310Side-effects see notes above; also reported, rashincluding rarely Stevens-Johnson syndrome (see alsoRash above)Indication and doseHIV infection in combination with other antiretroviraldrugs. By mouthWith low-dose ritonavirChild 6–18 yearsBody-weight 25–39 kg 18 mg/kg (max. 700 mg)twice dailyBody-weight over 39 kg 700 mg twice dailyNote 700 mg fosamprenavir is equivalent to approx. 600 mgamprenavirTelzir c (ViiV) ATablets, f/c, pink, fosamprenavir (as calcium) 700 mg,net price 60-tab pack = £258.97Oral suspension, fosamprenavir (as calcium) 50 mg/mL, net price 225-mL pack (grape-bubblegum-andpeppermint-flavoured) (with 10-mL oral syringe) =£69.06. Counselling, administrationExcipients include propylene glycolAdministration In children, oral suspension should be taken withfoodLOPINAVIR WITH RITONAVIRCautions see notes above; concomitant use with drugsthat prolong QT or PR interval; cardiac conductiondisorders, structural heart disease; pancreatitis (seebelow); interactions: Appendix 1 (lopinavir, ritonavir)Pancreatitis Signs and symptoms suggestive of pancreatitis(including raised serum lipase) should be evaluated—discontinueif pancreatitis diagnosedContra-indications see notes aboveHepatic impairment see notes above; also avoid oralsolution—high propylene glycol content; manufactureradvises avoid tablets in severe impairmentRenal impairment avoid oral solution due to highpropylene glycol contentPregnancy avoid oral solution due to high propyleneglycol content; manufacturer advises use tablets onlyif potential benefit outweighs risk (toxicity in animalstudies)Breast-feeding see p. 310

BNFC 2011–2012 5.3.1 HIV infection 317Side-effects see notes and Cautions above; alsoelectrolyte disturbances; less commonly dysphagia,appetite changes, weight changes, cholecystitis,hypertension, myocardial infarction, palpitation,thrombophlebitis, vasculitis, chest pain, oedema,dyspnoea, cough, agitation, anxiety, amnesia, ataxia,hypertonia, confusion, depression, abnormal dreams,extrapyramidal effects, neuropathy, influenza-likesyndrome, Cushing’s syndrome, hypothyroidism,menorrhagia, amenorrhoea, sexual dysfunction,breast enlargement, dehydration, nephritis, hypercalciuria,lactic acidosis, arthralgia, hyperuricaemia,abnormal vision, otitis media, tinnitus, dry mouth,sialadenitis, mouth ulceration, peridontitis, acne, alopecia,dry skin, sweating, skin discoloration, nail disorders;rarely prolonged PR intervalIndication and doseSee preparationsKaletra c (Abbott) ATablets, pale yellow, f/c, lopinavir 100 mg, ritonavir25 mg, net price 60-tab pack = £76.85. Label: 25DoseHIV infection in combination with other antiretroviraldrugs. By mouthChild 2–18 years with body-weight under 40 kgBody surface area 0.5–0.9 m 2 2 tablets twice dailyBody surface area 0.9–1.4 m 2 3 tablets twice dailyTablets, yellow, f/c, lopinavir 200 mg, ritonavir 50 mg,net price 120-tab pack = £307.39. Label: 25DoseHIV infection in combination with other antiretroviraldrugs. By mouthChild 2–18 years with body surface area greater than1.4 m 2 or body-weight 40 kg and over 2 tablets twicedailyOral solution, lopinavir 400 mg, ritonavir 100 mg/5 mL, net price 5 60-mL packs = £307.39. Label: 21Excipients include propylene glycol 153 mg/mL (see Excipients, p. 2),alcohol 42%DoseHIV infection in combination with other antiretroviraldrugs. By mouthChild 2–18 years 2.9 mL/m 2 (max. 5 mL) twice dailywith foodCounselling Oral solution tastes bitterNELFINAVIRCautions see notes above; interactions: Appendix 1(nelfinavir)Contra-indications see notes aboveHepatic impairment see notes above; also manufactureradvises cautionRenal impairment manufacturer advises cautionPregnancy manufacturer advises use only if potentialbenefit outweighs risk—no information availableBreast-feeding see p. 310Side-effects see notes above; also reported, feverLicensed use not licensed for use in children under 3yearsIndication and doseHIV infection in combination with other antiretroviraldrugsFor dose, consult Guidelines (see notes above)Viracept c (Roche) ATablets, blue, f/c, nelfinavir (as mesilate) 250 mg, netprice 300-tab pack = £257.32. Label: 21RITONAVIRCautions see notes above; concomitant use with drugsthat prolong PR interval; cardiac conduction disorders,structural heart disease; pancreatitis (see below);interactions: Appendix 1 (ritonavir)Pancreatitis Signs and symptoms suggestive of pancreatitis(including raised serum lipase) should be evaluated—discontinueif pancreatitis diagnosedContra-indications see notes aboveHepatic impairment see notes above; also avoid indecompensated liver disease; in severe impairmentwithout decompensation, use ‘booster’ doses withcaution (avoid treatment doses)Pregnancy manufacturer advises use only if potentialbenefit outweighs risk—toxicity in animal studiesBreast-feeding see p. 310Side-effects see notes and Cautions above; alsodiarrhoea (may impair absorption—close monitoringrequired), vasodilatation, cough, throat irritation,anxiety, perioral and peripheral paraesthesia, hyperaesthesia,fever, decreased blood-thyroxine concentration,electrolyte disturbances, raised uric acid, drymouth, mouth ulcers, and sweating; less commonlyincreased prothrombin time and dehydration; syncope,postural hypotension, seizures, menorrhagia,and renal failure also reportedIndication and doseLow-dose ritonavir to increase the effect ofatazanavir. By mouthChild 6–18 yearsBody-weight 15–20 kg 80–100 mg once dailyBody-weight over 20 kg 100 mg once dailyLow-dose ritonavir to increase the effect ofdarunavir. By mouthChild 6–18 yearsBody-weight 20–30 kg 50 mg twice dailyBody-weight 30–40 kg 60 mg twice dailyBody-weight over 40 kg 100 mg twice dailyLow-dose ritonavir to increase the effect offosamprenavir. By mouthChild 6–18 yearsBody-weight 25–33 kg 3 mg/kg twice dailyBody-weight over 33 kg 100 mg twice dailyLow-dose ritonavir to increase the effect ofsaquinavir. By mouthChild 16–18 years 100 mg twice daily5 Infections

318 5.3.1 HIV infection BNFC 2011–20125 InfectionsLow-dose ritonavir to increase the effect oftipranavir. By mouthChild 2–12 years 150 mg/m 2 (max. 200 mg)twice dailyChild 12–18 years 200 mg twice dailyNorvir c (Abbott) ATablets, f/c, ritonavir 100 mg, net price 30-tab pack =£19.44. Label: 21, 25Oral solution, sugar-free, ritonavir 400 mg/5 mL, netprice 5 90-mL packs (with measuring cup) =£403.20. Label: 21, counselling, administrationExcipients include alcohol, propylene glycolCounselling Oral solution contains 43% alcohol; bitter tastecan be masked by mixing with chocolate milk; do not mixwith water, measuring cup must be dryAdministration of ritonavir and didanosine should be separatedby at least 2 hoursWith lopinavirSee under Lopinavir with ritonavirSAQUINAVIRCautions see notes above; monitor ECG before startingtreatment and then on day 3 or 4 of treatment—discontinue if QT interval over 480 milliseconds, if QTinterval more than 20 milliseconds above baseline, orif prolongation of PR interval; concomitant use ofgarlic (avoid garlic capsules—reduces plasma-saquinavirconcentration); interactions: Appendix 1(saquinavir)Counselling Children and their carers should be told how torecognise signs of arrhythmia and advised to seek medicalattention if symptoms such as palpitation or syncopedevelopContra-indications see notes above; predisposition tocardiac arrhythmias (including congenital QT prolongation,bradycardia, history of symptomaticarrhythmias, heart failure with reduced left ventricularejection fraction, electrolyte disturbances, concomitantuse of drugs that prolong QT or PR interval);concomitant use of drugs that increase plasmasaquinavirconcentration (avoid unless no alternativetreatment available)Hepatic impairment see notes above; also manufactureradvises caution in moderate impairment; avoidin decompensated liver diseaseRenal impairment use with caution if estimatedglomerular filtration rate less than 30 mL/minute/1.73 m 2Pregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding see p. 310Side-effects see notes above; also dyspnoea,increased appetite, peripheral neuropathy, convulsions,changes in libido, renal impairment, drymouth, and alopeciaIndication and doseHIV infection in combination with other antiretroviraldrugs in children previously treatedwith antiretroviral therapy. By mouthWith low-dose ritonavirChild 16–18 years 1 g twice dailyHIV infection in combination with other antiretroviraldrugs in children not previouslytreated with antiretroviral therapy. By mouthWith low-dose ritonavirChild 16–18 years 500 mg twice daily for 7 daysthen 1 g twice dailyInvirase c (Roche) ACapsules, brown/green, saquinavir (as mesilate)200 mg, net price 270-cap pack = £226.14. Label: 21Tablets, orange, f/c, saquinavir (as mesilate) 500 mg,net price 120-tab pack = £251.26. Label: 21TIPRANAVIRCautions see notes above; also patients at risk ofincreased bleeding from trauma, surgery, or otherpathological conditions; concomitant use of drugsthat increase risk of bleeding; interactions: Appendix1 (tipranavir)Hepatotoxicity Potentially life-threatening hepatotoxicityreported; monitor liver function before treatment then every2 weeks for 1 month, then every 3 months. Discontinue ifsigns or symptoms of hepatitis develop or if liver-functionabnormality develops (consult product literature)Contra-indications see notes aboveHepatic impairment see notes above; also manufactureradvises caution in mild impairment; avoid inmoderate or severe impairment—no informationavailablePregnancy manufacturer advises use only if potentialbenefit outweighs risk—toxicity in animal studiesBreast-feeding see p. 310Side-effects see notes above; also dyspnoea, anorexia,peripheral neuropathy, influenza-like symptoms,renal impairment, and photosensitivity; rarelydehydrationIndication and doseHIV infection resistant to other protease inhibitors,in combination with other antiretroviraldrugs in children previously treated with antiretroviralsFor dose, see preparationsAptivus c (Boehringer Ingelheim) TACapsules, pink, tipranavir 250 mg, net price 120-cappack = £441.00. Label: 5, 21Excipients include ethanol 100 mg per capsuleDoseWith low-dose ritonavir. By mouthChild 12–18 years 500 mg twice dailyOral solution, toffee-and mint-flavoured, tipranavir100 mg/mL, net price 95-mL pack = £129.65.Label: 5, 21, counselling, crystallisationExcipients include vitamin E 78 mg/mLDoseWith low-dose ritonavir. By mouthChild 2–12 years 375 mg/m 2 (max. 500 mg) twice dailyNote The bioavailability of Aptivus c oral solution is higherthan that of the capsules; the oral solution is notinterchangeable with the capsules on a milligram-for-milligrambasisCounselling Children and carers should be told to observethe oral solution for crystallisation; the bottle should bereplaced if more than a thin layer of crystals form (dosesshould continue to be taken at the normal time until thebottle is replaced)

BNFC 2011–2012 5.3.1 HIV infection 319Non-nucleoside reverse transcriptaseinhibitorsEFAVIRENZCautions history of mental illness or seizures; monitorliver function if receiving other hepatotoxic drugs;interactions: Appendix 1 (efavirenz)Rash Rash, usually in the first 2 weeks, is the most commonside-effect; discontinue if severe rash with blistering, desquamation,mucosal involvement or fever; if rash mild ormoderate, may continue without interruption—usuallyresolves within 1 monthPsychiatric disorders Children or their carers should beadvised to seek immediate medical attention if symptomssuch as severe depression, psychosis or suicidal ideationoccurContra-indications acute porphyria (but see section9.8.2)Hepatic impairment in mild to moderate liver disease,monitor for dose-related side-effects (e.g. CNSeffects) and liver function; avoid in severe impairment;greater risk of hepatic side-effects in chronichepatitis B or CRenal impairment manufacturer advises caution insevere renal failure—no information availablePregnancy manufacturer advises avoid (effectivecontraception required during treatment and for 12weeks after treatment); use efavirenz only if no alternativeavailableBreast-feeding see p. 310Side-effects rash including Stevens-Johnsonsyndrome (see Rash above); abdominal pain, diarrhoea,nausea, vomiting; anxiety, depression, sleepdisturbances, abnormal dreams, dizziness, headache,fatigue, impaired concentration (administration atbedtime especially in first 2–4 weeks reduces CNSeffects); pruritus; less commonly pancreatitis, hepatitis,flushing, psychosis, mania, suicidal ideation,amnesia, ataxia, tremor, convulsions, gynaecomastia,blurred vision, tinnitus; rarely hepatic failure, photosensitivity;also reported raised serum cholesterol (seeLipodystrophy syndrome, p. 310); see also Osteonecrosis,p. 311Indication and doseSee preparationsSustiva c (Bristol-Myers Squibb) ACapsules, efavirenz 50 mg (yellow/white), net price30-cap pack = £16.73; 100 mg (white), 30-cap pack =£33.41; 200 mg (yellow), 90-cap pack = £200.27.Label: 23DoseHIV infection in combination with other antiretroviraldrugs. By mouthChild 3–18 yearsBody-weight 13–15 kg 200 mg once dailyBody-weight 15–20 kg 250 mg once dailyBody-weight 20–25 kg 300 mg once dailyBody-weight 25–32.5 kg 350 mg once dailyBody-weight 32.5–40 kg 400 mg once dailyBody-weight 40 kg and over 600 mg once dailyAdministration Capsules may be opened and contentsadded to food (contents have a peppery taste) [unlicenseduse]Tablets, f/c, yellow, efavirenz 600 mg, net price 30-tabpack = £200.27. Label: 23DoseHIV infection in combination with other antiretroviraldrugs. By mouthChild body-weight over 40 kg 600 mg once dailyOral solution, sugar-free, strawberry and mint flavour,efavirenz 30 mg/mL, net price 180-mL pack =£53.84DoseHIV infection in combination with other antiretroviraldrugs. By mouthChild 3–5 yearsBody-weight 13–15 kg 360 mg once dailyBody-weight 15–20 kg 390 mg once dailyBody-weight 20–25 kg 450 mg once dailyBody-weight 25–32.5 kg 510 mg once dailyChild 5–18 yearsBody-weight 13–15 kg 270 mg once dailyBody-weight 15–20 kg 300 mg once dailyBody-weight 20–25 kg 360 mg once dailyBody-weight 25–32.5 kg 450 mg once dailyBody-weight 32.5–40 kg 510 mg once dailyBody-weight 40 kg and over 720 mg once dailyNote The bioavailability of Sustiva c oral solution is lowerthan that of the capsules and tablets; the oral solution is notinterchangeable with either capsules or tablets on amilligram-for-milligram basisWith emtricitabine and tenofovirSee under TenofovirETRAVIRINECautions interactions: Appendix 1 (etravirine)Hypersensitivity reactions Rash, usually in the secondweek, is the most common side-effect and appears morefrequently in females. Life-threatening hypersensitivityreactions reported usually during week 3–6 of treatment andcharacterised by rash, eosinophilia, and systemic symptoms(including fever, general malaise, myalgia, arthralgia, blistering,oral lesions, conjunctivitis, and hepatitis). Discontinuepermanently if hypersensitivity reaction or severe rashdevelop. If rash mild or moderate (without signs of hypersensitivityreaction), may continue without interruption—usually resolves within 2 weeksCounselling Children and carers should be told how torecognise hypersensitivity reactions and advised to seekimmediate medical attention if hypersensitivity reaction orsevere rash developContra-indications acute porphyria (but see section9.8.2)Hepatic impairment use with caution in moderateimpairment; avoid in severe impairment—no informationavailable; greater risk of hepatic side-effects inchronic hepatitis B or CPregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding see p. 310Side-effects rash (including Stevens-Johnsonsyndrome rarely and toxic epidermal necrolysis veryrarely; see also Hypersensitivity Reactions above);gastro-oesophageal reflux, nausea, abdominal pain,flatulence, gastritis; hypertension; peripheral neuropathy;diabetes, hyperlipidaemia (see also Lipody-5 Infections

320 5.3.1 HIV infection BNFC 2011–2012strophy Syndrome, p. 310); renal failure; anaemia; lesscommonly pancreatitis, haematemesis, hepatitis,chest pain, bronchospasm, drowsiness, malaise,gynaecomastia, blurred vision, dry mouth, andsweating; also reported, haemorrhagic stroke; see alsoOsteonecrosis, p. 311Licensed use not licensed for use in childrenIndication and doseIn combination with other antiretroviral drugs(including a boosted protease inhibitor) for HIVinfection resistant to other non-nucleosidereverse transcriptase inhibitors and proteaseinhibitorsFor dose, consult Guidelines (see notes above)Administration for children with swallowing difficulties,tablets may be dispersed in a glass of water justbefore administrationIntelence c (Janssen) TATablets, etravirine 100 mg, net price 120-tab pack =£301.27. Label: 21counselling, rash, and hypersensitivity reactionsNote Dispense in original container (contains desiccant)and rash, see Hepatic Disease above), arthralgia,anaemia, and granulocytopenia; very rarely neuropsychiatricreactions; see also Osteonecrosis, p. 311Licensed use tablets, not licensed for use in childrenweighing less than 50 kg or with body surface arealess than 1.25 m 2Indication and doseHIV infection in combination with other antiretroviraldrugs. By mouthNeonate 14–28 days 150–200 mg/m 2 once dailyfor first 14 days, then (if no rash present)150–200 mg/m 2 twice dailyChild 1 month–18 years 150–200 mg/m 2 (max.200 mg) once daily for first 14 days, then (if no rashpresent) 150–200 mg/m 2 (max. 200 mg) twicedaily or 300–400 mg/m 2 (max. 400 mg) once dailyNote Initial dose titration should not exceed 28 days; if rashnot resolved within 28 days, alternative treatment should besought. If treatment interrupted for more than 7 days, restartusing the lower dose for the first 14 days as for new treatment5 InfectionsNEVIRAPINECautions chronic hepatitis B or C, high CD4 cell count,and females (all at greater risk of hepatic side-effects);interactions: Appendix 1 (nevirapine)Hepatic disease Potentially life-threatening hepatotoxicityincluding fatal fulminant hepatitis reported usually in first 6weeks; close monitoring required during first 18 weeks;monitor liver function before treatment then every 2 weeksfor 2 months then after 1 month and then regularly; discontinuepermanently if abnormalities in liver function testsaccompanied by hypersensitivity reaction (rash, fever,arthralgia, myalgia, lymphadenopathy, hepatitis, renalimpairment, eosinophilia, granulocytopenia); suspend ifsevere abnormalities in liver function tests but no hypersensitivityreaction—discontinue permanently if significantliver function abnormalities recur; monitor patient closely ifmild to moderate abnormalities in liver function tests with nohypersensitivity reactionRash Rash, usually in first 6 weeks, is most common sideeffect;incidence reduced if introduced at low dose and doseincreased gradually; monitor closely for skin reactions duringfirst 18 weeks; discontinue permanently if severe rash or ifrash accompanied by blistering, oral lesions, conjunctivitis,facial oedema, general malaise or hypersensitivity reactions;if rash mild or moderate may continue without interruptionbut dose should not be increased until rash resolvesCounselling Children and carers should be told how torecognise hypersensitivity reactions and advised to discontinuetreatment and seek immediate medical attention ifsevere skin reaction, hypersensitivity reactions or symptomsof hepatitis developContra-indications acute porphyria (but see section9.8.2); post-exposure prophylaxisHepatic impairment manufacturer advises caution inmoderate impairment; avoid in severe impairment;see also Hepatic Disease, abovePregnancy although manufacturer advises caution,may be appropriate to use if clearly indicated; see alsop. 310Breast-feeding see p. 310Side-effects rash including Stevens-Johnsonsyndrome and rarely, toxic epidermal necrolysis (seealso Cautions above); nausea, hepatitis (see alsoHepatic Disease above), headache; less commonlyvomiting, abdominal pain, fatigue, fever, and myalgia;rarely diarrhoea, angioedema, anaphylaxis, hypersensitivityreactions (may involve hepatic reactionsViramune c (Boehringer Ingelheim) ATablets, nevirapine 200 mg, net price 14-tab pack =£39.67, 60-tab pack = £170.00. Counselling, hypersensitivityreactionsSuspension, nevirapine 50 mg/5 mL, net price 240-mL pack = £50.40. Counselling, hypersensitivityreactionsOther antiretroviralsENFUVIRTIDECautionsHypersensitivity reactions Hypersensitivity reactionsincluding rash, fever, nausea, vomiting, chills, rigors, lowblood pressure, respiratory distress, glomerulonephritis, andraised liver enzymes reported; discontinue immediately ifany signs or symptoms of systemic hypersensitivity developand do not rechallengeCounselling Children and carers should be told how torecognise signs of hypersensitivity, and advised to discontinuetreatment and seek prompt medical attention ifsymptoms developHepatic impairment manufacturer advises caution—no information available; chronic hepatitis B or C(possibly greater risk of hepatic side-effects)Pregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding see p. 310Side-effects injection-site reactions; pancreatitis,gastro-oesophageal reflux disease, anorexia, weightloss; hypertriglyceridaemia; peripheral neuropathy,asthenia, tremor, anxiety, nightmares, irritability,impaired concentration, vertigo; pneumonia, sinusitis,influenza-like illness; diabetes mellitus; haematuria;renal calculi, lymphadenopathy; myalgia; conjunctivitis;dry skin, acne, erythema, skin papilloma; lesscommonly hypersensitivity reactions (see Cautions);see also Osteonecrosis, p. 311

BNFC 2011–2012 5.3.2 Herpesvirus infections 321Indication and doseHIV infection in combination with other antiretroviraldrugs for resistant infection or forchildren intolerant to other antiretroviral regimens. By subcutaneous injectionChild 6–16 years 2 mg/kg (max. 90 mg) twicedailyChild 16–18 years 90 mg twice dailyAdministration for subcutaneous injection, reconstitutewith 1.1 mL Water for Injections and allow tostand (for up to 45 minutes) to dissolve; do not shakeor invert vialFuzeon c (Roche) AInjection, powder for reconstitution, enfuvirtide108 mg (= enfuvirtide 90 mg/mL when reconstitutedwith 1.1 mL Water for Injections), net price 108-mgvial = £18.03 (with solvent, syringe, and alcoholswabs). Counselling, hypersensitivity reactionsMARAVIROCCautions cardiovascular disease; chronic hepatitis Bor C; interactions: Appendix 1 (maraviroc)Hepatic impairment use with cautionRenal impairment if estimated glomerular filtrationrate less than 80 mL/minute/1.73 m 2 , consult productliteraturePregnancy manufacturer advises use only if potentialbenefit outweighs risk—toxicity in animal studiesBreast-feeding see p. 310Side-effects nausea, vomiting, abdominal pain, dyspepsia,constipation, diarrhoea; cough; dizziness,paraesthesia, asthenia, sleep disturbances, headache,weight loss; muscle spasms, back pain; taste disturbances;rash, pruritus; less commonly pancreatitis,hepatic cirrhosis, rectal bleeding, myocardial infarction,myocardial ischaemia, bronchospasm, seizures,hallucinations, loss of consciousness, polyneuropathy,pancytopenia, neutropenia, lymphadenopathy, renalfailure, polyuria, and myositis; see also Osteonecrosis,p. 311Licensed use not licensed for use in childrenIndication and doseCCR5–tropic HIV infection in combination withother antiretroviral drugs in children previouslytreated with antiretroviralsFor dose, consult Guidelines (see notes above)Celsentri c (ViiV) TATablets, blue, f/c, maraviroc 150 mg, net price 60-tabpack = £519.14; 300 mg, 60-tab pack = £519.14RALTEGRAVIRCautions risk factors for myopathy or rhabdomyolysis;interactions: Appendix 1 (raltegravir)Hepatic impairment chronic hepatitis B or C (greaterrisk of hepatic side-effects); use with caution in severeimpairment—no information availablePregnancy manufacturer advises avoid—toxicity inanimal studiesBreast-feeding see p. 310Side-effects diarrhoea, nausea, vomiting, abdominalpain, flatulence, hypertriglyceridaemia, dizziness,headache, insomnia, abnormal dreams, asthenia, rash(Stevens-Johnson syndrome reported); less commonlygastritis, hepatitis, pancreatitis, dry mouth,gastro-oesophageal reflux, taste disturbances, pain onswallowing, peptic ulcer, constipation, rectal bleeding,lipodystrophy (see Lipodystrophy Syndrome, p. 310),palpitation, ventricular extrasystoles, bradycardia,hypertension, flushing, chest pain, oedema, dysphonia,epistaxis, nasal congestion, drowsiness, anxiety,appetite changes, confusion, impaired memory andattention, depression, pyrexia, chills, carpal tunnelsyndrome, tremor, peripheral neuropathy, erectiledysfunction, gynaecomastia, menopausal symptoms,osteopenia, renal failure, nocturia, polydipsia, anaemia,thrombocytopenia, neutropenia, arthralgia,myalgia, rhabdomyolysis, visual disturbances, tinnitus,gingivitis, glossitis, acne, pruritus, hyperhidrosis,dry skin, skin papilloma, and alopecia; also reportedsuicidal ideation; see also Osteonecrosis, p. 311Indication and doseIn combination with other antiretroviral drugsfor HIV infection resistant to multiple antiretrovirals. By mouthChild 16–18 years 400 mg twice dailyIsentress c (MSD) TATablets, pink, f/c, raltegravir (as potassium salt)400 mg, net price 60-tab pack = £616.22. Label: 255.3.2 Herpesvirus infections5.3.2.1 Herpes simplex and varicella–zosterinfection5.3.2.2 Cytomegalovirus infection5.3.2.1 Herpes simplex and varicella–zoster infectionThe two most important herpesvirus pathogens areherpes simplex virus (herpesvirus hominis) and varicella–zostervirus.Herpes simplex infections Herpes infection of themouth and lips and in the eye is generally associatedwith herpes simplex virus serotype 1 (HSV-1); otherareas of the skin may also be infected, especially inimmunodeficiency. Genital infection is most often associatedwith HSV-2 and also HSV-1. Treatment of herpessimplex infection should start as early as possible andusually within 5 days of the appearance of the infection.In individuals with good immune function, mild infectionof the eye (ocular herpes, section 11.3.3) and of thelips (herpes labialis or cold sores, section 13.10.3) istreated with a topical antiviral drug. Primary herpeticgingivostomatitis is managed by changes to diet andwith analgesics (section 12.3.2). Severe infection, neonatalherpes infection or infection in immunocompromisedindividuals requires treatment with a systemicantiviral drug. Primary or recurrent genital herpes simplexinfection is treated with an antiviral drug given bymouth. Persistance of a lesion or recurrence in animmunocompromised child may signal the developmentof resistance.5 Infections

322 5.3.2 Herpesvirus infections BNFC 2011–20125 InfectionsSpecialist advice should be sought for systemic treatmentof herpes simplex infection in pregnancy.Varicella–zoster infections Regardless of immunefunction and the use of any immunoglobulins, neonateswith chickenpox should be treated with a parenteralantiviral to reduce the risk of severe disease. Oraltherapy is not recommended as absorption is variable.Chickenpox in otherwise healthy children between 1month and 12 years is usually mild and antiviral treatmentis not usually required. Chickenpox is more severein adolescents than in children; antiviral treatmentstarted within 24 hours of the onset of rash may reducethe duration and severity of symptoms in otherwisehealthy adolescents. Antiviral treatment is generallyrecommended in immunocompromised patients andthose at special risk (e.g. because of severe cardiovascularor respiratory disease or chronic skin disorder); insuch cases, an antiviral is given for 10 days with at least7 days of parenteral treatment.In pregnancy severe chickenpox may cause complications,especially varicella pneumonia. Specialist adviceshould be sought for the treatment of chickenpox duringpregnancy.Neonates and children who have been exposed tochickenpox and are at special risk of complicationsmay require prophylaxis with varicella-zoster immunoglobulin(see under Disease-specific Immunoglobulins,section 14.5.2). Prophylactic intravenous aciclovirshould be considered for neonates whose mothersdevelop chickenpox 4 days before to 2 days afterdelivery.In herpes zoster (shingles) systemic antiviral treatmentcan reduce the severity and duration of pain, reducecomplications, and reduce viral shedding. Treatmentwith the antiviral should be started within 72 hours ofthe onset of rash and is usually continued for 7–10 days.Immunocompromised patients at high risk of disseminatedor severe infection should be treated with a parenteralantiviral drug. Chronic pain which persists afterthe rash has healed (postherpetic neuralgia) requiresspecific management (section 4.7.3).Choice Aciclovir is active against herpesviruses butdoes not eradicate them. Uses of aciclovir include systemictreatment of varicella–zoster and the systemicand topical treatment of herpes simplex infections ofthe skin (section 13.10.3) and mucous membranes (section7.2.2). It is used by mouth for severe herpeticstomatitis (see also p. 545). Aciclovir eye ointment (section11.3.3) is used for herpes simplex infections of theeye; it is combined with systemic treatment forophthalmic zoster.Famciclovir, a prodrug of penciclovir, is similar toaciclovir and is licensed in adults for use in herpeszoster and genital herpes; there is limited informationavailable on use in children. Penciclovir itself is used as acream for herpes simplex labialis (section 13.10.3).Valaciclovir is an ester of aciclovir, licensed in adults forherpes zoster and herpes simplex infections of the skinand mucous membranes (including genital herpes); it isalso licensed in children over 12 years for preventingcytomegalovirus disease following solid organ transplantation.Valaciclovir may be used for the treatmentof mild herpes zoster in immunocompromised childrenover 12 years; treatment should be initiated underspecialist supervision.ACICLOVIR(Acyclovir)Cautions maintain adequate hydration (especially withinfusion or high doses, or during renal impairment);interactions: Appendix 1 (aciclovir)Renal impairment see Cautions above; also risk ofneurological reactions increased; use normal intravenousdose every 12 hours if estimated glomerularfiltration rate 25–50 mL/minute/1.73 m 2 (every 24hours if estimated glomerular filtration rate 10–25 mL/minute/1.73 m 2 ); consult product literature forintravenous dose if estimated glomerular filtrationrate less than 10 mL/minute/1.73 m 2 . For herpeszoster, use normal oral dose every 8 hours if estimatedglomerular filtration rate 10–25 mL/minute/1.73 m 2 (every 12 hours if estimated glomerular filtrationrate less than 10 mL/minute/1.73 m 2 ). Forherpes simplex, use normal oral dose every 12 hours ifestimated glomerular filtration rate less than 10 mL/minute/1.73 m 2Pregnancy not known to be harmful—manufacturersadvise use only when potential benefit outweighs riskBreast-feeding significant amount in milk after systemicadministration; not known to be harmful butmanufacturers advise cautionSide-effects nausea, vomiting, abdominal pain, diarrhoea,headache, fatigue, rash, urticaria, pruritus,photosensitivity; very rarely hepatitis, jaundice, dyspnoea,neurological reactions (including dizziness,confusion, hallucinations, convulsions, ataxia, dysarthria,and drowsiness), acute renal failure, anaemia,thrombocytopenia, and leucopenia; on intravenousinfusion, severe local inflammation (sometimes leadingto ulceration), and very rarely agitation, tremors,psychosis and feverLicensed use tablets and suspension not licensed forsuppression of herpes simplex or for treatment ofherpes zoster in children (age range not specified bymanufacturer); intravenous infusion not licensed forherpes zoster in children under 18 years; tablets andsuspension not licensed for attenuation of chickenpox(if varicella-zoster immunoglobulin not indicated)in children under 18 yearsIndication and doseHerpes simplex treatment. By mouthChild 1 month–2 years 100 mg 5 times daily,usually for 5 days (longer if new lesions appearduring treatment or if healing incomplete); dosedoubled if immunocompromised or if absorptionimpairedChild 2–18 years 200 mg 5 times daily, usually for5 days (longer if new lesions appear during treatmentor if healing incomplete); dose doubled ifimmunocompromised or if absorption impaired. By intravenous infusionNeonate 20 mg/kg every 8 hours for 14 days (21days if CNS involvement)Child 1–3 months 20 mg/kg every 8 hours for 14days (21 days if CNS involvement)Child 3 months–12 years 250 mg/m 2 every 8hours usually for 5 days, doubled to 500 mg/m 2every 8 hours if CNS involvement (given for up to21 days) or if immunocompromised

BNFC 2011–2012 5.3.2 Herpesvirus infections 323Child 12–18 years 5 mg/kg every 8 hours usuallyfor 5 days, doubled to 10 mg/kg every 8 hours ifCNS involvement (given for up to 21 days) or ifimmunocompromisedNote To avoid excessive dose in obese patients parenteraldose should be calculated on the basis of idealweight for heightHerpes simplex prophylaxis in the immunocompromised. By mouthChild 1 month–2 years 100–200 mg 4 times dailyChild 2–18 years 200–400 mg 4 times dailyHerpes simplex suppression. By mouthChild 12–18 years 400 mg twice daily or 200 mg4 times daily; increased to 400 mg 3 times daily ifrecurrences occur on standard suppressive therapyor for suppression of genital herpes during latepregnancy (from 36 weeks gestation); therapyinterrupted every 6–12 months to reassess recurrencefrequency—consider restarting after two ormore recurrencesChickenpox and herpes zoster infection. By mouthChild 1 month–2 years 200 mg 4 times daily for 5daysChild 2–6 years 400 mg 4 times daily for 5 daysChild 6–12 years 800 mg 4 times daily for 5 daysChild 12–18 years 800 mg 5 times daily for 7 days. By intravenous infusionNeonate 10–20 mg/kg every 8 hours for at least 7daysChild 1–3 months 10–20 mg/kg every 8 hours forat least 7 daysChild 3 months–12 years 250 mg/m 2 every 8hours usually for 5 days, dose doubled if immunocompromisedChild 12–18 years 5 mg/kg every 8 hours usuallyfor 5 days, dose doubled if immunocompromisedNote To avoid excessive dose in obese patients parenteraldose should be calculated on the basis of idealweight for heightProphylaxis of chickenpox after delivery (seenotes above). By intravenous infusionNeonate 10 mg/kg every 8 hours; continued untilserological tests confirm absence of virusAttenuation of chickenpox if varicella–zosterimmunoglobulin not indicated. By mouthChild 1 month–18 years 10 mg/kg 4 times dailyfor 7 days starting 1 week after exposureHerpesvirus skin infections section 13.10.3Herpesvirus eye infections section 11.3.3Administration for intravenous infusion, reconstituteto 25 mg/mL with Water for Injections or SodiumChloride 0.9% then dilute to concentration of 5 mg/mL with Sodium Chloride 0.9% or Sodium Chlorideand Glucose and give over 1 hour; alternatively, maybe administered in a concentration of 25 mg/mLusing a suitable infusion pump and central venousaccess and given over 1 hourAciclovir (Non-proprietary) ATablets, aciclovir 200 mg, net price 25-tab pack =£4.45; 400 mg, 56-tab pack = £8.10; 800 mg, 35-tabpack = £10.21. Label: 9Brands include Virovir cDental prescribing on NHS Aciclovir Tablets 200 mg or800 mg may be prescribedDispersible tablets, aciclovir 200 mg, net price 25-tab pack = £2.05; 400 mg, 56-tab pack = £7.24;800 mg, 35-tab pack = £7.02. Label: 9Suspension, aciclovir 200 mg/5 mL, net price125 mL = £38.22; 400 mg/5 mL, 100 mL = £41.55.Label: 9Dental prescribing on NHS Aciclovir Oral Suspension200 mg/5 mL may be prescribedIntravenous infusion, powder for reconstitution,aciclovir (as sodium salt), net price 250-mg vial =£9.13; 500-mg vial = £20.22Electrolytes Na + 1.1 mmol/250-mg vialIntravenous infusion, aciclovir (as sodium salt),25 mg/mL, net price 10-mL (250-mg) vial = £10.37;20-mL (500-mg) vial = £19.21; 40-mL (1-g) vial =£40.44Electrolytes Na + 1.16 mmol/250-mg vialZovirax c (GSK) ATablets, all dispersible, f/c, aciclovir 200 mg, net price25-tab pack = £17.71; 800 mg (scored, ShinglesTreatment Pack), 35-tab pack = £65.80. Label: 9Suspension, both off-white, sugar-free, aciclovir200 mg/5 mL (banana-flavoured), net price 125 mL =£29.53; 400 mg/5 mL (Double Strength Suspension,orange-flavoured), 100 mL = £33.01. Label: 9Intravenous infusion, powder for reconstitution,aciclovir (as sodium salt), net price 250-mg vial =£9.96; 500-mg vial = £17.72Electrolytes Na + 1.1 mmol/250-mg vialVALACICLOVIRNote Valaciclovir is a pro-drug of aciclovirCautions see under AciclovirHepatic impairment manufacturer advises cautionwith high doses used for preventing cytomegalovirusdisease—no information available in childrenRenal impairment maintain adequate hydration; forherpes zoster, 1 g every 12 hours if estimated glomerularfiltration rate 30–50 mL/minute/1.73 m 2 (1 gevery 24 hours if estimated glomerular filtration rate10–30 mL/minute/1.73 m 2 ; 500 mg every 24 hours ifestimated glomerular filtration rate less than 10 mL/minute/1.73 m 2 ); for treatment of herpes simplex,500 mg (1 g in immunocompromised or HIV-positivechildren) every 24 hours if estimated glomerularfiltration rate less than 30 mL/minute/1.73 m 2 ; fortreatment of herpes labialis, if estimated glomerularfiltration rate 30–50 mL/minute/1.73 m 2 , initially 1 g,then 1 g 12 hours after initial dose (if estimatedglomerular filtration rate 10–30 mL/minute/1.73 m 2 ,initally 500 mg, then 500 mg 12 hours after initial5 Infections

324 5.3.2 Herpesvirus infections BNFC 2011–20125 Infectionsdose; if estimated glomerular filtration rate less than10 mL/minute/1.73 m 2 , 500 mg as a single dose); forsuppression of herpes simplex, 250 mg (500 mg inimmunocompromised or HIV-positive children) every24 hours if estimated glomerular filtration rate lessthan 30 mL/minute/1.73 m 2 ; reduce dose accordingto estimated glomerular filtration rate for cytomegalovirusprophylaxis following solid organ transplantation(consult product literature)Pregnancy see under AciclovirBreast-feeding see under AciclovirSide-effects see under Aciclovir but neurologicalreactions more frequent with high dosesLicensed use not licensed for treatment of herpeszoster in children; not licensed for treatment orsuppression of herpes simplex infection in immunocompromisedor HIV-positive childrenIndication and doseHerpes zoster in immunocompromised. By mouthChild 12–18 years 1 g 3 times daily for at least 7days (continue for 2 days after crusting of lesions)Treatment of herpes simplex. By mouthChild 12–18 years first episode, 500 mg twicedaily for 5 days, longer if new lesions appear duringtreatment or if healing incomplete (1 g twice dailyfor 10 days in immunocompromised or HIV-positivechildren); recurrent infection, 500 mg twicedaily for 3–5 days (1 g twice daily for 5–10 days inimmunocompromised or HIV-positive children)Treatment of herpes labialis. By mouthChild 12–18 years initially 2 g, then 2 g 12 hoursafter initial doseSuppression of herpes simplex. By mouthChild 12–18 years 500 mg daily in 1–2 divideddoses (in immunocompromised or HIV-positivechildren, 500 mg twice daily); therapy interruptedevery 6–12 months to reassess recurrence frequency—considerrestarting after two or morerecurrencesPrevention of cytomegalovirus disease followingsolid organ transplantation (preferablystarting within 72 hours of transplantation). By mouthChild 12–18 years 2 g 4 times daily usually for 90daysValaciclovir (Non-proprietary) ATablets, valaciclovir 500 mg, net price 10-tab pack =£19.43, 42 tab-pack = £79.04. Label: 9Valtrex c (GSK) ATablets, f/c, valaciclovir (as hydrochloride) 250 mg,net price 60-tab pack = £123.28; 500 mg, 10-tab pack= £20.59, 42-tab pack = £86.30. Label: 95.3.2.2 Cytomegalovirus infectionRecommendations for the optimum maintenance therapyof cytomegalovirus (CMV) infections and the durationof treatment are subject to rapid change.Ganciclovir is related to aciclovir but it is more activeagainst cytomegalovirus; it is also much more toxic thanaciclovir and should therefore be prescribed underspecialist supervision and only when the potential benefitoutweighs the risks. Ganciclovir is administered byintravenous infusion for the initial treatment of CMVinfection. The use of ganciclovir may also be consideredfor symptomatic congenital CMV infection. Ganciclovircauses profound myelosuppression when given withzidovudine; the two should not normally be giventogether particularly during initial ganciclovir therapy.The likelihood of ganciclovir resistance increases inpatients with a high viral load or in those who receivethe drug over a long duration; cross-resistance to cidofoviris common.Valaciclovir (section 5.3.2.1) is licensed for use inchildren over 12 years for prevention of cytomegalovirusdisease following renal transplantation.Foscarnet is also active against cytomegalovirus; it istoxic and can cause renal impairment.Cidofovir is given in combination with probenecid forCMV retinitis in AIDS patients when ganciclovir andfoscarnet are contra-indicated. Cidofovir is nephrotoxic.There is limited information on its use in children.For local treatment of CMV retinitis, see section 11.3.3.GANCICLOVIRCautions close monitoring of full blood count (severedeterioration may require correction and possiblytreatment interruption); history of cytopenia; potentialcarcinogen and teratogen; radiotherapy; ensureadequate hydration during intravenous administration;vesicant—infuse into vein with adequate flowpreferably using plastic cannula; possible risk of longtermcarcinogenic or reproductive toxicity; interactions:Appendix 1 (ganciclovir)Contra-indications hypersensitivity to valganciclovir,ganciclovir, aciclovir, or valaciclovir; abnormally lowhaemoglobin, neutrophil, or platelet counts (consultproduct literature)Renal impairment reduce dose if estimated glomerularfiltration rate less than 70 mL/minute/1.73 m 2 ;consult product literaturePregnancy avoid—teratogenic risk; ensure effectivecontraception during treatment and barrier contraceptionfor males during and for at least 90 days aftertreatmentBreast-feeding avoid—no information availableSide-effects diarrhoea, nausea, vomiting, dyspepsia,abdominal pain, constipation, flatulence, dysphagia,taste disturbance, hepatic dysfunction; dyspnoea,chest pain, cough; headache, insomnia, convulsions,dizziness, peripheral neuropathy, depression, anxiety,confusion, abnormal thinking, fatigue, weight loss,anorexia; infection, pyrexia, night sweats; anaemia,leucopenia, thrombocytopenia, pancytopenia, renalimpairment; myalgia, arthralgia; macular oedema,retinal detachment, vitreous floaters, eye pain; earpain; dermatitis, pruritus; injection-site reactions; lesscommonly mouth ulcers, pancreatitis, arrhythmias,

BNFC 2011–2012 5.3.3 Viral hepatitis 325hypotension, anaphylactic reactions, psychosis, tremor,male infertility, haematuria, disturbances inhearing and vision, and alopeciaLicensed use not licensed for use in childrenIndication and doseLife-threatening or sight-threatening cytomegalovirusinfections in immunocompromisedpatients only; prevention of cytomegalovirusdisease duringimmunosuppressive therapy following organtransplantation. By intravenous infusionChild 1 month–18 years initially (induction)5 mg/kg every 12 hours for 14–21 days for treatmentor for 7–14 days for prevention; maintenance(for patients at risk of relapse of retinitis), 6 mg/kgdaily on 5 days per week or 5 mg/kg daily untiladequate recovery of immunity; if retinitis progressesinitial induction treatment may berepeatedCongenital cytomegalovirus infection of theCNS. By intravenous infusionNeonate 6 mg/kg every 12 hours for 6 weeksLocal treatment of CMV retinitis section 11.3.3Administration for intravenous infusion, reconstitutewith Water for Injections (500 mg/10 mL) then diluteto a concentration of not more than 10 mg/mL withGlucose 5% or Sodium Chloride 0.9% and give over 1hourCymevene c (Roche) AIntravenous infusion, powder for reconstitution,ganciclovir (as sodium salt). Net price 500-mg vial =£29.77Electrolytes Na + 2 mmol/500-mg vialCaution in handling Ganciclovir is toxic and personnelshould be adequately protected during handling andadministration; if solution comes into contact with skin ormucosa, wash off immediately with soap and waterFOSCARNET SODIUMCautions monitor electrolytes, particularly calciumand magnesium; monitor serum creatinine everysecond day during induction and every week duringmaintenance; ensure adequate hydration; avoid rapidinfusion; interactions: Appendix 1 (foscarnet)Renal impairment reduce dose; consult product literaturePregnancy avoidBreast-feeding avoid—present in milk in animalstudiesSide-effects nausea, vomiting, diarrhoea (occasionallyconstipation and dyspepsia), abdominal pain,anorexia; changes in blood pressure and ECG; headache,fatigue, mood disturbances (including psychosis),asthenia, paraesthesia, convulsions, tremor, dizziness,and other neurological disorders; rash;impairment of renal function including acute renalfailure; hypocalcaemia (sometimes symptomatic) andother electrolyte disturbances; abnormal liver functiontests; decreased haemoglobin concentration,leucopenia, granulocytopenia, thrombocytopenia;thrombophlebitis if given undiluted by peripheral vein;genital irritation and ulceration (due to high concentrationsexcreted in urine); isolated reports of pancreatitisLicensed use not licensed for use in childrenIndication and doseCMV disease. By intravenous infusionChild 1 month–18 years induction 60 mg/kgevery 8 hours for 2–3 weeks then maintenance60 mg/kg daily, increased to 90–120 mg/kg if tolerated;if disease progresses on maintenance dose,repeat induction regimenMucocutaneous herpes simplex infection. By intravenous infusionChild 1 month–18 years 40 mg/kg every 8 hoursfor 2–3 weeks or until lesions healAdministration for intravenous infusion, give undilutedsolution via a central venous catheter; alternativelydilute to a concentration of 12 mg/mL withGlucose 5% or Sodium Chloride 0.9% for administrationvia a peripheral vein; give over at least 1 hour(give doses greater than 60 mg/kg over 2 hours)Foscavir c (Clinigen) AIntravenous infusion, foscarnet sodium hexahydrate24 mg/mL, net price 250-mL bottle = £34.495.3.3 Viral hepatitisTreatment for viral hepatitis should be initiated by aspecialist in hepatology or infectious diseases. Themanagement of uncomplicated acute viral hepatitis islargely symptomatic. Hepatitis B and hepatitis C virusesare major causes of chronic hepatitis. For details onimmunisation against hepatitis A and B infections, seesection 14.4 (active immunisation) and section 14.5(passive immunisation).Chronic hepatitis B Interferon alfa (section 8.2.4),peginterferon alfa-2a, lamivudine (section 5.3.1), adefovirdipivoxil, entecavir, and tenofovir disoproxilhave a role in the treatment of chronic hepatitis B inadults, but their role in children has not been wellestablished. Specialist supervision is required for themanagement of chronic hepatitis B.Tenofovir, or a combination of tenofovir with eitheremtricitabine or lamivudine, may be used with otherantiretrovirals, as part of ‘highly active antiretroviraltherapy’ (section 5.3.1) in children who require treatmentfor both HIV and chronic hepatitis B. If childreninfected with both HIV and chronic hepatitis B onlyrequire treatment for chronic hepatitis B, they shouldreceive antivirals that are not active against HIV. Managementof these children should be co-ordinatedbetween HIV and hepatology specialists.Chronic hepatitis C Treatment should be consideredfor children with moderate or severe liver disease.Specialist supervision is required and the regimen ischosen according to the genotype of the infecting virus5 Infections

326 5.3.4 Influenza BNFC 2011–20125 Infectionsand the viral load. A combination of ribavirin (section5.3.5) with either interferon alfa (section 8.2.4) orpeginterferon alfa-2b is licensed for use in childrenover 3 years with chronic hepatitis C. A combination ofpeginterferon alfa (BNF Section 8.2.4) and ribavirin ispreferred.5.3.4 InfluenzaFor advice on immunisation against influenza, see section14.4.Oseltamivir and zanamivir reduce replication of influenzaA and B viruses by inhibiting viral neuraminidase.They are most effective for the treatment of influenza ifstarted within a few hours of the onset of symptoms;oseltamivir is licensed for use within 48 hours of the firstsymptoms while zanamivir is licensed for use within 36hours of the first symptoms. In otherwise healthy individualsthey reduce the duration of symptoms by about1–1.5 days. For further information on the treatment ofinfluenza, see NICE guidance, below.Oseltamivir and zanamivir are licensed for post-exposureprophylaxis of influenza when influenza is circulatingin the community. Oseltamivir should be givenwithin 48 hours of exposure to influenza while zanamivirshould be given within 36 hours of exposure toinfluenza (see also NICE guidance, below). Oseltamivirand zanamivir are also licensed for use in exceptionalcircumstances (e.g. when vaccination does not cover theinfecting strain) to prevent influenza in an epidemic.There is evidence that some strains of influenza A virushave reduced susceptibility to oseltamivir, but mayretain susceptibility to zanamivir. Resistance to oseltamivirmay be greater in severely immunocompromisedchildren.Oseltamivir in children under 1 year of age Dataon the use of oseltamivir in children under 1 year of ageis limited. Furthermore, oseltamivir may be ineffectivein neonates because they may not be able to metaboliseoseltamivir to its active form. However, oseltamivir canbe used (under specialist supervision) for the treatmentor post-exposure prophylaxis of influenza in childrenunder 1 year of age. The Department of Health hasadvised (May 2009) that during a pandemic, treatmentwith oseltamivir can be overseen by healthcare professionalsexperienced in assessing children.Amantadine is licensed for prophylaxis and treatmentof influenza A in children over 10 years of age, but it isno longer recommended (see NICE guidance, below).Information on pandemic influenza, avian influenza,and swine influenza can be found at www.hpa.org.uk.Pregnancy and breast-feeding Although safetydata are limited, either oseltamivir or zanamivir can beused in women who are pregnant or breast-feedingwhen the potential benefit outweighs the risk (e.g. duringa pandemic). Zanamivir is the preferred drug duringpregnancy; however, oseltamivir is recommended duringsevere infection or when zanamivir cannot be used.Oseltamivir is the preferred drug in women who arebreast-feeding.NICE guidanceOseltamivir, zanamivir, and amantadine forprophylaxis and treatment of influenza(September 2008 and February 2009)The drugs described here are not a substitute forvaccination, which remains the most effective way ofpreventing illness from influenza.. Amantadine is not recommended for prophylaxisor treatment of influenza.. Oseltamivir or zanamivir are not recommendedfor seasonal prophylaxis against influenza.. When influenza is circulating in the community1 , either oseltamivir or zanamivir is recommended(in accordance with UK licensing) forpost-exposure prophylaxis in at-risk patientswho are not effectively protected by influenzavaccine, and who have been in close contactwith someone suffering from influenza-like illnessin the same household or residential setting.Oseltamivir should be given within 48hours of exposure to influenza while zanamivirshould be given within 36 hours of exposure toinfluenza.. When influenza is circulating in the community1 , oseltamivir or zanamivir is recommended(in accordance with UK licensing) for the treatmentof influenza in at-risk patients who canstart treatment within 48 hours (within 36 hoursfor zanamivir) of the onset of symptoms.. During local outbreaks of influenza-like illness,when there is a high level of certainty that influenzais present, either oseltamivir or zanamivirmay be used for post-exposure prophylaxis ortreatment in at-risk patients (regardless of influenzavaccination) living in long-term residentialor nursing homes.At-risk 2 patients are those who have one or more ofthe following conditions:. chronic respiratory disease (including asthma);. chronic heart disease;. chronic renal disease;. chronic liver disease;. chronic neurological disease;. immunosuppression;. diabetes mellitus.This guidance does not cover the circumstances of apandemic, an impending pandemic, or a widespreadepidemic of a new strain of influenza to which thereis little or no immunity in the community.OSELTAMIVIRRenal impairment reduce dose by 50% if estimatedglomerular filtration rate 10–30 mL/minute/1.73 m 2 ;avoid if estimated glomerular filtration rate less than10 mL/minute/1.73 m 2Pregnancy use only if potential benefit outweighs risk(e.g. during a pandemic); see also above1. National surveillance schemes, including those run by theHealth Protection Agency, should be used to indicate wheninfluenza is circulating in the community.2. The Department of Health in England has advised(November 2010) that ‘at risk patients’ also includesfemales who are pregnant.

BNFC 2011–2012 5.3.5 Respiratory syncytial virus 327Breast-feeding amount probably too small to beharmful; use only if potential benefit outweighs risk;(e.g. during a pandemic); see also p. 326Side-effects nausea, vomiting, abdominal pain, diarrhoea;headache; conjunctivitis; less commonly eczema;also reported hepatitis, gastro-intestinal bleeding,arrhythmias, neuropsychiatric disorders,thrombocytopenia, visual disturbances, Stevens-Johnson syndrome, and toxic epidermal necrolysisLicensed use not licensed for use in children under 1year unless there is a pandemicIndication and dosePrevention of influenza. By mouthChild under 1 month (see notes above) 2 mg/kgonce daily for 10 days for post-exposure prophylaxisChild 1–3 months (see notes above) 2.5 mg/kgonce daily for 10 days for post-exposure prophylaxisChild 3 months–1 year (see notes above) 3 mg/kg once daily for 10 days for post-exposureprophylaxisChild 1–13 yearsBody-weight under 15 kg 30 mg once daily for10 days for post-exposure prophylaxis; for up to 6weeks during an epidemicBody-weight 15–23 kg 45 mg once daily for 10days for post-exposure prophylaxis; for up to 6weeks during an epidemicBody-weight 23–40 kg 60 mg once daily for 10days for post-exposure prophylaxis; for up to 6weeks during an epidemicBody-weight over 40 kg 75 mg once daily for 10days for post-exposure prophylaxis; for up to 6weeks during an epidemicChild 13–18 years 75 mg once daily for 10 daysfor post-exposure prophylaxis; for up to 6 weeksduring an epidemicTreatment of influenza. By mouthChild under 1 month (see notes above) 2 mg/kgtwice daily for 5 daysChild 1–3 months (see notes above) 2.5 mg/kgtwice daily for 5 daysChild 3 months–1 year (see notes above) 3 mg/kg twice daily for 5 daysChild 1–13 yearsBody-weight under 15 kg 30 mg twice daily for 5daysBody-weight 15–23 kg 45 mg twice daily for 5daysBody-weight 23–40 kg 60 mg twice daily for 5daysBody-weight over 40 kg 75 mg twice daily for 5daysChild 13–18 years 75 mg twice daily for 5 daysAdministration if suspension not available, capsulescan be opened and the contents mixed with a smallamount of sweetened food, such as sugar water orchocolate syrup, just before administration1Tamiflu c (Roche) ACapsules, oseltamivir (as phosphate) 30 mg (yellow),net price 10-cap pack = £7.71; 45 mg (grey), 10-cappack = £15.41; 75 mg (grey-yellow), 10-cap pack =£15.41. Label: 9Oral suspension, sugar-free, tutti-frutti-flavoured,oseltamivir (as phosphate) for reconstitution withwater, 60 mg/5 mL, net price 75 mL = £15.41. Label: 9Excipients include sorbitol 1.7 g/5 mLNote Solutions prepared by ‘Special Order’ manufacturersmay be a different concentration1. D except for the treatment and prophylaxis of influenza asindicated in the notes above and NICE guidance; endorseprescription ‘SLS’ZANAMIVIRCautions asthma and chronic pulmonary disease (riskof bronchospasm—short-acting bronchodilatorshould be available; avoid in severe asthma unlessclose monitoring possible and appropriate facilitiesavailable to treat bronchospasm); uncontrolledchronic illness; other inhaled drugs should be administeredbefore zanamivirPregnancy use only if potential benefit outweighs risk(e.g. during a pandemic); see also p. 326Breast-feeding amount probably too small to beharmful; use only if potential benefit outweighs risk(e.g. during a pandemic); see also p. 326Side-effects very rarely bronchospasm, respiratoryimpairment, angioedema, urticaria, and rash; alsoreported neuropsychiatric disorders, Stevens-Johnsonsyndrome, toxic epidermal necrolysisIndication and dosePost-exposure prophylaxis of influenza. By inhalation of powderChild 5–18 years 10 mg once daily for 10 daysPrevention of influenza during an epidemic. By inhalation of powderChild 5–18 years 10 mg once daily for up to 28daysTreatment of influenza. By inhalation of powderChild 5–18 years 10 mg twice daily for 5 days (forup to 10 days if resistance to oseltamivir suspected)1Relenza c (GSK) ADry powder for inhalation disks containing 4 blistersof zanamivir 5 mg/blister, net price 5 disks with Diskhalerc device = £16.361. D except for the treatment and prophylaxis of influenza asindicated in the notes above and NICE guidance; endorseprescription ‘SLS’5.3.5 Respiratory syncytialvirusRibavirin inhibits a wide range of DNA and RNAviruses. It is licensed for administration by inhalationfor the treatment of severe bronchiolitis caused by the5 Infections

328 5.3.5 Respiratory syncytial virus BNFC 2011–20125 Infectionsrespiratory syncytial virus (RSV) in infants, especiallywhen they have other serious diseases. However, thereis no evidence that ribavirin produces clinically relevantbenefit in RSV bronchiolitis. Ribavirin is given by mouthwith peginterferon alfa or interferon alfa for the treatmentof chronic hepatitis C infection (see Viral Hepatitis,section 5.3.3). Ribavirin is also effective in Lassafever and has also been used parenterally in the treatmentof life-threatening RSV, parainfluenza virus, andadenovirus infections in immunocompromised children[unlicensed indications].Palivizumab is a monoclonal antibody licensed forpreventing serious lower respiratory-tract diseasecaused by respiratory syncytial virus in children athigh risk of the disease; it should be prescribed underspecialist supervision and on the basis of the likelihoodof hospitalisation.Palivizumab is recommended for:. children under 9 months of age with chronic lungdisease (defined as requiring oxygen for at least 28days from birth) and who were born preterm 1 ;. children under 6 months of age with haemodynamicallysignificant, acyanotic congenital heart diseasewho were born preterm 1 .Palivizumab should be considered for:. children under 2 years of age with severe combinedimmunodeficiency syndrome;. children under 1 year of age who require long-termventilation;. children 1–2 years of age who require long-termventilation and have an additional co-morbidity(including cardiac disease or pulmonary hypertension).PALIVIZUMABCautions moderate to severe acute infection or febrileillness; thrombocytopenia; serum-palivizumab concentrationmay be reduced after cardiac surgery;hypersensitivity to humanised monoclonal antibodiesSide-effects fever, injection-site reactions, nervousness;less commonly diarrhoea, vomiting, constipation,haemorrhage, rhinitis, cough, wheeze, pain,drowsiness, asthenia, hyperkinesia, leucopenia, andrash; also reported, apnoea, hypersensitivity reactions(including anaphylaxis), convulsions and thrombocytopeniaLicensed use not licensed in children with congenitalimmunodeficiency or in children born at 35weeks gestation or less and older than 6 months(licensed in children under 6 months)Indication and dosePrevention of serious disease caused by respiratorysyncytial virus infection (see notesabove). By intramuscular injection (preferably in anterolateralthigh)Neonate 15 mg/kg once a month during season ofRSV risk1. For details of the preterm age groups included in therecommendations, see Immunisation against InfectiousDisease (2006), available at www.dh.gov.uk/immunisationChild 1 month–2 years 15 mg/kg once a monthduring season of RSV risk (child undergoing cardiacbypass surgery, 15 mg/kg as soon as stableafter surgery, then once a month during season ofrisk); injection volume over 1 mL should be dividedbetween 2 or more sitesSynagis c (Abbott) TAInjection, powder for reconstitution, palivizumab, netprice 50-mg vial = £360.40; 100-mg vial = £663.11RIBAVIRIN(Tribavirin)CautionsSpecific cautions for inhaled treatment Maintain standardsupportive respiratory and fluid management therapy;monitor electrolytes closely; monitor equipment for precipitation;pregnant women (and those planning pregnancy)should avoid exposure to aerosolSpecific cautions for systemic treatment Excludepregnancy before treatment in females of childbearing age;effective contraception essential during treatment and for 4months after treatment in females and for 7 months aftertreatment in males of childbearing age; routine monthlypregnancy tests recommended; condoms must be used ifpartner of male patient is pregnant (ribavirin excreted insemen); cardiac disease (assessment including ECG recommendedbefore and during treatment—discontinue if deterioration);determine full blood count, platelets, electrolytes,serum creatinine, liver function tests and uric acid beforestarting treatment and then on weeks 2 and 4 of treatment,then as indicated clinically—adjust dose if adverse reactionsor laboratory abnormalities develop (consult product literature);eye examination recommended before oral treatment;eye examination also recommended during oral treatment ifpre-existing ophthalmological disorder or if decrease invision reported—discontinue treatment if ophthalmologicaldisorder deteriorates or if new ophthalmological disorderdevelops; test thyroid function before treatment and thenevery 3 months; risk of growth retardation, the reversibilityof which is uncertain—if possible, consider starting treatmentafter pubertal growth spurtInteractions: Appendix 1 (ribavirin)Contra-indicationsSpecific contra-indications for systemic treatmentSevere, uncontrolled cardiac disease in children with chronichepatitis C; haemoglobinopathies; severe debilitating medicalconditions; severe hepatic dysfunction or decompensatedcirrhosis; autoimmune disease (including autoimmunehepatitis); history of severe psychiatric conditionHepatic impairment no dosage adjustment required;use oral ribavirin with caution in severe hepatic dysfunctionor decompensated cirrhosisRenal impairment plasma-ribavirin concentrationincreased; manufacturer advises avoid oral ribavirin ifestimated glomerular filtration rate less than 50 mL/minute/1.73 m 2 ; manufacturer advises use intravenouspreparation with caution if estimated glomerularfiltration rate less than 30 mL/minute/1.73 m 2Pregnancy avoid; teratogenicity in animal studies; seealso Cautions aboveBreast-feeding avoid—no information availableSide-effectsSpecific side-effects for inhaled treatment Worseningrespiration, bacterial pneumonia, and pneumothoraxreported; rarely non-specific anaemia and haemolysisSpecific side-effects for oral treatment Haemolytic anaemia(anaemia may be improved by epoetin); also (in combinationwith peginterferon alfa or interferon alfa) nausea,vomiting, dyspepsia, abdominal pain, flatulence, constipation,diarrhoea, colitis, chest pain, palpitation, tachycardia,peripheral oedema, changes in blood pressure, syncope,flushing, pallor, cough, dyspnoea, tachypnoea, headache,dizziness, hyperkinesia, asthenia, impaired concentrationand memory, sleep disturbances, abnormal dreams, anxiety,depression, suicidal ideation, psychoses, dysphagia, weightloss, dysphonia, paraesthesia, hypoaesthesia, ataxia, hypertonia,influenza-like symptoms, growth retardation (includ-

BNFC 2011–2012 5.4 Antiprotozoal drugs 329ing decrease in height and weight), thyroid disorders,hyperglycaemia, menstrual disturbances, virilism, breastpain, testicular pain, sexual dysfunction, micturition disorders,leucopenia, thrombocytopenia, lymphadenopathy,dehydration, hypocalcaemia, myalgia, arthralgia, hyperuricaemia,visual disturbances, eye pain, dry eyes, hearingimpairment, tinnitus, earache, dry mouth, taste disturbances,mouth ulcers, stomatitis, glossitis, tooth disorder, gingivitis,alopecia, pruritus, dry skin, skin discoloration, rash (includingvery rarely Stevens-Johnson syndrome and toxic epidermalnecrolysis), increased sweating, psoriasis, photosensitivity,and acne; less commonly pancreatitis, gastrointestinalbleeding, and hypertriglyceridaemia; rarely pepticulcer, arrhythmias, cardiomyopathy, myocardial infarction,pericarditis, stroke, interstitial pneumonitis, pulmonaryembolism, seizures, renal failure, vasculitis, rheumatoidarthritis, systemic lupus erythematosus, sarcoidosis, opticneuropathy, and retinal haemorrhage; very rarely aplasticanaemia and peripheral ischaemiaLicensed use inhalation licensed for use in children(age range not specified by manufacturer); intravenouspreparation not licensedIndication and doseBronchiolitis. By aerosol inhalation or nebulisation (via smallparticle aerosol generator)Child 1 month–2 years inhale solution containing20 mg/mL for 12–18 hours for at least 3 days; max.7 daysLife-threatening RSV, parainfluenza virus, andadenovirus infection in immunocompromisedchildren (seek expert advice). By intravenous infusion over 15 minutesChild 1 month–18 years 33 mg/kg as a singledose, then 16 mg/kg every 6 hours for 4 days, then8 mg/kg every 8 hours for 3 daysChronic hepatitis C (in combination with interferonalfa or peginterferon alfa) in previouslyuntreated children without liver decompensation. By mouthChild over 3 years; body-weight under 47 kg15 mg/kg daily in 2 divided dosesChild body-weight 47–50 kg 200 mg in themorning and 400 mg in the eveningChild body-weight 50–65 kg 400 mg twice dailyChild body-weight 65–86 kg 400 mg in themorning and 600 mg in the eveningChild body-weight 86–105 kg 600 mg twicedailyChild body-weight over 105 kg 600 mg in themorning and 800 mg in the eveningRebetol c (Schering-Plough) ACapsules, ribavirin 200 mg, net price 84-cap pack =£160.90, 140-cap pack = £267.81, 168-cap pack =£321.38. Label: 21Oral solution, ribavirin 200 mg/5 mL, net price100 mL (bubble-gum-flavoured) = £67.08. Label: 21Virazole c (Meda) AInhalationU, ribavirin 6 g for reconstitution with300 mL water for injections. Net price 3 6-g vials =£349.00Intravenous infusion, 100 mg/mL, 10-mL ampAvailable on a named-patient basis from Valeant5.4 Antiprotozoal drugs5.4.1 Antimalarials5.4.2 Amoebicides5.4.3 Trichomonacides5.4.4 Antigiardial drugs5.4.5 Leishmaniacides5.4.6 Trypanocides5.4.7 Drugs for toxoplasmosis5.4.8 Drugs for pneumocystis pneumoniaAdvice on specific problems available from:Advice for healthcare professionalsHPA (Health Protection Agency) MalariaReference Laboratorywww.hpa.org.uk/infections/topics_az/malariaNational Travel Health Network andCentreTravel Medicine Team, Health Protection,Scotland(registered users of Travax only)www.travax.nhs.uk(for registered users of the NHS Travaxwebsite only)(020) 7637 0248(Fax)(prophylaxis only)0845 602 6712(0141) 300 1100(weekdays 2–4p.m. only)Birmingham (0121) 424 0357Liverpool (0151) 705 3100London 0845 155 5000(treatment)Oxford (01865) 225 430Advice for travellersHospital for Tropical Diseases, Travel 020 7950 7799Healthlinewww.fitfortravel.nhs.ukWHO advice on international travel and healthwww.who.int/ithNational Travel Health Network andCentre (NaTHNaC)www.nathnac.org/travel/index.htm5.4.1 AntimalarialsRecommendations on the prophylaxis and treatment ofmalaria reflect guidelines agreed by UK malaria specialists.Choice will depend on the age of the child (seebelow).The centres listed above should be consulted for adviceon special problems.Treatment of malariaIf the infective species is not known, or if the infection ismixed, initial treatment should be as for falciparum5 Infections

330 5.4.1 Antimalarials BNFC 2011–20125 Infectionsmalaria with quinine, Malarone c (proguanil withatovaquone), or Riamet c (artemether with lumefantrine).Falciparum malaria can progress rapidly inunprotected children and antimalarial treatment shouldbe considered in those with features of severe malariaand possible exposure, even if the initial blood tests forthe organism are negative.Falciparum malaria (treatment)Falciparum malaria (malignant malaria) is caused byPlasmodium falciparum. In most parts of the world P.falciparum is now resistant to chloroquine which shouldnot therefore be given for treatment.Quinine, Malarone c (proguanil with atovaquone), orRiamet c (artemether with lumefantrine) can be given bymouth if the child can swallow and retain tablets andthere are no serious manifestations (e.g. impairedconsciousness); quinine should be given by intravenousinfusion (see below) if the child is seriously ill or unableto take tablets. Mefloquine is now rarely used fortreatment because of concerns about resistance.Oral. Quinine is well tolerated by children although thesalts are bitter.The dosage regimen for quinine by mouth is:10 mg/kg (of quinine salt 1 ; max. 600 mg) every 8hours for 7 daystogether with or followed byeither clindamycin 7–13 mg/kg (max. 450 mg)every 8 hours for 7 days [unlicensed indication]or, in children over 12 years, doxycycline 200 mgonce daily for 7 daysIf the parasite is likely to be sensitive, pyrimethaminewith sulfadoxine as a single dose [unlicensed] may begiven (instead of either clindamycin or doxycycline)together with, or after, a course of quinine.The dose regimen for pyrimethamine with sulfadoxineby mouth is:Child up to 4 years and body-weight over 5 kgpyrimethamine 12.5 mg with sulfadoxine 250 mg asa single doseChild 5–6 years pyrimethamine 25 mg with sulfadoxine500 mg as a single doseChild 7–9 years pyrimethamine 37.5 mg with sulfadoxine750 mg as a single doseChild 10–14 years pyrimethamine 50 mg with sulfadoxine1 g as a single doseChild 14–18 years pyrimethamine 75 mg with sulfadoxine1.5 g as a single doseAlternatively, Malarone c , or Riamet c may be giveninstead of quinine. It is not necessary to give clindamycin,doxycycline, or pyrimethamine with sulfadoxineafter Malarone c or Riamet c treatment.The dose regimen for Malarone c by mouth is:Child body-weight 5–8 kg, 2 ‘paediatric’ tabletsonce daily for 3 daysChild body-weight 9–10 kg, 3 ‘paediatric’ tabletsonce daily for 3 daysChild body-weight 11–20 kg, 1 ‘standard’ tabletonce daily for 3 daysChild body-weight 21–30 kg, 2 ‘standard’ tabletsonce daily for 3 days1. Valid for quinine hydrochloride, dihydrochloride, andsulphate; not valid for quinine bisulphate which containsa correspondingly smaller amount of quinine.Child body-weight 31–40 kg, 3 ‘standard’ tabletsonce daily for 3 daysChild body-weight over 40 kg, 4 ‘standard’ tabletsonce daily for 3 daysThe dose regimen for Riamet c by mouth is:Child body-weight 5–15 kg 1 tablet initially, followedby 5 further doses of 1 tablet each given at 8,24, 36, 48, and 60 hours (total 6 tablets over 60hours)Child body-weight 15–25 kg 2 tablets initially, followedby 5 further doses of 2 tablets each given at 8,24, 36, 48, and 60 hours (total 12 tablets over 60hours)Child body-weight 25–35 kg 3 tablets initially, followedby 5 further doses of 3 tablets each given at 8,24, 36, 48, and 60 hours (total 18 tablets over 60hours)Child 12–18 years and body-weight over 35 kg, 4tablets initially followed by 5 further doses of 4tablets each given at 8, 24, 36, 48, and 60 hours(total 24 tablets over 60 hours)Parenteral. If the child is seriously ill or unable toswallow tablets, quinine should be given by intravenousinfusion. The dose regimen for quinine by intravenousinfusion is calculated on a mg/kg basis:Neonates and children, loading dose 2 ; 3 of 20 mg/kg(up to maximum 1.4 g) of quinine salt 1 infused over4 hours then 8 hours after the start of the loadingdose, maintenance dose of 10 mg/kg 4 (up to maximum700 mg) of quinine salt 1 infused over 4 hoursevery 8 hours (until child can swallow tablets tocomplete the 7-day course together with or followedby either clindamycin or doxycycline asabove).Specialist advice should be sought in difficult cases (e.g.very high parasite count, deterioration on optimal dosesof quinine, infection acquired in quinine-resistant areasof south-east Asia) because intravenous artesunatemay be available for ‘named-patient’ use.Pregnancy Falciparum malaria is particularly dangerousin pregnancy, especially in the last trimester. Thetreatment doses of oral and intravenous quinine givenabove (including the loading dose) can safely be given inpregnancy. Clindamycin [unlicensed indication] shouldbe given for 7 days with or after quinine. Doxycyclineshould be avoided in pregnancy (affects teeth and skeletaldevelopment in fetus); pyrimethamine with sulfadoxine,Malarone c , and Riamet c are also best avoideduntil more information is available. Specialist adviceshould be sought in difficult cases (e.g. very highparasite count, deterioration on optimal doses ofquinine, infection acquired in quinine-resistant areas ofsouth east Asia) because intravenous artesunate may beavailable for ‘named patient’ use.2. In intensive care units the loading dose can alternatively begiven as quinine salt 1 7 mg/kg infused over 30 minutesfollowed immediately by 10 mg/kg over 4 hours then (after8 hours) maintenance dose as described.3. Important: the loading dose of 20 mg/kg should not beused if the patient has received quinine or mefloquineduring the previous 12 hours4. Maintenance dose should be reduced to 5–7 mg/kg ofquinine salt 1 in children with severe renal impairment,severe hepatic impairment, or if parenteral treatment isrequired for more than 48 hours.

BNFC 2011–2012 5.4.1 Antimalarials 331Benign malarias (treatment)Benign malaria is usually caused by Plasmodium vivaxand less commonly by P. ovale and P. malariae.Chloroquine 1 is the drug of choice for the treatmentof benign malarias (but chloroquine-resistant P. vivaxinfection has been reported from Indonesia, NewGuinea and some adjacent islands).Chloroquine alone is adequate for P. malariae infectionsbut in the case of P. vivax and P. ovale, aradicalcure (to destroy parasites in the liver and thus preventrelapses) is required. This is achieved with primaquine 2given after the chloroquine.The dosage regimen of chloroquine by mouth for benignmalaria in children is:initial dose of 10 mg/kg of base (max. 620 mg) thena single dose of 5 mg/kg of base (max. 310 mg) after 6–8hours thena single dose of 5 mg/kg of base (max. 310 mg) daily for2 daysFor a radical cure, primaquine 2 [unlicensed] is thengiven to children over 6 months of age; specialist adviceshould be sought for children under 6 months of age.Primaquine is given in a dose of 250 micrograms/kg(max. 15 mg) daily for 14 days in P. ovale infection or500 micrograms/kg (max. 30 mg) daily for 14 days in P.vivax infection.Parenteral If the child is unable to take oral therapy,quinine can be given by intravenous infusion. The doseis 10 mg/kg 3 (max. 700 mg) of quinine salt 4 infused over4 hours every 8 hours, changed to oral chloroquine assoon as the child’s condition permits.Pregnancy Treatment doses of chloroquine can begiven for benign malaria. In the case of P. vivax or P.ovale, however, the radical cure with primaquine shouldbe postponed until the pregnancy is over; insteadchloroquine should be continued at a dose of 10 mg/kg (max. 310 mg) each week during the pregnancy.Prophylaxis against malariaThe recommendations on prophylaxis reflect guidelinesagreed by UK malaria specialists; the advice is aimed atresidents of the UK who travel to endemic areas. Thechoice of drug for a particular child should take intoaccount:. risk of exposure to malaria;. extent of drug resistance;1. For the treatment of chloroquine-resistant benign malariaMalarone c [unlicensed indication], quinine, or Riamet c[unlicensed indication] can be used; as with chloroquine,primaquine should be given for radical cure.2. Before starting primaquine, blood should be tested forglucose-6-phosphate dehydrogenase (G6PD) activity sincethe drug can cause haemolysis in G6PD-deficient patients.Specialist advice should be obtained in G6PD deficiency. Inmild G6PD deficiency, primaquine in a dose of 750 micrograms/kg(max. 45 mg) once a week for 8 weeks, hasbeen found useful and without undue harmful effects.3. Maintenance dose should be reduced to 5–7 mg/kg ofquinine salt 4 in children with severe renal impairment,severe hepatic impairment, or if parenteral treatment isrequired for more than 48 hours.4. Valid for quinine hydrochloride, dihydrochloride, andsulphate; not valid for quinine bisulphate which containsa correspondingly smaller amount of quinine.. efficacy of the recommended drugs;. side-effects of the drugs;. patient-related factors (e.g. age, pregnancy, renal orhepatic impairment, compliance with prophylacticregimen).Prophylactic doses are based on guidelines agreed byUK malaria experts and may differ from advice inproduct literature. Weight is a better guide than age.If in doubt obtain advice from specialist centre, seep. 329.Protection against bites Prophylaxis is not absolute,and breakthrough infection can occur with any ofthe drugs recommended. Personal protection againstbeing bitten is very important. Mosquito nets impregnatedwith permethrin provide the most effective barrierprotection against insects (infants should sleep with amosquito net stretched over the cot or baby carrier);mats and vaporised insecticides are also useful. Diethyltoluamide(DEET) 20–50% in lotions, sprays, or roll-onformulations is safe and effective when applied to theskin of adults and children over 2 months of age. It canalso be used during pregnancy and breast-feeding. Theduration of protection varies according to the concentrationof DEET and is longest for DEET 50%. Longsleeves and trousers worn after dusk also provide protection.Length of prophylaxis In order to determine toleranceand to establish habit, prophylaxis should generallybe started one week (preferably 2–3 weeks in the case ofmefloquine) before travel into an endemic area (or if notpossible at earliest opportunity up to 1 or 2 days beforetravel); Malarone c or doxycycline prophylaxis shouldbe started 1–2 days before travel. Prophylaxis should becontinued for 4 weeks after leaving (except forMalarone c prophylaxis which should be stopped 1week after leaving).In those requiring long-term prophylaxis, chloroquineand proguanil may be used for periods of over 5 years.Mefloquine is licensed for use up to 1 year (although ithas been used for up to 3 years without undue problems).Doxycycline can be used for up to 2 years.Malarone c is licensed for use for up to 28 days butcan be used for up to 1 year (and possibly longer) withcaution. Specialist advice should be sought for longtermprophylaxis.Return from malarial region It is important to beaware that any illness that occurs within 1 year andespecially within 3 months of return might be malariaeven if all recommended precautions against malariawere taken. Travellers and carers of children shouldbe warned of this and told that if they develop anyillness particularly within 3 months of their returnthey should go immediately to a doctor and specificallymention their exposure to malaria.Epilepsy Both chloroquine and mefloquine are unsuitablefor malaria prophylaxis in children with a history ofepilepsy. In areas without chloroquine resistance, proguanilalone is recommended; in areas with chloroquineresistance, doxycycline or Malarone c may be considered.The metabolism of doxycycline may be influencedby antiepileptics (see interactions: Appendix 1 (tetracyclines)).5 Infections

332 5.4.1 Antimalarials BNFC 2011–20125 InfectionsAsplenia Asplenic children (or those with severesplenic dysfunction) are at particular risk of severemalaria. If travel to malarious areas is unavoidable,rigorous precautions are required against contractingthe disease.Renal impairment Avoidance (or dosage reduction)of proguanil is recommended since it is excreted by thekidneys. Malarone c should not be used for prophylaxisin children with estimated glomerular filtration rate lessthan 30 mL/minute/1.73 m 2 . Chloroquine is only partiallyexcreted by the kidneys and reduction of the dosefor prophylaxis is not required except in severeimpairment. Mefloquine is considered to be appropriateto use in renal impairment and does not require dosagereduction. Doxycycline is also considered to be appropriate.Pregnancy Travel to malarious areas should beavoided during pregnancy; if travel is unavoidable,effective prophylaxis must be used. Chloroquine andproguanil can be given in the usual doses duringpregnancy, but these drugs are not appropriate formost areas because their effectiveness has declined,particularly in sub-saharan Africa; in the case of proguanil,folic acid 5 mg daily should be given. The centreslisted on p. 329 should be consulted for advice onprophylaxis in chloroquine-resistant areas. Althoughthe manufacturer advises that mefloquine should notbe used during pregnancy, particularly in the first trimester,unless the potential benefit outweighs the risk,studies of mefloquine in pregnancy (including use inthe first trimester) indicate that it can be considered fortravel to chloroquine-resistant areas. Doxycycline iscontra-indicated during pregnancy. Malarone c shouldbe avoided during pregnancy unless there is no suitablealternative.Breast-feeding Prophylaxis is required in breast-fedinfants; although antimalarials are present in milk, theamounts are too variable to give reliable protection.October), Kyrgystan (but low risk in south-west, seebelow), Libya, most tourist areas of Turkey (but low riskin Adana and border with Syria, see below), Uzbekistan(extreme south-east only):chemoprophylaxis not recommended but avoidmosquito bites and consider malaria if fever presentsLow risk Risk low in Armenia (June–October), Azerbaijan(southern border areas, June–September), Egypt(El Faiyum only, June–October), Iran (northern borderwith Azerbaijan, May–October; variable risk in ruralsouth-east provinces; see below), rural north Iraq(May–November), Kyrgystan (south-west, May–October),north border of Syria (May–October), Turkey(plain around Adana and east of there, border withSyria, March–November):preferablychloroquine or (if chloroquine not appropriate) proguanilhydrochlorideVariable risk Risk variable and chloroquine resistancepresent in Afghanistan (below 2000 m, May–November),Iran (rural south-east provinces, March–November, seealso Low Risk above), Oman (remote rural areas only),Saudi Arabia (south-west and rural areas of westernregion; no risk in Mecca, Medina, Jeddah, or highaltitudeareas of Asir Province), Tajikistan (June–October),Yemen (no risk in Sana’a):chloroquine + proguanil hydrochloride or (ifchloroquine + proguanil not appropriate and childover 12 years) doxycyclineSpecific recommendationsWhere a journey requires two regimens, the regimen forthe higher risk area should be used for the wholejourney. Those travelling to remote or little-visitedareas may require expert advice.Risk may vary in different parts of a country—checkunder all risk levelsImportant Settled immigrants and their carers (orlong-term visitors) to the UK may be unaware thatthey will have lost some of their immunity and alsothat the areas where they previously lived may nowbe malariousNorth Africa, the Middle East, and CentralAsiaVery low risk Risk very low in Algeria, Egypt (but lowrisk in El Faiyum, see below), Georgia (south-east, July–Sub-Saharan AfricaNo chemoprophylaxis recommended for Cape Verde(some risk on São Tiago) and Mauritius (but avoidmosquito bites and consider malaria if fever presents)Very high risk Risk very high (or locally very high)and chloroquine resistance very widespread in Angola,Benin, Botswana (northern half, November–June), BurkinaFaso, Burundi, Cameroon, Central African Republic,Chad, Comoros, Congo, Democratic Republic of theCongo (formerly Zaïre), Djibouti, Equatorial Guinea,Eritrea, Ethiopia (below 2000 m; no risk in AddisAbaba), Gabon, Gambia, Ghana, Guinea, Guinea-Bissau,Ivory Coast, Kenya, Liberia, Madagascar, Malawi, Mali,Mauritania (all year in south; July–October in north),Mozambique, Namibia (all year along Kavango andKunene rivers; November–June in northern third),Niger, Nigeria, Principe, Rwanda, São Tomé, Senegal,Sierra Leone, Somalia, South Africa (low-altitude areasof Mpumalanga and Limpopo Provinces, KrugerNational Park, and north-east KwaZulu-Natal as farsouth as Jozini), Sudan, Swaziland, Tanzania, Togo,Uganda, Zambia, Zimbabwe (all year in Zambezi valley;

BNFC 2011–2012 5.4.1 Antimalarials 333November–June in other areas below 1200 m; risk negligiblein Harare and Bulawayo):mefloquine or doxycycline (if child over 12) orMalarone cNote In Zimbabwe and neighbouring countries, pyrimethaminewith dapsone (also known as Deltaprim c ) prophylaxis is usedby local residents (sometimes with chloroquine—this regimenis not recommended).under Great Risk, below), Vietnam (cities, coastbetween Ho Chi Minh and Hanoi, and Mekong Riveruntil close to Cambodian border; substantial risk inother areas, see below):chemoprophylaxis not recommended but avoidmosquito bites and consider malaria if fever presentsSouth AsiaLow risk Risk low in Bangladesh (but high risk inChittagong Hill Tracts, see below), India (Kerala [southernstates], Tamil Nadu, Karnataka, Southern AndhraPradesh [including Hyderabad], Mumbai, Rajasthan[including Jaipur], Uttar Pradesh [including Agra], Haryana,Uttaranchal, Himachal Pradesh, Jammu, Kashmir,Punjab, Delhi; variable risk in other areas, see below;high risk in Assam), Sri Lanka (but variable risk north ofVavuniya, see below):chemoprophylaxis not recommended but avoidmosquito bites and consider malaria if fever presentVariable risk Risk variable and some chloroquineresistance in Indonesia (very low risk in Bali, and citiesbut substantial risk in Irian Jaya [West Papua] andLombok, see below), rural Philippines below 600 m(no risk in cities, Cebu, Bohol, and Catanduanes), deepforests of peninsular Malaysia and Sarawak (but substantialrisk in Sabah, see below):chloroquine + proguanil hydrochloride or (ifchloroquine + proguanil not appropriate) mefloquineor doxycycline or Malarone cVariable risk Risk variable and chloroquine resistanceusually moderate in southern districts of Bhutan, India(low risk in some areas, see above; high risk in Assam,see below), Nepal (below 1500 m, especially Terai districts;no risk in Kathmandu), Pakistan (below 2000 m),Sri Lanka (north of Vavuniya; low risk in other areas, seeabove):chloroquine + proguanil hydrochloride or (ifchloroquine + proguanil not appropriate) mefloquineor doxycycline or Malarone cSubstantial risk Risk substantial and drug resistancecommon in Cambodia (no risk or very low risk in someareas, see above; great risk in western provinces, seebelow), China (Yunnan and Hainan; chloroquineprophylaxis appropriate for other remote areas; seealso Very Low Risk above), East Timor, Irian Jaya[West Papua], Laos (no risk in Vientiane), Lombok,Malaysia (Sabah; see also Very Low Risk and VariableRisk above), Myanmar (formerly Burma; see also GreatRisk below), Vietnam (very low risk in some areas, seeabove):mefloquine or doxycycline (if child over 12) orMalarone c5 InfectionsHigh risk Risk high and chloroquine resistance high inBangladesh (only in Chittagong Hill Tracts; low risk inother areas, see above), India (Assam only; see also LowRisk and Variable Risk above):mefloquine or doxycycline (if child over 12) orMalarone c or (if mefloquine, doxycycline, orMalarone c not appropriate) chloroquine + proguanilhydrochlorideGreat risk and drug resistance present Risk greatand widespread chloroquine and mefloquine resistancepresent in western provinces of Cambodia (see alsoVery Low Risk and Substantial Risk above), bordersof Thailand with Cambodia, Laos and Myanmar (verylow risk in Chang Rai and Kwai Bridge, see above),Myanmar (eastern Shan State):doxycycline (if child over 12) or Malarone cSouth-East AsiaVery low risk Risk very low in Bali, Brunei, Cambodia(Angkor Wat and Siem Reap, but no risk in Phnom Penh;substantial risk in other areas, see below; great risk inwestern provinces, see below), main tourist areas ofChina (but substantial risk in Yunnan and Hainan, seebelow; chloroquine prophylaxis appropriate for otherremote areas), Hong Kong, Korea (both North andSouth), Malaysia (both East and West including CameronHighlands, but substantial risk in Sabah [except KotaKinabalu], and variable risk in deep forests, see below),Singapore, Thailand (important: regional risk exists, seeOceaniaRisk Risk high and chloroquine resistance high inPapua New Guinea (below 1800 m), Solomon Islands,Vanuatu:doxycycline (if child over 12) or mefloquine orMalarone c

334 5.4.1 Antimalarials BNFC 2011–20125 InfectionsCentral and South America and theCaribbeanVery low risk Risk very low in Jamaica:chemoprophylaxis not recommended but avoidmosquito bites and consider malaria if fever presentsVariable to low risk Risk variable to low in Argentina(rural areas along northern borders only), rural Belize(except Belize district), Costa Rica (Limon Provinceexcept Puerto Limon and northern canton of Pococci),Dominican Republic, El Salvador (Santa Ana province inwest), Guatemala (below 1500 m), Haiti, Honduras,Mexico (states of Oaxaca and Chiapas), Nicaragua,Panama (west of Panama Canal but variable to highrisk east of Panama Canal, see below), rural Paraguay:chloroquine or (if chloroquine not appropriate) proguanilhydrochlorideVariable to high risk Risk variable to high andchloroquine resistance present in rural areas of Bolivia(below 2500 m; see below for Amazon basin area),Ecuador (below 1500 m; no malaria in GalapagosIslands and Guayaquil; see below for Esmeraldas Province),Panama (east of Panama Canal), Peru (ruralareas east of the Andes and west of the Amazon basinarea below 1500 m; see below for Amazon basin area),Venezuela (north of Orinoco river; high risk south of andincluding Orinoco river and Amazon basin area, seebelow; Caracas free of malaria):chloroquine + proguanil hydrochloride or (ifchloroquine + proguanil not appropriate) mefloquineor doxycycline (if child over 12) or Malarone cHigh risk Risk high and marked chloroquine resistancein Bolivia (Amazon basin area; see also variable tohigh risk above), Brazil (throughout ‘Legal Amazon’ areawhich includes the Amazon basin area, Mato Grossoand Maranhao only; elsewhere very low risk—no chemoprophylaxis),Colombia (most areas below 800 m),Ecuador (Esmeraldas Province; variable to high risk inother areas, see above), French Guiana, all interiorregions of Guyana, Peru (Amazon basin area; see alsovariable to high risk above), Suriname (except Paramariboand coast), Venezuela (Amazon basin area, areassouth of and including Orinoco river; see also variableto high risk above):mefloquine or doxycycline (if child over 12) orMalarone cStandby treatment [unlicensed]Children and their carers visiting remote, malariousareas for prolonged periods should carry standbytreatment if they are likely to be more than 24 hoursaway from medical care. Self-medication should beavoided if medical help is accessible.In order to avoid excessive self-medication, thetraveller should be provided with written instructionsthat urgent medical attention should be soughtif fever (388C or more) develops 7 days (or more)after arriving in a malarious area and that self-treatmentis indicated if medical help is not availablewithin 24 hours of fever onset.In view of the continuing emergence of resistantstrains and of the different regimens required fordifferent areas expert advice should be sought onthe best treatment course for an individual traveller.A drug used for chemoprophylaxis should not beconsidered for standby treatment for the same traveller.Artemether with lumefantrineArtemether with lumefantrine is licensed for the treatmentof acute uncomplicated falciparum malaria.ARTEMETHER WITH LUMEFANTRINECautions electrolyte disturbances, concomitant usewith other drugs known to cause QT-interval prolongation;monitor patients unable to take food (greaterrisk of recrudescence); avoid in acute porphyria(section 9.8.2); interactions: Appendix 1 (artemetherwith lumefantrine)Skilled tasks Dizziness may affect performance of skilledtasksContra-indications history of arrhythmias, of clinicallyrelevant bradycardia, and of congestive heartfailure accompanied by reduced left ventricular ejectionfraction; family history of sudden death or ofcongenital QT interval prolongationHepatic impairment manufacturer advises caution insevere impairment—monitor ECG and plasmapotassium concentrationRenal impairment manufacturer advises caution insevere impairment—monitor ECG and plasmapotassium concentrationPregnancy toxicity in animal studies with artemether;manufacturer advises use only if potential benefitoutweighs riskBreast-feeding manufacturer advises avoid breastfeedingfor at least 1 week after last dose; present inmilk in animal studiesSide-effects abdominal pain, anorexia, diarrhoea,vomiting, nausea; palpitation, prolonged QT interval;cough; headache, dizziness, sleep disturbances, asthenia,paraesthesia; arthralgia, myalgia; pruritus, rash;less commonly ataxia, hypoaesthesia, clonusIndication and doseTreatment of acute uncomplicated falciparummalaria see p. 330Treatment of benign malaria see p. 331

BNFC 2011–2012 5.4.1 Antimalarials 335Administration tablets may be crushed just beforeadministrationRiamet c (Novartis) TATablets, yellow, artemether 20 mg, lumefantrine120 mg, net price 24-tab pack = £22.50. Label: 21,counselling, skilled tasksChloroquineChloroquine is used for the prophylaxis of malaria inareas of the world where the risk of chloroquine-resistantfalciparum malaria is still low. It is also used withproguanil when chloroquine-resistant falciparum malariais present but this regimen may not give optimalprotection (see specific recommendations by country,p. 332).Chloroquine is no longer recommended for the treatmentof falciparum malaria owing to widespread resistance,nor is it recommended if the infective species isnot known or if the infection is mixed; in these casestreatment should be with quinine, Malarone c , orRiamet c (for details, see p. 329). It is still recommendedfor the treatment of benign malarias (for details, seep. 331).CHLOROQUINECautions may exacerbate psoriasis, neurological disorders(avoid for prophylaxis if history of epilepsy, seenotes above), may aggravate myasthenia gravis,severe gastro-intestinal disorders, G6PD deficiency(see section 9.1.5); ophthalmic examination with longtermtherapy; avoid concurrent therapy with hepatotoxicdrugs—other interactions: Appendix 1(chloroquine and hydroxychloroquine)Hepatic impairment use with caution in moderate tosevere impairmentRenal impairment manufacturers advise caution; seealso Prophylaxis Against Malaria, p. 332Pregnancy benefit of prophylaxis and treatment inmalaria outweighs risk; see also Benign Malarias(treatment), p. 331 and Prophylaxis Against Malaria,p. 332Breast-feeding amount in milk probably too small tobe harmful; see also Prophylaxis Against Malaria,p. 332Side-effects gastro-intestinal disturbances, headache;also hypotension, convulsions, visual disturbances,depigmentation or loss of hair, skin reactions (rashes,pruritus); rarely, bone-marrow suppression, hypersensitivityreactions such as urticaria and angioedema;other side-effects (not usually associated withmalaria prophylaxis or treatment), see under Antimalarials,section 10.1.3; very toxic in overdosage—immediate advice from poisons centres essential (seealso p. 29)Indication and doseProphylaxis of malaria. By mouthDose (expressed as chloroquine base) preferablystarted 1 week before entering endemic area andcontinued for 4 weeks after leaving (see notesabove)Child up to 12 weeks, body-weight under 6 kg37.5 mg once weeklyChild 12 weeks–1 year, body-weight 6–10 kg75 mg once weeklyChild 1–4 years, body-weight 10–16 kg112.5 mg once weeklyChild 4–8 years, body-weight 16–25 kg 150 mgonce weekly (or 155 mg once weekly if tabletsused)Child 8–13 years, body-weight 25–45 kg225 mg once weekly (or 232.5 mg once weekly iftablets used)Child over 13 years, body-weight over 45 kg310 mg once weeklyCounselling Warn travellers about importance ofavoiding mosquito bites, importance of taking prophylaxisregularly, and importance of immediate visit todoctor if ill within 1 year and especially within 3 monthsof return. For details, see notes aboveTreatment of benign malaria see p. 331Note Chloroquine doses in BNFC may differ from those inproduct literature1Avloclor c (AstraZeneca) ATablets, scored, chloroquine phosphate 250 mg(: chloroquine base 155 mg). Net price 20-tab pack =£1.22. Label: 5, counselling, prophylaxis, see above1Malarivon c (Wallace Mfg) ASyrup, chloroquine phosphate 80 mg/5 mL (:chloroquine base 50 mg/5 mL), net price 75 mL =£8.75. Label: 5, counselling, prophylaxis, see above1Nivaquine c (Sanofi-Aventis) ASyrup, golden, chloroquine sulphate 68 mg/5 mL(: chloroquine base 50 mg/5 mL), net price 100 mL= £4.60. Label: 5, counselling, prophylaxis, see aboveWith proguanilFor cautions and side-effects of proguanil see Proguanil;for dose see Chloroquine and Proguanil1Paludrine/Avloclor c (AstraZeneca)Tablets, travel pack of 14 tablets of chloroquinephosphate 250 mg (: chloroquine base 155 mg) and98 tablets of proguanil hydrochloride 100 mg, netprice 112-tab pack = £8.79. Label: 5, 21, counselling,prophylaxis, see aboveMefloquineMefloquine is used for the prophylaxis of malaria inareas of the world where there is a high risk of chloroquine-resistantfalciparum malaria (for details, see specificrecommendations by country, p. 332).Mefloquine is now rarely used for the treatment offalciparum malaria because of increased resistance. Itis rarely used for the treatment of benign malariasbecause better tolerated alternatives are available.Mefloquine should not be used for treatment if it hasbeen used for prophylaxis.1. Can be sold to the public provided it is licensed andlabelled for the prophylaxis of malaria. Drugs for malariaprophylaxis not prescribable on the NHS; health authoritiesmay investigate circumstances under which antimalarialsare prescribed5 Infections

336 5.4.1 Antimalarials BNFC 2011–20125 InfectionsMEFLOQUINECautions cardiac conduction disorders; epilepsy(avoid for prophylaxis); not recommended in infantsunder 3 months (5 kg); interactions: Appendix 1(mefloquine)Skilled tasks Dizziness or a disturbed sense of balance mayaffect performance of skilled tasks; effects may persist for upto 3 weeksContra-indications hypersensitivity to quinine; avoidfor prophylaxis if history of psychiatric disorders(including depression) or convulsionsHepatic impairment avoid for chemoprophylaxis insevere liver diseasePregnancy manufacturer advises adequate contraceptionduring prophylaxis and for 3 months afterstopping (teratogenicity in animal studies), but seealso p. 332Breast-feeding present in milk but risk to infantminimal; see also, p. 332Side-effects nausea, vomiting, dyspepsia, abdominalpain, diarrhoea; headache, dizziness, sleep disturbances;less frequently anorexia, bradycardia, fatigue,abnormal dreams, fever, tinnitus, and neuropsychiatricreactions (including sensory and motor neuropathies,tremor, ataxia, anxiety, depression, panicattacks, agitation, hallucinations, psychosis, convulsions);rarely suicidal ideation; very rarely pneumonitis;also reported, circulatory disorders (includinghypotension and hypertension), chest pain,tachycardia, palpitation, cardiac conduction disorders,oedema, dyspnoea, encephalopathy, leucopenia,leucocytosis, thrombocytopenia, muscle weakness,myalgia, arthralgia, visual disturbances, vestibulardisorders, rash (including Stevens-Johnsonsyndrome), pruritus, and alopeciaLicensed use not licensed for use in children under5 kg body-weight and under 3 monthsIndication and doseProphylaxis of malaria preferably started 2½weeks before entering endemic area and continuedfor 4 weeks after leaving (see notes above). By mouthChild body-weight 5–16 kg 62.5 mg once weeklyChild body-weight 16–25 kg 125 mg onceweeklyChild body-weight 25–45 kg 187.5 mg onceweeklyChild body-weight over 45 kg 250 mg onceweeklyLong-term chemoprophylaxis Mefloquine prophylaxiscan be taken for up to 1 yearCounselling Inform travellers and carers of childrentravelling about adverse reactions of mefloquine and, ifthey occur, to seek medical advice on alternative antimalarialsbefore the next dose is due. Also warn travellersand carers of children travelling about importance ofavoiding mosquito bites, importance of taking prophylaxisregularly, and importance of immediate visit todoctor if ill within 1 year and especially within 3 monthsof return. For details, see notes aboveNote Mefloquine doses in BNFC may differ from those inproduct literature1. Drugs for malaria prophylaxis not prescribable on theNHS; health authorities may investigate circumstancesunder which antimalarials prescribedAdministration Tablet may be crushed and mixedwith food such as jam or honey just before administration1Lariam c (Roche) ATablets, scored, mefloquine (as hydrochloride)250 mg. Net price 8-tab pack = £14.53. Label: 21, 25,27, counselling, skilled tasks, prophylaxis, see abovePrimaquinePrimaquine is used to eliminate the liver stages of P.vivax or P. ovale following chloroquine treatment (fordetails, see p. 331).PRIMAQUINECautions G6PD deficiency (test blood, see underBenign Malarias (treatment), p. 331); systemic diseasesassociated with granulocytopenia (e.g. juvenileidiopathic arthritis, lupus erythematosus); interactions:Appendix 1 (primaquine)Pregnancy risk of neonatal haemolysis andmethaemoglobinaemia in third trimester; see also,p. 331Breast-feeding no information available; theoreticalrisk of haemolysis in G6PD-deficient infantsSide-effects nausea, vomiting, anorexia, abdominalpain; less commonly methaemoglobinaemia, haemolyticanaemia especially in G6PD deficiency, leucopeniaLicensed use not licensedIndication and doseAdjunct in the treatment of Plasmodium vivaxand P. ovale malaria (eradication of liverstages) for dose see Benign Malarias, p. 331Primaquine (Non-proprietary)Tablets, primaquine (as phosphate) 7.5 mg or 15 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809ProguanilProguanil is used (usually with chloroquine, but occasionallyalone) for the prophylaxis of malaria, (fordetails, see specific recommendations by country,p. 332).Proguanil used alone is not suitable for the treatment ofmalaria; however, Malarone c (a combination ofatovaquone with proguanil) is licensed for the treatmentof acute uncomplicated falciparum malaria.Malarone c is also used for the prophylaxis offalciparum malaria in areas of widespread mefloquineor chloroquine resistance. Malarone c is also used as analternative to mefloquine or doxycycline. Malarone c isparticularly suitable for short trips to highly chloroquineresistantareas because it needs to be taken only for 7days after leaving an endemic area.PROGUANIL HYDROCHLORIDECautions interactions: Appendix 1 (proguanil)Renal impairment (see notes under Prophylaxisagainst malaria). Use half normal dose if estimatedglomerular filtration rate 20–60 mL/minute/1.73 m 2 .Use one-quarter normal dose on alternate days if

BNFC 2011–2012 5.4.1 Antimalarials 337estimated glomerular filtration rate 10–20 mL/minute/1.73m 2 . Use one-quarter normal dose onceweekly if estimated glomerular filtration rate less than10 mL/minute/1.73 m 2 ; increased risk of haematologicaltoxicity.Pregnancy benefit of prophylaxis in malaria outweighsrisk; adequate folate supplements should be given tomother; see also p. 332Breast-feeding amount in milk probably too small tobe harmful when used for malaria prophylaxis; seealso p. 332Side-effects mild gastric intolerance, diarrhoea, andconstipation; occasionally mouth ulcers and stomatitis;very rarely cholestasis, vasculitis, skin reactionsand hair lossIndication and doseProphylaxis of malaria preferably started 1 weekbefore entering endemic area and continued for 4weeks after leaving (see notes above). By mouthChild up to 12 weeks, body-weight under 6 kg25 mg once dailyChild 12 weeks–1 year, body-weight 6–10 kg50 mg once dailyChild 1–4 years, body-weight 10–16 kg 75 mgonce dailyChild 4–8 years, body-weight 16–25 kg 100 mgonce dailyChild 8–13 years, body-weight 25–45 kg150 mg once dailyChild over 13 years, body-weight over 45 kg200 mg once dailyCounselling Warn travellers and carers of children travellingabout importance of avoiding mosquito bites,importance of taking prophylaxis regularly, and importanceof immediate visit to doctor if ill within 1 year andespecially within 3 months of return. For details, seenotes aboveNote Proguanil doses in BNFC may differ from those inproduct literatureAdministration Tablets may be crushed and mixedwith food such as milk, jam or honey just beforeadministration1Paludrine c (AstraZeneca)Tablets, scored, proguanil hydrochloride 100 mg. Netprice 98-tab pack = £7.43. Label: 21, counselling,prophylaxis, see aboveWith chloroquineSee under ChloroquinePROGUANIL HYDROCHLORIDE WITHATOVAQUONECautions diarrhoea or vomiting (reduced absorptionof atovaquone); efficacy not evaluated in cerebral orcomplicated malaria (including hyperparasitaemia,pulmonary oedema or renal failure); interactions: seeAppendix 1 (proguanil, atovaquone)Renal impairment avoid for malaria prophylaxis and,if possible, for treatment if estimated glomerular filtrationrate less than 30 mL/minute/1.73 m 21. Can be sold to the public provided it is licensed andlabelled for the prophylaxis of malaria. Drugs for malariaprophylaxis not prescribable on the NHS; health authoritiesmay investigate circumstances under which antimalarialsare prescribedPregnancy manufacturer advises avoid unless essentialBreast-feeding use only if no suitable alternativeavailable; see also Breast-feeding, p. 332Side-effects abdominal pain, nausea, vomiting, diarrhoea;cough; headache, dizziness, insomnia, abnormaldreams, depression, anorexia, fever; rash, pruritus;less frequently stomatitis, palpitation, anxiety, blooddisorders, hyponatraemia, and hair loss; also reportedhepatitis, cholestasis, tachycardia, hallucinations, seizures,vasculitis, mouth ulcers, and Stevens-JohnsonsyndromeIndication and doseSee preparationsCounselling Warn travellers about importance of avoidingmosquito bites, importance of taking prophylaxis regularly,and importance of immediate visit to doctor if ill within 1year and especially within 3 months of return. For details,see notes above2Malarone c (GSK) ATablets (‘standard’), pink, f/c, proguanil hydrochloride100 mg, atovaquone 250 mg. Net price 12-tabpack = £25.21. Label: 21, counselling, prophylaxis, seeaboveDoseProphylaxis of malaria started 1–2 days before enteringendemic area and continued for 1 week after leaving. By mouthChild body-weight over 40 kg 1 tablet dailyTreatment of malaria. By mouthChild body-weight 11–21 kg 1 tablet daily for 3 daysChild body-weight 21–31 kg 2 tablets once daily for 3daysChild body-weight 31–40 kg 3 tablets once daily for 3daysChild body-weight over 40 kg 4 tablets once daily for 3days2Malarone c Paediatric (GSK) APaediatric tablets, pink, f/c proguanil hydrochloride25 mg, atovaquone 62.5 mg, net price 12-tab pack =£6.26. Label: 21, counselling, prophylaxis, see aboveDoseProphylaxis of malaria started 1–2 days before enteringendemic area and continued for 1 week after leaving. By mouthChild body-weight 11–21 kg 1 tablet once dailyChild body-weight 21–31 kg 2 tablets once dailyChild body-weight 31–40 kg 3 tablets once dailyChild body-weight over 40 kg use Malarone c (‘standard’)tablets, see aboveTreatment of malaria. By mouthChild body-weight 5–9 kg 2 tablets once daily for 3daysChild body-weight 9–11 kg 3 tablets once daily for 3daysChild body-weight 11 kg and over use Malarone c(‘standard’) tablets, see aboveAdministration tablets may be crushed and mixed with food ormilky drink just before administration2. Drugs for malaria prophylaxis not prescribable on theNHS; health authorities may investigate circumstancesunder which antimalarials prescribed5 Infections

338 5.4.1 Antimalarials BNFC 2011–20125 InfectionsPyrimethaminePyrimethamine should not be used alone, but is usedwith sulfadoxine.Pyrimethamine with sulfadoxine is not recommendedfor the prophylaxis of malaria, but can be used in thetreatment of falciparum malaria with (or following)quinine.PYRIMETHAMINE WITHSULFADOXINECautions see under Pyrimethamine (section 5.4.7) andunder Co-trimoxazole (section 5.1.8); not recommendedfor prophylaxis (severe side-effects on longtermuse); interactions: Appendix 1 (pyrimethamine,sulfonamides)Contra-indications see under Pyrimethamine (section5.4.7) and under Co-trimoxazole (section 5.1.8); sulfonamideallergyPregnancy possible teratogenic risk in first trimester aspyrimethamine is a folate antagonist; in third trimester—riskof neonatal haemolysis and methaemoglobinaemia;fear of increased risk of neonatal kernicterusappears unfounded; see also p. 330Breast-feeding small risk of neonatal kernicterus injaundiced infants; risk of haemolysis in G6PD-deficientchild due to sulfadoxineSide-effects see under Pyrimethamine (section 5.4.7)and under Co-trimoxazole (section 5.1.8); pulmonaryinfiltrates (e.g. eosinophilic or allergic alveolitis)reported—discontinue if cough or shortness of breathLicensed use not licensed for use in children ofbody-weight under 5 kgIndication and doseAdjunct to quinine in treatment of Plasmodiumfalciparum malaria see p. 330Prophylaxis not recommended by UK malariaexpertsPyrimethamine with sulfadoxine (Non-proprietary)ATablets, scored, pyrimethamine 25 mg, sulfadoxine500 mg, net price 3-tab pack = 74pNote Also known as Fansidar cAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Contra-indications haemoglobinuria, myastheniagravis, optic neuritis, tinnitusHepatic impairment for treatment of malaria insevere impairment, reduce parenteral maintenancedose to 5–7 mg/kg of quinine saltRenal impairment for treatment of malaria in severeimpairment, reduce parenteral maintenance dose to5–7 mg/kg of quinine saltPregnancy risk of teratogenesis with high doses in firsttrimester; but in malaria benefit of treatment outweighsrisk, see also p. 330Breast-feeding present in milk but not known to beharmfulSide-effects cinchonism, including tinnitus, hearingimpairment, vertigo, headache, nausea, vomiting,abdominal pain, diarrhoea, visual disturbances(including temporary blindness), confusion; cardiovasculareffects (see Cautions); dyspnoea; hypersensitivityreactions including angioedema, rashes,hot and flushed skin; hypoglycaemia (especially afterparenteral administration); blood disorders (includingthrombocytopenia and intravascular coagulation);acute renal failure; muscle weakness; photosensitivity;very toxic in overdosage—immediate advice frompoisons centres essential (see also p. 29)Licensed use injection not licensedIndication and doseTreatment of malaria see p. 330Note Quinine (anhydrous base) 100 mg : quinine bisulphate169 mg : quinine dihydrochloride 122 mg : quinine hydrochloride122 mg : quinine sulphate 121 mg. Quinine bisulphate300-mg tablets are available but provide less quininethan 300 mg of the dihydrochloride, hydrochloride, or sulphateAdministration for intravenous infusion, dilute to aconcentration of 2 mg/mL (max. 30 mg/mL in fluidrestriction) with Glucose 5% or Sodium Chloride 0.9%and give over 4 hoursQuinine Sulphate (Non-proprietary) ATablets, coated, quinine sulphate 200 mg, net price28-tab pack = £2.20; 300 mg, 28-tab pack = £2.12Quinine Dihydrochloride (Non-proprietary) AInjection, quinine dihydrochloride 300 mg/mL. Fordilution and use as an infusion. 1- and 2-mL ampsAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Note Intravenous injection of quinine is so hazardous that ithas been superseded by infusionQuinineQuinine is not suitable for the prophylaxis of malaria.Quinine is used for the treatment of falciparum malariaor if the infective species is not known or if the infectionis mixed (for details see p. 329).QUININECautions cardiac disease (including atrial fibrillation,conduction defects, heart block)—monitor ECG duringparenteral treatment; monitor blood glucose andelectrolyte concentration during parenteral treatment;G6PD deficiency (see section 9.1.5); interactions:Appendix 1 (quinine)TetracyclinesDoxycycline (section 5.1.3) is used in children over 12years for the prophylaxis of malaria in areas of widespreadmefloquine or chloroquine resistance. Doxycyclineis also used as an alternative to mefloquine orMalarone c (for details, see specific recommendationsby country, p. 332).Doxycycline is also used as an adjunct to quinine in thetreatment of falciparum malaria (for details see p. 330).DOXYCYCLINECautions section 5.1.3Contra-indications section 5.1.3

BNFC 2011–2012 5.4.2 Amoebicides 339Hepatic impairment section 5.1.3Renal impairment section 5.1.3Pregnancy section 5.1.3Breast-feeding section 5.1.3Side-effects section 5.1.3Licensed use not licensed for use in children under12 yearsIndication and doseProphylaxis of malaria preferably started 1–2 daysbefore entering endemic area and continued for 4weeks after leaving (see notes above). By mouthChild over 12 years 100 mg once dailyTreatment of falciparum malaria see p. 330PreparationsSection 5.1.35.4.2 AmoebicidesMetronidazole is the drug of choice for acute invasiveamoebic dysentery since it is very effective againstvegetative forms of Entamoeba histolytica which cancause ulceration of the large intestine. Tinidazole is alsoeffective. Metronidazole and tinidazole are also activeagainst amoebae which may have migrated to the liver.Treatment with metronidazole (or tinidazole) is followedby a 10-day course of diloxanide furoate.Diloxanide furoate is the drug of choice for asymptomaticpatients with E. histolytica cysts in the faeces;metronidazole and tinidazole are relatively ineffective.Diloxanide furoate is relatively free from toxic effectsand the usual course is of 10 days, given alone forchronic infections or following metronidazole or tinidazoletreatment.For amoebic abscesses of the liver metronidazole iseffective; tinidazole is an alternative. Aspiration of theabscess is indicated where it is suspected that it mayrupture or where there is no improvement after 72 hoursof metronidazole; the aspiration may need to berepeated. Aspiration aids penetration of metronidazoleand, for abscesses with large volume of pus, if carriedout in conjunction with drug therapy, may reduce theperiod of disability.Diloxanide furoate is not effective against hepaticamoebiasis, but a 10-day course should be given atthe completion of metronidazole or tinidazole treatmentto destroy any amoebae in the gut.DILOXANIDE FUROATEPregnancy manufacturer advises avoid—no informationavailableBreast-feeding manufacturer advises avoidSide-effects flatulence, vomiting, urticaria, pruritusLicensed use not licensed for use in children under25 kg body-weightIndication and doseChronic amoebiasis and as adjunct to metronidazoleor tinidazole in acute amoebiasis. By mouthChild 1 month–12 years 6.6 mg/kg 3 times dailyfor 10 daysChild 12–18 years 500 mg 3 times daily for 10daysDiloxanide (Sovereign) ATablets, diloxanide furoate 500 mg, net price 30-tabpack = £93.50. Label: 9Extemporaneous formulations available seeExtemporaneous Preparations, p. 6METRONIDAZOLECautions section 5.1.11Hepatic impairment section 5.1.11Pregnancy section 5.1.11Breast-feeding section 5.1.11Side-effects section 5.1.11Indication and doseAnaerobic infections section 5.1.11Invasive intestinal amoebiasis, extra-intestinalamoebiasis (including liver abscess). By mouthChild 1–3 years 200 mg 3 times daily for 5 days inintestinal infection (for 5–10 days in extra-intestinalinfection)Child 3–7 years 200 mg 4 times daily for 5 days inintestinal infection (for 5–10 days in extra-intestinalinfection)Child 7–10 years 400 mg 3 times daily for 5 daysin intestinal infection (for 5–10 days in extraintestinalinfection)Child 10–18 years 800 mg 3 times daily for 5 daysin intestinal infection (for 5–10 days in extraintestinalinfection)Urogenital trichomoniasis. By mouthChild 1–3 years 50 mg 3 times daily for 7 daysChild 3–7 years 100 mg twice daily for 7 daysChild 7–10 years 100 mg 3 times daily for 7 daysChild 10–18 years 200 mg 3 times daily for 7 daysor 400–500 mg twice daily for 5–7 days, or 2 g as asingle doseGiardiasis. By mouthChild 1–3 years 500 mg once daily for 3 daysChild 3–7 years 600–800 mg once daily for 3 daysChild 7–10 years 1 g once daily for 3 daysChild 10–18 years 2 g once daily for 3 days or400 mg 3 times daily for 5 days or 500 mg twicedaily for 7–10 daysPreparationsSection 5.1.115 Infections

340 5.4.3 Trichomonacides BNFC 2011–20125 InfectionsTINIDAZOLECautions see under Metronidazole (section 5.1.11);avoid in acute porphyria (section 9.8.2); interactions:Appendix 1 (tinidazole)Pregnancy manufacturer advises avoid in first trimesterBreast-feeding present in milk—manufactureradvises avoid breast-feeding during and for 3 daysafter stopping treatmentSide-effects see under Metronidazole (section 5.1.11)Licensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseIntestinal amoebiasis. By mouthChild 1 month–12 years 50–60 mg/kg (max. 2 g)once daily for 3 daysChild 12–18 years 2 g once daily for 2–3 daysAmoebic involvement of liver. By mouthChild 1 month–12 years 50–60 mg/kg (max. 2 g)once daily for 5 daysChild 12–18 years 1.5–2 g once daily for 3–6 daysUrogenital trichomoniasis and giardiasis. By mouthChild 1 month–12 years single dose of 50–75 mg/kg (max. 2 g) (repeated once if necessary)Child 12–18 years single dose of 2 g (repeatedonce if necessary)Fasigyn c (Pfizer) ATablets, f/c, tinidazole 500 mg, net price 16-tab pack= £11.04. Label: 4, 9, 21, 255.4.3 TrichomonacidesMetronidazole (section 5.4.2) is the treatment of choicefor Trichomonas vaginalis infection. Contact tracing isrecommended and sexual contacts should be treatedsimultaneously. If metronidazole is ineffective, tinidazole(section 5.4.2) may be tried.5.4.4 Antigiardial drugsMetronidazole (section 5.4.2) is the treatment of choicefor Giardia lamblia infections. Tinidazole (section5.4.2) may be used as an alternative to metronidazole.5.4.5 LeishmaniacidesCutaneous leishmaniasis frequently heals spontaneouslybut if skin lesions are extensive or unsightly,treatment is indicated, as it is in visceral leishmaniasis(kala-azar). Leishmaniasis should be treated under specialistsupervision.Sodium stibogluconate, an organic pentavalent antimonycompound, is the treatment of choice for visceralleishmaniasis. The dose is 20 mg/kg daily (max. 850 mg)for at least 20 days by intramuscular or intravenousinjection; the dosage varies with different geographicalregions and expert advice should be obtained. Skinlesions can also be treated with sodium stibogluconate.Amphotericin is used with or after an antimony compoundfor visceral leishmaniasis unresponsive to theantimonial alone; side-effects may be reduced byusing liposomal amphotericin (AmBisome c —section5.2) at a dose of 1–3 mg/kg daily for 10–21 days to acumulative dose of 21–30 mg/kg or at a dose of 3 mg/kg for 5 consecutive days followed by a single dose of3 mg/kg 6 days later. Abelcet c , a lipid formulation ofamphotericin is also likely to be effective but lessinformation is available.Pentamidine isetionate (pentamidine isethionate) (section5.4.8) has been used in antimony-resistant visceralleishmaniasis, but although the initial response is oftengood, the relapse rate is high; it is associated withserious side-effects. Other treatments include paromomycin[unlicensed], available from ‘special-order’ manufacturersor specialist importing companies, see p. 809SODIUM STIBOGLUCONATECautions intravenous injections must be given slowlyover 5 minutes (to reduce risk of local thrombosis)and stopped if coughing or substernal pain; mucocutaneousdisease (see below); monitor ECG before andduring treatment; heart disease (withdraw if conductiondisturbances occur); treat intercurrent infection(e.g. pneumonia)Mucocutaneous disease Successful treatment of mucocutaneousleishmaniasis may induce severe inflammationaround the lesions (may be life-threatening if pharyngeal ortracheal involvement)—may require corticosteroidHepatic impairment use with cautionRenal impairment avoid in significant impairmentPregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding amount probably too small to beharmfulSide-effects anorexia, nausea, vomiting, abdominalpain; ECG changes; coughing (see Cautions); headache,lethargy, arthralgia, myalgia; rarely jaundice,flushing, bleeding from nose or gum, substernal pain(see Cautions), vertigo, fever, sweating, and rash; alsoreported pancreatitis and anaphylaxis; pain andthrombosis on intravenous administration, intramuscularinjection also painfulLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseLeishmaniasis for dose, see notes aboveAdministration injection should be filtered immediatelybefore administration using a filter of 5 micronsor less; see also Cautions abovePentostam c (GSK) AInjection, sodium stibogluconate equivalent to pentavalentantimony 100 mg/mL. Net price 100-mLbottle = £66.43

BNFC 2011–2012 5.4.6 Trypanocides 3415.4.6 TrypanocidesThe prophylaxis and treatment of trypanosomiasis isdifficult and differs according to the strain of organism.Expert advice should therefore be obtained.5.4.7 Drugs for toxoplasmosisMost infections caused by Toxoplasma gondii are selflimiting,and treatment is not necessary. Exceptions arechildren with eye involvement (toxoplasma choroidoretinitis),and those who are immunosuppressed. Toxoplasmicencephalitis is a common complication ofAIDS. The treatment of choice is a combination ofpyrimethamine and sulfadiazine, given for severalweeks (expert advice essential). Pyrimethamine is afolate antagonist, and adverse reactions to this combinationare relatively common (folinic acid supplements(see p. 418) and weekly blood counts needed). Alternativeregimens use combinations of pyrimethaminewith clindamycin or clarithromycin or azithromycin.Long-term secondary prophylaxis is required after treatmentof toxoplasmosis in immunocompromisedpatients; prophylaxis should continue until immunityrecovers.If toxoplasmosis is acquired in pregnancy, transplacentalinfection may lead to severe disease in the fetus;specialist advice should be sought on management.Spiramycin may reduce the risk of transmission ofmaternal infection to the fetus. When there is evidenceof placental or fetal infection, pyrimethamine may begiven with sulfadiazine and folinic acid after the firsttrimester.In neonates without signs of toxoplasmosis, but born tomothers known to have become infected, spiramycin isgiven while awaiting laboratory results. If toxoplasmosisis confirmed in the infant, pyrimethamine and sulfadiazineare given for 12 months, together with folinic acid.PYRIMETHAMINECautions blood counts required with prolonged treatment;history of seizures—avoid large loading doses;interactions: Appendix 1 (pyrimethamine)Hepatic impairment manufacturer advises cautionRenal impairment manufacturer advises cautionPregnancy theoretical teratogenic risk in first trimester(folate antagonist); adequate folate supplementshould be given to motherBreast-feeding present in milk—avoid breast-feedingduring toxoplasmosis treatment; avoid other folateantagonistsSide-effects depression of haematopoiesis with highdoses, rashes, insomniaLicensed use not licensed for use in children under 5yearsIndication and doseToxoplasmosis in pregnancy (in combinationwith sulfadiazine and folinic acid (section 8.1)),see notes above. By mouthChild 12–18 years 50 mg once daily until deliveryCongenital toxoplasmosis (in combination withsulfadiazine and folinic acid (section 8.1)),. By mouthNeonate 1 mg/kg twice daily for 2 days, then1 mg/kg once daily for 6 months, then 1 mg/kg 3times a week for 6 monthsMalaria no dose stated because not recommendedaloneDaraprim c (GSK) AUTablets, scored, pyrimethamine 25 mg. Net price 30-tab pack = £2.60Extemporaneous formulations available seeExtemporaneous Preparations, p. 6SPIRAMYCINCautions cardiac disease, arrhythmias (including predispositionto QT interval prolongation)Contra-indications sensitivity to other macrolidesHepatic impairment use with cautionBreast-feeding present in breast milkSide-effects gastro-intestinal disturbances includingnausea, vomiting, diarrhoea; dizziness, headache;rash; hepatotoxicity; rarely, prolongation of QTinterval, thrombocytopenia and vasculitisLicensed use not licensedIndication and doseToxoplasmosis in pregnancy see notes above. By mouthChild 12–18 years 1.5 g twice daily until deliveryChemoprophylaxis of congenital toxoplasmosis. By mouthNeonate 50 mg/kg twice dailySpiramycin (Non-proprietary)Tablets, spiramycin 750 000 units (250 mg); 1.5 millionunits (500 mg); 3 million units (1 g)Syrup, spiramycin 75 000 units/mL (25 mg/mL)Note 3000 units : 1 mg spiramycinAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809SULFADIAZINE(Sulphadiazine)Cautions see under Co-trimoxazole, section 5.1.8;interactions: Appendix 1 (sulfonamides)Contra-indications see under Co-trimoxazole, section5.1.8Hepatic impairment use with caution in mild tomoderate impairment; avoid in severe impairmentRenal impairment use with caution in mild to moderateimpairment; avoid in severe impairment; highrisk of crystalluriaPregnancy risk of neonatal haemolysis andmethaemoglobinaemia in third trimester; fear ofincreased risk of kernicterus in neonates appears tobe unfoundedBreast-feeding small risk of kernicterus in jaundicedinfants and of haemolysis in G6PD-deficient infants5 Infections

342 5.4.8 Drugs for pneumocystis pneumonia BNFC 2011–20125 InfectionsSide-effects see under Co-trimoxazole, section 5.1.8;also hypothyroidism, benign intracranial hypertension,optic neuropathyLicensed use not licensed for use in toxoplasmosisIndication and doseToxoplasmosis in pregnancy (in combinationwith pyrimethamine and folinic acid (section8.1)), see notes above. By mouthChild 12–18 years 1 g 3 times daily until deliveryCongenital toxoplasmosis (in combination withpyrimethamine and folinic acid (section 8.1)). By mouthNeonate 50 mg/kg twice daily for 12 monthsSulfadiazine (Non-proprietary) ATablets, sulfadiazine 500 mg, net price 56-tab pack =£37.50. Label: 9, 27Extemporaneous formulations available seeExtemporaneous Preparations, p. 65.4.8 Drugs for pneumocystispneumoniaPneumonia caused by Pneumocystis jirovecii (Pneumocystiscarinii) occurs in immunosuppressed children; itis a common cause of pneumonia in AIDS. Pneumocystispneumonia should generally be treated by thoseexperienced in its management. Blood gas measurementis used to assess disease severity.TreatmentThe recommended duration of treatment is generally14–21 days.Mild to moderate disease Co-trimoxazole (section5.1.8) in high dosage is the drug of choice for thetreatment of mild to moderate pneumocystis pneumonia.Atovaquone or a combination of dapsone with trimethoprim5 mg/kg every 6–8 hours (section 5.1.8) isgiven by mouth for the treatment of mild to moderatedisease [unlicensed indication] in children who cannottolerate co-trimoxazole.A combination of clindamycin (section 5.1.6) andprimaquine (section 5.4.1) may be used in the treatmentof mild to moderate disease [unlicensed indication];this combination is associated with considerabletoxicity.Severe disease Co-trimoxazole (section 5.1.8) inhigh dosage, given by mouth or by intravenous infusion,is the drug of choice for the treatment of severepneumocystis pneumonia. Pentamidine isetionategiven by intravenous infusion is an alternative for childrenwho cannot tolerate co-trimoxazole, or who havenot responded to it. Pentamidine isetionate is a potentiallytoxic drug that can cause severe hypotensionduring or immediately after infusion. If there is clinicalimprovement after 7–10 days of intravenous therapywith pentamidine isetionate, patients can be switched tooral treatment (e.g. atovaquone) to complete 21 daystreatment.Corticosteroid treatment can be lifesaving in those withsevere pneumocystis pneumonia (see Adjunctive Therapybelow).Adjunctive therapy In moderate to severe pneumocystisinfections associated with HIV infection, prednisolone(section 6.3.2) is given by mouth in a dose of2 mg/kg (max. 80 mg daily) for 5 days (alternatively,hydrocortisone may be given parenterally); the dose isthen reduced over the next 16 days and then stopped.Corticosteroid treatment should ideally be started at thesame time as the anti-pneumocystis therapy and certainlyno later than 24–72 hours afterwards. The corticosteroidshould be withdrawn before anti-pneumocystistreatment is complete.ProphylaxisProphylaxis against pneumocystis pneumonia should begiven to all children with a history of this infection, andto all HIV-infected infants aged 1 month–1 year. Prophylaxisagainst pneumocystis pneumonia should also beconsidered for severely immunocompromised children.Prophylaxis should continue until immunity recoverssufficiently. It should not be discontinued if the childhas oral candidiasis, continues to lose weight, or isreceiving cytotoxic therapy or long-term immunosuppressanttherapy.Co-trimoxazole (section 5.1.8) by mouth is the drug ofchoice for prophylaxis against pneumocystis pneumonia.Co-trimoxazole may be used in infants born tomothers with a high risk of transmission of infection.Inhaled pentamidine isetionate is better tolerated thanparenteral pentamidine. Intermittent inhalation of pentamidineisetionate is used for prophylaxis againstpneumocystis pneumonia in children unable to tolerateco-trimoxazole. It is effective but children may be proneto extrapulmonary infection. Alternatively, dapsone canbe used.ATOVAQUONECautions initial diarrhoea and difficulty in taking withfood may reduce absorption (and require alternativetherapy); other causes of pulmonary disease should besought and treated; interactions: Appendix 1 (atovaquone)Hepatic impairment manufacturer advises caution—monitor more closelyRenal impairment manufacturer advises caution—monitor more closelyPregnancy manufacturer advises avoid unless potentialbenefit outweighs risk—no information availableBreast-feeding manufacturer advises avoidSide-effects nausea, diarrhoea, vomiting, headache,insomnia, fever, anaemia, neutropenia, hyponatraemia,rash, pruritus; also reported, Stevens-JohnsonsyndromeLicensed use not licensed for use in children

BNFC 2011–2012 5.4.8 Drugs for pneumocystis pneumonia 343Indication and doseTreatment of Pneumocystis jirovecii (P. carinii)pneumonia in children intolerant of co-trimoxazole. By mouthChild 1–3 months 15–20 mg/kg twice daily withfood (particularly high fat) for 14–21 daysChild 3 months–2 years 22.5 mg/kg twice dailywith food (particularly high fat) for 14–21 daysChild 2–18 years 15–20 mg/kg (max. 750 mg)twice daily with food (particularly high fat) for 14–21 daysWellvone c (GSK) ASuspension, sugar-free, atovaquone 750 mg/5 mL,net price 226 mL (tutti-frutti-flavoured) = £405.31.Label: 21With proguanil hydrochlorideSee section 5.4.1DAPSONECautions cardiac or pulmonary disease; anaemia(treat severe anaemia before starting); susceptibilityto haemolysis including G6PD deficiency (section9.1.5); avoid in acute porphyria (section 9.8.2); interactions:Appendix 1 (dapsone)Blood disorders On long-term treatment, children and theircarers should be told how to recognise signs of blooddisorders and advised to seek immediate medical attention ifsymptoms such as fever, sore throat, rash, mouth ulcers,purpura, bruising or bleeding developPregnancy neonatal haemolysis and methaemoglobinaemiareported in third trimester; folic acid5 mg daily should be given to mother throughoutpregnancyBreast-feeding haemolytic anaemia; although significantamount in milk, risk to infant very small unlessinfant is G6PD deficientSide-effects haemolysis, methaemoglobinaemia,neuropathy, allergic dermatitis (rarely including toxicepidermal necrolysis and Stevens-Johnsonsyndrome), anorexia, nausea, vomiting, tachycardia,headache, insomnia, psychosis, hepatitis, agranulocytosis;dapsone syndrome (rash with fever andeosinophilia)—discontinue immediately (mayprogress to exfoliative dermatitis, hepatitis, hypoalbuminaemia,psychosis and death)Licensed use not licensed for treatment of P. jiroveciipneumonia; monotherapy not licensed forchildren for prophylaxis of P. jirovecii pneumoniaIndication and doseTreatment of Pneumocystis jirovecii (P. carinii)pneumonia (in combination with trimethoprim). By mouthChild 1 month–12 years 2 mg/kg (max. 100 mg)once dailyChild 13–18 years 100 mg once dailyProphylaxis of Pneumocystis jirovecii (P. carinii)pneumonia. By mouthChild 1 month–18 years 2 mg/kg (max. 100 mg)once dailyDapsone (Non-proprietary) ATablets, dapsone 50 mg, net price 28-tab pack =£32.53; 100 mg 28-tab pack = £47.44. Label: 8PENTAMIDINE ISETIONATECautions risk of severe hypotension following administration(monitor blood pressure before startingtreatment, during administration, and at regularintervals until treatment concluded; child should belying down when receiving drug parenterally); hypokalaemia,hypomagnesaemia, coronary heart disease,bradycardia, history of ventricular arrhythmias, concomitantuse with other drugs known to prolong Q-Tinterval; hypertension or hypotension; hyperglycaemiaor hypoglycaemia; leucopenia, thrombocytopenia,or anaemia; carry out laboratory monitoringaccording to product literature; care required to protectpersonnel during handling and administration;interactions: Appendix 1 (pentamidine isetionate)Hepatic impairment use with cautionRenal impairment reduce intravenous dose forpneumocystis pneumonia if creatinine clearance lessthan 10 mL/minute: in life-threatening infection, use4 mg/kg once daily for 7–10 days, then 4 mg/kg onalternate days to complete course of at least 14 doses;in less severe infection, use 4 mg/kg on alternate daysfor at least 14 dosesPregnancy manufacturer advises avoid unless essentialBreast-feeding manufacturer advises avoid unlessessential—no information availableSide-effects severe reactions, sometimes fatal, due tohypotension, hypoglycaemia, pancreatitis, and arrhythmias;also leucopenia, thrombocytopenia, acuterenal failure, hypocalcaemia; also reported: azotaemia,abnormal liver-function tests, anaemia, hyperkalaemia,nausea and vomiting, dizziness, syncope,flushing, hyperglycaemia, rash, and taste disturbances;Stevens-Johnson syndrome reported; oninhalation, bronchoconstriction (may be prevented byprior use of bronchodilators), cough and shortness ofbreath; discomfort, pain, induration, abscess formation,and muscle necrosis at injection siteLicensed use nebuliser solution not licensed forprimary prevention of pneumocystis pneumoniaIndication and doseTreatment of Pneumocystis jirovecii (P. carinii)pneumonia. By intravenous infusionChild 1 month–18 years 4 mg/kg once dailyProphylaxis of Pneumocystis jirovecii (P. carinii)pneumonia. By inhalation of nebulised solution (using suitableequipment—consult product literature)Child 5–18 years 300 mg every 4 weeks or150 mg every 2 weeksVisceral leishmaniasis (kala-azar, section5.4.5). By deep intramuscular injectionChild 1–18 years 3–4 mg/kg on alternate days tomax. total of 10 injections; course may be repeatedif necessary5 Infections

344 5.5 Anthelmintics BNFC 2011–20125 InfectionsCutaneous leishmaniasis. By deep intramuscular injectionChild 1–18 years 3–4 mg/kg once or twiceweekly until condition resolves (but see also section5.4.5)Trypanosomiasis. By deep intramuscular injection or intravenousinfusionChild 1–18 years 4 mg/kg daily or on alternatedays to total of 7–10 injectionsAdministration Direct intravenous injection should beavoided whenever possible and never given rapidly;intramuscular injections should be deep and preferablygiven into the buttock.For intravenous infusion, reconstitute 300 mg with 3–5 mL Water for Injections (displacement value may besignificant), then dilute required dose with 50–250 mLGlucose 5% or Sodium Chloride 0.9%; give over atleast 60 minutesPentacarinat c (Sanofi-Aventis) AInjection, powder for reconstitution, pentamidineisetionate, net price 300-mg vial = £30.45Caution in handling Pentamidine isetionate is toxic andpersonnel should be adequately protected during handlingand administration—consult product literatureNote Pentacarinat c Injection (dissolved in water forinjection) may be used for nebulisation5.5.1 Drugs for threadworms(pinworms, Enterobius vermicularis)Anthelmintics are effective in threadworm infections,but their use needs to be combined with hygienicmeasures to break the cycle of auto-infection. All membersof the family require treatment.Adult threadworms do not live for longer than 6 weeksand for development of fresh worms, ova must beswallowed and exposed to the action of digestive juicesin the upper intestinal tract. Direct multiplication ofworms does not take place in the large bowel. Adultfemale worms lay ova on the perianal skin which causespruritus; scratching the area then leads to ova beingtransmitted on fingers to the mouth, often via food eatenwith unwashed hands. Washing hands and scrubbingnails before each meal and after each visit to the toilet isessential. A bath taken immediately after rising willremove ova laid during the night.Mebendazole is the drug of choice for treating threadworminfection in children over 6 months. It is given as asingle dose; as reinfection is very common, a seconddose may be given after 2 weeks.Piperazine is available in combination with sennosidesas a single-dose preparation.5.5 Anthelmintics5.5.1 Drugs for threadworms5.5.2 Ascaricides5.5.3 Drugs for tapeworm infections5.5.4 Drugs for hookworms5.5.5 Schistosomicides5.5.6 Filaricides5.5.7 Drugs for cutaneous larva migrans5.5.8 Drugs for strongyloidiasisAdvice on prophylaxis and treatment of helminth infectionsis available from the following specialist centres:Birmingham (0121) 424 0357Scottish Centre for Infection andEnvironmental Health (registeredusers of Travax only)(0141) 300 1100(weekdays 2–4 p.m.only)Liverpool (0151) 708 9393London (020) 7387 9300(treatment adviceonly)MEBENDAZOLECautions interactions: Appendix 1 (mebendazole)Note The patient information leaflet in the Vermox c packincludes the statement that it is not suitable for womenknown to be pregnant or for children under 2 yearsPregnancy manufacturer advises avoid—toxicity inanimal studiesBreast-feeding amount present in milk too small tobe harmful but manufacturer advises avoidSide-effects abdominal pain; less commonly diarrhoea,flatulence, rash; very rarely hepatitis, convulsions,neutropenia, urticaria, alopecia, Stevens-Johnson syndrome, toxic epidermal necrolysisLicensed use not licensed for use in children under 2yearsIndication and doseThreadworms. By mouthChild 6 months—18 years 100 mg as a singledose; if reinfection occurs second dose may beneeded after 2 weeksWhipworms, hookworms (section 5.5.4). By mouthChild 1—18 years 100 mg twice daily for 3 daysRoundworms (section 5.5.2). By mouthChild 1—2 years 100 mg twice daily for 3 daysChild 2—18 years 100 mg twice daily for 3 days or500 mg as a single dose

BNFC 2011–2012 5.5.2 Ascaricides 3451Mebendazole (Non-proprietary) ATablets, chewable, mebendazole 100 mg1. Mebendazole tablets can be sold to the public if supplied fororal use in the treatment of enterobiasis in children over 2years provided its container or package is labelled to show amax. single dose of 100 mg and it is supplied in a containeror package containing not more than 800 mgVermox c (Janssen) ATablets, orange, scored, chewable, mebendazole100 mg. Net price 6-tab pack = £1.36Oral suspension, mebendazole 100 mg/5 mL (banana-flavoured).Net price 30 mL = £1.595.5.2 Ascaricides(common roundworm infections)Mebendazole (section 5.5.1) is effective against Ascarislumbricoides and is generally considered to be the drugof choice.Levamisole [unlicensed] (available from ‘special-order’manufacturers or specialist importing companies, seep. 809) is an alternative when mebendazole cannot beused. It is very well tolerated; mild nausea or vomitinghas been reported in about 1% of treated patients.Piperazine may be given in a single dose, see Piperazine,above.PIPERAZINECautions epilepsyNote Packs on sale to the general public carry a warning toavoid in epilepsy, liver or kidney disease, and to seek medicaladvice in pregnancyHepatic impairment manufacturer advises avoidRenal impairment use with caution; avoid in severerenal impairment; risk of neurotoxicityPregnancy not known to be harmful but manufactureradvises avoid in first trimesterBreast-feeding present in milk—manufactureradvises avoid breast-feeding for 8 hours after dose(express and discard milk during this time)Side-effects nausea, vomiting, colic, diarrhoea, allergicreactions including urticaria, bronchospasm, andrare reports of arthralgia, fever, Stevens-Johnsonsyndrome and angioedema; rarely dizziness, muscularinco-ordination (‘worm wobble’); drowsiness, nystagmus,vertigo, blurred vision, confusion and cloniccontractions in children with neurological or renalabnormalitiesIndication and doseSee under preparation, belowWith sennosidesFor cautions, contra-indications, side-effects of sennasee section 1.6.2Pripsen c (Thornton & Ross)Oral powder, piperazine phosphate 4 g, total sennosides(calculated as sennoside B) 15.3 mg/sachet. Netprice two-dose sachet pack = £1.98. Label: 13Dose(stirred into milk or water)LEVAMISOLECautions epilepsy; juvenile idiopathic arthritis; Sjögren’ssyndromeContra-indications blood disordersHepatic impairment use with caution—dose adjustmentmay be necessaryPregnancy embryotoxic in animal studies, avoid ifpossibleBreast-feeding no information availableSide-effects nausea, vomiting, diarrhoea; dizziness,headache; on prolonged treatment taste disturbances,insomnia, convulsions, influenza-like syndrome,blood disorders, vasculitis, arthralgia, myalgia, rashLicensed use not licensedIndication and doseRoundworm (Ascaris lumbricoides). By mouthChild 1 month–18 years 2.5–3 mg/kg (max.150 mg) as a single doseHookworm. By mouthChild 1 month–18 years 2.5 mg/kg (max.150 mg) as a single dose repeated after 7 days ifsevereNephrotic syndrome (specialist supervisionsection 6.3.2). By mouthChild 1month–18 years 2.5 mg/kg (max. 150 mg)on alternate daysLevamisole (Non-proprietary) ATablets, levamisole (as hydrochloride) 50 mg Label: 4Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 8095 InfectionsThreadworms. By mouthChild 3 months–1 year 1 level 2.5-mL spoonful as asingle dose in the morning, repeated after 14 daysChild 1–6 years 1 level 5-mL spoonful as a single dose inthe morning, repeated after 14 daysChild 6–18 years content of 1 sachet as a single dose (inthe morning), repeated after 14 daysRoundworms first dose as for threadworms; repeat atmonthly intervals for up to 3 months if reinfection risk5.5.3 Drugs for tapeworminfectionsTaenicidesNiclosamide [unlicensed] (available from ‘specialorder’manufacturers or specialist importing companies,see p. 809) is the most widely used drug for tapeworminfections and side-effects are limited to occasional

346 5.5.4 Drugs for hookworms BNFC 2011–2012gastro-intestinal upset, lightheadedness, and pruritus; itis not effective against larval worms. Fears of developingcysticercosis in Taenia solium infections haveproved unfounded. All the same, an antiemetic can begiven before treatment and a laxative can be given 2hours after niclosamide.Praziquantel [unlicensed] is available from Merck Serono(Cysticide c ); it is as effective as niclosamide and isgiven to children over 4 years of age as a single dose of5–10 mg/kg after a light breakfast (or as a single dose of25 mg/kg for Hymenolepis nana).Praziquantel [unlicensed] is available from Merck Serono(Cysticide c ) and is effective against all humanschistosomes. In children over 4 years the dose is20 mg/kg followed after 4–6 hours by a further dose of20 mg/kg (20 mg/kg 3 times daily for one day for S.japonicum infections). No serious adverse effects havebeen reported. Of all the available schistosomicides, ithas the most attractive combination of effectiveness,broad-spectrum activity, and low toxicity.5 InfectionsHydatid diseaseCysts caused by Echinococcus granulosus grow slowlyand asymptomatic children do not always require treatment.Surgical treatment remains the method of choicein many situations. Albendazole [unlicensed] (availablefrom ‘special-order’ manufacturers or specialist importingcompanies, see p. 809 is used in conjunction withsurgery to reduce the risk of recurrence or as primarytreatment in inoperable cases. Albendazole is given tochildren over 2 years of age in a dose of 7.5 mg/kg twicedaily (max. 400 mg twice daily) for 28 days followed by14-day break and then repeated for up to 2–3 cycles.Alveolar echinococcosis due to E. multilocularis isusually fatal if untreated. Surgical removal with albendazolecover is the treatment of choice, but where effectivesurgery is impossible, repeated cycles of albendazole(for a year or more) may help. Careful monitoringof liver function is particularly important during drugtreatment.5.5.4 Drugs for hookworms(ancylostomiasis, necatoriasis)Hookworms live in the upper small intestine and drawblood from the point of their attachment to their host.An iron-deficiency anaemia may occur and, if present,effective treatment of the infection requires not onlyexpulsion of the worms but treatment of the anaemia.Mebendazole (section 5.5.1) has a useful broad-spectrumactivity, and is effective against hookworms.Albendazole [unlicensed] (available from ‘specialorder’manufacturers or specialist importing companies,see p. 809) given as a single dose of 400 mg in childrenover 2 years, is an alternative. Levamisole is alsoeffective (section 5.5.2).5.5.5 Schistosomicides(bilharziasis)Adult Schistosoma haematobium worms live in thegenito-urinary veins and adult S. mansoni in those ofthe colon and mesentery. S. japonicum is more widelydistributed in veins of the alimentary tract and portalsystem.5.5.6 FilaricidesDiethylcarbamazine [unlicensed] (available from ‘special-order’manufacturers or specialist importing companies,see p. 809) is effective against microfilariae andadult worms of Loa loa, Wuchereria bancrofti, andBrugia malayi. To minimise reactions, treatment inchildren over 1 month is commenced with a dose ofdiethylcarbamazine citrate 1 mg/kg in divided doses onthe first day and increased gradually over 3 days to6 mg/kg daily (3 mg/kg daily if child under 10 years) individed doses; length of treatment varies according toinfection type, and usually gives a radical cure for theseinfections. Close medical supervision is necessary particularlyin the early phase of treatment. In heavy infectionsthere may be a febrile reaction, and in heavy Loaloa infection there is a small risk of encephalopathy. Insuch cases specialist advice should be sought, andtreatment must be given under careful in-patient supervisionand stopped at the first sign of cerebral involvement.Ivermectin [unlicensed] (available from ‘special-order’manufacturers or specialist importing companies, seep. 809) is very effective in onchocerciasis and it is nowthe drug of choice. In children over 5 years, a singledose of 150 micrograms/kg by mouth produces a prolongedreduction in microfilarial levels. Retreatment atintervals of 6 to 12 months depending on symptomsmust be given until the adult worms die out. Reactionsare usually slight and most commonly take the form oftemporary aggravation of itching and rash. Diethylcarbamazineor suramin should no longer be used foronchocerciasis because of their toxicity.5.5.7 Drugs for cutaneous larvamigrans(creeping eruption)Dog and cat hookworm larvae may enter human skinwhere they produce slowly extending itching tracksusually on the foot. Single tracks can be treated withtopical tiabendazole (no commercial preparation available).Multiple infections respond to ivermectin,albendazole or tiabendazole (thiabendazole) bymouth (all unlicensed and available from ‘specialorder’manufacturers or specialist importing companies,see p. 809).

BNFC 2011–2012 5.5.8 Drugs for strongyloidiasis 3475.5.8 Drugs for strongyloidiasisAdult forms of Strongyloides stercoralis live in the gutand produce larvae which penetrate the gut wall andinvade the tissues, setting up a cycle of auto-infection.Ivermectin [unlicensed] in a dose of 200 micrograms/kg daily for 2 days is the treatment of choice for chronicStrongyloides infection in children over 5 years.Albendazole [unlicensed] is an alternative in childrenover 2 years given in a dose of 400 mg twice daily for 3days, repeated after 3 weeks if necessary.Both of these drugs are available from ‘special-order’manufacturers or specialist importing companies, seep. 809.5 Infections

348 BNFC 2011–20126 Endocrine system6 Endocrine system6.1 Drugs used in diabetes 3486.1.1 Insulins 3496.1.1.1 Short-acting insulins 3526.1.1.2 Intermediate- and long-actinginsulins 3536.1.1.3 Hypodermic equipment 3566.1.2 Antidiabetic drugs 3576.1.2.1 Sulfonylureas 3586.1.2.2 Biguanides 3596.1.2.3 Other antidiabetic drugs 3606.1.3 Diabetic ketoacidosis 3606.1.4 Treatment of hypoglycaemia 3616.1.5 Treatment of diabetic nephropathyand neuropathy 3626.1.6 Diagnostic and monitoringdevices for diabetes mellitus 3636.2 Thyroid and antithyroid drugs 3656.2.1 Thyroid hormones 3656.2.2 Antithyroid drugs 3676.3 Corticosteroids 3696.3.1 Replacement therapy 3696.3.2 Glucocorticoid therapy 3706.4 Sex hormones 3776.4.1 Female sex hormones 3776.4.1.1 Oestrogens 3776.4.1.2 Progestogens 3786.4.2 Male sex hormones and antagonists3796.4.3 Anabolic steroids 3816.5 Hypothalamic and pituitary hormones3826.5.1 Hypothalamic and anterior pituitaryhormones including growthhormone 3826.5.2 Posterior pituitary hormones andantagonists 3856.6 Drugs affecting bone metabolism3886.6.1 Calcitonin 3886.6.2 Bisphosphonates 3886.7 Other endocrine drugs 3916.7.1 Bromocriptine and otherdopaminergic drugs 3916.7.2 Drugs affecting gonadotrophins 3916.7.3 Metyrapone 3916.7.4 Somatomedins 391This chapter includes advice on the drug managementof the following:Adrenal suppression during illness, trauma orsurgery, p. 371Serious infections in patients taking corticosteroids,p. 371Nephrotic syndrome, p. 371Delayed puberty, p. 377Precocious puberty, p. 380Diabetes insipidus, p. 385For hormonal contraception, see section 7.3.6.1 Drugs used in diabetes6.1.1 Insulins6.1.2 Antidiabetic drugs6.1.3 Diabetic ketoacidosis6.1.4 Treatment of hypoglycaemia6.1.5 Treatment of diabetic nephropathyand neuropathy6.1.6 Diagnostic and monitoring devices fordiabetes mellitusDiabetes mellitus occurs because of a lack of insulin orresistance to its action. It is diagnosed by measuringfasting or random blood-glucose concentration (andoccasionally by oral glucose tolerance test). Althoughthere are many subtypes, the two principle classes ofdiabetes are type 1 diabetes and type 2 diabetes.Type 1 diabetes, (formerly referred to as insulin-dependentdiabetes mellitus (IDDM)), is due to a deficiency ofinsulin following autoimmune destruction of pancreaticbeta cells and is the most common form of diabetes inchildren. Children with type 1 diabetes require administrationof insulin.Type 2 diabetes, (formerly referred to as non-insulindependentdiabetes mellitus (NIDDM)), is rare in childrenbut the incidence is increasing, particularly inadolescents, as obesity increases. It results fromreduced secretion of insulin or from peripheral resistanceto the action of insulin, or from a combination ofboth. Although children may be controlled on diet alone,many require oral antidiabetic drugs or insulin to maintainsatisfactory control. There is limited informationavailable on the use of oral anti-diabetic drugs in children(see section 6.1.2). In overweight individuals, type2 diabetes may be prevented by losing weight andincreasing physical activity.Genetic defects of beta-cell function (formerly referredto as maturity-onset diabetes of the young (MODY)),describes a number of rare disease states, characterisedby onset of mild hyperglycaemia, generally before 25years of age. A sulfonylurea, such as gliclazide (p. 359),may be effective in these patients.

BNFC 2011–2012 6.1.1 Insulins 349Treatment of diabetes Treatment should be aimed atalleviating symptoms and minimising the risk of longtermcomplications (see below).Diabetes is a strong risk factor for cardiovascular diseaselater in life. Other risk factors for cardiovasculardisease (smoking, hypertension, obesity and hyperlipidaemia)should be addressed. The use of an ACE inhibitor(section 2.5.5.1) and of a lipid-regulating drug (section2.12) can be beneficial in children with diabetes and ahigh cardiovascular disease risk. For reference to the useof an ACE inhibitor in the management of diabeticnephropathy, see section 6.1.5.Prevention of diabetic complications Althoughrare, retinopathy, neuropathy and nephropathy canoccur in children with diabetes. Screening for complicationsshould begin 5 years after diagnosis of diabetes orfrom 12 years of age. Optimal glycaemic control in bothtype 1 diabetes and type 2 diabetes reduces, in the longterm, the risk of microvascular complications includingretinopathy, development of proteinuria and to someextent neuropathy.A measure of the total glycosylated (or glycated) haemoglobin(HbA 1 ) or a specific fraction (HbA 1c ) providesa good indication of long-term glycaemic control. Overallit is ideal to aim for an HbA 1c concentration of 48–59 mmol/mol or less (reference range 20–42 mmol/mol), but this cannot always be achieved and for thoseusing insulin there is a significantly increased risk ofdisabling hypoglycaemia.Measurement of HbA 1cHbA 1c values were previously aligned to the assayused in the Diabetes Control and ComplicationsTrial (DCCT) and expressed as a percentage. Anew standard, specific for HbA 1c , has been createdby the International Federation of Clinical Chemistryand Laboratory Medicine (IFCC), whichexpresses HbA 1c values in mmol of glycosylatedhaemoglobin per mol of haemoglobin. From 1June 2011 UK laboratories will only express resultsin IFCC-standardised units (mmol/mol).Equivalent valuesIFCC-HbA 1c (mmol/mol) DCCT-HbA 1c (%)42 6.048 6.553 7.059 7.564 8.075 9.0Laboratory measurement of serum-fructosamine concentrationis technically simpler and cheaper than themeasurement of HbA 1c and can be used to assesscontrol over short periods of time, particularly whenHbA 1c monitoring is invalid (e.g. disturbed erythrocyteturnover or abnormal haemoglobin type).Tight control of blood pressure in hypertensive childrenwith type 2 diabetes may reduce mortality significantlyand protects visual acuity (by reducing considerably therisks of maculopathy and retinal photocoagulation) (seealso section 2.5).Driving Information on the requirements for drivingvehicles by individuals receiving treatment for diabetesis available in the BNF (section 6.1) or from the DVLA atwww.dvla.gov.uk/medical.aspx.6.1.1 InsulinsInsulin is a polypeptide hormone that plays a key role inthe regulation of carbohydrate, fat, and protein metabolism.There are differences in the amino-acid sequenceof animal insulins, human insulins, and the human insulinanalogues. Human sequence insulin may be producedsemisynthetically by enzymatic modification ofporcine insulin (emp) or biosynthetically by recombinantDNA technology using bacteria (crb, prb) or yeast(pyr).Immunological resistance to insulin action is uncommon.Preparations of human sequence insulin shouldtheoretically be less immunogenic than other insulinpreparations, but no real advantage has been shown intrials.Insulin is inactivated by gastro-intestinal enzymes, andmust therefore be given by injection; the subcutaneousroute is ideal in most circumstances. Insulin is usuallyinjected into the thighs, buttocks, or abdomen; absorptionfrom a limb site can be increased if the limb is usedin strenuous exercise after the injection. Generally, subcutaneousinsulin injections cause few problems; lipodystrophymay occur and is a factor in poor glycaemiccontrol. Lipodystrophy can be minimised by using differentinjection sites in rotation. Local allergic reactionsare rare.Insulin should be given to all children with type 1diabetes; it may also be needed to treat type 2 diabeteseither when other methods cannot control the conditionor during periods of acute illness or peri-operatively.Insulin is required in all instances of ketoacidosis (section6.1.3), which can develop rapidly in children.NHS Diabetes guidanceSafe and Effective Use of Insulin inHospitalised Patients (March 2010)Available at www.diabetes.nhs.ukManagement of diabetes with insulin The aim oftreatment is to achieve the best possible control ofblood-glucose concentration without making the childor carer obsessional and to avoid disabling hypoglycaemia;close co-operation is needed between the childor carer and the medical team to achieve good controland thereby reduce the risk of complications.Insulin preparations can be divided into 3 types:. those of short duration which have a relativelyrapid onset of action, namely soluble insulin andthe rapid-acting insulin analogues, insulin aspart,insulin glulisine, and insulin lispro (section 6.1.1.1);. those with an intermediate action, e.g. isophaneinsulin (section 6.1.1.2); and. those whose action is slower in onset and lasts forlong periods, e.g. protamine zinc insulin, insulindetemir, and insulin glargine (section 6.1.1.2).6 Endocrine system

350 6.1.1 Insulins BNFC 2011–20126 Endocrine systemThe duration of action of a particular type of insulin canvary from one child to another, and needs to be assessedindividually.Mixtures of insulin preparations may be required andappropriate combinations have to be determined for theindividual child. Treatment should be started with severaldoses of short-acting insulin (soluble insulin or arapid-acting insulin analogue) given throughout the daywith a longer-acting insulin given once or twice daily.Alternatively, for those who have difficulty with, orprefer not to use, multiple daily injection regimens orin whom such regimens fail to achieve adequate glycaemiccontrol, a mixture of premixed short- and intermediate-actinginsulins (most commonly in a proportionof 30% soluble insulin and 70% isophane insulin) can begiven twice daily. The dose of short-acting or rapidactinginsulin (or the proportion of the short-actingsoluble insulin component in premixed insulin) can beincreased in those with excessive postprandial hyperglycaemia.The dose of insulin is increased graduallyaccording to the child’s individual requirements, takingcare to avoid troublesome hypoglycaemia.Initiation of insulin may be followed by a partial remissionphase or ‘honeymoon period’ when lower doses ofinsulin are required than are subsequently necessary tomaintain glycaemic control.Examples of insulin regimens. Multiple injection regimen: short-acting insulin orrapid-acting insulin analogue, before mealsWith intermediate-acting or long-acting insulin,once or twice daily;. Short-acting insulin or rapid-acting insulin analoguemixed with intermediate-acting insulin, twice daily(before breakfast and the main evening meal);. Short-acting insulin or rapid-acting insulin analoguemixed with intermediate-acting insulin, beforebreakfastWith short-acting or rapid-acting insulin analoguealone, before afternoon snack or the main eveningmeal, and intermediate-acting insulin or long-actinginsulin, at bedtime;. Continuous subcutaneous insulin infusion (seebelow).Insulin requirements Most prepubertal childrenrequire around 0.6–0.8 units/kg/day of insulin afterthe initial temporary remission phase. Unless the childhas a very sedentary life-style, a requirement for higherdoses may indicate poor compliance, poor absorption ofinsulin from the injection site (e.g. because of lipohypertrophicsites), or the beginning of puberty. Duringpuberty up to 1.5–2 units/kg/day of insulin may berequired, especially during growth spurts. Around 1year after menarche or after the growth spurt in boys,the dose may need to be adjusted to avoid excessiveweight gain. Insulin requirements can be increased byinfection, stress, and accidental or surgical trauma.Insulin requirements can be reduced in very activeindividuals, in those with certain endocrine disorders(e.g. Addison’s disease, hypopituitarism), or in coeliacdisease. Insulin requirements should be assessed frequentlyin all these circumstances.Hepatic impairment Insulin requirements may bedecreased in patients with hepatic impairment.Renal impairment Insulin requirements may fall inpatients with renal impairment and therefore dosereduction may be necessary. The compensatoryresponse to hypoglycaemia is impaired in renal impairment.Pregnancy and breast-feeding During pregnancyand breast-feeding, insulin requirements may alter anddoses should be assessed frequently by an experienceddiabetes physician. The dose of insulin generally needsto be increased in the second and third trimesters ofpregnancy. The short-acting insulin analogues, insulinaspart and insulin lispro, are not known to be harmful,and may be used during pregnancy and breast-feeding.The safety of long-acting insulin analogues in pregnancyhas not been established, therefore isophane insulin isrecommended where longer-acting insulins are needed.Insulin administration Insulin is generally given bysubcutaneous injection; the injection site should berotated to prevent lipodystrophy. Injection devices(‘pens’) (section 6.1.1.3), which hold the insulin in acartridge and meter the required dose, are convenientto use. Insulin syringes (for use with needles) are lesspopular with children and carers, but may be requiredfor insulins not available in cartridge form.For intensive insulin regimens multiple subcutaneousinjections (3 or more times daily) are usually recommended.Short-acting insulins (soluble insulin, insulin aspart,insulin glulisine, and insulin lispro) can also be givenby continuous subcutaneous infusion using a portableinfusion pump. This device delivers a continuous basalinsulin infusion and patient-activated bolus doses atmeal times. This technique can be useful for childrenwho suffer recurrent hypoglycaemia or marked morningrise in blood-glucose concentration despite optimisedmultiple-injection regimens (see also NICE guidancebelow). Children on subcutaneous insulin infusionmust be highly motivated, able to monitor their bloodglucoseconcentration or have it monitored by a carer,and have expert training, advice, and supervision froman experienced healthcare team.NICE guidanceContinuous subcutaneous insulin infusionfor the treatment of diabetes mellitus (type1) (July 2008)Continuous subcutaneous insulin infusion is recommendedas an option in children over 12 years withtype 1 diabetes:. who suffer repeated or unpredictable hypoglycaemia,whilst attempting to achieve optimalglycaemic control with multiple-injection regimens,or. whose glycaemic control remains inadequate(HbA 1c over 8.5% [69 mmol/mol]) despite optimisedmultiple-injection regimens (including theuse of long-acting insulin analogues whereappropriate).Continuous subcutaneous insulin infusion is alsorecommended as an option for children under 12years with type 1 diabetes for whom multiple-injectionregimens are considered impractical or inappropriate.Children on insulin pumps should undergoa trial of multiple-injection therapy between the agesof 12 and 18 years.

BNFC 2011–2012 6.1.1 Insulins 351Soluble insulin by the intravenous route is reserved forurgent treatment e.g in diabetic ketoacidosis, and forfine control in serious illness and in the peri-operativeperiod (see under Diabetes and Surgery, below).Monitoring All carers and children need to be trainedto monitor blood-glucose concentrations (section 6.1.6).Since blood-glucose concentration varies substantiallythroughout the day, ‘normoglycaemia’ cannot always beachieved throughout a 24-hour period without causingdamaging hypoglycaemia. It is therefore best to recommendthat children should maintain a blood-glucoseconcentration of between 4 and 10 mmol/litre formost of the time (4–8 mmol/litre before meals andless than 10 mmol/litre after meals), while acceptingthat on occasions, for brief periods, it will be above thesevalues; efforts should be made to prevent the bloodglucoseconcentration from falling below 4 mmol/litre.Children using multiple injection regimens shouldunderstand how to adjust their insulin dose accordingto their carbohydrate intake. With fixed-dose insulinregimens, the carbohydrate intake needs to be regulated,and should be distributed throughout the day tomatch the insulin regimen. The intake of energy and ofsimple and complex carbohydrates should be adequateto allow normal growth and development but obesitymust be avoided.Hypoglycaemia Hypoglycaemia is a potential problemfor all children using insulin, and they and theircarers should be given careful instruction on how toavoid it.Very tight control of diabetes lowers the blood-glucoseconcentration needed to trigger hypoglycaemic symptoms;an increase in the frequency of hypoglycaemicepisodes may reduce the warning symptoms experiencedby the child. Loss of warning of hypoglycaemiaamong insulin-treated children can be a serious hazard,especially for cyclists and drivers.To restore the warning signs, episodes of hypoglycaemiamust be minimised; this involves appropriate adjustmentof insulin type, dose, and frequency, togetherwith suitable timing and quantity of meals and snacks.Diabetes and surgery Children with type 1 diabetesshould undergo surgery in centres with facilities for, andexpertise in, the care of children with diabetes. Detailedlocal protocols should be available to all healthcareprofessionals involved in the treatment of these children.Children with type 1 diabetes who require surgery:. should be admitted to hospital for general anaesthesia;. should receive insulin, even if they are fasting, toavoid ketoacidosis;. should receive glucose infusion when fasting beforean anaesthetic to prevent hypoglycaemia;. should have careful monitoring of blood-glucoseconcentration because surgery may cause hyperglycaemia.Elective surgery Surgery in children with diabetes isbest scheduled early on the list, preferably in the morning.If glycaemic control is poor it is advisable to admitthe child well in advance of surgery. On the eveningbefore surgery, blood-glucose should be measured frequently,especially before meals and snacks and at bedtime;urine should be tested for ketones. The usualevening or bedtime insulin and bedtime snack shouldbe given. Ketosis or severe hypoglycaemia require correction,preferably by overnight intravenous infusion(section 6.1.3 and section 6.1.4), and the surgery mayneed to be postponed.For minor procedures that require fasting, a slightmodification of the usual regimen may be all that isnecessary e.g. for early morning procedures delay insulinand food until immediately after the procedure.For other types of elective surgery, consult local treatmentprotocols.Emergency surgery Intravenous fluids and an insulininfusion should be started immediately (see IntravenousFluids and Continuous Insulin Infusion, below). If ketoacidosisis present the recommendations for diabeticketoacidosis should be followed (section 6.1.3).Intravenous fluids and continuous insulin infusionBlood-glucose and plasma-electrolyte concentrationsmust be measured frequently in a child receiving intravenoussupport. Intravenous infusion should be continueduntil after the child starts to eat and drink. Thefollowing infusions should be used and adjusted accordingto the child’s fluid and electrolyte requirements:. Constant infusion of sodium chloride 0.45% andglucose 5% intravenous infusion together withpotassium chloride 20 mmol/litre (provided thatplasma-potassium concentration is not raised) at arate determined by factors such as volume depletionand age; the amount of potassium chlorideinfused is adjusted according to plasma electrolytemeasurements;. Constant infusion of soluble insulin 1 unit/mL insodium chloride 0.9% intravenous infusion initiallyat a rate of 0.025 units/kg/hour (up to 0.05 units/kg/hour if the child is unwell), then adjusted accordingto blood-glucose concentration (frequent monitoringnecessary) in line with locally agreed protocolsand the child’s volume depletion and age;. Blood-glucose concentration should be maintainedbetween 5 and 10 mmol/litre. If the glucose concentrationfalls below 5 mmol/litre, glucose 10 %intravenous infusion may be required; conversely, ifthe glucose concentration persistently exceeds14 mmol/litre, sodium chloride 0.9% intravenousinfusion should be substituted;. The insulin infusion may be stopped temporarily for10–15 minutes if blood-glucose concentration fallsbelow 4 mmol/litre.The usual subcutaneous insulin regimen should bestarted before the first meal (but the dose may need tobe 10–20% higher than usual if the child is still bedboundor unwell) and the intravenous insulin infusionstopped 1 hour later. If glycaemic control is not adequatelyachieved, additional insulin can be given in thefollowing ways:. additional doses of soluble insulin at any of the 4injection times (before meals or bedtime) or. temporary addition of intravenous insulin infusionto subcutaneous regimen or. complete reversion to intravenous insulin infusion(particularly if the child is unwell).Neonatal hyperglycaemia Newborn babies are relativelyintolerant of glucose, especially in the first week of6 Endocrine system

352 6.1.1 Insulins BNFC 2011–20126 Endocrine systemlife and if premature. If intravenous glucose is necessarye.g. for total parenteral nutrition, infuse at a lower ratefor 6–12 hours and the glucose intolerance shouldresolve. Insulin is not needed for such transient glucoseintolerance, but may be needed if blood-glucose concentrationis persistently high.Neonatal diabetes Neonatal diabetes is a rare conditionthat presents with acidosis, dehydration, hyperglycaemia,and rarely ketosis; it responds to continuousinsulin infusion. When the neonate is stable, treatmentcan be switched to subcutaneous insulin given once ortwice a day. Treatment is normally required for 4–6weeks in transient forms, but may be required permanentlyin some cases.6.1.1.1 Short-acting insulinsSoluble insulin is a short-acting form of insulin. Formaintenance regimens it is usual to inject it 15 to 30minutes before meals.Soluble insulin is the most appropriate form of insulinfor use in diabetic emergencies and at the time ofsurgery. It can be given intravenously and intramuscularly,as well as subcutaneously.When injected subcutaneously, soluble insulin has arapid onset of action (30 to 60 minutes), a peak actionbetween 2 and 4 hours, and a duration of action of up to8 hours.When injected intravenously, soluble insulin has a veryshort half-life of only about 5 minutes and its effectdisappears within 30 minutes.The rapid-acting human insulin analogues, insulinaspart, insulin glulisine, and insulin lispro, have afaster onset (10–20 minutes) and shorter duration ofaction (2–5 hours) than soluble insulin; as a result,compared with soluble insulin, fasting and preprandialblood-glucose concentrations are a little higher, postprandialblood-glucose concentration is a little lower,and hypoglycaemia occurs slightly less frequently.These rapid-acting insulins are ideal for prandial dosingin a multiple injection regimen in combination with along-acting insulin once or twice daily. Insulin aspart,insulin glulisine, and insulin lispro can be administeredby subcutaneous infusion (see Insulin Administration,above). Insulin aspart and insulin lispro can also beadministered intravenously and can be used as alternativesto soluble insulin for diabetic emergencies andat the time of surgery.INSULIN(Insulin Injection; Neutral Insulin; SolubleInsulin)A sterile solution of insulin (i.e. bovine or porcine) orof human insulin; pH 6.6–8.0Cautions section 6.1.1; interactions: Appendix 1(antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see notes above; transient oedema; localreactions and fat hypertrophy at injection site; rarelyhypersensitivity reactions including urticaria, rash;overdose causes hypoglycaemiaIndication and doseHyperglycaemia during illness, neonatal diabetes,neonatal hyperglycaemia. By intravenous infusionNeonate 0.02–0.125 units/kg/hour, adjustedaccording to blood-glucose concentration, see alsonotes aboveChild 1 month–18 years 0.025–0.1 units/kg/hour, adjusted according to blood-glucose concentration,see also notes aboveDiabetes mellitus. By subcutaneous injectionAccording to requirements (see notes above)Note Rotate injection site to reduce local reactions andfat hypertrophyDiabetic ketoacidosis section 6.1.3Surgery in children with diabetes section 6.1.1Administration For intravenous infusion, dilute to aconcentration of 1 unit/mL with Sodium Chloride0.9% and mix thoroughly; insulin may be adsorbed byplastics, flush giving set with 5 mL of infusion fluidcontaining insulin.Neonatal intensive care, dilute 5 units to a finalvolume of 50 mL with infusion fluid; an intravenousinfusion rate of 0.1 mL/kg/hour provides a dose of0.01 units/kg/hourHighly purified animalCounselling Show container to child or carer and confirmthe expected version is dispensedHypurin c Bovine Neutral (Wockhardt) AInjection, soluble insulin (bovine, highly purified)100 units/mL. Net price 10-mL vial = £18.48; cartridges(for Autopen c Classic) 5 3 mL = £27.72Hypurin c Porcine Neutral (Wockhardt) AInjection, soluble insulin (porcine, highly purified)100 units/mL. Net price 10-mL vial = £16.80; cartridges(for Autopen c Classic) 5 3 mL = £25.20Human sequenceCounselling Show container to child or carer and confirmthe expected version is dispensedActrapid c (Novo Nordisk) AInjection, soluble insulin (human, pyr) 100 units/mL.Net price 10-mL vial = £7.48Note Not recommended for use in subcutaneous insulininfusion pumps—may precipitate in catheter or needleHumulin S c (Lilly) AInjection, soluble insulin (human, prb) 100 units/mL.Net price 10-mL vial = £15.68; 5 3-mL cartridge (forAutopen c Classic or HumaPen c ) = £19.08Insuman c Rapid (Sanofi-Aventis) AInjection, soluble insulin (human, crb) 100 units/mL,net price 5 3-mL cartridge (for ClikSTAR c andOptiPen c Pro 1, and Autopen c 24) = £17.50; 5 3-mL Insuman c Rapid OptiSet c prefilled disposableinjection devices (range 2–40 units, allowing 2-unitdosage adjustment) = £17.50Note Not recommended for use in subcutaneous insulininfusion pumpsMixed preparationsSee Biphasic Isophane Insulin (section 6.1.1.2)

BNFC 2011–2012 6.1.1 Insulins 353INSULIN ASPART(Recombinant human insulin analogue)Cautions section 6.1.1; interactions: Appendix 1(antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under InsulinLicensed use not licensed for use in children under 2yearsIndication and doseDiabetes mellitus. By subcutaneous injectionImmediately before meals or when necessaryshortly after meals, according to requirements. By subcutaneous infusion, or intravenousinjection, or intravenous infusionAccording to requirementsAdministration for intravenous infusion, dilute to aconcentration of 0.05–1 unit/mL with Glucose 5% orSodium Chloride 0.9% and mix thoroughly; insulinmay be adsorbed by plastics, flush giving set with5 mL of infusion fluid containing insulin.NovoRapid c (Novo Nordisk) AInjection, insulin aspart (recombinant human insulinanalogue) 100 units/mL, net price 10-mL vial =£16.28; Penfill c cartridge (for Innovo c andNovoPen c devices) 5 3-mL = £28.84; 5 3-mLFlexPen c prefilled disposable injection devices (range1–60 units, allowing 1-unit dosage adjustment) =£32.00Counselling Show container to child or carer and confirmthe expected version is dispensedINSULIN GLULISINE(Recombinant human insulin analogue)Cautions section 6.1.1; interactions: Appendix 1(antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under InsulinLicensed use not licensed for children under 6 yearsIndication and doseDiabetes mellitus. By subcutaneous injectionImmediately before meals or when necessaryshortly after meals, according to requirements. By subcutaneous infusion or intravenous infusionAccording to requirementsApidra c (Sanofi-Aventis) AInjection, insulin glulisine (recombinant human insulinanalogue) 100 units/mL, net price 10-mL vial =£16.60; 5 3-mL cartridge (for ClikSTAR c , OptiPen cPro 1, and Autopen c 24) = £28.30; 5 3-mLOptiClik c cartridge (for OptiClik c Pen) = £30.27; 5 3-mL Apidra c Optiset c prefilled disposable injectiondevices (range 2–40 units, allowing 2-unit dosageadjustment) = £28.30; 5 3-mL Apidra c SoloStar cprefilled disposable injection devices (range 1–80 units, allowing 1-unit dosage adjustment) = £25.00Counselling Show container to patient and confirm thatpatient is expecting the version dispensedNote The Scottish Medicines Consortium (p. 3) has advised(October 2008) that Apidra c is accepted for restricted usewithin NHS Scotland for the treatment of children over 6 yearswith diabetes mellitus in whom the use of a short-acting insulinanalogue is appropriateINSULIN LISPRO(Recombinant human insulin analogue)Cautions section 6.1.1; children under 12 years (useonly if benefit likely compared to soluble insulin);interactions: Appendix 1 (antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under InsulinIndication and doseDiabetes mellitus. By subcutaneous injectionShortly before meals or when necessary shortlyafter meals, according to requirements. By subcutaneous infusion, or intravenousinjection, or intravenous infusionAccording to requirementsAdministration For intravenous infusion, dilute to aconcentration of 0.1–1 unit/mL with Glucose 5% orSodium Chloride 0.9% and mix thoroughly; insulinmay be adsorbed by plastics, flush giving set with5 mL of infusion fluid containing insulin.Humalog c (Lilly) AInjection, insulin lispro (recombinant human insulinanalogue) 100 units/mL, net price 10-mL vial =£16.61; 5 3-mL cartridge (for Autopen c Classic orHumaPen c ) = £28.31; 5 3-mL Humalog cKwikPen prefilled disposable injection devices (range1–60 units, allowing 1-unit dosage adjustment) =£29.46Counselling Show container to child or carer and confirmthe expected version is dispensed6.1.1.2 Intermediate- and long-actinginsulinsWhen given by subcutaneous injection, intermediateandlong-acting insulins have an onset of action ofapproximately 1–2 hours, a maximal effect at 4–12hours, and a duration of 16–35 hours. Some are giventwice daily in conjunction with short-acting (soluble)insulin, and others are given once daily. Soluble insulincan be mixed with intermediate and long-acting insulins(except insulin detemir and insulin glargine), essentiallyretaining the properties of the two components,although there may be some blunting of the initial effectof the soluble insulin component (especially on mixingwith protamine zinc insulin, see below).Close monitoring of blood glucose is essential whenintroducing a change to the insulin regimen; the totaldaily dose as well as any concomitant treatment mayneed to be adjusted.6 Endocrine system

354 6.1.1 Insulins BNFC 2011–20126 Endocrine systemIsophane insulin is a suspension of insulin with protamine;it is of particular value for initiation of twice-dailyinsulin regimens. Isophane can be mixed with solubleinsulin before injection but ready-mixed preparationsmay be more appropriate (biphasic isophane insulin,biphasic insulin aspart, or biphasic insulin lispro).Insulin zinc suspension (30% amorphous, 70% crystalline)has a more prolonged duration of action.Protamine zinc insulin is usually given once daily withshort-acting (soluble) insulin. It has the drawback ofbinding with the soluble insulin when mixed in thesame syringe and is now rarely used.Insulin detemir and insulin glargine are long-actinghuman insulin analogues with a prolonged duration ofaction; insulin detemir is given once or twice daily andinsulin glargine is given once daily. These long-actinginsulins are ideal for once or twice daily dosing in amultiple injection regimen in combination with a shortactinginsulin before meals.NICE (May 2009) has recommended that, if insulin isrequired in patients with type 2 diabetes, insulin detemiror insulin glargine may be considered for those:. who require assistance with injecting insulin or. whose lifestyle is significantly restricted by recurrentsymptomatic hypoglycaemia or. who would otherwise need twice-daily basal insulininjections in combination with oral antidiabeticdrugs or. who cannot use the device needed to inject isophaneinsulin.INSULIN DETEMIR(Recombinant human insulin analogue—longacting)Cautions section 6.1.1; interactions: Appendix 1(antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under Insulin (section 6.1.1.1)Licensed use not licensed for use in children under 6yearsIndication and doseDiabetes mellitus. By subcutaneous injectionChild over 6 years according to requirementsLevemir c (Novo Nordisk) AInjection, insulin detemir (recombinant human insulinanalogue) 100 units/mL, net price 5 3-mL cartridge(for NovoPen c devices) = £42.00; 5 3-mL FlexPen cprefilled disposable injection device (range 1–60 units,allowing 1-unit dosage adjustment) = £42.00; 5 3-mL Levemir InnoLet c prefilled disposable injectiondevices (range 1–50 units, allowing 1-unit dosageadjustment) = £44.85Counselling Show container to child or carer and confirmthe expected version is dispensedINSULIN GLARGINE(Recombinant human insulin analogue—longacting)Cautions section 6.1.1; interactions: Appendix 1(antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under Insulin (section 6.1.1.1)Licensed use not licensed for use in children under 6yearsIndication and doseDiabetes mellitus. By subcutaneous injectionAccording to requirementsLantus c (Sanofi-Aventis) AInjection, insulin glargine (recombinant human insulinanalogue) 100 units/mL, net price 10-mL vial =£26.00; 5 3-mL cartridge (for ClikSTAR c ,OptiPen c Pro 1, and Autopen c 24) = £39.00; 5 3-mL OptiClik c cartridge (for OptiClik c Pen) = £40.36;5 3-mL Lantus c OptiSet c prefilled disposableinjection devices (range 2–40 units, allowing 2-unitdosage adjustment) = £39.00; 5 3-mL Lantus cSoloStar c prefilled disposable injection devices(range 1–80 units, allowing 1-unit dosage adjustment)= £40.36Note The Scottish Medicines Consortium (p. 3) has advised(October 2002) that insulin glargine is accepted for restricteduse within NHS Scotland for the treatment of type 1 diabetes:. in those who are at risk of or experience unacceptablefrequency or severity of nocturnal hypoglycaemia onattempting to achieve better hypoglycaemic control duringtreatment with other insulins. as a once daily insulin therapy for patients who require acarer to administer their insulin.It is not recommended for routine use in patients with type 2diabetes unless they suffer from recurrent episodes ofhypoglycaemia or require assistance with their insulininjections.Counselling Show container to child or carer and confirmthe expected version is dispensedINSULIN ZINC SUSPENSION(Insulin Zinc Suspension (Mixed)—long acting)A sterile neutral suspension of bovine insulin or of humaninsulin in the form of a complex obtained by the addition of asuitable zinc salt; consists of rhombohedral crystals (10–40 microns) and of particles of no uniform shape (not exceeding2 microns)Cautions section 6.1.1; interactions: Appendix 1(antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under Insulin (section 6.1.1.1)Indication and doseDiabetes mellitus. By subcutaneous injectionAccording to requirements

BNFC 2011–2012 6.1.1 Insulins 355Highly purified animalHypurin c Bovine Lente (Wockhardt) AInjection, insulin zinc suspension (bovine, highlypurified) 100 units/mL. Net price 10-mL vial = £27.72Counselling Show container to child or carer and confirmthe expected version is dispensedISOPHANE INSULIN(Isophane Insulin Injection; Isophane ProtamineInsulin Injection; Isophane Insulin(NPH)—intermediate acting)A sterile suspension of bovine or porcine insulin or of humaninsulin in the form of a complex obtained by the addition ofprotamine sulphate or another suitable protamineCautions section 6.1.1; interactions: Appendix 1(antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under Insulin (section 6.1.1.1); protaminemay cause allergic reactionsIndication and doseDiabetes mellitus. By subcutaneous injectionAccording to requirementsHighly purified animalCounselling Show container to child or carer and confirmthe expected version is dispensedHypurin c Bovine Isophane (Wockhardt) AInjection, isophane insulin (bovine, highly purified)100 units/mL. Net price 10-mL vial = £27.72; cartridges(for Autopen c Classic) 5 3 mL = £41.58Hypurin c Porcine Isophane (Wockhardt) AInjection, isophane insulin (porcine, highly purified)100 units/mL. Net price 10-mL vial = £25.20; cartridges(for Autopen c Classic) 5 3 mL = £37.80Human sequenceCounselling Show container to child or carer and confirmthe expected version is dispensedInsulatard c (Novo Nordisk) AInjection, isophane insulin (human, pyr) 100 units/mL. Net price 10-mL vial = £7.48; Insulatard Penfill ccartridge (for Innovo c , or Novopen c devices) 5 3 mL = £22.90; 5 3-mL Insulatard InnoLet cprefilled disposable injection devices (range 1–50 units, allowing 1-unit dosage adjustment) = £20.40Humulin I c (Lilly) AInjection, isophane insulin (human, prb) 100nits/mL,net price 10-mL vial = £15.68; 5 3-mL cartridge (forAutopen c Classic or HumaPen c ) = £19.08; 5 3-mLHumulin 1 KwikPen c prefilled disposable injectiondevices (range 1–60 units, allowing 1-unit dosageadjustment) = £21.70Insuman c Basal (Sanofi-Aventis) AInjection, isophane insulin (human, crb) 100 units/mL, net price 5-mL vial = £5.61; 5 3-mL cartridge(for ClikSTAR c and OptiPen c Pro 1, and Autopen c24) = £17.50; 5 3-mL Insuman c Basal OptiSet cprefilled disposable injection devices (range 2–40 units, allowing 2-unit dosage adjustment) = £17.50Mixed preparationsSee Biphasic Isophane Insulin (p. 356)PROTAMINE ZINC INSULIN(Protamine Zinc Insulin Injection—long acting)A sterile suspension of insulin in the form of a complexobtained by the addition of a suitable protamine and zincchloride; this preparation was included in BP 1980 but is notincluded in BP 1988Cautions section 6.1.1; see also notes above; interactions:Appendix 1 (antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under Insulin (section 6.1.1.1); protaminemay cause allergic reactionsIndication and doseDiabetes mellitus. By subcutaneous injectionAccording to requirementsHypurin c Bovine Protamine Zinc (Wockhardt) AInjection, protamine zinc insulin (bovine, highly purified)100 units/mL. Net price 10-mL vial = £27.72Counselling Show container to child or carer and confirmthe expected version is dispensedBiphasic insulinsBiphasic insulins are pre-mixed insulin preparationscontaining various combinations of short-acting (soluble)or rapid-acting (analogue) insulin and an intermediate-actinginsulin.The percentage of short-acting insulin varies from 10%to 50%. These preparations should be administered bysubcutaneous injection up to 15 minutes before or soonafter a meal.BIPHASIC INSULIN ASPART(Intermediate-acting insulin)Cautions section 6.1.1; interactions: Appendix 1(antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under Insulin (section 6.1.1.1); protaminemay cause allergic reactionsIndication and doseDiabetes mellitus. By subcutaneous injectionUp to 10 minutes before or soon after a meal,according to requirementsNovoMix c 30 (Novo Nordisk) AInjection, biphasic insulin aspart (recombinanthuman insulin analogue), 30% insulin aspart, 70%insulin aspart protamine, 100 units/mL, net price 5 3-mL Penfill c cartridges (for Innovo c and NovoPen cdevices) = £28.84; 5 3-mL FlexPen c prefilleddisposable injection devices (range 1–60 units, allowing1-unit dosage adjustment) = £32.00Counselling Show container to child or carer and confirmthe expected version is dispensed; the proportions of the twocomponents should be checked carefully (the order in whichthe proportions are stated may not be the same in othercountries)6 Endocrine system

356 6.1.1 Insulins BNFC 2011–20126 Endocrine systemBIPHASIC INSULIN LISPRO(Intermediate-acting insulin)Cautions see section 6.1.1 and Insulin Lispro; interactions:Appendix 1 (antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under Insulin (section 6.1.1.1); protaminemay cause allergic reactionsIndication and doseDiabetes mellitus. By subcutaneous injectionUp to 15 minutes before or soon after a meal,according to requirementsHumalog c Mix25 (Lilly) AInjection, biphasic insulin lispro (recombinant humaninsulin analogue), 25% insulin lispro, 75% insulinlispro protamine, 100 units/mL, net price 10-mL vial= £16.61; 5 3-mL cartridge (for Autopen c Classic orHumaPen c ) = £29.46; 5 3-mL Humalog c Mix25KwikPen prefilled disposable injection devices (range1–60 units allowing 1-unit dosage adjustment) =£30.98Counselling Show container to child or carer and confirmthe expected version is dispensed; the proportions of the twocomponents should be checked carefully (the order in whichthe proportions are stated may not be the same in othercountries)Humalog c Mix50 (Lilly) AInjection, biphasic insulin lispro (recombinant humaninsulin analogue), 50% insulin lispro, 50% insulinlispro protamine, 100 units/mL, net price 5 3-mLcartridge (for Autopen c Classic or HumaPen c )=£29.46; 5 3-mL Humalog c Mix50 KwikPenprefilled disposable injection devices (range 1–60 units, allowing 1-unit dosage adjustment) = £30.98Counselling Show container to child or carer and confirmthe expected version is dispensed; the proportions of the twocomponents should be checked carefully (the order in whichthe proportions are stated may not be the same in othercountries)BIPHASIC ISOPHANE INSULIN(Biphasic Isophane Insulin Injection—intermediateacting)A sterile buffered suspension of either porcine or human insulincomplexed with protamine sulphate (or another suitable protamine)in a solution of insulin of the same speciesCautions section 6.1.1; interactions: Appendix 1(antidiabetics)Hepatic impairment section 6.1.1Renal impairment section 6.1.1Pregnancy section 6.1.1Breast-feeding section 6.1.1Side-effects see under Insulin (section 6.1.1.1); protaminemay cause allergic reactionsIndication and doseDiabetes mellitus. By subcutaneous injectionAccording to requirementsHighly purified animalCounselling Show container to child or carer and confirmthe expected version is dispensed; the proportions of the twocomponents should be checked carefully (the order in whichthe proportions are stated may not be the same in othercountries)Hypurin c Porcine 30/70 Mix (Wockhardt) AInjection, biphasic isophane insulin (porcine, highlypurified), 30% soluble, 70% isophane, 100 units/mL,net price 10-mL vial = £16.80; cartridges (for Autopenc Classic) 5 3 mL = £25.20Human sequenceCounselling Show container to child or carer and confirmthe expected version is dispensed; the proportions of the twocomponents should be checked carefully (the order in whichthe proportions are stated may not be the same in othercountries)Humulin M3 c (Lilly) AInjection, biphasic isophane insulin (human, prb),30% soluble, 70% isophane, 100 units/mL, net price10-mL vial = £15.68; 5 3-mL cartridge (for Autopenc Classic or HumaPen c ) = £19.08; 5 3-mLHumulin M3 KwikPen c prefilled disposable injectiondevices (range 1–60 units, allowing 1-unit dosageadjustment) = £21.70Insuman c Comb 15 (Sanofi-Aventis) AInjection, biphasic isophane insulin (human, crb),15% soluble, 85% isophane, 100 units/mL, net price 5 3-mL cartridge (for ClikSTAR c , Optipen c Pro 1and Autopen c 24) = £17.50; 5 3-mL Insuman cComb 15 OptiSet c prefilled disposable injectiondevices (range 2–40 units, allowing 2-unit dosageadjustment) = £17.50Insuman c Comb 25 (Sanofi-Aventis) AInjection, biphasic isophane insulin (human, crb),25% soluble, 75% isophane, 100 units/mL, net price5-mL vial = £5.61; 5 3-mL cartridge (forClikSTAR c , OptiPen c Pro 1, and Autopen c 24) =£17.50; 5 3-mL Insuman c Comb 25 OptiSet cprefilled disposable injection devices (range 2–40 units, allowing 2-unit dosage adjustment) = £17.50;5 3-mL Insuman c Comb 25 SoloStar prefilleddisposable injection devices (range 1–80 units, allowing1-unit dosage adjustment) = £19.80Insuman c Comb 50 (Sanofi-Aventis) AInjection, biphasic isophane insulin (human, crb),50% soluble, 50% isophane, 100 units/mL, net price; 5 3-mL cartridge (for ClikSTAR c , OptiPen c Pro 1,and Autopen c 24) = £17.50; 5 3-mL Insuman cComb 50 OptiSet c prefilled disposable injectiondevices (range 2–40 units, allowing 2-unit dosageadjustment) = £17.506.1.1.3 Hypodermic equipmentCarers and children should be advised on the safedisposal of lancets, single-use syringes, and needles.Suitable arrangements for the safe disposal of contaminatedwaste must be made before these products areprescribed for patients who are carriers of infectiousdiseases.

BNFC 2011–2012 6.1.2 Antidiabetic drugs 357Injection devicesAutopen c (Owen Mumford)Injection device; Autopen c 24 (for use with Sanofi-Aventis3-mL insulin cartridges), allowing 1-unit dosage adjustment,max. 21 units (single-unit version) or 2 unit dosage adjustment,max. 42 units (2 unit version), net price (both) =£15.73; Autopen c Classic (for use with Lilly and Wockhardt3-mL insulin cartridges), allowing 1-unit dosage adjustment,max. 21 units (single-unit version) or 2 unit dosage adjustment,max. 42 units (2-unit version), net price (all) = £15.97ClikSTAR c (Sanofi-Aventis)Injection device, for use with Lantus c , Apidra c , andInsuman c 3-mL insulin cartridges; allowing 1-unit doseadjustment, max. 80 units, net price = £25.00HumaPen c Luxura (Lilly)Injection device, for use with Humulin c and Humalog c 3-mL cartridges; allowing 1-unit dosage adjustment, max.60 units, net price = £26.36HumaPen c Luxura HD (Lilly)Injection device, for use with Humulin c and Humalog c 3-mL cartridges; allowing 0.5-unit dosage adjustment, max.30 units, net price = £26.36NovoPen c (Novo Nordisk)Injection device; for use with Penfill c insulin cartridges;NovoPen c Junior (for 3-mL cartridges), allowing 0.5-unitdosage adjustment, max. 35 units, net price = £24.79;NovoPen c 3 Demi (for 3-mL cartridges), allowing 0.5-unitdosage adjustment, max. 35 units, net price = £25.21;NovoPen c 4 (for 3-mL cartridges), allowing 1-unit dosageadjustment, max. 60 units, net price = £26.56OptiClik c (Sanofi-Aventis)Injection device, for use with Lantus OptiClik c or ApidraOptiClik c insulin cartridges, allowing 1-unit dosage adjustment,max. 80 units, net price = £20.13OptiPen c Pro 1 (Sanofi-Aventis)Injection device, for use with Insuman c insulin cartridges;allowing 1-unit dosage adjustment, max. 60 units, net price =£22.00LancetsLancets—sterile, single use (Drug Tariff)BD Micro-Fine c + 100 = £3.16, 200 = £6.13; CareSens c 100= £2.95; Cleanlet Fine c 100 = £3.19, 200 = £6.13; Fastclix c204 = £9.20; 1 Finepoint c 100 = £3.54; 1 FreeStyle c 200 =£7.02; 1 Microlet c (formerly Ascenscia Microlet c ) 100 =£3.76, 200 = £7.17; 1 Milward Steri-Let c , 23 gauge, 100 =£3.00, 200 = £5.70, 28 gauge, 100 = £3.00, 200 = £5.70;1 Monolet c 100 = £3.28, 200 = £6.24; Monolet c Extra 100 =£3.28; MPD Ultra Thin c , 100 = £3.30, 200 = £6.50;Multiclix c 204 = £9.27; One Touch Comfort c 200 = £7.22;1 One Touch UltraSoft c 100 = £3.61; 2 Softclix c 200 = £7.40;2 Softclix XL c 50 = £1.85; Thin Lancets, 200 = £7.16; 1 UniletComforTouch c 100 = £3.60, 200 = £6.83; Unilet Eco c 100 =£2.94, 200 = £5.49; 1 Unilet General Purpose Superlite c 100= £3.67, 200 = £6.96; Unistik 3 Comfort c , 28-gauge, 100 =£6.24, 200 = £12.20; Unistik 3 Extra c , 21-gauge, 100 = £6.24,200 = £12.20; Unistik 3 Normal c , 23-gauge, 100 = £6.24,200 = £12.20; Universal c , 200 = £6.37; Vitrex Soft c , 23-gauge, 100 = £3.00, 200 = £5.70; Vitrex Gentle c 28-gauge,100 = £3.19, 200 = £6.13; WaveSense Ultra-Thin c 28-gauge,200 = £6.90, 33-gauge, 200 = £6.90Compatible finger-pricking devices (unless indicated otherwise,see footnotes), all D: B-D Optimus c , Glucolet c , Monojector c ,Penlet II c , Soft Touch c1. D Autolet c and D Autolet Impression c are alsocompatible finger-pricking devices2. Use D Softclix c finger-pricking deviceNeedlesHypodermic Needle, Sterile single use (Drug Tariff)For use with reusable glass syringe, sizes 0.5 mm (25G),0.45 mm (26G), 0.4 mm (27G). Net price 100-needle pack =£2.74Brands include Microlance c , Monoject cNeedles for Prefilled and Reusable Pen Injectors (DrugTariff)Screw on, needle length 6.1 mm or less, net price 100-needlepack = £12.53; 6.2–9.9 mm, 100-needle pack = £8.89; 10 mmor more, 100-needle pack = £8.89Brands include BD Micro-Fine c +, Comfort Point c , NovoFine c ,Novofine Autocover c , NovoTwist c , Unifine c PentipsSnap on, needle length 6.1 mm or less, net price 100-needlepack = £12.02; 6.2–9.9 mm, 100-needle pack = £8.52; 10 mmor more, 100-needle pack = £8.52Brands include Penfine cSyringesHypodermic Syringe (Drug Tariff)Calibrated glass with Luer taper conical fitting, for use withU100 insulin. Net price 0.5 mL and 1 mL = £9.22Brands include Abcare cPre-Set U100 Insulin Syringe (Drug Tariff)Calibrated glass with Luer taper conical fitting, supplied withdosage chart and strong box, for blind patients. Net price1 mL = £21.99U100 Insulin Syringe with Needle (Drug Tariff)Disposable with fixed or separate needle for single use orsingle patient-use, colour coded orange. Needle length 8 mm,diameters 0.33 mm (29G), 0.3 mm (30G), net price 10 (withneedle), 0.3 mL = £1.38, 0.5 mL = £1.33; needle length12 mm, diameters 0.45 mm (26G), 0.4 mm (27G), 0.36 mm(28G), 0.33 mm (29G), net price 10 (with needle), 0.3 mL =£1.45; 0.5 mL = £1.43; 1 mL = £1.44Brands include BD Micro-Fine c +, Clinipak c , Insupak c , Monojectc Ultra, Omnikan c , Plastipak cAccessoriesNeedle Clipping (Chopping) Device (Drug Tariff)Consisting of a clipper to remove needle from its hub andcontainer from which cut-off needles cannot be retrieved;designed to hold 1200 needles, not suitable for use withlancets. Net price = £1.35Brands include BD Safe-Clip cSharpsguard (Drug Tariff)Net price 1-litre sharpsbin = 85p6.1.2 Antidiabetic drugs6.1.2.1 Sulfonylureas6.1.2.2 Biguanides6.1.2.3 Other antidiabetic drugsOral antidiabetic drugs are used for the treatment oftype 2 diabetes mellitus. They should be prescribed onlyif the child fails to respond adequately to restriction ofenergy and carbohydrate intake and an increase inphysical activity. They should be used to augment theeffect of diet and exercise, and not to replace them.In children, type 2 diabetes does not usually occur untiladolescence and information on the use of oral antidiabeticdrugs in children is limited. Treatment with oralantidiabetic drugs should be initiated under specialistsupervision only; the initial dose should be at the lower6 Endocrine system

358 6.1.2 Antidiabetic drugs BNFC 2011–20126 Endocrine systemend of the adult dose range and then adjusted accordingto response.Metformin (section 6.1.2.2) is the oral antidiabetic drugof choice because there is most experience with thisdrug in children. If dietary changes and metformin donot control the diabetes adequately, either a sulfonylurea(section 6.1.2.1) or insulin (section 6.1.1) can beadded.Alternatively, oral therapy may be substituted with insulin.When insulin is added to oral therapy, it is generallygiven at bedtime as isophane or long-acting insulin, andwhen insulin replaces an oral regimen it may be given astwice-daily injections of a biphasic insulin (or isophaneinsulin mixed with soluble insulin), or a multiple injectionregimen. Weight gain and hypoglycaemia may becomplications of insulin therapy but weight gain can bereduced if the insulin is given in combination with metformin.Pregnancy and breast-feeding During pregnancy,women with pre-existing diabetes can be treated withmetformin [unlicensed use], either alone or in combinationwith insulin (section 6.1.1). Metformin can becontinued, or glibenclamide resumed, during breastfeedingfor those with pre-existing diabetes. Womenwith gestational diabetes may be treated, with or withoutconcomitant insulin (section 6.1.1), with glibenclamidefrom 11 weeks gestation (after organogenesis)[unlicensed use] or with metformin [unlicensed use].Women with gestational diabetes should discontinuehypoglycaemic treatment after giving birth.Other oral hypoglycaemic drugs are contra-indicated inpregnancy and breast-feeding.6.1.2.1 SulfonylureasThe sulfonylureas are not the first choice oral antidiabeticsin children. They act mainly by augmentinginsulin secretion and consequently are effective onlywhen some residual pancreatic beta-cell activity is present;during long-term administration they also have anextrapancreatic action. All can cause hypoglycaemia butthis is uncommon and usually indicates excessivedosage. Sulfonylurea-induced hypoglycaemia can persistfor many hours and must always be treated inhospital.Sulfonylureas are considered for children in whom metforminis contra-indicated or not tolerated. Severalsulfonylureas are available but experience in childrenis limited; choice is determined by side-effects and theduration of action as well as the child’s age and renalfunction. Glibenclamide, a long-acting sulfonylurea, isassociated with a greater risk of hypoglycaemia and forthis reason is generally avoided in children. Shorteractingalternatives, such as tolbutamide, may be preferred.Insulin therapy should be instituted temporarily duringintercurrent illness (such as coma, infection, and trauma).Sulfonylureas should be omitted on the morning ofsurgery; insulin is often required because of the ensuinghyperglycaemia in these circumstances.Sulfonylureas can be useful in the management ofcertain forms of diabetes that result from genetic defectsof beta-cell function; there is most experience withgliclazide.Cautions Sulfonylureas encourage weight gain andshould be prescribed only if poor control and symptomspersist despite adequate attempts at dieting; metformin(section 6.1.2.2) is considered the drug of choice inchildren.Contra-indications Sulfonylureas should be avoidedwhere possible in acute porphyria (section 9.8.2). Sulfonylureasare contra-indicated in the presence of ketoacidosis.Hepatic impairment Sulfonylureas should be avoidedor a reduced dose should be used in severe hepaticimpairment, because there is an increased risk of hypoglycaemia.Jaundice may occur.Renal impairment Sulfonylureas should be used withcare in those with mild to moderate renal impairment,because of the hazard of hypoglycaemia; they should beavoided where possible in severe renal impairment. Ifnecessary, the short-acting drug tolbutamide can beused in renal impairment, as can gliclazide which isprincipally metabolised in the liver, but careful monitoringof blood-glucose concentration is essential; care isrequired to use the lowest dose that adequately controlsblood glucose.Pregnancy The use of sulfonylureas in pregnancyshould generally be avoided because of the risk of neonatalhypoglycaemia; however, glibenclamide can beused during the second and third trimesters ofpregnancy in women with gestational diabetes, seesection 6.1.2.Breast-feeding The use of sulfonylureas (exceptglibenclamide [unlicensed use], see section 6.1.2) inbreast-feeding should be avoided because there is atheoretical possibility of hypoglycaemia in the infant.Side-effects Side-effects of sulfonylureas are generallymild and infrequent and include gastro-intestinaldisturbances such as nausea, vomiting, diarrhoea andconstipation.Sulfonylureas can occasionally cause a disturbance inliver function, which rarely leads to cholestatic jaundice,hepatitis, and hepatic failure. Hypersensitivity reactionscan occur, usually in the first 6–8 weeks of therapy. Theyconsist mainly of allergic skin reactions which progressrarely to erythema multiforme or exfoliative dermatitis,fever, and jaundice; photosensitivity has rarely beenreported with glipizide. Blood disorders are also rarebut include leucopenia, thrombocytopenia, agranulocytosis,pancytopenia, haemolytic anaemia, and aplasticanaemia.GLIBENCLAMIDECautions see notes above; interactions: Appendix 1(antidiabetics)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes above

BNFC 2011–2012 6.1.2 Antidiabetic drugs 359Breast-feeding see notes aboveSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseType 2 diabetes mellitus, maturity-onset diabetesof the young (specialist managementonly, see notes above). By mouthChild 12–18 years initially 2.5 mg daily with orimmediately after breakfast, adjusted according toresponse, max. 15 mg dailyGlibenclamide (Non-proprietary) ATablets, glibenclamide 2.5 mg, net price 28-tab pack= 95p; 5 mg, 28-tab pack = £1.07GLICLAZIDECautions see notes above; interactions: Appendix 1(antidiabetics)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseType 2 diabetes mellitus, maturity-onset diabetesof the young (specialist managementonly, see notes above). By mouthChild 12–18 years initially 20 mg once daily withbreakfast, adjusted according to response; up to160 mg as a single dose; max. 160 mg twice dailyGliclazide (Non-proprietary) ATablets, gliclazide 40 mg, net price 28-tab pack =£3.36; 80 mg, 28-tab pack = £1.10, 60-tab pack = £1.52Brands include DIAGLYK c , c ZicronDiamicron c (Servier) ATablets, scored, gliclazide 80 mg, net price 60-tabpack = £4.38Tolbutamide (Non-proprietary) ATablets, tolbutamide 500 mg. Net price 28-tab pack =£1.74Extemporaneous formulations available seeExtemporaneous Preparations, p. 66.1.2.2 BiguanidesMetformin, the only available biguanide, has a differentmode of action from the sulfonylureas, and is not interchangeablewith them. It exerts its effect mainly bydecreasing gluconeogenesis and by increasing peripheralutilisation of glucose; since it acts only in thepresence of endogenous insulin it is effective only ifthere are some residual functioning pancreatic isletcells.Metformin is the drug of first choice in children withtype 2 diabetes, in whom strict dieting has failed tocontrol diabetes. When the combination of strict dietand metformin treatment fails, other options to beconsidered under specialist management only, include:. combining with insulin (section 6.1.1) but weightgain and hypoglycaemia can be problems (weightgain minimised if insulin given at night);. combining with a sulfonylurea (section 6.1.2.1)(reports of increased hazard with this combinationremain unconfirmed).Insulin treatment is almost always required in medicaland surgical emergencies; insulin should also be substitutedbefore elective surgery (omit metformin on themorning of surgery and give insulin if required).Hypoglycaemia does not usually occur with metformin;other advantages are the lower incidence of weight gainand lower plasma-insulin concentration. It does notexert a hypoglycaemic action in non-diabetic subjectsunless given in overdose.Gastro-intestinal side-effects are initially common withmetformin, and may persist in some children, particularlywhen high doses are given. A slow increase in dosemay improve tolerability.Very rarely, metformin can provoke lactic acidosiswhich is most likely to occur in children with renalimpairment, see Lactic Acidosis below.6 Endocrine systemTOLBUTAMIDECautions see notes above; interactions: Appendix 1(antidiabetics)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also headache, tinnitusLicensed use not licensed for use in childrenIndication and doseType 2 diabetes mellitus (see notes above), specialistmanagement only. By mouthChild 12–18 years 0.5–1.5 g (max. 2 g) daily individed doses with or immediately after meals oras a single dose with or immediately after breakfastMETFORMIN HYDROCHLORIDECautions see notes above; determine renal functionbefore treatment and at least annually (at least twice ayear in patients with additional risk factors for renalimpairment, or if deterioration suspected); interactions:Appendix 1 (antidiabetics)Lactic acidosis Use with caution in renal impairment—increased risk of lactic acidosis; avoid in significant renalimpairment. Withdraw or interrupt treatment in those at riskof tissue hypoxia or sudden deterioration in renal function,such as those with dehydration, severe infection, shock,sepsis, acute heart failure, respiratory failure, or hepaticimpairmentContra-indications ketoacidosis; use of generalanaesthesia (suspend metformin on the morning ofsurgery and restart when renal function returns tobaseline)Iodine-containing X-ray contrast media Intravascularadministration of iodinated contrast agents can cause renalfailure, which can increase the risk of lactic acidosis with

360 6.1.3 Diabetic ketoacidosis BNFC 2011–20126 Endocrine systemmetformin—see Lactic Acidosis above. Suspend metforminprior to the test; restart no earlier than 48 hours after the testif renal function has returned to baselineHepatic impairment withdraw if tissue hypoxia likelyRenal impairment see under CautionsPregnancy used in pregnancy for both pre-existingand gestational diabetes—see also Pregnancy andBreast-feeding, p. 358Breast-feeding may be used during breast–feeding—see also Pregnancy and Breast-feeding, p. 358Side-effects anorexia, nausea, vomiting, diarrhoea(usually transient), abdominal pain, taste disturbance;rarely lactic acidosis (withdraw treatment), decreasedvitamin-B 12 absorption, erythema, pruritus and urticaria;hepatitis also reportedLicensed use not licensed for use in children under10 yearsIndication and doseDiabetes mellitus (see notes above) specialistsupervision only. By mouthChild 8–10 years initially 200 mg once dailyadjusted according to response at intervals of atleast 1 week; max. 2 g daily in 2–3 divided dosesChild 10–18 years initially 500 mg once dailyadjusted according to response at intervals of atleast 1 week; max. 2 g daily in 2–3 divided dosesMetformin (Non-proprietary) ATablets, coated, metformin hydrochloride 500 mg, netprice 28-tab pack = £1.07, 84-tab pack= £1.57;850 mg, 56-tab pack = £1.67. Label: 21Oral solution, sugar-free, metformin hydrochloride500 mg/5 mL, net price 100 mL = £62.48. Label: 21Brands include Metsol cGlucophage c (Merck Serono) ATablets, f /c, metformin hydrochloride 500 mg, netprice 84-tab pack = £2.88; 850 mg, 56-tab pack =£3.20. Label: 21Oral powder, sugar-free, metformin hydrochloride500 mg/sachet, net price 30-sachet pack = £3.29, 60-sachet pack = £6.58; 1 g/sachet, 30-sachet pack =£6.58, 60-sachet pack = £13.16. Label: 13, 21, counselling,administrationExcipients include aspartame (section 9.4.1)Counselling The contents of each sachet should be mixedwith 150 mL of water and taken immediatelyThe Scottish Medicines Consortium (p. 3) has advised(March 2010) that Glucophage c oral powder is accepted forrestricted use within NHS Scotland for the treatment of type2 diabetes mellitus in patients who are unable to swallow thesolid dosage form.6.1.2.3 Other antidiabetic drugsThere is little experience of the use of acarbose inchildren. It has been used in older children; therapyshould be initiated by an appropriate expert.The use of nateglinide in combination with a sulfonylureais generally reserved for the management of somesubtypes of diabetes resulting from genetic defects ofbeta-cell function or other syndromes of diabetes andrequires specialist management.6.1.3 Diabetic ketoacidosisThe management of diabetic ketoacidosis involves thereplacement of fluid and electrolytes and the administrationof insulin. Guidelines for the Management ofDiabetic Ketoacidosis, published by the British Societyof Paediatric Endocrinology and Diabetes 1 , should befollowed. Clinically well children with mild ketoacidosiswho are dehydrated up to 5% usually respond to oralrehydration and subcutaneous insulin. For those who donot respond, or are clinically unwell, or are dehydratedby more than 5%, insulin and replacement fluids arebest given by intravenous infusion.. To restore circulating volume for children in shock,give 10 mL/kg sodium chloride 0.9% as a rapidinfusion, repeat as necessary up to a maximum of30 mL/kg.. Further fluid should be given by intravenous infusionat a rate that replaces deficit and providesmaintenance over 48 hours; initially use sodiumchloride 0.9%, changing to sodium chloride0.45% and glucose 5% after 12 hours if responseis adequate and plasma-sodium concentration isstable.. Include potassium chloride in the fluids unlessanuria is suspected, adjust according to plasmapotassiumconcentration.. Insulin infusion is necessary to switch off ketogenesisand reverse acidosis; it should not be starteduntil at least 1 hour after the start of intravenousrehydration fluids.. Soluble insulin should be diluted (and mixed thoroughly)with sodium chloride 0.9% intravenousinfusion to a concentration of 1 unit/mL andinfused at a rate of 0.1 units/kg/hour.. Sodium bicarbonate infusion (1.26% or 2.74%) israrely necessary and is used only in cases ofextreme acidosis (blood pH less than 6.9) andshock, since the acid-base disturbance is normallycorrected by treatment with insulin.. Once blood glucose falls to 14 mmol/litre, glucoseintravenous infusion 5% or 10% should be addedto the fluids.. The insulin infusion rate can be reduced to no lessthan 0.05 units/kg/hour when blood-glucose concentrationhas fallen to 14 mmol/litre and blood pHis greater than 7.3 and a glucose infusion has beenstarted (see above); it is continued until the child isready to take food by mouth. Subcutaneous insulincan then be started.. The insulin infusion should not be stopped until 1hour after starting subcutaneous soluble or longactinginsulin, or 10 minutes after starting subcutaneousinsulin aspart, or insulin glulisine, or insulinlispro.Hyperosmolar hyperglycaemic state or hyperosmolarhyperglycaemic nonketotic coma occurs rarely in children.Treatment is similar to that of diabetic ketoacidosis,although lower rates of insulin infusion and slowerrehydration may be required.1. Available at www.bsped.org.uk

BNFC 2011–2012 6.1.4 Treatment of hypoglycaemia 3616.1.4 Treatment ofhypoglycaemiaPrompt treatment of hypoglycaemia in children fromany cause is essential as severe hypoglycaemia maycause subsequent neurological damage. Hyperinsulinism,fatty acid oxidation disorders and glycogen storagedisease are less common causes of acute hypoglycaemiain children.Initially glucose 10–20 g is given by mouth either inliquid form or as granulated sugar or sugar lumps.Approximately 10 g of glucose is available from nondietversions of Lucozade c Energy Original 55 mL,Coca-Cola c 100 mL, and Ribena c Blackcurrant 19 mL(to be diluted), 2 teaspoons of sugar, and also from 3sugar lumps 1 . If necessary this can be repeated in 10–15minutes. After initial treatment, a snack providingsustained availability of carbohydrate (e.g. a sandwich,fruit, milk, or biscuits) or the next meal, if it is due, canprevent blood-glucose concentration from falling again.Hypoglycaemia which causes unconsciousness or seizuresis an emergency. Glucagon, a polypeptide hormoneproduced by the alpha cells of the islets of Langerhans,increases blood-glucose concentration bymobilising glycogen stored in the liver. In hypoglycaemia,if sugar cannot be given by mouth, glucagoncan be given by injection. Carbohydrates should begiven as soon as possible to restore liver glycogen;glucagon is not appropriate for chronic hypoglycaemia.Glucagon can be issued to parents or carers of insulintreatedchildren for emergency use in hypoglycaemicattacks. It is often advisable to prescribe it on an ‘ifnecessary’ basis for hospitalised insulin-treated children,so that it can be given rapidly by the nurses duringa hypoglycaemic emergency. If not effective in 10minutes intravenous glucose should be given.Alternatively, 5 mL/kg of glucose intravenous infusion10% (500 mg/kg of glucose) (section 9.2.2) can be givenintravenously into a large vein through a large-gaugeneedle; care is required since this concentration isirritant especially if extravasation occurs. Glucose intravenousinfusion 50% is not recommended, as it is veryviscous and hypertonic. Close monitoring is necessary,particularly in the case of an overdose with a long-actinginsulin because further administration of glucose maybe required. Children whose hypoglycaemia is causedby an oral antidiabetic drug should be transferred tohospital because the hypoglycaemic effects of thesedrugs can persist for many hours.Glucagon is not effective in the treatment of hypoglycaemiadue to fatty acid oxidation or glycogen storagedisorders.Neonatal hypoglycaemia Neonatal hypoglycaemiaat birth is treated with glucose intravenous infusion10% given at a rate of 5 mL/kg/hour. An initial dose of2.5 mL/kg over 5 minutes may be required if hypoglycaemiais severe enough to cause loss of consciousnessor seizures. Mild asymptomatic persistent hypoglycaemiamay respond to a single dose of glucagon. Glucagonhas also been used in the short-term managementof endogenous hyperinsulinism.1. Proprietary products of quick-acting carbohydrate (e.g.GlucoGel c , Dextrogel c , Hypo-Fit c ) are available onprescription for the patient to keep to hand in case ofhypoglycaemiaGLUCAGONCautions see notes above, insulinoma, glucagonoma;ineffective in chronic hypoglycaemia, starvation, andadrenal insufficiency; delayed hypoglycaemia whenused as a diagnostic test—deaths reported (ensure ameal is eaten before discharge)Contra-indications phaeochromocytomaSide-effects nausea, vomiting, diarrhoea, hypokalaemia,rarely hypersensitivity reactionsLicensed use unlicensed for growth hormone testand hyperinsulinismIndication and doseHypoglycaemia associated with diabetes. By subcutaneous, intramuscular, or intravenousinjectionNeonate 20 micrograms/kgChild 1 month–2 years 500 microgramsChild 2–18 years, body-weight less than 25 kg500 micrograms; body-weight over 25 kg 1 mgEndogenous hyperinsulinism. By intramuscular or intravenous injectionNeonate 200 micrograms/kg (max. 1 mg) as asingle doseChild 1 month–2 years 1 mg as a single dose. By continuous intravenous infusionNeonate 1–18 micrograms/kg/hour, adjustedaccording to response (max. 50 micrograms/kg/hour)Child 1 month–2 years 1–10 micrograms/kg/hour, increased if necessaryAdministration Do not add to infusion fluids containingcalcium—precipitation may occurDiagnosis of growth hormone secretion specialistcentre only (section 6.5.1). By intramuscular injectionChild 1month–18 years 100 micrograms/kg(max. 1 mg) as a single dose; dose may vary,consult local guidelinesBeta-blocker poisoning, see p. 29Note 1 unit of glucagon = 1 mg of glucagon1GlucaGen c HypoKit (Novo Nordisk) AInjection, powder for reconstitution, glucagon (rys) ashydrochloride with lactose, net price 1-mg vial withprefilled syringe containing water for injection =£11.521. A restriction does not apply where administration is forsaving life in emergencyChronic hypoglycaemiaDiazoxide is useful in the management of chronic hypoglycaemiadue to excessive insulin secretion, either froma tumour involving the islets of Langerhans or frompersisting hyperinsulinaemic hypoglycaemia of infancy(nesidioblastosis, see also glucagon above). Diazoxidehas no place in the management of acute hypoglycaemia.Chlorothiazide 3–5 mg/kg twice daily (section6 Endocrine system

362 6.1.5 Treatment of diabetic nephropathy and neuropathy BNFC 2011–20126 Endocrine system2.2.1) reduces diazoxide-induced sodium and waterretention and has the added benefit of potentiating theglycaemic effect of diazoxide.If diazoxide and chlorothiazide fail to suppress excessiveglucose requirements in chronic hypoglycaemiathen octreotide or nifedipine (section 2.6.2) can beadded. Octreotide suppresses secretion of growth hormone,but growth is unlikely to be affected in the longterm.DIAZOXIDECautions ischaemic heart disease; monitor bloodpressure, during prolonged use monitor white cell andplatelet count, and regularly assess growth, bone, andpsychological development; avoid the intravenousroute if possible; extravasation can cause tissuenecrosis and single doses of 300 mg have been associatedwith angina and cerebral and myocardialinfarction; interactions: Appendix 1 (diazoxide)Renal impairment increased sensitivity to hypotensiveand hyperglycaemic effect; dose reduction maybe requiredPregnancy prolonged use in second or third trimestersmay produce alopecia and impaired glucose tolerancein neonate; inhibits uterine activitySide-effects anorexia, nausea, vomiting, hyperuricaemia,sodium and water retention, hyperglycaemia,hypotension, oedema, tachycardia, arrhythmias,extrapyramidal effects; hypertrichosis on prolongedtreatmentIndication and doseChronic intractable hypoglycaemia. By mouth or by intravenous injectionNeonate initially 5 mg/kg twice daily to establishresponse, adjust dose according to response; usualmaintenance dose 1.5–3 mg/kg 2–3 times daily; upto 7 mg/kg 3 times daily may be required in somecases, higher doses unlikely to be beneficialChild 1 month–18 years initially 1.7 mg/kg 3times daily then adjusted according to response;usual maintenance dose 1.5–3 mg/kg 2–3 timesdaily; up to 5 mg/kg 3 times daily may be requiredin some cases, higher doses unlikely to be beneficialHypertensive emergencies and resistanthypertension section 2.5.1.1Eudemine c (UCB Pharma) ATablets, diazoxide 50 mg, net price 100 = £44.64Injection, see section 2.5.1Extemporaneous formulations available seeExtemporaneous Preparations, p. 6OCTREOTIDECautions avoid abrupt withdrawal of short-actingoctreotide—see Side-effects below; in insulinoma(risk of increased depth and duration of hypoglycaemia—monitorclosely when initiating treatment andchanging doses); diabetes mellitus (antidiabeticrequirements may be reduced); monitor thyroidfunction on long-term therapy; interactions: Appendix1 (octreotide)Pregnancy possible effect on fetal growth, avoidunless benefit outweighs risk; effective contraceptionrequired during treatmentBreast-feeding avoid unless essential—present inmilk in animal studiesSide-effects anorexia, nausea, vomiting, abdominalpain, bloating, flatulence, diarrhoea, constipation, andsteatorrhoea (administer between meals or at bedtimeto reduce gastro-intestinal side-effects); bradycardia,dyspnoea, headache, dizziness; postprandial glucosetolerance may be impaired, rarely persistent hyperglycaemiawith chronic administration; hypoglycaemiahas also been reported; reduced gall bladdermotility and bile flow; gallstones reported after longtermtreatment; abrupt withdrawal of subcutaneousoctreotide is associated with biliary colic and pancreatitis;rash, alopecia; pain and irritation at injectionsite—sites should be rotated; rarely pancreatitisshortly after administration; hepatitis also reportedLicensed use not licensed in childrenIndication and dosePersistent hyperinsulinaemic hypoglycaemiaunresponsive to diazoxide and glucose. By subcutaneous injectionNeonate initially 2–5 micrograms/kg every 6–8hours, adjusted according to response; up to7 micrograms/kg every 4 hours may rarely berequiredChild 1 month–18 years initially 1–2 micrograms/kgevery 4–6 hours, dose adjustedaccording to response; up to 7 micrograms/kgevery 4 hours may rarely be requiredBleeding from oesophageal or gastric varices. By continuous intravenous infusionChild 1 month–18 years 1 microgram/kg/hour,higher doses may be required initially; when noactive bleeding reduce dose over 24 hours; usualmax. 50 micrograms/hourAdministration for intravenous infusion, dilute withSodium Chloride 0.9% to a concentration of 10–50%Sandostatin c (Novartis) AInjection, octreotide (as acetate) 50 micrograms/mL,net price 1-mL amp = £2.98; 100 micrograms/mL, 1-mL amp = £5.60; 200 micrograms/mL 5-mL vial =£69.66; 500 micrograms/mL, 1-mL amp = £27.106.1.5 Treatment of diabeticnephropathy andneuropathyDiabetic nephropathyRegular review of diabetic children over 12 years of ageshould include an annual test for microalbuminuria (theearliest sign of nephropathy). If reagent strip tests(Micral-Test II c D or Microbumintest c D) are used

BNFC 2011–2012 6.1.6 Diagnostic and monitoring devices for diabetes mellitus 363and prove positive, the result should be confirmed bylaboratory analysis of a urine sample. Microalbuminuriacan occur transiently during puberty; if it persists (atleast 3 positive tests) treatment with an ACE inhibitor(section 2.5.5.1) or an angiotensin-II receptor antagonist(section 2.5.5.2) under specialist guidance should beconsidered; to minimise the risk of renal deterioration,blood pressure should be carefully controlled (section2.5).ACE inhibitors can potentiate the hypoglycaemic effectof insulin and oral antidiabetic drugs; this effect is morelikely during the first weeks of combined treatment andin children with renal impairment.For the treatment of hypertension in diabetes, see section2.5.Diabetic neuropathyClinical neuropathy is rare in children whose diabetes iswell controlled.UrinalysisTests for glucose range from reagent strips specific toglucose to reagent tablets which detect all reducingsugars. Clinitest c is rarely used now; Clinistix c issuitable for screening purposes only. It is rarelynecessary for children to test themselves for ketonesunless they become unwell—see also Blood Monitoring,above.Microalbuminuria can be detected with Micral-TestII c D but this should be followed by confirmation inthe laboratory, since false positive results are common.GlucoseClinistix c (Bayer Diabetes Care)Reagent strips, for detection of glucose in urine. Net price50-strip pack = £3.27Clinitest c (Bayer Diabetes Care)Reagent tablets, for detection of glucose and other reducingsubstances in urine. Net price 36-tab pack = £2.00Diabur-Test 5000 c (Roche Diagnostics)Reagent strips, for detection of glucose in urine. Net price50-strip pack = £2.87Diastix c (Bayer Diabetes Care)Reagent strips, for detection of glucose in urine. Net price50-strip pack = £2.786.1.6 Diagnostic andmonitoring devices fordiabetes mellitusBlood monitoringBlood glucose monitoring using a meter gives a directmeasure of the glucose concentration at the time of thetest and can detect hypoglycaemia as well as hyperglycaemia.Carers and children should be properly trained inthe use of blood glucose monitoring systems and theappropriate action to take on the results obtained.Inadequate understanding of the normal fluctuationsin blood glucose can lead to confusion and inappropriateaction.Children using multiple injection regimens shouldunderstand how to adjust their insulin dose accordingto their carbohydrate intake. With fixed-dose insulinregimens, the carbohydrate intake needs to be regulated,and should be distributed throughout the day tomatch the insulin regimen.Note In the UK blood-glucose concentration is expressed inmmol/litre and Diabetes UK advises that these units should beused for self-monitoring of blood glucose. In other Europeancountries units of mg/100 mL (or mg/dL) are commonly used.It is advisable to check that the meter is pre-set in the correctunits.If the blood glucose level is high or if the child is unwell,blood ketones should be measured according to localguidelines in order to detect diabetic ketoacidosis (section6.1.3). Children and their carers should be trained inthe use of blood ketone monitoring systems and to takeappropriate action on the results obtained, includingwhen to seek medical attention.Medi-Test c Glucose (BHR)Reagent strips, for detection of glucose in urine. Net price50-strip pack = £2.33Mission c Glucose (Spirit)Reagent strips, for detection of glucose in urine. Net price50-strip pack = £2.29KetonesKetostix c (Bayer Diabetes Care)Reagent strips, for detection of ketones in urine. Net price50-strip pack = £2.95Ketur Test c (Roche Diagnostics)Reagent strips, for detection of ketones in urine. Net price50-strip pack = £2.76Mission c Ketone (Spirit)Reagent strips, for detection of ketones in urine. Net price50-strip pack = £2.50ProteinAlbustix c (Siemens)Reagent strips, for detection of protein in urine. Net price50-strip pack = £4.10Medi-Test c Protein 2 (BHR)Reagent strips, for detection of protein in urine. Net price50-strip pack = £3.27Other reagent strips available for urinalysisinclude:Combur-3 Test c D (glucose and protein—RocheDiagnostics), Clinitek Microalbumin c D (albumin andcreatinine—Siemens), Ketodiastix c D (glucose andketones—Bayer Diagnostics), Medi-Test Combi 2 c D(glucose and protein—BHR), Micral-Test II c D(albumin—Roche Diagnostics), Microalbustix c D(albumin and creatinine—Siemens), Uristix c D(glucose and protein—Siemens)6 Endocrine system

364 6.1.6 Diagnostic and monitoring devices for diabetes mellitus BNFC 2011–2012Meters and test strips6 Endocrine systemMeter (all D)Type ofmonitoringMeterretail priceCompatibletest stripsTest stripnet priceAccu-Chek c Active 1 Blood glucose Active c 50-strip pack= £15.16Accu-Chek c Blood glucose Advantage 50-strip packAdvantage 1 = £15.17Accu-Chek c Aviva Blood glucose £12.99 Aviva c 50-strip pack= £14.89Accu-Chek c Blood glucose Compact c 3 17-strip packCompact 1 = £15.29Accu-Chek cCompact PlusBlood glucose £12.99 Compact c 3 17-strip pack= £15.29Sensitivity Manufacturerrange(mmol/litre)0.6–33.3 RocheDiagnostics0.6–33.3 RocheDiagnostics0.6–33.3 RocheDiagnostics0.6–33.3 RocheDiagnostics0.6–33.3 RocheDiagnosticsAccu-Chek c Mobile Blood glucose £49.99 Mobile c 100 tests = £30.12 0.3–33.3 RocheDiagnosticsAccutrend c 1 Blood glucose BM-Accutest c 50-strip pack= £14.31Ascensia Breeze c 1 Blood glucose Ascensia c 5 10-disc packAutodisc= £14.62Ascensia Esprit c 2 1 Blood glucose Ascensia cAutodisc5 10-disc pack= £14.62Breeze 2 c Blood glucose £11.35 Breeze 2 c 5 10-disc pack= £14.34CareSens N c 2 Blood glucose CareSens N c 50-strip pack= £12.75Contour c Blood glucose £11.35 Contour cFormerly Ascensia cMicrofill50-strip pack= £14.74FreeStyle c 1 Blood glucose FreeStyle c 50-strip pack= £14.90FreeStyleBlood glucose FreeStyle c 50-strip packFreedom c 1 = £14.90FreeStyle Freedom Blood glucose £11.49 FreeStyle Lite c 50-strip packLite c = £14.90FreeStyle Lite c Blood glucose £14.94 FreeStyle Lite c 50-strip pack= £14.90FreeStyle Mini c 1 Blood glucose FreeStyle c 50-strip pack= £14.90GlucoMen c Glycó 1 Blood glucose GlucoMen c 50-strip pack= £13.67GlucoMen c GM Blood glucose £15.26 GlucoMen c GM 50-strip pack= £14.67GlucoMen c LX Blood glucose £14.94 GlucoMen c LX 50-strip pack= £14.65GlucoMen c LX PLUS Blood glucose £14.94 GlucoMen c LX 50-strip pack= £14.65GlucoMen c PC 1 Blood glucose GlucoMen c 50-strip pack= £13.67GlucoMen c Visio Blood glucose £10.34 GlucoMen c VisioSensor50-strip pack= £14.53Glucotrend c 1 Blood glucose Active c 50-strip pack= £14.76One Touch c II 1 Blood glucose One Touch c 50-strip pack= £14.591.1–33.3 RocheDiagnostics0.6–33.3 BayerDiabetesCare0.6–33.3 BayerDiabetesCare0.6–33.3 BayerDiabetesCare1.1–33.3 SpiritHealthcare0.6–33.3 BayerDiabetesCare1.1–27.8 Abbott1.1–27.8 Abbott1.1–27.8 Abbott1.1–27.8 Abbott1.1–27.8 Abbott1.1–33.3 MenariniDiagnostics0.6–33.3 MenariniDiagnostics1.1–33.3 MenariniDiagnostics1.1–33.3 MenariniDiagnostics1.1–33.3 MenariniDiagnostics1.1–33.3 MenariniDiagnostics0.6–33.3 RocheDiagnostics1.1–33.3 LifeScan1. Meter no longer available2. Free of charge from diabetes healthcare professionals

BNFC 2011–2012 6.2 Thyroid and antithyroid drugs 365Meter (all D)Type ofmonitoringMeterretail priceCompatibletest stripsTest stripnet priceOne Touch c Basic 1 Blood glucose One Touch c 50-strip pack= £14.59One Touch c Profile 1 Blood glucose One Touch c 50-strip pack= £14.59One Touch Ultra c 1 Blood glucose One Touch Ultra c 50-strip pack= £14.75One Touch Ultra 2 c Blood glucose £25.98 One Touch Ultra c 50-strip pack= £14.75One TouchBlood glucose £25.98 One Touch Ultra c 50-strip packUltraEasy c = £14.75One TouchBlood glucose One Touch Ultra c 50-strip packUltraSmart c 2 = £14.75One Touch cVerioProBlood glucose One Touch c Verio 50-strip pack= £14.99One Touch c Vita 2 Blood glucose One Touch c Vita 50-strip pack= £14.81Optium c 1 Blood ketones Optium c b-ketone 10-strip pack= £19.92Optium Xceed c Blood glucose £17.24 Optium Plus cFormerly Medisense cOptium Plus50-strip pack= £14.80Blood ketonesOptium c b-ketone 10-strip pack= £19.55PocketScan c 1 Blood glucose PocketScan c 50-strip pack= £14.41Prestige c Blood glucose £8.62 Prestige c 50-strip pack= £14.51TRUEone c Blood glucose n/a All-in-one teststrips and meter50-strip pack withmeter = £14.36TRUEresult c 2 Blood glucose £11.74 TRUEresult c 50-strip pack= £14.36TRUEresult twist c 2 Blood glucose £11.74 TRUEresult c 50-strip pack= £14.36TRUEtrack c Blood glucose £8.62 TRUEtrack c 50-strip pack= £14.25WaveSense Jazz c Blood glucose £24.99 WaveSense Jazz c 50-strip pack= £14.451. Meter no longer available2. Free of charge from diabetes healthcare professionalsSensitivity Manufacturerrange(mmol/litre)1.1–33.3 LifeScan1.1–33.3 LifeScan1.1–33.3 LifeScan1.1–33.3 LifeScan1.1–33.3 LifeScan1.1–33.3 LifeScan1.1–33.3 LifeScan1.1–33.3 LifeScan0–8.0 Abbott1.1–27.8 Abbott0–8.0 Abbott1.1–33.3 LifeScan1.4–33.3 NiproDiagnostics1.1–33.3 NiproDiagnostics1.1–33.3 NiproDiagnostics1.1–33.3 NiproDiagnostics1.1–33.3 NiproDiagnostics1.1–33.3 WaveSense6 Endocrine systemOral glucose tolerance testThe oral glucose tolerance test is used mainly fordiagnosis of impaired glucose tolerance; it is not recommendedor necessary for routine diagnostic use whensevere symptoms of hyperglycaemia are present. However,it is used for the investigation of insulin resistance,glycogen storage disease, and excessive growth hormonesecretion. In children who have less severe symptomsand blood-glucose concentrations that do notestablish or exclude diabetes (e.g. impaired fasting glycaemia),an oral glucose tolerance test may be required.A dose of 1.75 g/kg (max. 75 g) of anhydrous glucose isused. It is also used to establish the presence of gestationaldiabetes; this generally involves giving anhydrousglucose 75 g (equivalent to Glucose BP 82.5 g) by mouthto the fasting patient, and measuring blood-glucoseconcentration at intervals. The appropriate amount ofglucose should be given with 200–300 mL fluid. Alternativelyanhydrous glucose 75 g can be given as 113 mLPolycal c (Nutricia Clinical) with extra fluid to administera total volume of 200–300 mL.6.2 Thyroid and antithyroiddrugs6.2.1 Thyroid hormones6.2.2 Antithyroid drugs6.2.1 Thyroid hormonesThyroid hormones are used in hypothyroidism (juvenilemyxoedema), and also in diffuse non-toxic goitre, congenitalor neonatal hypothyroidism, and Hashimoto’s

366 6.2.1 Thyroid hormones BNFC 2011–20126 Endocrine systemthyroiditis (lymphadenoid goitre). Neonatal hypothyroidismrequires prompt treatment to facilitate normaldevelopment.Levothyroxine sodium (thyroxine sodium) is the treatmentof choice for maintenance therapy.Doses for congenital hypothyroidism and juvenile myxoedemashould be titrated according to clinicalresponse, growth assessment, and measurement ofplasma thyroxine and thyroid-stimulating hormone concentrations.In congenital hypothyroidism higher initialdoses may normalise metabolism more quickly, withassociated beneficial effects on mental development.Liothyronine sodium has a similar action to levothyroxinebut is more rapidly metabolised and has a morerapid effect; 20–25 micrograms is equivalent to approximately100 micrograms of levothyroxine. Its effectsdevelop after a few hours and disappear within 24 to48 hours of discontinuing treatment. It may be used insevere hypothyroid states when a rapid response isdesired.Liothyronine by intravenous injection is the treatment ofchoice in hypothyroid coma. Adjunctive therapyincludes intravenous fluids, hydrocortisone, and treatmentof infection; assisted ventilation is often required.LEVOTHYROXINE SODIUM(Thyroxine sodium)Cautions panhypopituitarism or predisposition toadrenal insufficiency (initiate corticosteroid therapybefore starting levothyroxine); cardiac disorders(monitor ECG; start at low dose and carefully titrate);long-standing hypothyroidism, diabetes insipidus,diabetes mellitus (dose of antidiabetic drugs includinginsulin may need to be increased); interactions:Appendix 1 (thyroid hormones)Pregnancy monitor maternal serum-thyrotrophinconcentration—levothyroxine may cross the placentaand excessive maternal concentration can be detrimentalto fetusBreast-feeding amount too small to affect tests forneonatal hypothyroidismSide-effects usually at excessive dosage includediarrhoea, vomiting; anginal pain, arrhythmias, palpitation,tachycardia, benign intracranial hypertension;tremor, restlessness, excitability, insomnia,headache, flushing, sweating, fever, heat intolerance,weight loss, nervousness; craniosynostosis and prematureclosure of epiphyses; menstrual irregularities;eosinophilia, liver dysfunction; muscle cramps, muscularweakness; transient hair loss; hypersensitivityreactions including rash, pruritus and oedema alsoreportedIndication and doseHypothyroidismNote Levothyroxine equivalent to 100 micrograms/m 2 /day can be used as a guide to the requirements inchildren. By mouthNeonate initially 10–15 micrograms/kg once daily(max. 50 micrograms daily), adjusted in steps of5 micrograms/kg every 2 weeks or as necessary;usual maintenance dose 20–50 micrograms dailyChild 1 month–2 years initially 5 micrograms/kgonce daily (max. 50 micrograms daily) adjusted insteps of 10–25 micrograms daily every 2–4 weeksuntil metabolism normalised; usual maintenancedose 25–75 micrograms dailyChild 2–12 years initially 50 micrograms oncedaily adjusted in steps of 25 micrograms dailyevery 2–4 weeks until metabolism normalised;usual maintenance dose 75–100 micrograms dailyChild 12–18 years initially 50 micrograms oncedaily adjusted in steps of 25–50 micrograms dailyevery 3–4 weeks until metabolism normalised;usual maintenance dose 100–200 microgramsdailyLevothyroxine (Non-proprietary) ATablets, levothyroxine sodium 25 micrograms, netprice 28-tab pack = £2.22; 50 micrograms, 28-tab pack= £1.09; 100 micrograms, 28-tab pack = £1.09Brands include Eltroxin cOral solution, levothyroxine sodium 25 micrograms/5 mL, net price 100 mL = £42.75; 50 micrograms/5 mL, 100 mL = £44.90; 100 micrograms/5 mL,100 mL = £52.75Brands include Evotrox c (sugar-free)Note All strengths of levothyroxine oral solution by Almusand branded as Evotrox c , have been reformulated (August2010) leading to an increase in potency of approximately10%; the manufacturer advises that the recommended dosehas not changed, but recommends increased monitoring ofpatients on these preparations as dose adjustments may benecessaryLIOTHYRONINE SODIUM(L-Tri-iodothyronine sodium)Cautions severe and prolonged hypothyroidism (initiatecorticosteroid therapy in adrenal insufficiency);cardiac disorders (monitor ECG; start at low dose andcarefully titrate); diabetes insipidus, diabetes mellitus(dose of antidiabetic drugs including insulin may needto be increased); interactions: Appendix 1 (thyroidhormones)Pregnancy does not cross the placenta in significantamounts; monitor maternal thyroid function tests—dosage adjustment may be necessaryBreast-feeding amount too small to affect tests forneonatal hypothyroidismSide-effects usually at excessive dosage includediarrhoea; anginal pain, arrhythmias, palpitation,tachycardia; restlessness, excitability, headache,flushing, sweating, weight loss; muscle cramps,muscle weaknessLicensed use unlicensed for use in childrenIndication and doseSee also notes aboveHypothyroidism. By mouthChild 12–18 years initially 10–20 microgramsdaily gradually increased to 60 micrograms daily in2–3 divided doses. By slow intravenous injection(replacement for oral levothyroxine)Convert daily levothyroxine dose to liothyronine(see notes above for approximate equivalence) andgive in 2–3 divided doses, adjusted according toresponse

BNFC 2011–2012 6.2.2 Antithyroid drugs 367Hypothyroid coma. By slow intravenous injectionChild 12–18 years 5–20 micrograms repeatedevery 12 hours or up to every 4 hours if necessary;alternatively initially 50 micrograms then 25 microgramsevery 8 hours reducing to 25 microgramstwice dailyLiothyronine sodium (Goldshield) ATablets, scored, liothyronine sodium 20 micrograms,net price 28-tab pack = £26.15Triiodothyronine (Goldshield) AInjection, powder for reconstitution, liothyroninesodium (with dextran). Net price 20-microgram amp= £37.926.2.2 Antithyroid drugsAntithyroid drugs are used for hyperthyroidism either toprepare children for thyroidectomy or for long-termmanagement. In the UK carbimazole is the most commonlyused drug. Propylthiouracil should be reservedfor children who are intolerant of, or who experiencesensitivity reactions to, carbimazole (sensitivity is notnecessarily displayed to both drugs), and for whomother treatments are inappropriate. Both drugs act primarilyby interfering with the synthesis of thyroid hormones.Treatment in children should be undertaken by a specialist.Neutropenia and agranulocytosisDoctors are reminded of the importance of recognisingbone marrow suppression induced by carbimazoleand the need to stop treatment promptly.1. Children and their carers should be asked toreport symptoms and signs suggestive of infection,especially sore throat.2. A white blood cell count should be performed ifthere is any clinical evidence of infection.3. Carbimazole should be stopped promptly ifthere is clinical or laboratory evidence of neutropenia.Carbimazole or propylthiouracil are initially given inlarge doses to block thyroid function. This dose iscontinued until the child becomes euthyroid, usuallyafter 4 to 8 weeks, and is then gradually reduced to amaintenance dose of 30–60% of the initial dose. Alternativelyhigh-dose treatment is continued in combinationwith levothyroxine replacement (blocking-replacementregimen); this is particularly useful when doseadjustment proves difficult. Treatment is usually continuedfor 12 to 24 months. The blocking-replacementregimen is not suitable during pregnancy. Hypothyroidismshould be avoided particularly during pregnancy asit can cause fetal goitre.When substituting, carbimazole 1 mg is consideredequivalent to propylthiouracil 10 mg but the dose mayneed adjusting according to response.Rashes and pruritus are common with carbimazole butthey can be treated with antihistamines without discontinuingtherapy; alternatively propylthiouracil can besubstituted. If a child on carbimazole develops a sorethroat it should be reported immediately because of therare complication of agranulocytosis (see Neutropeniaand Agranulocytosis, above).Iodine has been used as an adjunct to antithyroid drugsfor 10 to 14 days before partial thyroidectomy; however,there is little evidence of a beneficial effect. Iodineshould not be used for long-term treatment becauseits antithyroid action tends to diminish.Radioactive sodium iodide ( 131 I) solution is used increasinglyfor the treatment of thyrotoxicosis at all ages,particularly where medical therapy or compliance is aproblem, in patients with cardiac disease, and in patientswho relapse after thyroidectomy.Propranolol (section 2.4) is useful for rapid relief ofthyrotoxic symptoms and can be used in conjunctionwith antithyroid drugs or as an adjunct to radioactiveiodine. Beta-blockers are also useful in neonatal thyrotoxicosisand in supraventricular arrhythmias due tohyperthyroidism. Propranolol has been used in conjunctionwith iodine to prepare mildly thyrotoxic patients forsurgery but it is preferable to make the patient euthyroidwith carbimazole. Laboratory tests of thyroid functionare not altered by beta-blockers. Most experience intreating thyrotoxicosis has been gained with propranololbut atenolol (section 2.4) is also used.Thyrotoxic crisis (‘thyroid storm’) requires emergencytreatment with intravenous administration of fluids,propranolol and hydrocortisone as sodium succinate,as well as oral iodine solution and carbimazole orpropylthiouracil which may need to be administeredby nasogastric tube.Neonatal hyperthyroidism is treated with carbimazoleor propylthiouracil, usually for 8 to 12 weeks. In severesymptomatic disease iodine may be needed to block thethyroid and propranolol required to treat peripheralsymptoms.Pregnancy Radioactive iodine therapy is contra-indicatedduring pregnancy. Propylthiouracil and carbimazolecan be given but the blocking-replacement regimen(see above) is not suitable. Rarely, carbimazole hasbeen associated with congenital defects, including aplasiacutis of the neonate—use carbimazole in pregnancyonly if propylthiouracil is not suitable. Both propylthiouraciland carbimazole cross the placenta and in highdoses can cause fetal goitre and hypothyroidism—thelowest dose that will control the hyperthyroid stateshould be used (requirements in Graves’ disease tendto fall during pregnancy).Breast-feeding Carbimazole and propylthiouracil arepresent in breast milk but this does not preclude breastfeedingas long as neonatal development is closelymonitored and the lowest effective dose is used.CARBIMAZOLEHepatic impairment use with caution in mild tomoderate impairment; avoid in severe hepaticimpairmentPregnancy see notes above6 Endocrine system

368 6.2.2 Antithyroid drugs BNFC 2011–20126 Endocrine systemBreast-feeding amount in milk may be sufficient toaffect neonatal thyroid function, therefore lowesteffective dose should be used; see notes aboveSide-effects nausea, mild gastro-intestinal disturbances,taste disturbance, hepatic disorders (includinghepatitis and jaundice), headache, fever, malaise, rash,pruritus, arthralgia; rarely myopathy, alopecia, bonemarrow suppression (including pancytopenia andagranulocytosis, see Neutropenia and Agranulocytosisabove), hypersensitivity reactionsIndication and doseHyperthyroidism (including Graves’ disease). By mouthNeonate initially 750 micrograms/kg daily in singleor divided doses until euthyroid then adjust asnecessary (see notes above); higher initial doses(up to 1 mg/kg daily) are occasionally required,particularly in thyrotoxic crisisChild 1 month–12 years initially 750 micrograms/kg(max. 30 mg) daily in single or divideddoses until euthyroid then adjusted as necessary(see notes above); higher initial doses occasionallyrequired, particularly in thyrotoxic crisisChild 12–18 years initially 30 mg daily in singleor divided doses until euthyroid then adjusted asnecessary (see notes above); higher initial dosesoccasionally required, particularly in thyrotoxiccrisisCounselling Warn child and carers to tell doctorimmediately if sore throat, mouth ulcers, bruising, fever,malaise, or non-specific illness developsCarbimazole (Non-proprietary) ATablets, carbimazole 5 mg, net price 100-tab pack =£4.53; 20 mg, 100-tab pack = £16.83. Counselling,blood disorder symptomsNeo-Mercazole c (Amdipharm) ATablets, both pink, carbimazole 5 mg, net price 100-tab pack = £3.85; 20 mg, 100-tab pack = £11.44.Counselling, blood disorder symptomsAdministration tablets may be crushed in water and usedimmediatelyExtemporaneous formulations available seeExtemporaneous Preparations, p. 6IODINE AND IODIDECautions not for long-term treatmentPregnancy neonatal goitre and hypothyroidism; seealso notes aboveBreast-feeding stop breast-feeding; danger of neonatalhypothyroidism or goitre; appears to be concentratedin milk; see also notes aboveSide-effects hypersensitivity reactions including coryza-likesymptoms, headache, lacrimation, conjunctivitis,pain in salivary glands, laryngitis, bronchitis,rashes; on prolonged treatment depression,insomnia, impotence; goitre in infants of motherstaking iodidesIndication and doseSee under preparationAqueous Iodine Oral SolutionOral solution, iodine 5%, potassium iodide 10% inpurified water, freshly boiled and cooled, total iodine130 mg/mL, net price 500 mL = £6.24. Label: 27DoseNeonatal thyrotoxicosis. By mouthNeonate 0.05–0.1 mL 3 times dailyThyrotoxicosis (pre-operative). By mouthNeonate 0.1–0.3 mL 3 times dailyChild 1 month–18 years 0.1–0.3 mL 3 times dailyThyrotoxic crisis. By mouthChild 1 month—1 year 0.2–0.3 mL 3 times dailyAdministration Dilute well with milk or waterPROPYLTHIOURACILCautions monitor for hepatotoxicityHepatotoxicity Severe hepatic reactions have beenreported, including fatal cases and cases requiring livertransplant—discontinue if significant liver-enzyme abnormalitiesdevelopCounselling Patients should be told how to recognise signsof liver disorder and advised to seek prompt medical attentionif symptoms such as anorexia, nausea, vomiting, fatigue,abdominal pain, jaundice, dark urine, or pruritus developHepatic impairment reduce dose (see also Hepatotoxicityabove)Renal impairment estimated glomerular filtrationrate 10–50 mL/minute/1.73 m 2 , use 75% of normaldose; estimated glomerular filtration rate less than10 mL/minute/1.73 m 2 , use 50% of normal dosePregnancy see notes aboveBreast-feeding monitor infant’s thyroid status butamount in milk probably too small to affect infant;high doses may affect neonatal thyroid function; seealso notes aboveSide-effects see under Carbimazole; leucopenia;rarely cutaneous vasculitis, thrombocytopenia,aplastic anaemia, hypoprothrombinaemia, hepaticdisorders (including hepatitis, hepatic failure,encephalopathy, hepatic necrosis; see also Hepatotoxicityabove), nephritis, lupus erythematous-likesyndromesLicensed use not licensed for use in children under 6years of ageIndication and doseHyperthyroidism (including Graves’ disease). By mouthNeonate initially 2.5–5 mg/kg twice daily untileuthyroid then adjusted as necessary (see notesabove); higher doses occasionally required, particularlyin thyrotoxic crisisChild 1 month–1 year initially 2.5 mg/kg 3 timesdaily until euthyroid then adjusted as necessary(see notes above); higher doses occasionallyrequired, particularly in thyrotoxic crisisChild 1–5 years initially 25 mg 3 times daily untileuthyroid then adjusted as necessary (see notesabove); higher doses occasionally required, particularlyin thyrotoxic crisis

BNFC 2011–2012 6.3 Corticosteroids 369Child 5–12 years initially 50 mg 3 times daily untileuthyroid then adjusted as necessary (see notesabove); higher doses occasionally required, particularlyin thyrotoxic crisisChild 12–18 years initially 100 mg 3 times dailyadministered until euthyroid then adjusted asnecessary (see notes above); higher doses occasionallyrequired, particularly in thyrotoxic crisisPropylthiouracil (Non-proprietary) ATablets, propylthiouracil 50 mg, net price 56-tab pack= £47.11, 100-tab pack = £67.38Extemporaneous formulations available seeExtemporaneous Preparations, p. 6PROPRANOLOL HYDROCHLORIDECautions see section 2.4Contra-indications see section 2.4Hepatic impairment section 2.4Renal impairment section 2.4Pregnancy section 2.4Breast-feeding section 2.4Side-effects see section 2.4Indication and doseHyperthyroidism with autonomic symptoms,thyrotoxicosis, thyrotoxic crisis. By mouthNeonate initially 250–500 micrograms/kg every6–8 hours, adjusted according to responseChild 1 month–18 years initially 250–500 micrograms/kgevery 8 hours, then adjusted accordingto response; doses up to 1 mg/kg every 8 hoursoccasionally required, max. 40 mg every 8 hours. By intravenous injection over 10 minutesNeonate initially 20–50 micrograms/kg every 6–8hours, adjusted according to responseChild 1 month–18 years initially 25–50 micrograms/kg(max. 5 mg) every 6–8 hours, adjustedaccording to responsePreparationsSee section 2.46.3 Corticosteroids6.3.1 Replacement therapy6.3.2 Glucocorticoid therapy6.3.1 Replacement therapyThe adrenal cortex normally secretes hydrocortisone(cortisol) which has glucocorticoid activity and weakmineralocorticoid activity. It also secretes the mineralocorticoidaldosterone.In deficiency states, physiological replacement is bestachieved with a combination of hydrocortisone (section6.3.2) and the mineralocorticoid fludrocortisone;hydrocortisone alone does not usually provide sufficientmineralocorticoid activity for complete replacement.In Addison’s disease or following adrenalectomy,hydrocortisone by mouth is usually required. This isgiven in 2–3 divided doses, the larger in the morning andthe smaller in the evening, mimicking the normal diurnalrhythm of cortisol secretion. The optimum dailydose is determined on the basis of clinical response.Glucocorticoid therapy is supplemented by fludrocortisone.In acute adrenocortical insufficiency, hydrocortisoneis given intravenously (preferably as sodium succinate)every 6 to 8 hours in sodium chloride intravenousinfusion 0.9%.In hypopituitarism, glucocorticoids should be given asin adrenocortical insufficiency, but since production ofaldosterone is also regulated by the renin-angiotensinsystem a mineralocorticoid is not usually required.Additional replacement therapy with levothyroxine(section 6.2.1) and sex hormones (section 6.4) shouldbe given as indicated by the pattern of hormone deficiency.In congenital adrenal hyperplasia, the pituitary glandincreases production of corticotropin to compensate forreduced formation of cortisol; this results in excessiveadrenal androgen production. Treatment is aimed atsuppressing corticotropin using hydrocortisone (section6.3.2). Careful and continual dose titration is required toavoid growth retardation and toxicity; for this reasonpotent, synthetic glucocorticoids such as dexamethasoneare usually reserved for use in adolescents.The dose is adjusted according to clinical response andmeasurement of adrenal androgens and 17-hydroxyprogesterone.Salt-losing forms of congenital adrenalhyperplasia (where there is a lack of aldosterone production)also require mineralocorticoid replacementand salt supplementation (particularly in early life).The dose of mineralocorticoid is adjusted according toelectrolyte concentration and plasma-renin activity.FLUDROCORTISONE ACETATECautions section 6.3.2; interactions: Appendix 1(corticosteroids)Contra-indications section 6.3.2Hepatic impairment see section 6.3.2Renal impairment see section 6.3.2Pregnancy see section 6.3.2Breast-feeding see section 6.3.2Side-effects section 6.3.2Indication and doseMineralocorticoid replacement in adrenocorticalinsufficiency. By mouthNeonate initially 50 micrograms once daily,adjusted according to response; usual range 50–200 micrograms daily; higher doses may berequiredChild 1 month–18 years initially 50–100 microgramsonce daily; maintenance 50–300 microgramsonce daily, adjusted according to responseNote Dose adjustment may be required if salt supplementsare administered6 Endocrine system

370 6.3.2 Glucocorticoid therapy BNFC 2011–2012Florinef c (Squibb) ATablets, scored, fludrocortisone acetate 100 micrograms.Net price 100-tab pack = £5.05. Label: 10,steroid cardExtemporaneous formulations available seeExtemporaneous Preparations, p. 6Note Bioavailability uncertain, tablets may result in morereliable absorption and may be dispersed in waterBetamethasone and dexamethasone also have a longduration of action and this, coupled with their lack ofmineralocorticoid action makes them particularly suitablefor conditions which require suppression of corticotropin(corticotrophin) secretion. Some esters of betamethasoneand of beclometasone (beclomethasone)exert a considerably more marked topical effect (e.g.on the skin or the lungs) than when given by mouth; useis made of this to obtain topical effects whilst minimisingsystemic side-effects (e.g. for skin applications andasthma inhalations).Deflazacort has a high glucocorticoid activity; it isderived from prednisolone.6.3.2 Glucocorticoid therapy6 Endocrine systemIn comparing the relative potencies of corticosteroids interms of their anti-inflammatory (glucocorticoid) effectsit should be borne in mind that high glucocorticoidactivity in itself is of no advantage unless it is accompaniedby relatively low mineralocorticoid activity (seeDisadvantages of Corticosteroids below). The mineralocorticoidactivity of fludrocortisone (section 6.3.1) isso high that its anti-inflammatory activity is of noclinical relevance. The table below shows equivalentanti-inflammatory doses.Equivalent anti-inflammatory doses of corticosteroidsThis table takes no account of mineralocorticoid effects,nor does it take account of variations in duration ofactionPrednisolone1 mg: Betamethasone 150 micrograms: Cortisone acetate 5 mg: Deflazacort 1.2 mg: Dexamethasone 150 micrograms: Hydrocortisone 4 mg: Methylprednisolone 800 micrograms: Triamcinolone 800 microgramsThe relatively high mineralocorticoid activity of cortisoneand hydrocortisone, and the resulting fluid retention,make them unsuitable for disease suppression on along-term basis. However, they can be used for adrenalreplacement therapy (section 6.3.1); hydrocortisone ispreferred because cortisone requires conversion in theliver to hydrocortisone. Hydrocortisone is used on ashort-term basis by intravenous injection for the emergencymanagement of some conditions. The relativelymoderate anti-inflammatory potency of hydrocortisonealso makes it a useful topical corticosteroid for themanagement of inflammatory skin conditions becauseside-effects (both topical and systemic) are less marked(section 13.4); cortisone is not active topically.Prednisolone has predominantly glucocorticoid activityand is the corticosteroid most commonly used by mouthfor long-term disease suppression.Betamethasone and dexamethasone have very highglucocorticoid activity in conjunction with insignificantmineralocorticoid activity. This makes them particularlysuitable for high-dose therapy in conditions where fluidretention would be a disadvantage.Use of corticosteroidsDosages of corticosteroids vary widely in different diseasesand in different children. If the use of a corticosteroidcan save or prolong life, as in exfoliativedermatitis, pemphigus, acute leukaemia or acute transplantrejection, high doses may need to be given,because the complications of therapy are likely to beless serious than the effects of the disease itself.When long-term corticosteroid therapy is used in somechronic diseases, the adverse effects of treatment maybecome greater than the disabilities caused by thedisease. To minimise side-effects the maintenancedose should be kept as low as possible.When potentially less harmful measures are ineffectivecorticosteroids are used topically for the treatment ofinflammatory conditions of the skin (section 13.4). Corticosteroidsshould be avoided or used only underspecialist supervision in psoriasis (section 13.5).Corticosteroids are used both topically (by rectum) andsystemically (by mouth or intravenously) in the managementof ulcerative colitis and Crohn’s disease (section1.5 and section 1.7.2).Use can be made of the mineralocorticoid activity offludrocortisone to treat postural hypotension in autonomicneuropathy.High-dose corticosteroids should be avoided for themanagement of septic shock. However, low-dose hydrocortisonecan be used in septic shock (section 2.7.1) thatis resistant to volume expansion and catecholamines,and is accompanied by suspected or proven adrenalinsufficiency.The suppressive action of glucocorticoids on the hypothalamic-pituitary-adrenalaxis is greatest and mostprolonged when they are given at night. In most adultsa single dose of 1 mg of dexamethasone at night issufficient to inhibit corticotropin secretion for 24hours. This is the basis of the ‘overnight dexamethasonesuppression test’ for diagnosing Cushing’s syndrome.Betamethasone and dexamethasone are also appropriatefor conditions where water retention would be adisadvantage.A corticosteroid can be used in the management ofraised intracranial pressure or cerebral oedema thatoccurs as a result of malignancy (see also p. 19); highdoses of betamethasone or dexamethasone are generallyused. However, a corticosteroid should not be usedfor the management of head injury or stroke because itis unlikely to be of benefit and may even be harmful.

BNFC 2011–2012 6.3.2 Glucocorticoid therapy 371In acute hypersensitivity reactions, such as angioedemaof the upper respiratory tract and anaphylaxis, corticosteroidsare indicated as an adjunct to emergency treatmentwith adrenaline (epinephrine) (section 3.4.3). Insuch cases hydrocortisone (as sodium succinate) byintravenous injection may be required.In the management of asthma, corticosteroids are preferablyused by inhalation (section 3.2) but systemictherapy along with bronchodilators is required for theemergency treatment of severe acute asthma (section3.1.1).Betamethasone is used in women at risk of pretermdelivery to reduce the incidence of neonatal respiratorydistress syndrome [unlicensed use].Dexamethasone should not be used routinely for theprophylaxis and treatment of chronic lung disease inneonates because of an association with adverse neurologicaleffects.Corticosteroids may be useful in conditions such asauto-immune hepatitis, rheumatoid arthritis, and sarcoidosis;they may also lead to remissions of acquiredhaemolytic anaemia (section 9.1.3) and thrombocytopenicpurpura (section 9.1.4).High doses of a corticosteroid (usually prednisolone) areused in the treatment of glomerular kidney disease,including nephrotic syndrome. The condition frequentlyrecurs; a corticosteroid given in high doses and forprolonged periods may delay relapse but the higherincidence of adverse effects limits the overall benefit.Those who suffer frequent relapses may be treated withprednisolone given in a low dose (daily or on alternatedays) for 3–6 months; the dose should be adjusted tominimise effects on growth and development. Otherdrugs used in the treatment of glomerular kidney diseaseinclude levamisole (section 5.5.2), cyclophosphamideand chlorambucil (section 8.1.1), and ciclosporin(section 8.2.2). Congenital nephrotic syndrome may beresistant to corticosteroids and immunosuppressants;indometacin (section 10.1.1) and an ACE inhibitorsuch as captopril (section 2.5.5.1) have been used.Corticosteroids can improve the prognosis of seriousconditions such as systemic lupus erythematosus andpolyarteritis nodosa; the effects of the disease processmay be suppressed and symptoms relieved, but theunderlying condition is not cured, although it mayultimately remit. It is usual to begin therapy in theseconditions at fairly high dose and then to reduce thedose to the lowest commensurate with disease control.For other references to the use of corticosteroids seePrescribing in Palliative Care (p. 18), section 8.2.2(immunosuppression), section 10.1.2 (rheumatic diseases),section 11.4 (eye), section 12.1.1 (otitis externa),section 12.2.1 (allergic rhinitis), and section 12.3.1 (aphthousulcers).AdministrationWhenever possible local treatment with creams, intraarticularinjections, inhalations, eye-drops, or enemasshould be used in preference to systemic treatment. Thesuppressive action of a corticosteroid on cortisol secretionis least when it is given as a single dose in themorning. In an attempt to reduce pituitary-adrenalsuppression further, the total dose for two days cansometimes be taken as a single dose on alternatedays; alternate-day administration has not been verysuccessful in the management of asthma (section 3.2).Pituitary-adrenal suppression can also be reduced bymeans of intermittent therapy with short courses. Insome conditions it may be possible to reduce the dose ofcorticosteroid by adding a small dose of an immunosuppressivedrug (section 8.2.1).Cautions and contra-indications ofcorticosteroidsAdrenal suppressionDuring prolonged therapy with corticosteroids, adrenalatrophy develops and can persist for years after stopping.Abrupt withdrawal after a prolonged period canlead to acute adrenal insufficiency, hypotension, ordeath (see Withdrawal of Corticosteroids, below). Withdrawalcan also be associated with fever, myalgia, arthralgia,rhinitis, conjunctivitis, painful itchy skin nodules,and weight loss.To compensate for a diminished adrenocorticalresponse caused by prolonged corticosteroid treatment,any significant intercurrent illness, trauma, or surgicalprocedure requires a temporary increase in corticosteroiddose, or if already stopped, a temporary reintroductionof corticosteroid treatment. To avoid aprecipitous fall in blood pressure during anaesthesia orin the immediate postoperative period, anaesthetistsmust know whether a patient is taking or has beentaking a corticosteroid. A regimen for corticosteroidreplacement may be necessary before and after surgery.Children on long-term corticosteroid treatment shouldcarry a Steroid Treatment Card (see p. 373) which givesguidance on minimising risk and provides details ofprescriber, drug, dosage and duration of treatment.InfectionsProlonged courses of corticosteroids increase susceptibilityto infections and severity of infections; clinicalpresentation of infections may also be atypical. Seriousinfections, e.g. septicaemia and tuberculosis, may reachan advanced stage before being recognised, and amoebiasisor strongyloidiasis may be activated or exacerbated(exclude before initiating a corticosteroid in thoseat risk or with suggestive symptoms). Fungal or viralocular infections may also be exacerbated (see alsosection 11.4.1).Chickenpox Unless they have had chickenpox, childrenreceiving oral or parenteral corticosteroids forpurposes other than replacement should be regardedas being at risk of severe chickenpox (see Steroid TreatmentCard). Manifestations of fulminant illness includepneumonia, hepatitis and disseminated intravascularcoagulation; rash is not necessarily a prominent feature.Passive immunisation with varicella–zoster immunoglobulin(section 14.5.2) is needed for exposed nonimmunechildren receiving systemic corticosteroids orfor those who have used them within the previous 3months. Confirmed chickenpox warrants specialist careand urgent treatment (section 5.3.2.1). Corticosteroidsshould not be stopped and dosage may need to beincreased.6 Endocrine system

372 6.3.2 Glucocorticoid therapy BNFC 2011–20126 Endocrine systemTopical, inhaled or rectal corticosteroids are less likelyto be associated with an increased risk of severechickenpox.Measles Children taking corticosteroids, and theircarers, should be advised to take particular care toavoid exposure to measles and to seek urgent medicaladvice if exposure occurs. Prophylaxis with intramuscularnormal immunoglobulin (section 14.5.1) may beneeded.Withdrawal of corticosteroidsThe magnitude and speed of dose reduction in corticosteroidwithdrawal should be determined on a case-bycasebasis, taking into consideration the underlyingcondition that is being treated, and individual patientfactors such as the likelihood of relapse and the durationof corticosteroid treatment. Gradual withdrawal of systemiccorticosteroids should be considered in thosewhose disease is unlikely to relapse and have:. received more than 40 mg prednisolone (or equivalent)daily for more than 1 week or 2 mg/kg daily for1 week or 1 mg/kg daily for 1 month;. been given repeat doses in the evening;. received more than 3 weeks’ treatment;. recently received repeated courses (particularly iftaken for longer than 3 weeks);. taken a short course within 1 year of stopping longtermtherapy;. other possible causes of adrenal suppression.Systemic corticosteroids may be stopped abruptly inthose whose disease is unlikely to relapse and who havereceived treatment for 3 weeks or less and who are notincluded in the patient groups described above.During corticosteroid withdrawal the dose may bereduced rapidly down to physiological doses (equivalentto prednisolone 2–2.5 mg/m 2 daily) and then reducedmore slowly. Assessment of the disease may be neededduring withdrawal to ensure that relapse does not occur.Psychiatric reactionsSystemic corticosteroids, particularly in high doses, arelinked to psychiatric reactions including euphoria, nightmares,insomnia, irritability, mood lability, suicidalthoughts, psychotic reactions, and behavioural disturbances.A serious paranoid state or depression with riskof suicide can be induced, particularly in children with ahistory of mental disorder. These reactions frequentlysubside on reducing the dose or discontinuing thecorticosteroid but they may also require specific management.Children and their carers should be advised toseek medical advice if psychiatric symptoms (especiallydepression and suicidal thoughts) occur and they shouldalso be alert to the rare possibility of such reactionsduring withdrawal of corticosteroid treatment.Systemic corticosteroids should be prescribed with carein those predisposed to psychiatric reactions, includingthose who have previously suffered corticosteroidinducedpsychosis, or who have a personal or familyhistory of psychiatric disorders.Advice to children and carersA patient information leaflet should be supplied toevery patient when a systemic corticosteroid isprescribed. Children and carers should especiallybe advised of the following (for details, see Infections,Adrenal Suppression, and Psychiatric Reactionsabove and Withdrawal of Corticosteroidsbelow):. Immunosupression Prolonged courses of corticosteroidscan increase susceptibility to infectionand serious infections can go unrecognised.Unless already immune, children are at risk ofsevere chickenpox and should avoid close contactwith people who have chickenpox or shingles.Similarly, precautions should also be takenagainst contracting measles;. Adrenal suppression If the corticosteroid isgiven for longer than 3 weeks, treatment mustnot be stopped abruptly. Adrenal suppressioncan last for a year or more after stopping treatmentand the child or carer must mention thecourse of corticosteroid when receiving treatmentfor any illness or injury;. Mood and behaviour changes Corticosteroidtreatment, especially with high doses, can altermood and behaviour early in treatment—thechild can become confused, irritable and sufferfrom delusion and suicidal thoughts. Theseeffects can also occur when corticosteroid treatmentis being withdrawn. Medical advice shouldbe sought if worrying psychological changesoccur;. Other serious effects Serious gastro-intestinal,musculoskeletal, and ophthalmic effects whichrequire medical help can also occur; for detailssee Side-effects of Corticosteroids, p. 373.Steroid treatment cards (see p. 373) should be issuedwhere appropriate. Doctors and pharmacists canobtain supplies of the card from:England and Wales3M Security Printing and Systems LimitedGorse Street, ChaddertonOldham, OL9 9QHTel: (0161) 683 2189Fax: (0161) 683 2188nhsforms@spsl.uk.comScotlandR.R. Donnelley Global Document Solutions20–22 South Gyle CrescentEdinburgh, EH12 9EBTel: (0131) 334 1229Fax: (0131) 334 5946ian.fruish@rrd.comNorthern IrelandPharmaceutical DirectorateBusiness Services Organisation2 Franklin StreetBelfast, BT2 8DQTel: (028) 9053 5652Other cautions and contra-indicationsOther cautions include: growth restriction—possiblyirreversible, frequent monitoring required if history of

BNFC 2011–2012 6.3.2 Glucocorticoid therapy 373Hepatic impairmentWhen corticosteroids are administered orally or parenterally,the plasma-drug concentration may be increasedin children with hepatic impairment. Corticosteroidsshould be used with caution in hepatic impairmentand the child should be monitored closely.Renal impairmentOral and parenteral preparations of corticosteroidsshould be used with caution in children with renalimpairment.•••••Pregnancy and breast-feedingThe benefit of treatment with corticosteroids duringpregnancy and breast-feeding outweighs the risk; pregnantwomen with fluid retention should be monitoredclosely. Corticosteroid cover will be required duringlabour.Following a review of the data on the safety of systemiccorticosteroids used in pregnancy and breast-feedingthe CSM (May 1998) concluded:. corticosteroids vary in their ability to cross theplacenta; betamethasone and dexamethasonecross the placenta readily while 88% of prednisoloneis inactivated as it crosses the placenta;. there is no convincing evidence that systemic corticosteroidsincrease the incidence of congenitalabnormalities such as cleft palate or lip;. when administration is prolonged or repeated duringpregnancy, systemic corticosteroids increasethe risk of intra-uterine growth restriction; there isno evidence of intra-uterine growth restriction followingshort-term treatment (e.g. prophylactictreatment for neonatal respiratory distresssyndrome);. any adrenal suppression in the neonate followingprenatal exposure usually resolves spontaneouslyafter birth and is rarely clinically important;. prednisolone appears in small amounts in breastmilk but maternal doses of up to 40 mg daily areunlikely to cause systemic effects in the infant;infants should be monitored for adrenal suppressionif the mothers are taking a higher dose.6 Endocrine systemtuberculosis (or X-ray changes), hypertension, congestiveheart failure, diabetes mellitus including familyhistory, osteoporosis, susceptibility to angle-closureglaucoma (including family history), ocular herpes simplex—riskof corneal perforation, severe affective disorders(particularly if history of steroid-induced psychosis—seealso Psychiatric Reactions above), epilepsy,peptic ulcer, hypothyroidism, history of steroid myopathy,ulcerative colitis, diverticulitis, recent intestinalanastomoses, thromboembolic disorders, myastheniagravis; interactions: Appendix 1 (corticosteroids)Other contra-indications include: systemic infection(unless specific therapy given); avoid live virus vaccinesin those receiving immunosuppressive doses (serumantibody response diminished)Side-effects of corticosteroidsOverdosage or prolonged use can exaggerate some ofthe normal physiological actions of corticosteroids leadingto mineralocorticoid and glucocorticoid side-effects.Corticosteroids suppress growth and can affect thedevelopment of puberty. It is important to use the lowesteffective dose; alternate-day regimens may be appropriateand limit growth reduction. For the effect ofcorticosteroids given in pregnancy, see Pregnancy andBreast-feeding, above.Mineralocorticoid side-effects include hypertension,sodium and water retention, and potassium, and calciumloss. They are most marked with fludrocortisone,but are significant with cortisone, hydrocortisone, corticotropin,and tetracosactide (tetracosactrin). Mineralocorticoidactions are negligible with the high potencyglucocorticoids, betamethasone and dexamethasone,and occur only slightly with methylprednisolone, prednisolone,and triamcinolone.

374 6.3.2 Glucocorticoid therapy BNFC 2011–20126 Endocrine systemGlucocorticoid side-effects include diabetes and osteoporosis(section 6.6); in addition high doses are associatedwith avascular necrosis of the femoral head.Muscle wasting (proximal myopathy) can also occur.Corticosteroid therapy is also weakly linked with pepticulceration; there is no conclusive evidence that the useof enteric-coated preparations of prednisolone reducesthe risk of peptic ulceration. See also Psychiatric Reactions,p. 372.High doses of corticosteroids can cause Cushing’ssyndrome, with moon face, striae, and acne; it is usuallyreversible on withdrawal of treatment, but this mustalways be gradually tapered to avoid symptoms ofacute adrenal insufficiency (important: see also AdrenalSuppression, p. 371).Side-effects can be minimised by using the lowesteffective dose for the minimum period possible.Other side effects include: gastro-intestinal effects: dyspepsia,abdominal distension, acute pancreatitis, oesophagealulceration and candidiasis; musculoskeletaleffects: muscle weakness, vertebral and long bone fractures,tendon rupture; endocrine effects: menstrual irregularitiesand amenorrhoea, hirsutism, weight gain,negative nitrogen and calcium balance, increased appetite;increased susceptibility to and severity of infection,reactivation of dormant tuberculosis; neuropsychiatriceffects: psychological dependence, insomnia, increasedintracranial pressure with papilloedema (usually afterwithdrawal), aggravation of schizophrenia, aggravationof epilepsy; ophthalmic effects: papilloedema, posteriorsubcapsular cataracts, corneal or scleral thinning andexacerbation of ophthalmic viral or fungal disease,increased intra-ocular pressure, exophthalmos, veryrarely angle-closure glaucoma; also impaired healing,petechiae, ecchymoses, facial erythema, suppression ofskin test reactions, urticaria, hyperhidrosis, skin atrophy,bruising, telangiectasia, myocardial rupture followingrecent myocardial infarction, congestive heart failure,leucocytosis, hyperglycaemia, hypersensitivity reactions(including anaphylaxis), thromboembolism,nausea, malaise, hiccups, headache, vertigo.For other references to the side-effects of corticosteroidssee section 1.5 (gastro-intestinal system), section3.2 (asthma), section 11.4 (eye) and section 13.4 (skin).BETAMETHASONECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes above; transient effect on fetalmovements and heart rateBreast-feeding see notes aboveSide-effects see notes aboveLicensed use Betnesol c tablets not licensed for useas mouthwashIndication and doseSuppression of inflammatory and allergic disorders;congenital adrenal hyperplasia; seealso notes above. By slow intravenous injection or by intravenousinfusionChild 1 month–1 year initially 1 mg repeated upto 4 times in 24 hours according to responseChild 1–6 years initially 2 mg repeated up to 4times in 24 hours according to responseChild 6–12 years initially 4 mg repeated up to 4times in 24 hours according to responseChild 12–18 years initially 4–20 mg repeated upto 4 times in 24 hours according to responseEye section 11.4.1Ear section 12.1.1Nose section 12.2.1Mouth section 12.3.1Administration For intravenous infusion, dilute withGlucose 5% or Sodium Chloride 0.9%Betnesol c (UCB Pharma) AInjection, betamethasone 4 mg (as sodium phosphate)/mL. Net price 1-mL amp = £1.17. Label: 10,steroid cardDEFLAZACORTCautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseInflammatory and allergic disorders. By mouthChild 1 month–12 years 0.25–1.5 mg/kg oncedaily or on alternate days; up to 2.4 mg/kg (max.120 mg) daily has been used in emergency situationsChild 12–18 years 3–18 mg once daily or onalternate days; up to 2.4 mg/kg (max. 120 mg)daily has been used in emergency situationsNephrotic syndrome. By mouthChild 1 month–18 years initially 1.5 mg/kg oncedaily (max. 120 mg) reduced to lowest effectivedose for maintenanceCalcort c (Sanofi-Aventis) ATablets, deflazacort 6 mg, net price 60-tab pack =£15.82. Label: 5, 10, steroid cardDEXAMETHASONECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also perineal irritationmay follow intravenous administration of the phosphateesterLicensed use consult product literature; not licensedfor use in bacterial meningitis

BNFC 2011–2012 6.3.2 Glucocorticoid therapy 375Indication and doseInflammatory and allergic disorders. By mouthChild 1 month–18 years 10–100 micrograms/kgdaily in 1–2 divided doses, adjusted according toresponse; up to 300 micrograms/kg daily may berequired in emergency situations. By intramuscular injection or slow intravenousinjection or infusionChild 1 month–12 years 83–333 micrograms/kgdaily in 1–2 divided doses; max. 20 mg dailyChild 12–18 years initially 0.4–20 mg dailyLife-threatening cerebral oedema. By intravenous injectionChild under 35 kg body-weight initially 16.7 mg,then 3.3 mg every 3 hours for 3 days, then 3.3 mgevery 6 hours for 1 day, then 1.7 mg every 6 hoursfor 4 days, then decrease by 0.8 mg dailyChild over 35 kg body-weight initially 20.8 mg,then 3.3 mg every 2 hours for 3 days, then 3.3 mgevery 4 hours for 1 day, then 3.3 mg every 6 hoursfor 4 days, then decrease by 1.7 mg dailyBacterial meningitis (see section 5.1). By slow intravenous injectionChild 3 months–18 years 150 micrograms/kg(max. 10 mg) every 6 hours for 4 days startingbefore or with first dose of antibacterialPhysiological replacement. By mouth or by slow intravenous injectionChild 1 month–18 years 250–500 micrograms/m 2 every 12 hours, adjusted according to responseCroup section 3.1Nausea and vomiting with chemotherapy section8.1Rheumatic disease section 10.1.2Eye section 11.4.1Administration for administration by mouth tabletsmay be dispersed in water or injection solution givenby mouthFor intravenous infusion dilute with Glucose 5% orSodium Chloride 0.9%; give over 15–20 minutesDexamethasone (Non-proprietary) ATablets, dexamethasone 500 micrograms, net price28-tab pack = £38.00; 2 mg, 50-tab pack = £7.46, 100-tab pack = £13.85. Label: 10, steroid card, 21Oral solution, sugar-free, dexamethasone (as sodiumphosphate) 2 mg/5 mL, net price 150-mL = £42.30.Label: 10, steroid card, 21Brands include Dexsol cInjection, dexamethasone (as sodium phosphate)3.3 mg/mL, net price 1-mL amp = 83p. Label: 10,steroid cardInjection, dexamethasone (as sodium phosphate)4 mg/mL, net price 1-mL amp = 83p, 2-mL vial =£1.27. Label: 10, steroid cardHYDROCORTISONECautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also phosphate esterassociated with paraesthesia and pain (particularly inthe perineal region)Indication and doseCongenital adrenal hyperplasia see also section6.3.1. By mouthNeonate 9–15 mg/m 2 in 3 divided doses, adjustedaccording to responseChild 1 month–18 years 9–15 mg/m 2 in 3divided doses, adjusted according to responseAcute adrenocortical insufficiency (Addisoniancrisis) see also notes above and section 6.3.1. By slow intravenous administrationNeonate initially 10 mg by slow intravenousinjection then 100 mg/m 2 daily by continuousintravenous infusion or in divided doses every 6–8hours; adjusted according to response; when stablereduce over 4–5 days to oral maintenance doseChild 1 month–12 years initially 2–4 mg/kg byslow intravenous injection or infusion then 2–4 mg/kg every 6 hours; adjusted according toresponse; when stable reduce over 4–5 days to oralmaintenance doseChild 12–18 years 100 mg every 6 to 8 hours byslow intravenous injection or infusionAdrenal hypoplasia, Addison’s disease, chronicmaintenance or replacement therapy. By mouthNeonate 8–10 mg/m 2 daily in 3 divided doses;higher doses may be neededChild 1 month–18 years 8–10 mg/m 2 daily in 3divided doses; higher doses may be neededNote Give larger doses in the morning and smaller dosesin the eveningInflammatory bowel disease—induction ofremission see also section 1.5.2. By intravenous injectionChild 2–18 years 2.5 mg/kg (max. 100 mg) every6 hours. By continuous intravenous infusionChild 2–18 years 10 mg/kg daily (max. 400 mgdaily)Acute hypersensitivity reactions, angioedemasee also section 3.4.3. By intramuscular or intravenous injectionChild under 6 months initially 25 mg 3 timesdaily, adjusted according to responseChild 6 months–6 years initially 50 mg 3 timesdaily, adjusted according to response6 Endocrine system

376 6.3.2 Glucocorticoid therapy BNFC 2011–20126 Endocrine systemChild 6–12 years initially 100 mg 3 times daily,adjusted according to responseChild 12–18 years initially 200 mg 3 times daily,adjusted according to responseHypotension resistant to inotropic treatmentand volume replacement (limited evidence). By intravenous injectionNeonate initially 2.5 mg/kg repeated if necessaryafter 4 hours, then 2.5 mg/kg every 6 hours for 48hours or until blood pressure recovers, then dosereduced gradually over at least 48 hoursChild 1 month–18 years 1 mg/kg (max. 100 mg)every 6 hoursSevere acute asthma p. 134Eye section 11.4.1Haemorrhoids section 1.7.2Rheumatic disease section 10.1.2Shock section 2.7.1Skin section 13.4Administration for intravenous administration, dilutewith Glucose 5% or Sodium Chloride 0.9%; for intermittentinfusion give over 20–30 minutes.For administration by mouth, injection solution maybe swallowed [unlicensed use] but consider phosphatecontent; alternatively Corlan c pellets (section12.3.1) may be swallowed [unlicensed use]—pelletsshould not be cut as may not provide appropriatedoseHydrocortisone c (Non-proprietary) ATablets, scored, hydrocortisone 10 mg, net price 30-tab pack = £44.25; 20 mg, 30-tab pack = £47.17.Label: 10, steroid card, 211Efcortesol c (Sovereign) AUInjection, hydrocortisone 100 mg (as sodium phosphate)/mL,net price 1-mL amp = £1.08, 5-mL amp =£4.89. Label: 10, steroid cardNote Paraesthesia and pain (particularly in the perinealregion) may follow intravenous injection of the phosphateester1. A restriction does not apply where administration is forsaving life in emergency1Solu-Cortef c (Pharmacia) AInjection, powder for reconstitution, hydrocortisone(as sodium succinate). Net price 100-mg vial = 92p,100-mg vial with 2-mL amp water for injections =£1.16. Label: 10, steroid card1. A restriction does not apply where administration is forsaving life in emergencyExtemporaneous formulations available seeExtemporaneous Preparations, p. 6METHYLPREDNISOLONECautions see notes above; rapid intravenous administrationof large doses associated with cardiovascularcollapseContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseInflammatory and allergic disorders. By mouth, slow intravenous injection or byintravenous infusionChild 1 month–18 years 0.5–1.7 mg/kg daily in2–4 divided doses depending on condition andresponseTreatment of graft rejection reactions. By intravenous injectionChild 1 month–18 years 10–20 mg/kg or 400–600 mg/m 2 (max. 1 g) once daily for 3 daysSevere erythema multiforme, lupus nephritis,systemic onset juvenile idiopathic arthritis. By intravenous injectionChild 1 month–18 years 10–30 mg/kg (max. 1 g)once daily or on alternate days for up to 3 dosesImmunosuppression section 8.2.2Rheumatic disease section 10.1.2Skin section 13.4Administration intravenous injection given over 30minutes; for intravenous infusion may be diluted withsodium chloride intravenous infusion 0.9% or 0.45%,or glucose intravenous infusion 5% or 10%Medrone c (Pharmacia) ATablets, scored, methylprednisolone 2 mg (pink), netprice 30-tab pack = £3.88; 4 mg, 30-tab pack = £6.19;16 mg, 30-tab pack = £17.17; 100 mg (blue), 20-tabpack = £48.32. Label: 10, steroid card, 21Solu-Medrone c (Pharmacia) AInjection, powder for reconstitution, methylprednisolone(as sodium succinate) (all with solvent).Net price 40-mg vial = £1.58; 125-mg vial = £4.75;500-mg vial = £9.60; 1-g vial = £17.30; 2-g vial =£32.86. Label: 10, steroid cardIntramuscular depotDepo-Medrone c (Pharmacia) AInjection (aqueous suspension), methylprednisoloneacetate 40 mg/mL. Net price 1-mL vial = £2.87; 2-mLvial = £5.15; 3-mL vial = £7.47. Label: 10, steroid cardDose. By deep intramuscular injection into gluteal muscleseek specialist advicePREDNISOLONECautions see notes above; also Duchenne’s musculardystrophy (possible transient rhabdomyolysis andmyoglobinuria following strenuous physical activity)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes above

BNFC 2011–2012 6.4 Sex hormones 377Breast-feeding see notes aboveSide-effects see notes aboveIndication and doseAutoimmune inflammatory disorders (includingjuvenile idiopathic arthritis, connective tissuedisorders and systemic lupus erythematosus). By mouthChild 1 month–18 years initially 1–2 mg/kg oncedaily (usual max. 60 mg daily), then reduced after afew days if appropriateAutoimmune hepatitis. By mouthChild 1 month–18 years initially 2 mg/kg oncedaily (max. 40 mg daily) then reduced to minimumeffective doseCorticosteroid replacement therapy. By mouthChild 12–18 years 2–2.5 mg/m 2 daily in 1–2divided doses adjusted according to responseInfantile spasms. By mouthChild 1 month–2 years initially 10 mg 4 timesdaily for 14 days (if seizures not controlled after 7days increase to 20 mg 3 times daily for 7 days);reduce dose gradually over 15 days until stopped(patients taking 40 mg daily, reduce dose in stepsof 10 mg every 5 days, then stop; patients taking60 mg daily, reduce dose to 40 mg daily for 5 days,then 20 mg daily for 5 days, then 10 mg daily for 5days, then stop)Idiopathic thrombocytopenic purpura. By mouthChild 1–10 years 1–2 mg/kg daily for max. 14days or 4 mg/kg daily for max. 4 daysNephrotic syndrome. By mouthChild 1 month–18 years initially 60 mg/m 2 oncedaily (max. 80 mg daily) for 4–6 weeks until proteinuriaceases then 40 mg/m 2 on alternate daysfor 4–6 weeks, then withdraw by reducing dosegradually; prevention of relapse 0.5–1 mg/kg oncedaily or on alternate days for 3–6 monthsAsthma see p. 146Prednisolone (Non-proprietary) ATablets, prednisolone 1 mg, net price 28-tab pack =93p; 5 mg, 28-tab pack = £1.03; 25 mg, 56-tab pack =£30.00. Label: 10, steroid card, 21Tablets, both e/c, prednisolone 2.5 mg, net price 28-tab pack = £4.65, 100-tab pack = £30.79; 5 mg, 28-tabpack = £4.73, 100-tab pack = £31.04. Label: 5, 10,steroid card, 25Brands include Deltacortril cSoluble tablets, prednisolone 5 mg (as sodiumphosphate), net price 30-tab pack = £8.95. Label: 10,steroid card, 13, 216.4 Sex hormones6.4.1 Female sex hormones6.4.2 Male sex hormones and antagonists6.4.3 Anabolic steroidsSex hormone replacement therapy is indicated in childrenfor the treatment of gonadotrophin deficiency,gonadal disorders, or delayed puberty that interfereswith quality of life. Indications include constitutionaldelay in puberty, congenital or acquired hypogonadotrophichypogonadism, hypergonadotrophic hypogonadism(Turner’s syndrome, Klinefelter’s syndrome),endocrine disorders (Cushing’s syndrome or hyperprolactinaemia),and chronic illnesses, such as cystic fibrosisor sickle-cell disease, that may affect the onset ofpuberty.Replacement therapy is generally started at the appropriateage for the development of puberty and should bemanaged by a paediatric endocrinologist. Patients withconstitutional delay, chronic illness, or eating disordersmay need only small doses of hormone supplements for4 to 6 months to induce puberty and endogenous sexhormone production, which is then sustained. Patientswith organic causes of hormone deficiency will requirelife-long replacement, adjusted to allow normal development.Inadequate treatment may lead to poor bone mineralisation,resulting in fractures and osteoporosis.6.4.1 Female sex hormones6.4.1.1 Oestrogens6.4.1.2 Progestogens6 Endocrine systemEar section 12.1.1Eye section 11.4.1Immunosuppression section 8.2.2Inflammatory bowel disease section 1.5.2Pneumocystis pneumonia section 5.4.8Rheumatic disease section 10.1.26.4.1.1 OestrogensOestrogens are necessary for the development offemale secondary sexual characteristics. If onset ofpuberty is delayed because of organic pathology,puberty can be induced with ethinylestradiol in increasingdoses, guided by breast staging and uterine scans.Cyclical progestogen replacement is added after 12–18months of oestrogen treatment (see section 6.4.1.2).Once the adult dosage of oestrogen has been reached(20 micrograms ethinylestradiol daily), it may be moreconvenient to provide replacement either as a low-doseoestrogen containing oral contraceptive formulation

378 6.4.1 Female sex hormones BNFC 2011–20126 Endocrine system[unlicensed indication] (see section 7.3.1) or as a combinedoestrogen and progestogen hormone replacementtherapy preparation [unlicensed indication] (see BNFsection 6.4.1.1). There is limited experience in the useof transdermal patches or gels in children; complianceand skin irritation are sometimes a problem.Ethinylestradiol is occasionally used, under specialistsupervision, for the management of hereditary haemorrhagictelangiectasia (but evidence of benefit is limited),for the prevention of tall stature, and in tests of growthhormone secretion (see below). Side-effects includenausea and fluid retention.Topical oestrogen creams are used in the treatment oflabial adhesions (see section 7.2.1)ETHINYLESTRADIOL(Ethinyloestradiol)Cautions see Combined Hormonal Contraceptives(section 7.3.1); interactions: Appendix 1 (Oestrogens)Contra-indications cardiovascular disease (sodiumretention with oedema), personal or family history ofthromboembolism, acute porphyria; see also CombinedHormonal Contraceptives (section 7.3.1)Hepatic impairment avoid in liver disease includingdisorders of hepatic excretion (e.g. Dubin-Johnson orRotor syndromes), infective hepatitis (until liverfunction returns to normal), and jaundicePregnancy avoidBreast-feeding avoidSide-effects nausea, vomiting, headache, breast tenderness,changes in body weight, fluid retention,depression, chorea, skin reactions, chloasma, hypertension,may irritate contact lenses, impairment ofliver function, hepatic tumours, rarely photosensitivity;see also Combined Hormonal Contraceptives(section 7.3.1)Licensed use unlicensed for use in childrenIndication and doseSee notes aboveInduction of sexual maturation in girls. By mouthInitially 2 micrograms daily, increasing every 6months to 5 micrograms, then to 10 micrograms,and then to 20 micrograms dailyNote after 12–18 months of treatment give progestogenfor 7 days of each 28-day cycleMaintenance of sexual maturation in girls. By mouth20 micrograms daily with cyclical progestogen for7 days of each 28-day cyclePrevention of tall stature in girls. By mouthGirls 2–12 years 20–50 micrograms dailyPituitary priming before growth hormonesecretion test in girls. By mouthGirls with bone age above 10 years 100 microgramsdaily for 3 days before testEthinylestradiol (Non-proprietary) ATablets, ethinylestradiol (unlicensed) 10 micrograms,net price 21-tab pack = £29.95; 50 micrograms, 21-tabpack = £38.20; 1 mg, 28-tab pack = £49.50Note 2 microgram tablets available from ‘special-order’manufacturers or specialist-importing companies, see p. 8096.4.1.2 ProgestogensThere are two main groups of progestogen, progesteroneand its analogues (dydrogesterone and medroxyprogesterone)and testosterone analogues (norethisteroneand norgestrel). The newer progestogens(desogestrel, norgestimate, and gestodene) are all derivativesof norgestrel; levonorgestrel is the active isomerof norgestrel and has twice its potency. Progesteroneand its analogues are less androgenic than the testosteronederivatives and neither progesterone nor dydrogesteronecauses virilisation.In delayed puberty cyclical progestogen is added after12–18 months of oestrogen therapy (section 6.4.1.1) toestablish a menstrual cycle; usually levonorgestrel30 micrograms or norethisterone 5 mg daily are usedfor the last 7 days of each 28 day cycle.Norethisterone is also used to postpone menstruationduring a cycle; treatment is started 3 days before theexpected onset of menstruation.NORETHISTERONECautions conditions that may worsen with fluidretention e.g. epilepsy, hypertension, migraine,asthma, cardiac dysfunction; susceptibility to thromboembolism(particular caution with high dose); historyof depression; diabetes (monitor closely); interactions:Appendix 1 (progestogens)Contra-indications history of liver tumours, severeliver impairment; severe arterial disease, undiagnosedvaginal bleeding; acute porphyria (section 9.8.2); historyduring pregnancy of idiopathic jaundice, severepruritus, or pemphigoid gestationisHepatic impairment caution; avoid if severeRenal impairment use with cautionPregnancy avoidBreast-feeding higher doses may suppress lactationand alter milk composition; use lowest effective doseSide-effects menstrual disturbances, premenstruallikesyndrome (including bloating, fluid retention,breast tenderness), weight gain, nausea, headache,dizziness, insomnia, drowsiness, depression; skinreactions (including urticaria, pruritus, rash, andacne), hirsutism and alopecia; jaundice and anaphylactoidreactions also reportedLicensed use not licensed for use in childrenIndication and doseSee notes aboveInduction and maintenance of sexual maturationin females (combined with an oestrogenafter 12–24 months oestrogen therapy). By mouth5 mg once daily for the last 7 days of a 28-day cycle

BNFC 2011–2012 6.4.2 Male sex hormones and antagonists 379Postponement of menstruation. By mouth5 mg 3 times daily, starting 3 days before expectedonset of menstruationNorethisterone (Non-proprietary) ATablets, norethisterone 5 mg, net price 30-tab pack =£2.18Primolut N c (Bayer Schering) ATablets, norethisterone 5 mg. Net price 30-tab pack =£1.89Utovlan c (Pharmacia) ATablets, norethisterone 5 mg, net price 30-tab pack =£1.40, 90-tab pack = £4.216.4.2 Male sex hormones andantagonistsAndrogens cause masculinisation; they are used asreplacement therapy in androgen deficiency, in delayedpuberty, and in those who are hypogonadal due to eitherpituitary or testicular disease.When given to patients with hypopituitarism androgenscan lead to normal sexual development and potency butnot to fertility. If fertility is desired, the usual treatment iswith gonadotrophins or pulsatile gonadotrophin-releasinghormone (section 6.5.1) which stimulates spermatogenesisas well as androgen production.Intramuscular depot preparations of testosteroneesters are preferred for replacement therapy. Testosteroneenantate or propionate or alternatively Sustanonc , which consists of a mixture of testosteroneesters and has a longer duration of action, can be used.For induction of puberty, depot testosterone injectionsare given monthly and the doses increased every 6 to 12months according to response. Single ester testosteroneinjections may need to be given more frequently.Implants of testosterone can be used for hypogonadism;the implants are replaced every 4 to 5 months.Oral testosterone undecanoate is used for induction ofpuberty. An alternative approach that promotes growthrather than sexual maturation uses oral oxandrolone(section 6.4.3).Chorionic gonadotrophin (section 6.5.1) has also beenused in delayed puberty in the male to stimulate endogenoustestosterone production, but has little advantageover testosterone.Caution should be used when androgens or chorionicgonadotrophin are used in treating boys with delayedpuberty since the fusion of epiphyses is hastened andmay result in short stature.Testosterone patches and topical gel are also availablebut experience of their use in children under 15 years islimited. Topical testosterone is applied to the penis inthe treatment of microphallus; an extemporaneouslyprepared cream should be used because the alcohol inproprietary gel formulations causes irritation.TESTOSTERONE AND ESTERSCautions cardiac impairment, hypertension, epilepsy,migraine, diabetes mellitus, skeletal metastases (riskof hypercalcaemia); interactions: Appendix 1 (testosterone)Contra-indications history of primary liver tumours,hypercalcaemia, nephrosisHepatic impairment avoid if possible—fluid retentionand dose-related toxicityRenal impairment use with caution—potential forfluid retentionPregnancy avoid; causes masculinisation of femalefetusBreast-feeding avoid; may cause masculinisation inthe female infant or precocious development in themale infant; high doses suppress lactationSide-effects headache, depression, gastro-intestinalbleeding, nausea, cholestatic jaundice, changes inlibido, gynaecomastia, polycythaemia, anxiety, asthenia,paraesthesia, hypertension, electrolyte disturbancesincluding sodium retention with oedema andhypercalcaemia, weight gain; increased bone growth;androgenic effects such as hirsutism, male-patternbaldness, seborrhoea, acne, pruritus; excessive frequencyand duration of penile erection, precocioussexual development and premature closure of epiphysesin pre-pubertal males, suppression of spermatogenesisin males and virilism in females; rarelyliver tumours; sleep apnoea also reported; withpatches and gel, local irritation and allergic reactionsLicensed use Sustanon 250 c and testosteroneenantate not licensed for use in childrenIndication and doseSee also under preparations; specialist use onlyInduction and maintenance of sexual maturationin males. By mouth (as testosterone undecanoate)Child over 12 years 40 mg on alternate daysincreasing according to response up to 120 mgdaily. By deep intramuscular injection (as testosteroneenantate)Child over 12 years 25–50 mg/m 2 every monthincreasing dose every 6–12 months according toresponseTreatment of microphallus. TopicallyApply 3 times daily for 3 weeksNote Use only specially manufactured preparation (seenotes above)OralRestandol c Testocaps (Organon) LCapsules, orange, testosterone undecanoate 40 mg inoily solution, net price 30-cap pack = £8.55; 60-cappack = £17.10. Label: 21, 25IntramuscularTestosterone Enantate (Non-proprietary) LInjection (oily), testosterone enantate 250 mg/mL,net price 1-mL amp = £13.33Sustanon 250 c (Organon) LInjection (oily), testosterone propionate 30 mg,testosterone phenylpropionate 60 mg, testosteroneisocaproate 60 mg, and testosterone decanoate100 mg/mL, net price 1-mL amp = £2.45Excipients include arachis (peanut) oil, benzyl alcohol (see Excipientsp. 2)6 Endocrine system

380 6.4.2 Male sex hormones and antagonists BNFC 2011–20126 Endocrine systemVirormone c (Nordic) LInjection, testosterone propionate 50 mg/mL, netprice 2-mL amp = £4.50DoseDelayed puberty in males. By intramuscular injection50 mg once weeklyImplantTestosterone (Organon) LImplant, testosterone 100 mg, net price = £7.40;200 mg = £13.79DoseMaintenance of sexual maturation in malesChild over 16 years 100–600 mg; 600 mg usually maintainsplasma-testosterone concentration within the normalrange for 4–5 monthsCreamTestosterone LCream, testosterone 5% (other strengths available)Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Anti-androgens and precociouspubertyThe gonadorelin stimulation test (section 6.5.1) is usedto distinguish between gonadotrophin-dependent (central)precocious puberty and gonadotrophin-independentprecocious puberty. Treatment requires specialistmanagement.Gonadorelin analogues, used in the management ofgonadotrophin-dependent precocious puberty, delaydevelopment of secondary sexual characteristics andgrowth velocity.Testolactone and cyproterone are used in the managementof gonadotrophin-independent precociouspuberty, resulting from McCune-Albright syndrome,familial male precocious puberty (testotoxicosis), hormone-secretingtumours, and ovarian and testicular disorders.Testolactone inhibits the aromatisation of testosterone,the rate limiting step in oestrogen synthesis.Cyproterone is a progestogen with anti-androgen properties.Spironolactone (section 2.2.3) is sometimes used incombination with testolactone because it has someandrogen receptor blocking properties.High blood concentration of sex hormones may activaterelease of gonadotrophin releasing hormone, leading todevelopment of secondary, central gonadotrophindependentprecocious puberty. This may require theaddition of gonadorelin analogues to prevent progressionof pubertal development and skeletal maturation.CYPROTERONE ACETATECautions blood counts initially and throughout treatment;monitor adrenocortical function regularly; diabetesmellitus (see also Contra-indications)Skilled tasks Fatigue and lassitude may impair performanceof skilled tasks (e.g. driving)Contra-indications severe diabetes (with vascularchanges), sickle-cell anaemia, liver disease includingDubin-Johnson and Rotor syndromes, previous orexisting liver tumours, malignant or wasting diseases,meningioma or history of meningioma, severedepression, history of thromboembolic disordersHepatic impairment monitor hepatic function regularly—dose-relatedtoxicity, see Side-effects belowSide-effects fatigue and lassitude, breathlessness,weight changes, reduced sebum production (mayclear acne), changes in hair pattern, gynaecomastia(rarely leading to galactorrhoea and benign breastnodules); rarely hypersensitivity reactions, rash andosteoporosis; inhibition of spermatogenesis (see notesabove); hepatotoxicity reported (including jaundice,hepatitis and hepatic failure)Hepatotoxicity Direct hepatic toxicity including jaundice,hepatitis and hepatic failure have been reported (usually afterseveral months) with cyproterone acetate 200–300 mg daily.Liver function tests should be performed before treatmentand whenever symptoms suggestive of hepatotoxicityoccur—if confirmed cyproterone should normally be withdrawnunless the hepatotoxicity can be explained by anothercause such as metastatic disease (in which case cyproteroneshould be continued only if the perceived benefit exceeds therisk)Licensed use unlicensed for use in childrenIndication and doseGonadotrophin-independent precociouspuberty) (specialist use only; see also notes above). By mouthInitially 25 mg twice daily, adjusted according toresponseCyproterone Acetate (Non-proprietary) ATablets, cyproterone acetate 50 mg, net price 56-tabpack = £31.54. Label: 21, counselling, drivingNote 10 mg tablets available from ‘special-order’ manufacturersor specialist-importing companies, see p. 809Androcur c (Bayer Schering) ATablets, scored, cyproterone acetate 50 mg, net price56-tab pack = £24.41. Label: 21, counselling, drivingTESTOLACTONECautions interactions: Appendix 1 (testolactone)Pregnancy avoidBreast-feeding no information availableSide-effects nausea, vomiting, anorexia, diarrhoea;hypertension; peripheral neuropathy; weight changes;changes in hair pattern; rarely hypersensitivity reactions,rashIndication and doseGonadotrophin-independent precociouspuberty (specialist use only; see also notes above). By mouth5 mg/kg 3–4 times daily; up to 10 mg/kg 4 timesdaily may be requiredTestolactone ATablets, testolactone 50 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809GOSERELINCautions monitor bone mineral densityContra-indications undiagnosed vaginal bleedingPregnancy avoidBreast-feeding avoidSide-effects changes in blood pressure, headache,mood changes including depression, hypersensitivityreactions including urticaria, pruritus, rash, asthma

BNFC 2011–2012 6.4.3 Anabolic steroids 381and anaphylaxis; changes in scalp and body hair,weight changes, withdrawal bleeding, ovarian cysts(may require withdrawal), breast swelling and tenderness(males and females), visual disturbances,paraesthesia, local reactions at injection siteLicensed use not licensed for use in childrenIndication and doseGonadotrophin-dependent precocious pubertySee notes above; for doses, see under preparationsbelowNote Injections may be required more frequently in somecasesAdministration Rotate injection site to prevent atrophyand nodule formationNovgos c (Genus) AImplant, goserelin (as acetate) 3.6 mg in prefilledsyringe, net price = £58.50Dose. Implant, by subcutaneous injection into anteriorabdominal wall3.6 mg every 28 daysZoladex c (AstraZeneca) AImplant, goserelin (as acetate) 3.6 mg in Safe-Systemc syringe applicator, net price each = £65.00Dose. Implant, by subcutaneous injection into anteriorabdominal wall3.6 mg every 28 daysZoladex c LA (AstraZeneca) AImplant, goserelin (as acetate) 10.8 mg in Safe-System c syringe applicator, net price each = £235.00Dose. Implant, by subcutaneous injection into anteriorabdominal wall10.8 mg every 12 weeksLEUPRORELIN ACETATECautions see GoserelinContra-indications see GoserelinPregnancy avoid—teratogenic in animal studiesBreast-feeding avoidSide-effects see GoserelinLicensed use not licensed for use in childrenIndication and doseGonadotrophin-dependent precocious pubertySee notes above; for doses, see under preparationsbelowNote Injections may be required more frequently in somecasesAdministration Rotate injection site to prevent atrophyand nodule formationProstap c SR (Wyeth) AInjection (microsphere powder for reconstitution),leuprorelin acetate, net price 3.75-mg vial with 1-mLvehicle-filled syringe = £75.24Dose. By subcutaneous or by intramuscular injection3.75 mg every four weeks (half this dose is sometimesused in children with body-weight under 20 kg)Prostap c 3 (Wyeth) AInjection (microsphere powder for reconstitution),leuprorelin acetate, net price 11.25-mg vial with 2-mLvehicle-filled syringe = £225.72Dose. By subcutaneous or by intramuscular injection11.25 mg every 12 weeksTRIPTORELINCautions see GoserelinContra-indications see GoserelinPregnancy avoidBreast-feeding avoidSide-effects see Goserelin; also gastro-intestinal disturbances;asthenia; arthralgiaIndication and doseGonadotrophin-dependent precocious pubertySee notes above; for doses, see under preparationsbelowAdministration rotate injection site to prevent atrophyand nodule formationDecapeptyl c SR (Ipsen) AInjection, (powder for suspension), m/r, triptorelin (asacetate), net price 11.25-mg vial (with diluent) =£207.00Dose. By intramuscular injection11.25 mg every 3 monthsNote Each vial includes an overage to allow accurateadministration of 11.25 mg doseGonapeptyl c Depot (Ferring) AInjection (powder for suspension), triptorelin (asacetate), net price 3.75-mg prefilled syringe (withprefilled syringe of vehicle) = £81.69Dose. By subcutaneous or intramuscular injectionBody-weight under 20 kg initially 1.875 mg on days 0,14, and 28, then 1.875 mg every 4 weeksBody-weight 20–30 kg initially 2.5 mg on days 0, 14,and 28, then 2.5 mg every 4 weeksBody-weight over 30 kg initially 3.75 mg on days 0, 14,and 28, then 3.75 mg every 4 weeks; discontinue whenbone maturation consistent with age over 12 years ingirls and over 13 years in boysNote May be given every 3 weeks if necessary6.4.3 Anabolic steroidsAnabolic steroids have some androgenic activity but ingirls they cause less virilisation than androgens. Theyare used in the treatment of some aplastic anaemias(section 9.1.3). Oxandrolone is used to stimulate latepre-pubertal growth prior to induction of sexual maturationin boys with short stature and in girls with Turner’ssyndrome; specialist management is required.OXANDROLONECautions see Testosterone (section 6.4.2); interactions:Appendix 1 (oxandrolone)Contra-indications see Testosterone (section 6.4.2)Hepatic impairment see Testosterone (section 6.4.2)6 Endocrine system

382 6.5 Hypothalamic and pituitary hormones BNFC 2011–20126 Endocrine systemRenal impairment see Testosterone (section 6.4.2)Pregnancy see Testosterone (section 6.4.2)Breast-feeding see Testosterone (section 6.4.2)Side-effects see Testosterone (section 6.4.2)Indication and doseStimulation of late pre-pubertal growth in boyswith short stature. By mouthBoys 10–18 years (or appropriate age) 1.25–2.5 mg daily for 3–6 monthsStimulation of late pre-pubertal growth in girlswith Turner’s syndrome. By mouthGirls in combination with growth hormone 0.625–2.5 mg dailyOxandroloneTablets, oxandrolone 2.5 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 8096.5 Hypothalamic andpituitary hormones6.5.1 Hypothalamic and anterior pituitaryhormones including growth hormone6.5.2 Posterior pituitary hormones andantagonistsUse of preparations in these sections requiresdetailed prior investigation of the patient and shouldbe reserved for specialist centres.6.5.1 Hypothalamic andanterior pituitaryhormones includinggrowth hormoneAnterior pituitary hormonesCorticotrophinsTetracosactide (tetracosactrin), an analogue of corticotropin(adrenocorticotrophic hormone, ACTH), is usedto test adrenocortical function; failure of plasma-cortisolconcentration to rise after administration of tetracosactideindicates adrenocortical insufficiency. A low-dosetest is considered by some clinicians to be more sensitivewhen used to confirm established, partial adrenalsuppression.Tetracosactide should be used with caution in patientswith allergic disorders e.g. asthma and should be givenonly if no other ACTH preparations have been givenpreviously. Tetracosactide depot injection (SynacthenDepot c ) is also used in the treatment of infantile spasms(see Infantile spasms, section 4.8.1) but it is contraindicatedin neonates because of the presence of benzylalcohol in the injection. Corticotropin-releasing factor,corticorelin, (also known as corticotropin-releasinghormone, CRH) is used to test anterior pituitaryfunction and secretion of corticotropin.TETRACOSACTIDE(Tetracosactrin)Cautions as for corticosteroids, section 6.3.2; important:risk of anaphylaxis (medical supervision; consultproduct literature); interactions: Appendix 1 (corticosteroids)Contra-indications as for corticosteroids, section6.3.2; avoid injections containing benzyl alcohol inneonates (see under preparations)Hepatic impairment see section 6.3.2Renal impairment see section 6.3.2Pregnancy avoid (but may be used diagnostically ifessential)Breast-feeding avoid (but may be used diagnosticallyif essential)Side-effects as for corticosteroids, section 6.3.2Licensed use not licensed for low-dose test foradrenocortical insufficiency or treatment of infantilespasmsIndication and doseSee notes above and under preparations belowSynacthen c (Alliance) AInjection, tetracosactide 250 micrograms (asacetate)/mL. Net price 1-mL amp = £2.70DoseDiagnosis of adrenocortical insuffiency (30-minutetest). By intramuscular or intravenous injectionStandard-dose test 145 micrograms/m 2 (max.250 micrograms) as a single doseLow-dose test 300 nanograms/m 2 as a single doseAdministration may be diluted in sodium chloride 0.9%to 250 nanograms/mLSynacthen Depot c (Alliance) AInjection (aqueous suspension), tetracosactideacetate 1 mg/mL, with zinc phosphate complex. Netprice 1-mL amp = £3.87Excipients include benzyl alcohol (avoid in neonates, see Excipientsp. 2)DoseInfantile spasms. By intramuscular injectionChild 1 month–2 years initially 500 micrograms onalternate days, adjusted according to responseCORTICORELIN(Corticotrophin-releasing hormone, CRH)Pregnancy avoidBreast-feeding avoidSide-effects flushing of face, neck and upper body,hypotension, mild sensation of taste or smellLicensed use not licensed

BNFC 2011–2012 6.5.1 Hypothalamic and anterior pituitary hormones 383Indication and doseTest of anterior pituitary function. By intravenous injection over 30 secondsChild 1 month–18 years 1 microgram/kg (max.100 micrograms) as a single doseCRH Ferring c (Shire) AInjection, corticorelin 100 microgramsGonadotrophinsGonadotrophins are occasionally used in the treatmentof hypogonadotrophic hypogonadism and associatedoligospermia. There is no justification for their use inprimary gonadal failure.Chorionic gonadotrophin is used in the investigation oftesticular function in suspected primary hypogonadismand incomplete masculinisation. It has also been used indelayed puberty in boys to stimulate endogenous testosteroneproduction, but it has little advantage overtestosterone (section 6.4.2).CHORIONIC GONADOTROPHIN(Human Chorionic Gonadotrophin; HCG)A preparation of a glycoprotein fraction secreted by the placentaand obtained from the urine of pregnant women havingthe action of the pituitary luteinising hormoneCautions cardiac impairment, asthma, epilepsy,migraine; prepubertal boys (risk of premature epiphysealclosure or precocious puberty)Contra-indications androgen-dependent tumoursRenal impairment use with cautionSide-effects oedema (reduce dose), headache, tiredness,mood changes, gynaecomastia, local reactionsLicensed use unlicensed in children for test of testicularfunctionIndication and doseTest of testicular function. By intramuscular injectionShort stimulation test:Child 1 month–18 years 1500–2000 units oncedaily for 3 daysProlonged stimulation test:Child 1 month–18 years 1500–2000 units twiceweekly for 3 weeksHypogonadotrophic hypogonadism. By intramuscular injectionChild 1 month–18 years 1000–2000 units twiceweekly, adjusted to responseUndescended testes. By intramuscular injectionChild 7–18 years initially 500 units 3 timesweekly (1000 units twice weekly if over 17 years);adjusted to response; up to 4000 units 3 timesweekly may be required; continue for 1–2 monthsafter testicular descentChoragon c (Ferring) LInjection, powder for reconstitution, chorionicgonadotrophin. Net price 5000-unit amp (with solvent)= £3.26. For intramuscular injectionPregnyl c (Organon) LInjection, powder for reconstitution, chorionicgonadotrophin. Net price 1500-unit amp = £2.12;5000-unit amp = £3.15 (both with solvent). For subcutaneousor intramuscular injectionGrowth hormoneGrowth hormone is used to treat proven deficiency ofthe hormone, Prader-Willi syndrome, Turner’ssyndrome, growth disturbance in children born smallfor gestational age, chronic renal insufficiency, and shortstature homeobox-containing gene (SHOX) deficiency(see NICE guidance below). Growth hormone is alsoused in Noonan syndrome and idiopathic short stature[unlicensed indications] under specialist management.Treatment should be initiated and monitored by apaediatrician with expertise in managing growth-hormonedisorders; treatment can be continued under ashared-care protocol by a general practitioner.Growth hormone of human origin (HGH; somatotrophin)has been replaced by a growth hormone ofhuman sequence, somatropin, produced using recombinantDNA technology.NICE guidanceSomatropin for the treatment of growthfailure in children (May 2010)Somatropin is recommended for children withgrowth failure who:. have growth-hormone deficiency;. have Turner’s syndrome;. have Prader-Willi syndrome;. have chronic renal insufficiency;. are born small for gestational age with subsequentgrowth failure at 4 years of age or later;. have short stature homeobox-containing gene(SHOX) deficiency.Treatment should be discontinued if growth velocityincreases by less than 50% from baseline in the firstyear of treatment.Mecasermin, a human insulin-like growth factor-I(rhIGF-I), is licensed to treat growth failure in childrenwith severe primary insulin-like growth factor-I deficiency(section 6.7.4).SOMATROPIN(Recombinant Human Growth Hormone)Cautions diabetes mellitus (adjustment of antidiabetictherapy may be necessary), papilloedema (see underSide-effects), relative deficiencies of other pituitaryhormones (notably hypothyroidism—manufacturersrecommend periodic thyroid function tests but limitedevidence of clinical value), history of malignant disease,disorders of the epiphysis of the hip (monitor forlimping), resolved intracranial hypertension (monitorclosely), initiation of treatment close to puberty notrecommended in child born small for gestational age;Silver-Russell syndrome; rotate subcutaneous injectionsites to prevent lipoatrophy; interactions:Appendix 1 (somatropin)Contra-indications evidence of tumour activity(complete antitumour therapy and ensure intracraniallesions inactive before starting); not to be used afterrenal transplantation or for growth promotion inchildren with closed epiphyses (or near closure in6 Endocrine system

384 6.5.1 Hypothalamic and anterior pituitary hormones BNFC 2011–20126 Endocrine systemPrader-Willi syndrome); severe obesity or severerespiratory syndrome in Prader-Willi syndromePregnancy interrupt treatment if pregnancy occursBreast-feeding absorption from milk unlikelySide-effects headache, funduscopy for papilloedemarecommended if severe or recurrent headache, visualproblems, nausea and vomiting occur—if papilloedemaconfirmed consider benign intracranial hypertension(rare cases reported); fluid retention (peripheraloedema), arthralgia, myalgia, carpal tunnelsyndrome, paraesthesia, antibody formation, hypothyroidism,insulin resistance, hyperglycaemia, hypoglycaemia,reactions at injection site; leukaemia inchildren with growth hormone deficiency alsoreportedLicensed use not licensed for use in NoonansyndromeIndication and doseGonadal dysgenesis (Turner’s syndrome). By subcutaneous injection45–50 micrograms/kg daily or 1.4 mg/m 2 dailyDeficiency of growth hormone. By subcutaneous or intramuscular injection23–39 micrograms/kg daily or 0.7–1 mg/m 2 dailyPrader-Willi syndrome. By subcutaneous injectionChildren with growth velocity greater than1 cm/year in combination with energy-restricteddiet, 35 micrograms/kg daily or 1 mg/m 2 daily;max. 2.7 mg dailyChronic renal insufficiency (renal functiondecreased to less than 50%). By subcutaneous injection45–50 micrograms/kg daily or 1.4 mg/m 2 daily(higher doses may be needed) adjusted if necessaryafter 6 monthsGrowth disturbance in children born small forgestational age whose growth has not caughtup by 4 years of age or later; Noonan syndrome. By subcutaneous injection35 micrograms/kg daily or 1 mg/m 2 dailySHOX deficiency. By subcutaneous injection45–50 micrograms/kg dailyGenotropin c (Pharmacia) LInjection, two-compartment cartridge containingpowder for reconstitution, somatropin (rbe) and diluent,net price 5.3-mg (16-unit) cartridge = £122.87, 12-mg (36-unit) cartridge = £278.20. For use with Genotropinc Pen D device (available free of chargefrom clinics). For subcutaneous injectionGoQuick c injection, two-compartment, multi-dosedisposable, prefilled pen containing powder forreconstitution, somatropin (rbe) and diluents, netprice 5.3-mg (16-unit) prefilled pen = £122.87; 12-mg(36-unit) prefilled pen = £278.20. For subcutaneousinjectionMiniQuick c injection, two-compartment single-dosesyringe containing powder for reconstitution, somatropin(rbe) and diluent, net price 0.2-mg (0.6-unit)syringe = £4.64; 0.4-mg (1.2-unit) syringe = £9.27; 0.6-mg (1.8-unit) syringe = £13.91; 0.8-mg (2.4-unit)syringe = £18.55; 1-mg (3-unit) syringe = £23.18; 1.2-mg (3.6-unit) syringe = £27.82; 1.4-mg (4.2-unit)syringe = £32.46; 1.6-mg (4.8-unit) syringe = £37.09;1.8-mg (5.4-unit) syringe = £41.73; 2-mg (6-unit)syringe = £46.37. For subcutaneous injectionHumatrope c (Lilly) LInjection, powder for reconstitution, somatropin(rbe), net price 6-mg (18-unit) cartridge = £108.00; 12-mg (36-unit) cartridge = £216.00; 24-mg (72-unit)cartridge = £432.00; all supplied with diluent. Forsubcutaneous or intramuscular injection; cartridgesfor subcutaneous injectionNorditropin c (Novo Nordisk) LSimpleXx c injection, somatropin (epr) 3.3 mg(10 units)/mL, net price 1.5-mL (5-mg, 15-unit)cartridge = £106.35; 6.7 mg (20 units)/mL, 1.5-mL(10-mg, 30-unit) cartridge = £212.70; 10 mg(30 units)/mL, 1.5-mL (15-mg, 45-unit) cartridge =£319.05. For use with appropriate NordiPen c Ddevice (available free of charge from clinics). Forsubcutaneous injectionNutropinAq c (Ipsen) LInjection, somatropin (rbe), net price 10 mg (30 units)2-mL cartridge = £203.00. For use with NutropinAq cPen D device (available free of charge from clinics).For subcutaneous injectionOmnitrope c (Sandoz) LInjection, somatropin (rbe) 3.3 mg (10 units)/mL, netprice 1.5 mL (5-mg, 15-unit) cartridge = £86.77;6.7 mg (20 units)/mL, 1.5 mL (10-mg, 30-unit) cartridge= £173.50. For use with Omnitrope Pen 5 c Dand Omnitrope Pen 10 c D devices respectively(available free of charge from clinics). For subcutaneousinjectionExcipients include benzyl alcohol (in 5-mg cartridge) (avoid in neonates,see Excipients, p. 2)Note Biosimilar medicine, see p. 2Saizen c (Merck Serono) LInjection, powder for reconstitution, somatropin(rmc), net price 1.33-mg (4-unit) vial (with diluent) =£29.28; 3.33-mg (10-unit) vial (with diluent) = £73.20.For subcutaneous or intramuscular injectionExcipients include benzyl alcohol (avoid in neonates, see Excipients,p. 2)Injection, somatropin (rmc), 5.83 mg (17.5 units)/mL,net price 1.03-mL (6-mg, 18-unit) cartridge = £139.08;8 mg (24 units)/mL, 1.5-mL (12-mg, 36-unit) cartridge= £278.16, 2.5-mL (20-mg, 60-unit) cartridge =£463.60. For use with cool.click c Dneedle-freedevice (available free of charge from clinics). Forsubcutaneous injectionClick.easy c , powder for reconstitution, somatropin(rmc), net price 8-mg (24-unit) vial (in Click.easy cdevice with diluent) = £185.44. For use withOne.click c D autoinjector device or cool.click c Dneedle-free device (both available free of charge fromclinics). For subcutaneous injectionExcipients include benzyl alcohol (in diluent for 3.33 mg vial) (avoid inneonates, see Excipients, p. 2)Note Saizen c 3.33 mg vial may be reconstituted withsodium chloride intravenous infusion or water for injectionsfor immediate use when administering to children under 3years of age

BNFC 2011–2012 6.5.2 Posterior pituitary hormones and antagonists 385Zomacton c (Ferring) LInjection, powder for reconstitution, somatropin(rbe), net price 4-mg (12-unit) vial (with diluent) =£79.69. For use with ZomaJet 2 Vision c D needlefreedevice (available free of charge from clinics) orwith needles and syringes; 10-mg (30-unit) vial (withdiluent) = £199.23, for use with ZomaJet Vision X cD needle-free device (available free of charge fromclinics) or with needles and syringes. For subcutaneousinjectionExcipients include benzyl alcohol (in 4-mg vial) (avoid in neonates, seeExcipients, p. 2)Hypothalamic hormonesGonadorelin when injected intravenously in post-pubertalgirls leads to a rapid rise in plasma concentrationsof both luteinising hormone (LH) and follicle-stimulatinghormone (FSH). It has not proved to be very helpful,however, in distinguishing hypothalamic from pituitarylesions. It is used in the assessment of delayed orprecocious puberty.Other growth hormone stimulation tests involve the useof insulin, glucagon, arginine, and clonidine [all unlicenseduses]. The tests should be carried out in specialistcentres.GONADORELIN(Gonadotrophin-releasing hormone; GnRH;LH–RH)Cautions pituitary adenomaPregnancy avoidBreast-feeding avoidSide-effects rarely nausea, headache, abdominalpain, increased menstrual bleeding; rarely, hypersensitivityreaction on repeated administration oflarge doses; irritation at injection siteLicensed use not licensed for use in children under 1yearIndication and doseAssessment of anterior pituitary function;assessment of delayed puberty. By subcutaneous or intravenous injectionChild 1–18 years 2.5 micrograms/kg (max.100 micrograms) as a single doseHRF c (Intrapharm) AInjection, powder for reconstitution, gonadorelin. Netprice 100-microgram vial (with diluent) = £13.72(hosp. only)Excipients include benzyl alcohol (avoid in neonates, see Excipientsp. 2)6.5.2 Posterior pituitaryhormones andantagonistsPosterior pituitary hormonesDiabetes insipidus Diabetes insipidus is caused byeither a deficiency of anti-diuretic hormone (ADH, vasopressin)secretion (cranial, neurogenic, or pituitary diabetesinsipidus) or by failure of the renal tubules to reactto secreted antidiuretic hormone (nephrogenic diabetesinsipidus).Vasopressin (antidiuretic hormone, ADH) is used in thetreatment of pituitary diabetes insipidus as is its analoguedesmopressin. Dosage is tailored to produce aregular diuresis every 24 hours to avoid water intoxication.Treatment may be required permanently or for alimited period only in diabetes insipidus following traumaor pituitary surgery.Desmopressin is more potent and has a longer durationof action than vasopressin; unlike vasopressin it has novasoconstrictor effect. It is given by mouth or intranasallyfor maintenance therapy, and by injection in thepostoperative period or in unconscious patients.Desmopressin is also used in the differential diagnosisof diabetes insipidus; following an intramuscular orintranasal dose, restoration of the ability to concentrateurine after water deprivation confirms a diagnosis ofpituitary diabetes insipidus. Failure to respond suggestsnephrogenic diabetes insipidus. Fluid input must bemanaged carefully to avoid hyponatraemia; this test isnot usually recommended in young children.In nephrogenic and partial pituitary diabetes insipidusbenefit may be gained from the paradoxical antidiureticeffect of thiazides (section 2.2.1) e.g. chlorothiazide 10–20 mg/kg (max. 500 mg) twice daily.Other uses Desmopressin is also used to boost factorVIII concentration in mild to moderate haemophilia andin von Willebrand’s disease; it is also used to test fibrinolyticresponse. For a comment on use of desmopressinin nocturnal enuresis see section 7.4.2.Vasopressin infusion is used to control variceal bleedingin portal hypertension, before introducing more definitivetreatment. Terlipressin, a derivative of vasopressin,and octreotide are used similarly but experience inchildren is limited.DESMOPRESSINCautions see under Vasopressin; less pressor activity,but still considerable caution in cardiovascular diseaseand in hypertension (not indicated for nocturnalenuresis or nocturia in these circumstances); alsoconsiderable caution in cystic fibrosis; in nocturia andnocturnal enuresis limit fluid intake from 1 hourbefore dose until 8 hours afterwards; in nocturiaperiodic blood pressure and weight checks needed tomonitor for fluid overload; interactions: Appendix 1(desmopressin)For cautions specifically relating to the use ofdesmopressin in nocturnal enuresis see section 7.4.2Hyponatraemic convulsions Patients being treated for primarynocturnal enuresis should be warned to avoid fluidoverload (including during swimming) and to stop takingdesmopressin during an episode of vomiting or diarrhoea(until fluid balance normal). The risk of hyponatraemicconvulsions can also be minimised by keeping to therecommended starting doses and by avoiding concomitantuse of drugs which increase secretion of vasopressin (e.g.tricyclic antidepressants)Contra-indications cardiac insufficiency and otherconditions treated with diuretics; psychogenic polydipsiaand polydipsia in alcohol dependenceRenal impairment use with caution; antidiureticeffect may be reduced6 Endocrine system

386 6.5.2 Posterior pituitary hormones and antagonists BNFC 2011–20126 Endocrine systemPregnancy small oxytocic effect in third trimester;increased risk of pre-eclampsiaBreast-feeding amount too small to be harmfulSide-effects fluid retention, and hyponatraemia (inmore serious cases with convulsions) on administrationwithout restricting fluid intake; stomach pain,headache, nausea, vomiting, allergic reactions, andemotional disturbance in children also reported;epistaxis, nasal congestion, rhinitis with nasal sprayLicensed use consult product literature for individualpreparations; not licensed for assessment ofantidiuretic hormone secretionIndication and doseAssessment of antidiuretic hormone secretion(congenital deficiency suspected) (specialist useonly). IntranasallyChild 1 month–2 years initially 100–500 nanogramsas a single doseAssessment of antidiuretic hormone secretion(congenital deficiency not suspected) (specialistuse only). IntranasallyChild 1 month–2 years 1–5 micrograms as asingle doseTest for suspected diabetes insipidus (waterdeprivation test). IntranasallyNeonate not recommended, use trial of treatmentChild 1 month–2 years 5–10 micrograms as asingle dose; not usually recommended, see notesaboveChild 2–12 years 10–20 micrograms as a singledose, see notes aboveChild 12–18 years 20 micrograms as a singledose, see notes above. By subcutaneous or intramuscular injectionNeonate not recommended, use trial of treatmentChild 1 month–2 years 400 nanograms as a singledose; not usually recommended, see notesaboveChild 2–12 years 0.5–1 microgram as a singledose, see notes aboveChild 12–18 years 1–2 micrograms as a singledose, see notes aboveDiabetes insipidus, treatment. By mouth(as desmopressin acetate)Neonate initially 1–4 micrograms 2–3 times daily,adjusted according to responseChild 1 month–2 years initially 10 micrograms 2–3 times daily, adjusted according to response(range 30-150 micrograms daily)Child 2–12 years initially 50 micrograms 2–3times daily, adjusted according to response (range100-800 micrograms daily)Child 12–18 years initially 100 micrograms 2–3times daily, adjusted according to response (range0.2–1.2 mg daily). Sublingually(as desmopressin base)Child 2–18 years initially 60 micrograms 3 timesdaily, adjusted according to response (range 40–240 micrograms 3 times daily). Intranasally(as desmopressin acetate)Neonate initially 100–500 nanograms, adjustedaccording to response (range 1.25–10 microgramsdaily in 1–2 divided doses)Child 1 month–2 years initially 2.5–5 micrograms1–2 times daily, adjusted according to responseChild 2–12 years initially 5–20 micrograms 1–2times daily, adjusted according to responseChild 12–18 years initially 10–20 micrograms 1–2times daily, adjusted according to response. By subcutaneous or intramuscular injectionNeonate initially 100 nanograms once daily,adjusted according to response (intramuscularroute only)Child 1 month–12 years initially 400 nanogramsonce daily, adjusted according to responseChild 12–18 years initially 1–4 micrograms oncedaily, adjusted according to responsePrimary nocturnal enuresis. By mouth(as desmopressin acetate)Child 5–18 years 200 micrograms at bedtime,increased to 400 micrograms at bedtime only iflower dose not effective (important: see alsoCautions), reassess after 3 months by withdrawingtreatment for at least 1 week. Sublingually(as desmopressin base)Child 5–18 years 120 micrograms at bedtime,increased to 240 micrograms at bedtime only iflower dose not effective (important: see alsoCautions); reassess after 3 months by withdrawingtreatment for at least 1 weekFibrinolytic response testing. By intravenous injection over 20 minutes or bysubcutaneous injectionChild 2–18 years 300 nanograms/kg as a singledose; blood sampled after 20 minutes for fibrinolyticactivityMild to moderate haemophilia and von Willebrand’sdisease. By intravenous infusion over 20 minutes or bysubcutaneous injectionChild 1 month–18 years 300 nanograms/kg as asingle dose immediately before surgery or aftertrauma; may be repeated at intervals of 12 hours ifno tachycardia

BNFC 2011–2012 6.5.2 Posterior pituitary hormones and antagonists 387. IntranasallyChild 1–18 years 4 micrograms/kg as a singledose, for pre-operative use give 2 hours beforeprocedureRenal function testing. IntranasallyChild 1 month–1 year 10 micrograms (emptybladder at time of administration and restrict fluidintake to 50% at next 2 feeds to avoid fluid overload)Child 1–15 years 20 micrograms (empty bladderat time of administration and restrict fluid intake to500 mL from 1 hour before until 8 hours afteradministration to avoid fluid overload)Child 15–18 years 40 micrograms (emptybladder at time of administration and restrict fluidintake to 500 mL from 1 hour before until 8 hoursafter administration to avoid fluid overload). By subcutaneous or intramuscular injectionChild 1 month–1 year 400 nanograms (emptybladder at time of administration and restrict fluidintake to 50% at next 2 feeds to avoid fluid overload)Child 1–18 years 2 micrograms (empty bladder attime of administration and restrict fluid intake to500 mL from 1 hour before until 8 hours afteradministration to avoid fluid overload)Desmotabs c (Ferring) ATablets, scored, desmopressin acetate 200 micrograms,net price 30-tab pack = £29.43. Counselling,fluid intake, see aboveNote tablets may be crushedDesmomelt c (Ferring) AOral lyophilisates, desmopressin (as acetate)120 micrograms, net price 30-tab pack = £30.34;240 micrograms, 30-tab pack = £60.68. Label: 26,counselling, fluid intake, see above. For sublingualadministrationDesmospray c (Ferring) ANasal spray, desmopressin acetate 10 micrograms/metered spray, net price 6-mL unit (60 meteredsprays) = £25.02. Counselling, fluid intake, see aboveNote Children requiring dose of less than 10 microgramsshould be given DDAVP c intranasal solutionLow dose Desmospray c ANasal spray, desmopressin acetate 2.5 micrograms/metered sprayAvailable from Ferring on a named-patient basisOctim c (Ferring) ANasal spray, desmopressin acetate 150 micrograms/metered spray, net price 2.5-mL unit (25 meteredsprays) = £576.60. Counselling, fluid intake, see aboveInjection, desmopressin acetate 15 micrograms/mL,net price 1-mL amp = £19.22Administration for intravenous infusion dilute with 50 mL ofSodium Chloride 0.9% and give over 20 minutesDesmopressin acetate (Non-proprietary) ATablets, desmopressin acetate 100 micrograms, netprice 90-tab pack = £50.57; 200 micrograms, 30-tabpack = £24.36, 90-tab pack = £69.82. Counselling,fluid intake, see aboveNasal spray, desmopressin acetate 10 micrograms/metered spray, net price 6-mL unit (60 meteredsprays) = £18.74. Counselling, fluid intake, see aboveBrands include Presinex cNote Children requiring dose of less than 10 microgramsshould be given DDAVP c intranasal solutionDDAVP c (Ferring) ATablets, both scored, desmopressin acetate100 micrograms, net price 90-tab pack = £44.12;200 micrograms, 90-tab pack = £88.23. Counselling,fluid intake, see aboveNote Tablets may be crushedOral lyophilisates, (DDAVP c Melt), desmopressin(as acetate) 60 micrograms, net price 100-tab pack =£50.53; 120 micrograms, 100-tab pack = £101.07;240 micrograms, 100-tab pack = £202.14. Label: 26,counselling, fluid intake, see notes above. Forsublingual administrationIntranasal solution, desmopressin acetate 100 micrograms/mL.Net price 2.5-mL dropper bottle andcatheter = £9.72. Counselling, fluid intake, see aboveAdministration May be diluted with Sodium Chloride 0.9% to aconcentration of 10 micrograms/mLInjection, desmopressin acetate 4 micrograms/mL.Net price 1-mL amp = £1.10Administration May be administered orally [unlicensed]; forintravenous infusion, higher doses used in mild to moderatehaemophilia and von Willebrand’s disease may be diluted with30–50 mL Sodium Chloride 0.9% intravenous infusionTERLIPRESSIN ACETATECautions see under VasopressinContra-indications see under VasopressinPregnancy avoidBreast-feeding no information availableSide-effects see under Vasopressin, but effects milderLicensed use unlicensed for use in childrenIndication and doseAdjunct in acute massive haemorrhage of gastro-intestinaltract or oesophageal varices(specialist use only). By intravenous injectionChild 12–18 years initially 2 mg then 1–2 mgevery 4–6 hours until bleeding is controlled; max.duration of treatment 72 hoursGlypressin c (Ferring) AInjection, powder for reconstitution, terlipressinacetate, net price 1-mg vial with 5 mL diluent = £18.47Injection, solution for injection, terlipressin acetate,0.12 mg/mL, net price 1-mg (8.5 mL) vial = £19.39Variquel c (IS Pharmaceuticals) AInjection, powder for reconstitution, terlipressinacetate, net price 1-mg vial with 5 mL diluent = £17.90VASOPRESSINCautions heart failure, hypertension, asthma, epilepsy,migraine or other conditions which might be aggravatedby water retention; avoid fluid overloadContra-indications vascular disease (especially diseaseof coronary arteries) unless extreme caution,6 Endocrine system

388 6.6 Drugs affecting bone metabolism BNFC 2011–20126 Endocrine systemchronic nephritis (until reasonable blood nitrogenconcentrations attained)Renal impairment see Contra-indicationsPregnancy oxytocic effect in third trimesterBreast-feeding not known to be harmfulSide-effects fluid retention, pallor, tremor, sweating,vertigo, headache, nausea, vomiting, belching, abdominalcramps, desire to defaecate, hypersensitivityreactions (including anaphylaxis), constriction ofcoronary arteries (may cause anginal attacks andmyocardial ischaemia), peripheral ischaemia andrarely gangreneLicensed use not licensed for use in childrenIndication and doseAdjunct in acute massive haemorrhage of gastro-intestinaltract or oesophageal varices(specialist use only). By continuous intravenous infusion (may alsobe infused directly into the superior mesentericartery)Child 1 month–18 years initially 0.3 units/kg(max. 20 units) over 20–30 minutes then 0.3 units/kg/hour, adjusted according to response (max.1 unit/kg/hour); if bleeding stops, continue atsame dose for 12 hours, then withdraw graduallyover 24–48 hours; max. duration of treatment 72hoursAdministration for intravenous infusion dilute withGlucose 5% or Sodium Chloride 0.9% to a concentrationof 0.2–1 unit/mLSynthetic vasopressinPitressin c (Goldshield) AInjection, argipressin (synthetic vasopressin)20 units/mL, net price 1-mL amp = £17.14 (hosp.only)6.6 Drugs affecting bonemetabolism6.6.1 Calcitonin6.6.2 BisphosphonatesThe two main disorders of bone metabolism that occurin children are rickets and osteoporosis. The two mostcommon forms of rickets are Vitamin D deficiencyrickets (section 9.6.4) and hypophosphataemic rickets(section 9.5.2). See also calcium (section 9.5.1.1).OsteoporosisOsteoporosis in children may be primary (e.g. osteogenesisimperfecta and idiopathic juvenile osteoporosis), orsecondary (e.g. due to inflammatory disorders, immobilisation,or corticosteroids); specialist management isrequired.Corticosteroid-induced osteoporosis To reducethe risk of osteoporosis doses of oral corticosteroidsshould be as low as possible and courses of treatment asshort as possible.6.6.1 CalcitoninCalcitonin is involved with parathyroid hormone in theregulation of bone turnover and hence in the maintenanceof calcium balance and homeostasis. Calcitonin(salmon) (salcatonin, synthetic or recombinant salmoncalcitonin) is used to lower the plasma-calcium concentrationin some patients with hypercalcaemia (notablywhen associated with malignant disease).CALCITONIN (SALMON)/SALCATONINCautions history of allergy (skin test advised); heartfailure; children—use for short periods only andmonitor bone growthContra-indications hypocalaemiaRenal impairment use with cautionPregnancy avoid unless essential, toxicity in animalstudiesBreast-feeding avoid unless essential, may inhibitlactationSide-effects nausea, vomiting, diarrhoea, abdominalpain, flushing, dizziness, headache, taste disturbances;musculoskeletal pain; with nasal spray nose andthroat irritation, rhinitis, sinusitis and epistaxis; lesscommonly diuresis, oedema, cough, visual disturbances,injection-site reactions, rash, hypersensitivityreactions including pruritusLicensed use not licensed in childrenIndication and doseHypercalcaemia (experience limited in children)(specialist use only). By subcutaneous or intramuscular injectionChild 1 month–18 years 2.5–5 units/kg every 12hours, max. 400 units every 6–8 hours, adjustedaccording to response (no additional benefit withover 8 units/kg every 6 hours). By slow intravenous infusionChild 1 month–18 years 5–10 units/kg over atleast 6 hoursOsteoporosis (specialist use only)Refer for specialist advice, experience very limitedAdministration for intravenous infusion, dilute injectionsolution (e.g. 400 units in 500 mL) with SodiumChloride 0.9% and give over at least 6 hours; glass orhard plastic containers should not be used; some lossof potency on dilution and administration—usediluted solution without delayMiacalcic c (Novartis) ANasal sprayT, calcitonin (salmon) 200 units/metered spray, net price 2-mL unit (approx. 14metered sprays) = £16.79Injection, calcitonin (salmon) 50 units/mL, net price1-mL amp = £3.42; 100 units/mL, 1-mL amp = £6.85;200 units/mL, 2-mL vial = £30.756.6.2 BisphosphonatesBisphosphonates are adsorbed on to hydroxyapatitecrystals in bone, slowing both their rate of growth and

BNFC 2011–2012 6.6.2 Bisphosphonates 389dissolution, and therefore reducing the rate of boneturnover.A bisphosphonate such as disodium pamidronate isused in the management of severe forms of osteogenesisimperfecta and other causes of osteoporosis in childrento reduce the number of fractures; the long-term effectsof bisphosphonates in children have not been established.Single doses of biphosphonates are also used tomanage hypercalaemia (section 9.5.1.2). Treatmentshould be initiated under specialist advice only.MHRA/CHM advice (October 2007 and November2009)The risk of osteonecrosis of the jaw is substantiallygreater for patients receiving intravenous bisphosphonatesin the treatment of cancer than for patientsreceiving oral bisphosphonates for osteoporosis orPaget’s disease.Risk factors for developing osteonecrosis of the jawthat should be considered are: potency of bisphosphonate(highest for zoledronate), route of administration,cumulative dose, duration and type ofmalignant disease, concomitant treatment, smoking,comorbid conditions, and history of dental disease.All patients receiving bisphosphonates for cancershould have a dental check-up (and any necessaryremedial work should be performed) before bisphosphonatetreatment. However, urgent bisphosphonatetreatment should not be delayed, and a dentalcheck-up should be carried out as soon as possible inthese patients. All other patients who are prescribedbisphosphonates should have a dental examinationonly if they have poor dental health.During bisphosphonate treatment patients shouldmaintain good oral hygiene, receive routine dentalcheck-ups, and report any oral symptoms.ALENDRONIC ACIDCautions upper gastro-intestinal disorders (dysphagia,symptomatic oesophageal disease, gastritis, duodenitis,or ulcers—see also under Contra-indications andSide-effects); history (within 1 year) of ulcers, activegastro-intestinal bleeding, or surgery of the uppergastro-intestinal tract; correct disturbances of calciumand mineral metabolism (e.g. vitamin-D deficiency,hypocalcaemia) before starting and monitor serumcalciumconcentration during treatment; considerdental check-up before initiating bisphosphonate (riskof osteonecrosis of the jaw, see MHRA/CHM advice,above); exclude other causes of osteoporosis; atypicalstress fractures reported (discontinue unless benefitsof continued treatment clearly outweigh risks); interactions:Appendix 1 (bisphosphonates)Contra-indications abnormalities of oesophagus andother factors which delay emptying (e.g. stricture orachalasia), hypocalcaemia,Renal impairment avoid if estimated glomerular filtrationrate is less than 35 mL/minute/1.73 m 2Pregnancy avoidBreast-feeding no information availableSide-effects oesophageal reactions (see below),abdominal pain and distension, dyspepsia, regurgitation,melaena, diarrhoea or constipation, flatulence,musculoskeletal pain, headache; rarely rash, pruritus,erythema, photosensitivity, uveitis, scleritis, transientdecrease in serum phosphate; nausea, vomiting, gastritis,peptic ulceration, hypersensitivity reactions(including urticaria and angioedema), and atypicalstress fractures with long term use also reported;myalgia, malaise, and fever at initiation of treatment;very rarely severe skin reactions (including Stevens-Johnson syndrome), osteonecrosis of the jaw (seeMHRA/CHM advice, above)Oesophageal reactions Severe oesophageal reactions(oesophagitis, oesophageal ulcers, oesophageal stricture andoesophageal erosions) have been reported; patients shouldbe advised to stop taking the tablets and to seek medicalattention if they develop symptoms of oesophageal irritationsuch as dysphagia, new or worsening heartburn, pain onswallowing or retrosternal painLicensed use not licensed for use in childrenIndication and doseSee notes above, specialist use onlyCounselling Swallow the tablets whole with a full glass ofwater on an empty stomach at least 30 minutes beforebreakfast (and any other oral medication); stand or sit uprightfor at least 30 minutes and do not lie down until after eatingbreakfast. Do not take the tablets at bedtime or before rising.Fosamax c (MSD) ATablets, alendronic acid (as sodium alendronate)10 mg, 28-tab pack = £23.12. Counselling, administrationFosamax c Once Weekly (MSD) ATablets, alendronic acid (as sodium alendronate)70 mg, net price 4-tab pack = £22.80. Counselling,administrationDISODIUM PAMIDRONATEDisodium pamidronate was formerly called aminohydroxypropylidenediphosphonatedisodium (APD)Cautions cardiac disease; previous thyroid surgery(risk of hypocalcaemia); monitor serum electrolytes,calcium, and phosphate—possibility of convulsionsdue to electrolyte changes; ensure adequate hydration;avoid concurrent use with other bisphosphonates;consider dental check-up before initiatingbisphosphonate (risk of osteonecrosis of the jaw, seeMHRA/CHM advice, above); interactions: Appendix1 (bisphosphonates)Skilled tasks Patients should be warned against driving,cycling, or performing skilled tasks immediately after treatment(somnolence or dizziness can occur)Hepatic impairment use with caution in severeimpairment—no information availableRenal impairment monitor renal function in renaldisease or predisposition to renal impairment (e.g. intumour-induced hypercalcaemia)Pregnancy avoid—toxicity in animal studiesBreast-feeding avoidSide-effects hypophosphataemia, transient rise inbody temperature, fever and influenza-like symptoms(sometimes accompanied by malaise, rigors, fatigue,and flushes); arthralgia, myalgia, bone pain, nausea,vomiting, headache, lymphocytopenia, hypomagnesaemia;rarely muscle cramps, anorexia, abdominalpain, diarrhoea, constipation, dyspepsia, agitation,confusion, dizziness, insomnia, somnolence, lethargy,anaemia, leucopenia, hypotension or hypertension,rash, pruritus, symptomatic hypocalcaemia (paraesthesia,tetany), hyperkalaemia or hypokalaemia,6 Endocrine system

390 6.6.2 Bisphosphonates BNFC 2011–2012hypernatraemia; osteonecrosis of the jaw (seeMHRA/CHM advice, p. 389); isolated cases of seizures,hallucinations, thrombocytopenia, haematuria,acute renal failure, deterioration of renal disease,conjunctivitis and other ocular symptoms; atrialfibrillation, and reactivation of herpes simplex andzoster also reported; also local reactions at injectionsiteLicensed use not licensed for use in childrenIndication and doseSee notes above, specialist use onlyRisedronate Sodium (Non-proprietary) ATablets, risedronate sodium 5 mg, net price 28-tabpack = £17.99; 30 mg, 28-tab pack = £143.95; 35 mg,4-tab pack = £19.12. Counselling, administration,food, and calcium (see above)Actonel c (Warner Chilcott) ATablets, f/c, risedronate sodium 5 mg (yellow), netprice 28-tab pack = £17.99; 30 mg (white), 28-tab pack= £143.95. Counselling, administration, food, andcalcium (see above)6 Endocrine systemDisodium pamidronate (Non-proprietary) AConcentrate for intravenous infusion, disodiumpamidronate 3 mg/mL, net price 5-mL vial = £27.50,10-mL vial = £55.00; 6 mg/mL, 10-mL vial = £95.00;9 mg/mL, 10-mL vial = £165.00; 15 mg/mL, 1-mLvial = £29.83, 2-mL vial = £59.66, 4-mL vial = £119.32,6-mL vial £170.46Aredia Dry Powder c (Novartis) AInjection, powder for reconstitution, disodium pamidronate,for use as an infusion. Net price 15-mg vial =£29.83; 30-mg vial = £59.66; 90-mg vial = £170.45 (allwith diluent)RISEDRONATE SODIUMCautions oesophageal abnormalities and other factorswhich delay transit or emptying (e.g. stricture orachalasia—see also under Side-effects); correcthypocalcaemia before starting, correct other disturbancesof bone and mineral metabolism (e.g. Vitamin-D deficiency) at onset of treatment; consider dentalcheck-up before initiating bisphosphonate (risk ofosteonecrosis of the jaw, see MHRA/CHM advice,p. 389); interactions: Appendix 1 (bisphosphonates)Contra-indications hypocalcaemia (see Cautionsabove)Renal impairment avoid if estimated glomerular filtrationrate is less than 30 mL/minute/1.73 m 2Pregnancy avoidBreast-feeding avoidSide-effects abdominal pain, dyspepsia, nausea,diarrhoea, constipation, headache, musculoskeletalpain; less commonly oesophagitis, oesophageal ulcer,dysphagia, gastritis, duodenitis, uveitis; rarely glossitis,oesophageal stricture; also reported gastroduodenalulceration, hepatic disorders, Stevens-Johnsonsyndrome, toxic epidermal necrolysis, hair loss,cutaneous vasculitis, osteonecrosis of the jaw (seeMHRA/CHM advice, p. 389)Oesophageal reactions Children and their carers should beadvised to stop taking the tablets and seek medical attentionif they develop symptoms of oesophageal irritation such asdysphagia, pain on swallowing, retrosternal pain, or heartburnLicensed use not licensed for use in childrenIndication and doseSee notes above, specialist use onlyCounselling Swallow tablets whole with full glass of water;on rising, take on an empty stomach at least 30 minutesbefore first food or drink of the day or, if taking at any othertime of the day, avoid food and drink for at least 2 hoursbefore or after risedronate (particularly avoid calcium containingproducts e.g. milk; also avoid iron and mineralsupplements and antacids); stand or sit upright for at least 30minutes; do not take tablets at bedtime or before risingActonel Once a Week c (Warner Chilcott) ATablets, f/c, orange, risedronate sodium 35 mg, netprice 4-tab pack = £19.12. Counselling, administration,food and calcium (see above)SODIUM CLODRONATECautions monitor renal and hepatic function andwhite cell count; also monitor serum calcium andphosphate periodically; renal dysfunction reported inpatients receiving concomitant NSAIDs; maintainadequate fluid intake during treatment; considerdental check-up before initiating bisphosphonate (riskof osteonecrosis of the jaw, see MHRA/CHM advice,p. 389); interactions: Appendix 1 (bisphosphonates)Contra-indications acute gastro-intestinal inflammatoryconditionsRenal impairment use half normal dose if estimatedglomerular filtration rate 10–30 mL/minute/1.73 m 2 ;avoid if estimated glomerular filtration rate less than10 mL/minute/1.73 m 2Pregnancy avoidBreast-feeding no information availableSide-effects nausea, diarrhoea; skin reactions; bronchospasm;very rarely osteonecrosis of the jaw (seeMHRA/CHM advice, p. 389)Licensed use not licensed for use in childrenIndication and doseSee notes above, specialist use onlyCounselling Avoid food for 1 hour before and after oraltreatment, particularly calcium-containing products e.g.milk; also avoid iron and mineral supplements and antacids;maintain adequate fluid intakeBonefos c (Bayer Schering) ACapsules, yellow, sodium clodronate 400 mg. Netprice 120-cap pack = £139.83. Counselling, food andcalciumTablets, f/c, scored, sodium clodronate 800 mg. Netprice 60-tab pack = £146.43. Counselling, food andcalciumClasteon c (Beacon) ACapsules, blue/white, sodium clodronate 400 mg, netprice 30-cap pack = £34.96, 120-cap pack = £139.83.Counselling, food and calciumLoron c (Roche) ALoron 520 c tablets, f/c, scored, sodium clodronate520 mg, net price 60-tab pack = £152.59. Label: 10,patient information leaflet, counselling, food andcalcium

BNFC 2011–2012 6.7.3 Metyrapone 3916.7 Other endocrine drugs6.7.1 Bromocriptine and otherdopaminergic drugs6.7.2 Drugs affecting gonadotrophins6.7.3 Metyrapone6.7.4 Somatomedins6.7.1 Bromocriptine and otherdopaminergic drugsClassification not used in BNF for Children.6.7.2 Drugs affectinggonadotrophinspain, allergic skin reactions, hypoadrenalism, hirsutismLicensed use licensed for use in childrenIndication and doseDifferential diagnosis of ACTH-dependentCushing’s syndrome. By mouthChild 1 month–18 years 15 mg/kg (or 300 mg/m 2 ) every 4 hours for 6 doses; minimum dose250 mg every 4 hours, max. 750 mg every 4 hoursManagement of Cushing’s syndrome. By mouthRange 250 mg–6 g daily, adjusted according tocortisol production; see notes aboveMetopirone c (Alliance) ACapsules, ivory, metyrapone 250 mg, net price 100-tab pack = £38.88. Label: 21, counselling, drivingClassification not used in BNF for Children. See section6.4.2 for use in precocious puberty.6.7.4 Somatomedins6.7.3 MetyraponeMetyrapone is a competitive inhibitor of 11b-hydroxylationin the adrenal cortex; the resulting inhibition ofcortisol (and to a lesser extent aldosterone) productionleads to an increase in ACTH production which, in turn,leads to increased synthesis and release of cortisolprecursors. It is used as a test of anterior pituitaryfunction.Most types of Cushing’s syndrome are treated surgically.Metyrapone may be useful to control the symptomsof the disease or to prepare the child for surgery.The dosages used are either low, and tailored to cortisolproduction, or high, in which case corticosteroid replacementtherapy is also needed.Ketoconazole (section 5.2.2) is also used by specialistsfor the management of Cushing’s syndrome [unlicensedindication].METYRAPONECautions gross hypopituitarism (risk of precipitatingacute adrenal failure); hypertension on long-termadministration; hypothyroidism (delayed response);many drugs interfere with diagnostic estimation ofsteroids; avoid in acute porphyria (section 9.8.2)Skilled tasks Drowsiness may affect the performance ofskilled tasks (e.g. driving)Contra-indications adrenocortical insufficiency (seeCautions)Hepatic impairment use with caution (delayedresponse)Pregnancy avoid (may impair biosynthesis of fetalplacentalsteroids)Breast-feeding avoid—no information availableSide-effects occasional nausea, vomiting, dizziness,headache, hypotension, sedation; rarely abdominalSomatomedins are a group of polypeptide hormonesstructurally related to insulin and commonly known asinsulin-like growth factors (IGFs). Mecasermin, ahuman insulin-like growth factor-I (rhIGF-I), is the principalmediator of the somatotropic effects of humangrowth hormone and is used to treat growth failure inchildren with severe primary insulin-like growth factor-Ideficiency.MECASERMIN(Recombinant human insulin-like growth factor-I;rhIGF-I)Cautions correct hypothyroidism before initiatingtreatment; diabetes mellitus (adjustment of antidiabetictherapy may be necessary), monitor ECG beforeand on termination of treatment (and during treatmentif ECG abnormal), papilloedema (see underSide-effects), monitor for disorders of the epiphysis ofthe hip (monitor for limping), monitor for signs oftonsillar hypertrophy (snoring, sleep apnoea, andchronic middle ear effusions)Contra-indications evidence of tumour activity (discontinuetreatment)Pregnancy avoid unless essential; contraceptionadvised in women of child-bearing potentialBreast-feeding avoidSide-effects headache, funduscopy for papilloedemarecommended if severe or recurrent headache, visualproblems, nausea and vomiting occur—if papilloedemaconfirmed consider benign intracranial hypertension(rare cases reported); cardiomegaly, ventricularhypertrophy, tachycardia; convulsions, sleepapnoea, night terrors, dizziness, nervousness; tonsillarhypertrophy (see Cautions above); hypoglycaemia(especially in first month, and in younger children),hyperglycaemia, gynaecomastia; arthralgia, myalgia;visual disturbance, impaired hearing; antibody formation;injection-site reactions (rotate site)6 Endocrine system

392 6.7.4 Somatomedins BNFC 2011–2012Indication and doseGrowth failure in children with severe primaryinsulin-like growth factor-I deficiency. By subcutaneous injectionChild 2–18 years initially 40 micrograms/kgtwice daily for 1 week, if tolerated increase dose insteps of 40 micrograms/kg to max. 120 micrograms/kgtwice daily; discontinue if no responsewithin 1 yearCounselling Dose should be administered just before orafter food; do not increase dose if a dose is missedNote Reduce dose if hypoglycaemia occurs despite adequatefood intake; withhold injection if patient unable to eatIncrelex c (Ipsen) AInjection, mecasermin 10 mg/mL, net price 4-mL vial= £605.00. Counselling, administrationExcipients include benzyl alcohol (avoid in neonates, see Excipients,p. 2)6 Endocrine system

BNFC 2011–2012 3937 Obstetrics, gynaecology,and urinary-tractdisorders7.1 Drugs used in obstetrics 3937.2 Treatment of vaginal and vulvalconditions 3937.2.1 Preparations for vaginal andvulval changes 3937.2.2 Vaginal and vulval infections 3947.3 Contraceptives 3967.3.1 Combined hormonal contraceptives3967.3.2 Progestogen-only contraceptives 4037.3.2.1 Oral progestogen-only contraceptives4037.3.2.2 Parenteral progestogen-onlycontraceptives 4047.3.2.3 Intra-uterine progestogen-onlydevice 4057.3.3 Spermicidal contraceptives 4067.3.4 Contraceptive devices 4067.3.5 Emergency contraception 4087.4 Drugs for genito-urinary disorders4097.4.1 Drugs for urinary retention 4097.4.2 Drugs for urinary frequency,enuresis, and incontinence 4107.4.3 Drugs used in urological pain 4127.4.4 Bladder instillations and urologicalsurgery 4127.4.5 Drugs for erectile dysfunction 4137.1 Drugs used in obstetricsThis section is not included in BNF for Children. SeeBNF for management of obstetrics.For the management of ductus arteriosus, see section2.14.7.2 Treatment of vaginal andvulval conditions7.2.1 Preparations for vaginal and vulvalchanges7.2.2 Vaginal and vulval infectionsPre-pubertal girls may be particularly susceptible tovulvovaginitis. Barrier preparations (section 13.2.2)applied after cleansing can be useful when the symptomsare due to non-specific irritation, but systemicdrugs are required in the treatment of bacterial infection(section 5.1) or threadworm infestation (section 5.5.1).Intravaginal preparations, particularly those that requirethe use of an applicator, are not generally suitable foryoung girls; topical preparations may be useful in someadolescent girls.In older girls symptoms are often restricted to the vulva,but infections almost invariably involve the vagina,which should also be treated; treatment should be asfor adults, see BNF section 7.2.2.7.2.1 Preparations for vaginaland vulval changes7 Obstetrics, gynaecology, and urinary-tract disordersTopical oestrogen creams containing estriol 0.01%(Gynest c ) are used in the treatment of labial adhesions(for details of preparation, see BNF section 7.2.1);treatment is usually restricted to symptomatic cases.Estriol cream should be applied to the adhesions onceor twice daily for 2–6 weeks; adhesions may recurfollowing treatment.

394 7.2.2 Vaginal and vulval infections BNFC 2011–20127 Obstetrics, gynaecology, and urinary-tract disorders7.2.2 Vaginal and vulvalinfectionsEffective specific treatments are available for the commonvaginal infections.Fungal infectionsVaginal fungal infections are not normally a problem inyounger girls but can occur in adolescents. Candidalvulvitis can be treated locally with cream, but is almostinvariably associated with vaginal infection whichshould also be treated. Vaginal candidiasis, rare ingirls before puberty, can be treated with antifungalpessaries or cream inserted high into the vagina (includingduring menstruation), however, these are not recommendedfor pre-pubertal girls and treatment with anexternal cream may be more appropriate. Single-doseintravaginal preparations offer an advantage when complianceis a problem. Local irritation can occur onapplication of vaginal antifungal products.Imidazole drugs (clotrimazole, econazole, fenticonazole,and miconazole) are effective against candida inshort courses of 1 to 3 days according to the preparationused; treatment can be repeated if initial course fails tocontrol symptoms or if symptoms recur. Vaginal applicationsmay be supplemented with antifungal cream forvulvitis and to treat other superficial sites of infection.Oral treatment of vaginal infection with fluconazole(section 5.2.1) may be considered for girls post-puberty.Vulvovaginal candidiasis in pregnancy Vulvovaginalcandidiasis is common during pregnancy and canbe treated with vaginal application of an imidazole (suchas clotrimazole), and a topical imidazole cream forvulvitis. Pregnant women need a longer duration oftreatment, usually about 7 days, to clear the infection.There is limited absorption of imidazoles from the skinand vagina. Oral antifungal treatment should be avoidedduring pregnancy.Recurrent vulvovaginal candidiasis Recurrent vulvovaginalcandidiasis is very rare in children, but canoccur if there are predisposing factors such as antibacterialtherapy, pregnancy, diabetes mellitus, and possiblyoral contraceptive use. Reservoirs of infection canalso lead to recontamination and should be treated;these include other skin sites such as the digits, nailbeds, and umbilicus, as well as the gastro-intestinal tractand the bladder. The sexual partner may also be thesource of re-infection and, if symptomatic, should betreated with a topical imidazole cream at the same time.Treatment against candida may need to be extended for6 months in recurrent vulvovaginal candidiasis. Somerecommended regimens suitable for older children [allunlicensed] include:. initially, fluconazole (section 5.2.1) 150 mg bymouth every 72 hours for 3 doses, then 150 mgonce every week for 6 months;. initially, intravaginal application of a topical imidazolefor 10–14 days, then clotrimazole 500-mgpessary once every week for 6 months.PREPARATIONS FOR VAGINAL ANDVULVAL CANDIDIASISCautions avoid intravaginal preparations (particularlythose that require use of an applicator) in young girlswho are not sexually active, unless there is no alternativePregnancy see notes aboveSide-effects occasional local irritationLicensed use consult product literature for individualpreparationsIndication and doseSee notes above and under preparations belowClotrimazole (Non-proprietary)Cream (topical), clotrimazole 1%, net price 20 g =£1.52, 50 g = £4.12Condoms effect on latex condoms and diaphragms not yet knownDoseApply to anogenital area 2–3 times dailyPessary, clotrimazole 500 mg, net price 1 pessarywith applicator = £3.13DoseInsert 1 pessary at night as a single dose; can be repeatedonce if necessaryCanesten c (Bayer Consumer Care)Cream (topical), clotrimazole 1%, net price 20 g =£2.14; 50 g = £3.50Excipients include benzyl alcohol, cetostearyl alcohol, polysorbatesCondoms damages latex condoms and diaphragmsDoseApply to anogenital area 2–3 times dailyThrush Cream (topical), clotrimazole 2%, net price20 g = £3.99Excipients include benzyl alcohol, cetostearyl alcohol, polysorbatesCondoms damages latex condoms and diaphragmsDoseApply to anogenital area 2–3 times dailyIntravaginal cream (10% VC c ) A, clotrimazole10%, net price 5-g applicator pack = £4.50Excipients include benzyl alcohol, cetostearyl alcohol, polysorbatesCondoms damages latex condoms and diaphragmsDoseInsert 5 g at night as a single dose; may be repeated onceif necessaryNote Brands for sale to the public include Canesten cInternal CreamCream Combi, clotrimazole 10% vaginal cream and2% topical cream, net price 5-g vaginal cream (withapplicator) and 10-g topical cream = £6.81Excipients include benzyl alcohol, cetostearyl alcohol, polysorbatesCondoms damages latex condoms and diaphragmsDoseSee under individual componentsPessaries, clotrimazole 200 mg, 3 pessaries withapplicator = £3.63Condoms damages latex condoms and diaphragmsDoseInsert 200 mg for 3 nights; course may be repeated onceif necessary

BNFC 2011–2012 7.2.2 Vaginal and vulval infections 395Pessary, clotrimazole 500 mg, net price 1 pessarywith applicator = £2.00Excipients none as listed in section 13.1.3Condoms damages latex condoms and diaphragmsDoseInsert 1 pessary at night as a single dose; may berepeated once if necessaryCombi, clotrimazole 500-mg pessary and cream(topical) 2%, net price 1 pessary and 10-g cream =£5.21Condoms damages latex condoms and diaphragmsDoseSee under individual componentsGyno-Daktarin c (Janssen) AOvule (= vaginal capsule) (Gyno-Daktarin 1 c ),miconazole nitrate 1.2 g in a fatty basis, net price 1ovule = £2.94Excipients include hydroxybenzoates (parabens)Condoms damages latex condoms and diaphragmsDoseInsert 1 ovule at night as a single dose; can be repeatedonce if necessaryGyno-Pevaryl c (Janssen) APessaries, econazole nitrate 150 mg, net price 3pessaries = £2.78Excipients none as listed in section 13.1.3Condoms damages latex condoms and diaphragmsDoseInsert 1 pessary for 3 nights; course can be repeated onceif necessaryPessary (Gyno-Pevaryl 1 c ), econazole nitrate150 mg, formulated for single-dose therapy, net price1 pessary with applicator = £2.95Excipients none as listed in section 13.1.3Condoms damages latex condoms and diaphragmsDoseInsert 1 pessary at night as a single dose; can be repeatedonce if necessaryGynoxin c (Recordati) AIntravaginal cream, fenticonazole nitrate 2%, netprice 30 g with applicator = £3.74Excipients include cetyl alcohol, hydrogenated wool fat, propyleneglycolCondoms damages latex condoms and diaphragmsDoseInsert 5-g applicatorful intravaginally twice daily for 3daysVaginal capsule, fenticonazole nitrate 200 mg, netprice 3 vaginal capsules = £2.42Excipients include hydroxybenzoates (parabens)Condoms damages latex condoms and diaphragmsDoseInsert 1 vaginal capsule at night for 3 nightsVaginal capsule, fenticonazole nitrate 600 mg, netprice 1 vaginal capsule = £2.62Excipients include hydroxybenzoates (parabens)Condoms damages latex condoms and diaphragmsDoseInsert 1 vaginal capsule at night as a single doseNizoral c (Janssen) ACream (topical), ketoconazole 2%, net price 30 g =£3.40Excipients include polysorbates, propylene glycol, stearyl alcoholCondoms effect on latex condoms and diaphragms not yet knownDoseApply to anogenital area once or twice dailyOther infectionsTrichomonal infections commonly involve the lowerurinary tract as well as the genital system and needsystemic treatment with metronidazole (section 5.1.11)or tinidazole (section 5.4.2).Bacterial infections with Gram-negative organisms areparticularly common in association with gynaecologicaloperations and trauma. Metronidazole is effectiveagainst certain Gram-negative organisms, especiallyBacteroides spp. and can be used prophylactically ingynaecological surgery.Clindamycin cream and metronidazole gel are indicatedfor bacterial vaginosis.The antiviral drugs aciclovir, famciclovir, and valaciclovircan be used in the treatment of genital infection dueto herpes simplex virus, the HSV type 2 being a majorcause of genital ulceration. They have a beneficial effecton virus shedding and healing, generally giving relieffrom pain and other symptoms. See section 5.3 forsystemic preparations, and section 13.10.3 for topicalpreparations.PREPARATIONS FOR OTHERVAGINAL INFECTIONSCautions avoid intravaginal preparations (particularlythose that require the use of an applicator) in younggirls who are not sexually active, unless there is noalternative.Dalacin c (Pharmacia) ACream, clindamycin 2% (as phosphate), net price 40-gpack with 7 applicators = £10.86Excipients include benzyl alcohol, cetostearyl alcohol, polysorbates,propylene glycolCondoms damages latex condoms and diaphragmsSide-effects irritation, cervicitis and vaginitis; poorly absorbedinto the blood—low risk of systemic effects, see section 5.1.6Licensed use not licensed for use in children under 12 yearsDoseBacterial vaginosisInsert 5-g applicatorful at night for 3–7 nightsZidoval c (Meda) AVaginal gel, metronidazole 0.75%, net price 40-g packwith 5 applicators = £4.31Excipients include disodium edetate, hydroxybenzoates (parabens),propylene glycolSide-effects local effects including irritation, candidiasis, abnormaldischarge, pelvic discomfortLicensed use not licensed for use in children under 18 yearsNote Not recommended during menstruation; someabsorption may occur, see section 5.1.11 for systemic effectsDoseBacterial vaginosisInsert 5-g applicatorful at night for 5 nights7 Obstetrics, gynaecology, and urinary-tract disorders

396 7.3 Contraceptives BNFC 2011–20127 Obstetrics, gynaecology, and urinary-tract disorders7.3 Contraceptives7.3.1 Combined hormonal contraceptives7.3.2 Progestogen-only contraceptives7.3.3 Spermicidal contraceptives7.3.4 Contraceptive devices7.3.5 Emergency contraceptionThe Fraser Guidelines 1 should be followed when prescribingcontraception for women under 16 years. TheUK Medical Eligibility Criteria for Contraceptive Use(available at www.fsrh.org) is published by the Faculty ofSexual and Reproductive Healthcare; it categorises therisks of using contraceptive methods with pre-existingmedical conditions.Hormonal contraception is the most effective methodof fertility control, but can have major and minor sideeffects,especially for certain groups of women. Hormonalcontraception should only be used by adolescentsafter menarche.Intra-uterine devices are a highly effective method ofcontraception but may produce undesirable local sideeffects.They may be used in women of all ages irrespectiveof parity but are less appropriate for those withan increased risk of pelvic inflammatory disease.Barrier methods alone (condoms, diaphragms, andcaps) are less effective but can be reliable for wellmotivatedcouples if used in conjunction with a spermicide.Occasionally sensitivity reactions occur. Afemale condom (Femidom c ) is also available; it isprelubricated but does not contain a spermicide.7.3.1 Combined hormonalcontraceptivesOral contraceptives containing an oestrogen and aprogestogen (‘combined oral contraceptives’) are effectivepreparations for general use. Advantages of combinedoral contraceptives include:. reliable and reversible;. reduced dysmenorrhoea and menorrhagia;. reduced incidence of premenstrual tension;. reduced risk of symptomatic fibroids and functionalovarian cysts;. less benign breast disease;. reduced risk of ovarian and endometrial cancer;. reduced risk of pelvic inflammatory disease.Combined oral contraceptives containing a fixedamount of an oestrogen and a progestogen in eachactive tablet are termed ‘monophasic’; those with varyingamounts of the two hormones are termed ‘phasic’. Atransdermal patch and a vaginal ring, both containing anoestrogen with a progestogen, are also available.1. See Department of Health Guidance (July 2004): Bestpractice guidance for doctors and other health professionalson the provision of advice and treatment to youngpeople under 16 on contraception, sexual and reproductivehealth. Available at www.dh.gov.ukChoice The majority of combined oral contraceptivescontain ethinylestradiol as the oestrogen component;mestranol and estradiol valerate are also used. Theethinylestradiol content of combined oral contraceptivesranges from 20 to 40 micrograms. Generally apreparation with the lowest oestrogen and progestogencontent which gives good cycle control and minimalside-effects in the individual woman is chosen.. Low strength preparations (containing ethinylestradiol20 micrograms) are particularly appropriate forwomen with risk factors for circulatory disease,provided a combined oral contraceptive is otherwisesuitable.. Standard strength preparations (containing ethinylestradiol30 or 35 micrograms or in 30–40 microgramphased preparations) are appropriate forstandard use—but see Risk of Venous Thromboembolismbelow. Phased preparations are generallyreserved for women who either do not have withdrawalbleeding or who have breakthrough bleedingwith monophasic products.The progestogens desogestrel, drospirenone, and gestodene(in combination with ethinylestradiol) may beconsidered for women who have side-effects (such asacne, headache, depression, weight gain, breast symptoms,and breakthrough bleeding) with other progestogens.However, women should be advised thatdesogestrel and gestodene have also been associatedwith an increased risk of venous thromboembolism.Drospirenone, a derivative of spironolactone, has antiandrogenicand anti-mineralocorticoid activity; it shouldbe used with care if an increased plasma-potassiumconcentration might be hazardous.The progestogen norelgestromin is combined with ethinylestradiolin a transdermal patch (Evra c ).The vaginal contraceptive ring contains the progestogenetonogestrel combined with ethinylestradiol(NuvaRing c ).Risk of venous thromboembolism There is anincreased risk of venous thromboembolic disease (particularlyduring the first year) in users of oral contraceptives,but this risk is considerably smaller than thatassociated with pregnancy (about 60 cases of venousthromboembolic disease per 100 000 pregnancies). Inall cases the risk of venous thromboembolism increaseswith age and in the presence of other risk factors forvenous thromboembolism, such as obesity.The incidence of venous thromboembolism in healthy,non-pregnant women who are not taking an oral contraceptiveis about 5–10 cases per 100 000 women peryear. For those using combined oral contraceptivescontaining second-generation progestogens, such aslevonorgestrel, this incidence is about 15 per 100 000women per year of use. The risk of venous thromboembolismwith transdermal patches may be slightlyincreased compared with combined oral contraceptivesthat contain levonorgestrel. Some studies have reporteda greater risk of venous thromboembolism in womenusing combined oral contraceptives containing thethird-generation progestogens desogestrel and gestodene;the incidence in these women is about 25 per100 000 women per year of use. The absolute risk ofvenous thromboembolism in women using combinedoral contraceptives containing these third-generation

BNFC 2011–2012 7.3.1 Combined hormonal contraceptives 397progestogens is very small and well below the riskassociated with pregnancy. The risk of venous thromboembolismin women using a combined oral contraceptivecontaining drospirenone may be between thatassociated with combined oral contraceptives containingsecond-generation progestogens and combined oralcontraceptives containing third-generation progestogens.The risk of venous thromboembolism associatedwith vaginal ring use compared to the risk with othercombined hormonal contraceptives is unknown.Provided that women are informed of the relative risksof venous thromboembolism and accept them, thechoice of oral contraceptive is for the woman togetherwith the prescriber jointly to make in light of herindividual medical history and any contra-indications.Travel Women taking oral contraceptives or using thepatch or vaginal ring are at an increased risk of deepveinthrombosis during travel involving long periods ofimmobility (over 5 hours). The risk may be reduced byappropriate exercise during the journey and possibly bywearing graduated compression hosiery.Missed pill The critical time for loss of contraceptiveprotection is when a pill is omitted at the beginning orend of a cycle (which lengthens the pill-free interval).If a woman forgets to take a pill, it should be taken assoon as she remembers, and the next one taken at thenormal time (even if this means taking 2 pills together).A missed pill is one that is 24 or more hours late; forwomen taking Qlaira c , see below. If a woman missesonly one pill, she should take an active pill as soon asshe remembers and then resume normal pill-taking. Noadditional precautions are necessary.If a woman misses 2 or more pills (especially from thefirst 7 in a packet), she may not be protected. She shouldtake an active pill as soon as she remembers and thenresume normal pill-taking. In addition, she must eitherabstain from sex or use an additional method of contraceptionsuch as a condom for the next 7 days. If these 7days run beyond the end of the packet, the next packetshould be started at once, omitting the pill-free interval(or, in the case of everyday (ED) pills, omitting the 7inactive tablets).A missed pill for a woman taking Qlaira c is one that is12 hours or more late; for information on how tomanage missed pills in women taking Qlaira c , refer toproduct literature.Emergency contraception (section 7.3.5) is recommendedif 2 or more combined oral contraceptivetablets are missed from the first 7 tablets in a packetand unprotected intercourse has occurred since finishingthe last packet.Delayed application or detached patch If a patchis partly detached for less than 24 hours, reapply to thesame site or replace with a new patch immediately; noadditional contraception is needed and the next patchshould be applied on the usual ‘change day’. If a patchremains detached for more than 24 hours or if the user isnot aware when the patch became detached, then stopthe current contraceptive cycle and start a new cycle byapplying a new patch, giving a new ‘Day 1’; an additionalnon-hormonal contraceptive must be used concurrentlyfor the first 7 days of the new cycle.If application of a new patch at the start of a new cycle isdelayed, contraceptive protection is lost. A new patchshould be applied as soon as remembered giving a new‘Day 1’; additional non-hormonal methods of contraceptionshould be used for the first 7 days of the newcycle. If intercourse has occurred during this extendedpatch-free interval, a possibility of fertilisation should beconsidered. If application of a patch in the middle of thecycle is delayed (i.e. the patch is not changed on day 8 orday 15):. for up to 48 hours, apply a new patch immediately;next patch ‘change day’ remains the same and noadditional contraception is required;. for more than 48 hours, contraceptive protectionmay have been lost. Stop the current cycle and starta new 4-week cycle immediately by applying a newpatch giving a new ‘Day 1’; additional non-hormonalcontraception should be used for the first 7 daysof the new cycle.If the patch is not removed at the end of the cycle (day22), remove it as soon as possible and start the nextcycle on the usual ‘change day’, the day after day 28; noadditional contraception is required.Expulsion, delayed insertion or removal, or brokenvaginal ring If the vaginal ring is expelled for lessthan 3 hours, rinse the ring with cool water and reinsertimmediately; no additional contraception is needed.If the ring remains outside the vagina for more than 3hours or if the user does not know when the ring wasexpelled, contraceptive protection may be reduced:. if ring expelled during week 1 or 2 of cycle, rinsering with cool water and reinsert; use additionalprecautions (barrier methods) for next 7 days;. if ring expelled during week 3 of cycle, either inserta new ring to start a new cycle or allow a withdrawalbleed and insert a new ring no later than 7 days afterring was expelled; latter option only available if ringwas used continuously for at least 7 days beforeexpulsion.If insertion of a new ring at the start of a new cycle isdelayed, contraceptive protection is lost. A new ringshould be inserted as soon as possible; additional precautions(barrier methods) should be used for the first 7days of the new cycle. If intercourse occurred during theextended ring-free interval, pregnancy should be considered.No additional contraception is required if the removal ofthe ring is delayed by up to 1 week (4 weeks of continuoususe). The 7-day ring-free interval should beobserved and subsequently a new ring should beinserted. Contraceptive protection may be reducedwith continuous use of the ring for more than 4weeks—pregnancy should be ruled out before insertinga new ring.If the ring breaks during use, remove it and insert a newring immediately; additional precautions (barrier methods)should be used for the first 7 days of the new cycle.Diarrhoea and vomiting Vomiting and persistent,severe diarrhoea can interfere with the absorption ofcombined oral contraceptives. If vomiting occurs within2 hours of taking a combined oral contraceptive anotherpill should be taken as soon as possible. In cases of7 Obstetrics, gynaecology, and urinary-tract disorders

398 7.3.1 Combined hormonal contraceptives BNFC 2011–20127 Obstetrics, gynaecology, and urinary-tract disorderspersistent vomiting or severe diarrhoea lasting morethan 24 hours, additional precautions should be usedduring and for 7 days (9 days for Qlaira c ) after recovery(see also under Missed pill, above). If the vomiting anddiarrhoea occurs during the last 7 tablets, the next pillfreeinterval should be omitted (in the case of ED tabletsthe inactive ones should be omitted).Interactions The effectiveness of combined oralcontraceptives, progestogen-only oral contraceptives(section 7.3.2.1), contraceptive patches, and vaginalrings can be considerably reduced by interaction withdrugs that induce hepatic enzyme activity (e.g. carbamazepine,modafinil, nelfinavir, nevirapine, oxcarbazepine,phenytoin, phenobarbital, primidone, ritonavir,St John’s Wort, topiramate, and, above all,rifabutin and rifampicin). A condom together with along-acting method, such as an injectable contraceptive,may be more suitable for patients with HIV infection orat risk of HIV infection; advice on the possibility ofinteraction with antiretroviral drugs should be soughtfrom HIV specialists.Women taking combined hormonal contraceptives whorequire enzyme-inducing drugs should be advised tochange to a contraceptive method that is unaffected byenzyme-inducers (e.g. some parenteral progestogenonlycontraceptives (p. 404), intra-uterine devices) forthe duration of treatment and for 4 weeks after stopping.If a change in contraceptive method is undesirable orinappropriate the following options should be discussed:. For a short course (2 months or less) of an enzymeinducingdrug (except rifampicin or rifabutin—seebelow), continue with a combined oral contraceptiveproviding ethinylestradiol 30 micrograms dailyand use a ‘tricycling’ regimen (i.e. taking 3 packetsof monophasic tablets without a break followed by ashortened tablet-free interval of 4 days [unlicenseduse]. Additional contraceptive precautions shouldalso be used whilst taking the enzyme-inducingdrug and for 4 weeks after stopping. Another optionis to follow the advice for long-term courses below.For women using combined hormonal contraceptivepatches or vaginal rings, additional contraceptiveprecautions are also required whilst taking theenzyme-inducing drug and for 4 weeks after stopping.If concomitant administration runs beyond the3 weeks of patch or vaginal ring use, a new treatmentcycle should be started immediately, without apatch-free or ring-free break.. For a long-term course (over 2 months) of anenzyme-inducing drug (except rifampicin or rifabutin—seebelow), adjust the dose of combined oralcontraceptive to provide at least ethinylestradiol50 micrograms daily [unlicensed use] and use a‘tricycling’ regimen (as above); continue for theduration of treatment with the enzyme-inducingdrug and for 4 weeks after stopping.If breakthrough bleeding occurs (and all othercauses are ruled out) it is recommended that thedose of ethinylestradiol is increased by incrementsof 10 micrograms up to a maximum of 70 microgramsdaily [unlicensed use], or to use additionalprecautions, or to change to a method unaffected byenzyme-inducing drugs.Contraceptive patches and vaginal rings are notrecommended for women taking enzyme-inducingdrugs over a long period.. For any course of rifampicin or rifabutin, an alternativemethod of contraception (such as an IUD) isalways recommended because they are suchpotent enzyme-inducing drugs. Since enzyme activitydoes not return to normal for several weeks afterstopping an enzyme-inducing drug, appropriatecontraceptive measures are required for 4 to 8weeks after stopping.Latest recommendations are that no additional contraceptiveprecautions are required when combined oralcontraceptives are used with antibacterials that do notinduce liver enzymes (e.g. ampicillin, doxycycline),unless diarrhoea or vomiting occur (see above)It is also recommended that no additional contraceptiveprecautions are required when contraceptive patches orvaginal rings are used with antibacterials that do notinduce liver enzymes. There have been concerns thatsome antibacterials that do not induce liver enzymesreduce the efficacy of combined oral contraceptives byimpairing the bacterial flora responsible for recyclingethinylestradiol from the large bowel; however, there isa lack of evidence to support this interaction.For information on interactions of oral progestogen-onlycontraceptives, see also p. 403; for information on interactionsof parenteral progestogen-only contraceptives,see also p. 404; for information on interactions of theintra-uterine progestogen-only device, see also p. 405;for information on interactions of hormonal emergencycontraception, see also p. 408.Surgery Oestrogen-containing contraceptives shouldpreferably be discontinued (and adequate alternativecontraceptive arrangements made) 4 weeks beforemajor elective surgery and all surgery to the legs orsurgery which involves prolonged immobilisation of alower limb; they should normally be recommenced atthe first menses occurring at least 2 weeks after fullmobilisation. A progestogen-only contraceptive may beoffered as an alternative and the oestrogen-containingcontraceptive restarted after mobilisation, as above.When discontinuation of an oestrogen-containing contraceptiveis not possible, e.g. after trauma or if a patientadmitted for an elective procedure is still on an oestrogen-containingcontraceptive, thromboprophylaxis(with unfractionated or low molecular weight heparinand graduated compression hosiery) is advised. Theserecommendations do not apply to minor surgery withshort duration of anaesthesia, e.g. laparoscopic sterilisationor tooth extraction, or to women using oestrogenfreehormonal contraceptives.Reason to stop immediately Combined hormonalcontraceptives should be stopped (pending investigationand treatment), if any of the following occur:. sudden severe chest pain (even if not radiating to leftarm);. sudden breathlessness (or cough with blood-stainedsputum);. unexplained swelling or severe pain in calf of one leg;. severe stomach pain;. serious neurological effects including unusual severe,prolonged headache especially if first time or gettingprogressively worse or sudden partial or complete lossof vision or sudden disturbance of hearing or otherperceptual disorders or dysphasia or bad fainting attackor collapse or first unexplained epileptic seizure or

BNFC 2011–2012 7.3.1 Combined hormonal contraceptives 399weakness, motor disturbances, very marked numbnesssuddenly affecting one side or one part of body;. hepatitis, jaundice, liver enlargement;. very high blood pressure;. prolonged immobility after surgery or leg injury;. detection of a risk factor which contra-indicates treatment(see Cautions and Contra-indications under CombinedHormonal Contraceptives below).COMBINED HORMONALCONTRACEPTIVESCautions see notes above; also risk factors for venousthromboembolism (see below and also notes above),arterial disease and migraine, see below; personal orfamily history of hypertriglyceridaemia (increased riskof pancreatitis); hyperprolactinaemia (seek specialistadvice); history of severe depression especially ifinduced by hormonal contraceptive; undiagnosedbreast mass; gene mutations associated with breastcancer (e.g. BRCA 1); sickle-cell disease; inflammatorybowel disease including Crohn’s disease;reduced efficacy of contraceptive patch in womenwith body-weight 90 kg; active trophoblastic disease(until return to normal of urine- and plasmagonadotrophinconcentration) —seek specialistadvice; interactions: see above and Appendix 1(oestrogens, progestogens)Risk factors for venous thromboembolism See also notesabove. Use with caution if any of following factors presentbut avoid if two or more factors present:. family history of venous thromboembolism in firstdegreerelative aged under 45 years (avoid contraceptivecontaining desogestrel or gestodene, or avoid ifknown prothrombotic coagulation abnormality e.g. factorV Leiden or antiphospholipid antibodies (includinglupus anticoagulant));. obesity—caution if obese according to BMI (adjusted forage and gender); in those who are markedly obese,avoid unless no suitable alternative;. long-term immobilisation e.g. in a wheelchair (avoid ifconfined to bed or leg in plaster cast);. history of superficial thrombophlebitis;. smoking.Risk factors for arterial disease Use with caution if anyone of following factors present but avoid if two or morefactors present:. family history of arterial disease in first degree relativeaged under 45 years (avoid if atherogenic lipid profile);. diabetes mellitus (avoid if diabetes complications present);. hypertension (avoid if blood pressure very high);. smoking (avoid if smoking 40 or more cigarettes daily);. obesity—caution if obese according to BMI (adjusted forage and gender); in those who are markedly obese,avoid unless no suitable alternative;. migraine without aura (avoid if migraine with aura(focal symptoms), or severe migraine frequently lastingover 72 hours despite treatment, or migraine treatedwith ergot derivatives).Migraine Women should report any increase in headachefrequency or onset of focal symptoms (discontinue immediatelyand refer urgently to neurology expert if focal neurologicalsymptoms not typical of aura persist for more than1 hour—see also Reason to stop immediately in notes above)Contra-indications see notes above; also personalhistory of venous or arterial thrombosis, severe ormultiple risk factors for arterial disease or for venousthromboembolism (see above), heart disease associatedwith pulmonary hypertension or risk of embolus;sclerosing treatment for varicose veins; migrainewith aura (see also above); transient cerebralischaemic attacks without headaches; systemic lupuserythematosus; acute porphyria (section 9.8.2); gallstones;history of haemolytic uraemic syndrome orhistory during pregnancy of pruritus, cholestaticjaundice, chorea, pemphigoid gestationis; history ofbreast cancer but can be used after 5 years if noevidence of disease and non-hormonal methodsunacceptable; undiagnosed vaginal bleedingHepatic impairment avoid in active liver diseaseincluding disorders of hepatic excretion (e.g. Dubin-Johnson or Rotor syndromes), infective hepatitis(until liver function returns to normal), and livertumoursPregnancy not known to be harmfulBreast-feeding avoid until weaning or for 6 monthsafter birth (adverse effects on lactation)Side-effects see notes above; also nausea, vomiting,abdominal cramps, changes in body-weight, liverimpairment, hepatic tumours; fluid retention,thrombosis (more common when factor V Leidenpresent or in blood groups A, B, and AB; see alsonotes above), hypertension, changes in lipid metabolism;headache, depression, chorea, nervousness,irritability; changes in libido, breast tenderness,enlargement, and secretion; reduced menstrual loss,‘spotting’ in early cycles, absence of withdrawalbleeding, amenorrhoea after discontinuation, changesin vaginal discharge, cervical erosion; contact lensesmay irritate, visual disturbances; leg cramps; skinreactions, chloasma, photosensitivity; rarely gallstonesand systemic lupus erythematosusBreast cancer There is a small increase in the risk of havingbreast cancer diagnosed in women taking the combined oralcontraceptive pill; this relative risk may be due to an earlierdiagnosis. In users of combined oral contraceptive pills thecancers are more likely to be localised to the breast. Themost important factor for diagnosing breast cancer appearsto be the age at which the contraceptive is stopped ratherthan the duration of use; any increase in the rate of diagnosisdiminishes gradually during the 10 years after stopping anddisappears by 10 yearsCervical cancer Use of combined oral contraceptives for 5years or longer is associated with a small increased risk ofcervical cancer; the risk diminishes after stopping and disappearsby about 10 years. The risk of cervical cancer withtransdermal patches and vaginal rings is not yet knownNote The possible small increase in the risk of breast cancerand cervical cancer should be weighed against the protectiveeffect against cancers of the ovary and endometriumLicensed use consult product literature for thelicensing status of individual preparationsIndication and doseContraception, menstrual symptoms (section6.4.1.2). By mouthEach tablet should be taken at approximately sametime each day; if delayed contraceptive protectionmay be lost (see Missed Pill, above)21-day combined (monophasic) preparations, 1tablet daily for 21 days; subsequent coursesrepeated after a 7-day interval (during whichwithdrawal bleeding occurs); first course usuallystarted on day 1 of cycle—if starting on day 4 ofcycle or later, additional precautions (barriermethods) necessary during first 7 daysEvery day (ED) combined (monophasic) preparations,1activetablet starting on day 1 of cycle(see also under preparations below)—if starting on7 Obstetrics, gynaecology, and urinary-tract disorders

400 7.3.1 Combined hormonal contraceptives BNFC 2011–20127 Obstetrics, gynaecology, and urinary-tract disordersday 4 of cycle or later, additional precautions(barrier methods) necessary during first 7 days;withdrawal bleeding occurs when inactive tabletsbeing taken; subsequent courses repeated withoutintervalPhasic preparations, see under individual preparationsbelowChanging to combined preparation containing differentprogestogen 21-day combined preparations: continuecurrent pack until last tablet and start first tablet ofnew brand the next day. If a 7-day break is taken beforestarting new brand, additional precautions (barriermethods) should be used during first 7 days (9 days forQlaira c ) of taking the new brandEvery Day (ED) combined preparations: start the newbrand (first tablet of a 21-day preparation or the firstactive tablet of an ED preparation) the day after takingthe last active tablet of previous brand (omitting theinactive tablets)Changing from progestogen-only tablet Start on day 1of menstruation or any day if amenorrhoea present andpregnancy has been excludedSecondary amenorrhoea (exclude pregnancy) Startany day, additional precautions (barrier methods)necessary during first 7 days (9 days for Qlaira c )After childbirth (not breast-feeding) Start 3 weeks afterbirth (increased risk of thrombosis if started earlier); laterthan 3 weeks postpartum additional precautions (barriermethods) necessary for first 7 days (9 days for Qlaira c )After abortion or miscarriage Start same day. By transdermal applicationApply first patch on day 1 of cycle, change patchon days 8 and 15; remove third patch on day 22and apply new patch after 7-day patch-free intervalto start subsequent contraceptive cycleNote If first patch applied later than day 1, additionalprecautions (barrier methods) should be used for the next7 daysChanging from combined oral contraception Applypatch on the first day of withdrawal bleeding; if nowithdrawal bleeding within 5 days of taking last activetablet, rule out pregnancy before applying first patch.Unless patch is applied on first day of withdrawalbleeding, additional precautions (barrier methods)should be used concurrently for first 7 daysChanging from progestogen-only method From animplant, apply first patch on the day implant removed;from an injection, apply first patch when next injectiondue; from oral progestogen, first patch may be started onany day after stopping pill. For all methods additionalprecautions (barrier methods) should be used concurrentlyfor first 7 daysAfter childbirth (not breast-feeding) Start 4 weeks afterbirth; if started later than 4 weeks after birth additionalprecautions (barrier methods) should be used for first 7daysAfter abortion or miscarriage Before 20 weeks’ gestationstart immediately; no additional contraceptionrequired if started immediately. After 20 weeks’ gestationstart on day 21 after abortion or on the first day of firstspontaneous menstruation; additional precautions (barriermethods) should be used for first 7 days afterapplying the patch. By vaginaInsert ring into vagina on day 1 of cycle and leavein for 3 weeks; remove ring on day 22; subsequentcourses repeated after 7-day ring-free interval(during which withdrawal bleeding occurs)Note If first ring inserted later than day 1, additionalprecautions (barrier methods) should be used for the next7 daysChanging from combined hormonal contraceptionInsert ring at the latest on the day after the usual tabletfree,patch-free, or placebo-tablet interval. If previouscontraceptive used correctly and pregnancy unlikely, canswitch to ring on any day of cycleChanging from progestogen-only method From animplant or intra-uterine progestogen-only device, insertring on the day implant or intra-uterine progestogen-onlydevice removed; from an injection, insert ring wheninjection next due; from oral preparation, first ring maybe inserted on any day after stopping pill. For all methodsadditional precautions (barrier methods) should be usedconcurrently for first 7 daysAfter first trimester abortion Start immediatelyAfter childbirth (not breast-feeding) or second trimesterabortion Start 4 weeks after birth or abortion; ifstarted later than 4 weeks after birth or abortion additionalprecautions (barrier methods) should be used forfirst 7 daysOral (low and standard strength)For information on these preparations, see CombinedOral Contraceptives table, p. 401Transdermal (standard strength)Ethinylestradiol with NorelgestrominSee Risk of Venous Thromboembolism (in notesabove) before prescribingEvra c (Janssen) APatches, self-adhesive (releasing ethinylestradiolapprox. 33.9 micrograms/24 hours and norelgestrominapprox. 203 micrograms/24 hours); net price 9-patch pack = £16.70. Counselling, administrationDose1 patch to be applied once weekly for three weeks,followed by a 7-day patch-free interval; subsequentcourses repeated after 7-day patch-free interval (duringwhich withdrawal bleeding occurs); for starting routinessee under Dose aboveNote Adhesives or bandages should not be used to holdpatch in place. If patch no longer sticky do not reapply butuse a new patch.The Scottish Medicines Consortium has advised (September2003) that Evra c patches should be restricted for use inwomen who are likely to comply poorly with combined oralcontraceptivesVaginal (low strength)Ethinylestradiol with EtonogestrelSee Risk of Venous Thromboembolism (in notesabove) before prescribingNuvaRing c (Organon) TAVaginal ring, releasing ethinylestradiol approx.15 micrograms/24 hours and etonogestrel approx.120 micrograms/24 hours, net price 3-ring pack =£27.00. Counselling, administrationDose1 ring to be inserted into the vagina for 3 weeks, removedon day 22; subsequent courses repeated after 7-day ringfreeinterval (during which withdrawal bleeding occurs);for starting routines see under Dose aboveCounselling The presence of the ring should be checkedregularly. In case of expulsion see Expulsion, DelayedInsertion or Removal, or Broken Vaginal Ring, p. 397

BNFC 2011–2012 7.3.1 Combined hormonal contraceptives 401Combined Oral ContraceptivesSee Risk of Venous Thromboembolism (in notes above) before prescribingType of preparation OestrogencontentProgestogencontentTabletsper cycleBrand Price, 3-cycle pack(unlessstated)1 Monophasic lowstrength (21-daypreparations)1 Monophasicstandard strength(21-daypreparations)3 Monophasicstandard strength(28-day ‘Every day’preparations)Ethinylestradiol20 microgramsEthinylestradiol30 microgramsEthinylestradiol35 microgramsMestranol50 microgramsEthinylestradiol30 microgramsEthinylestradiol30 microgramsDesogestrel150 microgramsGestodene75 microgramsNorethisteroneacetate 1 mgDesogestrel150 microgramsDrospirenone3 mgGestodene75 microgramsLevonorgestrel150 microgramsNorethisteroneacetate 1.5 mgNorgestimate250 microgramsNorethisterone500 microgramsNorethisterone1 mgNorethisterone1 mgGestodene75 microgramsLevonorgestrel150 microgramsManufacturer21 Gedarel c 20/150 £5.98 ConsilientMercilon c £7.97 Organon21 Femodette c £8.85 Bayer ScheringMillinette c 20/75 £6.37 ConsilientSunya 20/75 c £6.62 Stragen21 Loestrin 20 c £2.75 Galen21 Gedarel c 30/150 £4.93 ConsilientMarvelon c £6.45 Organon212 Yasmin c £14.70 Bayer Schering21 Femodene c £6.73 Bayer ScheringKatya 30/75 c £5.03 StragenMillinette c 30/75 £4.85 Consilient21 Levest c £2.55 MorningsideMicrogynon 30 c £2.82 Bayer ScheringOvranette c £2.20 WyethRigevidon c £1.89 Consilient21 Loestrin 30 c £3.95 Galen21 Cilest c 3-cyclepack =£2.87;6-cyclepack =£5.74Janssen21 Brevinor c £1.99 PharmaciaOvysmen c £1.49 Janssen21 Norimin c £2.28 Pharmacia21 Norinyl-1 c £2.19 Pharmacia21 active Femodene c ED £6.73 Bayer Schering7 inactive21 active Microgynon 30 £2.54 Bayer ScheringED c7 inactive7 Obstetrics, gynaecology, and urinary-tract disorders1. Dose 1 tablet daily for 21 days starting on day 1 of cycle; subsequent courses repeated after 7-day tablet-free interval (duringwhich withdrawal bleeding occurs); for starting routines see under Dose above2. Caution use with care if increased plasma-potassium concentration might be hazardous; renal impairment avoid if eGFR lessthan 30 mL/minute/1.73 m 23. Dose 1 tablet daily for 28 days, starting on day 1 of cycle with first active tablet (withdrawal bleeding occurs when inactivetablets being taken); subsequent courses repeated without interval; for starting routines see under Dose above

402 7.3.1 Combined hormonal contraceptives BNFC 2011–2012Combined Oral Contraceptives (continued)7 Obstetrics, gynaecology, and urinary-tract disordersSee Risk of Venous Thromboembolism (in notes above) before prescribingType of preparation1 Phasic standardstrength (21-daypreparations)2 Phasic standardstrength (28-day‘Every day’preparation)2 Phasic (28-day‘Every day’preparation)OestrogencontentEthinylestradiol30 microgramsEthinylestradiol40 microgramsEthinylestradiol30 microgramsEthinylestradiol30 microgramsEthinylestradiol40 microgramsEthinylestradiol30 microgramsEthinylestradiol35 microgramsEthinylestradiol35 microgramsEthinylestradiol35 microgramsEthinylestradiol35 microgramsEthinylestradiol35 microgramsEthinylestradiol35 microgramsEthinylestradiol35 microgramsEthinylestradiol35 microgramsEthinylestradiol30 microgramsEthinylestradiol40 microgramsEthinylestradiol30 microgramsEstradiolvalerate 3 mgEstradiolvalerate 2 mgEstradiolvalerate 2 mgEstradiolvalerate 1 mgProgestogencontentGestodene50 microgramsGestodene70 microgramsGestodene100 microgramsLevonorgestrel50 microgramsLevonorgestrel75 microgramsLevonorgestrel125 microgramsNorethisterone500 microgramsNorethisterone1mgNorethisterone500 microgramsNorethisterone1mgNorethisterone500 microgramsNorethisterone500 microgramsNorethisterone750 microgramsNorethisterone1mgLevonorgestrel50 microgramsLevonorgestrel75 microgramsLevonorgestrel125 microgramsDienogest 2 mgDienogest 3 mgTabletsper cycleBrand Price, 3-cycle pack(unlessstated)Manufacturer6 Triadene c £8.99 Bayer Schering5106 Logynon c £3.96 Bayer Schering510TriRegol c £2.87 Consilient7 BiNovum c £1.96 Janssen147 Synphase c 1-cyclepack =9£1.205Pharmacia7 TriNovum c £2.72 Janssen776 active Logynon ED c £3.82 Bayer Schering5 active10 active7 inactive2 active Qlaira c T £25.18 Bayer Schering5 active17 active2 active2 inactive1. Dose 1 tablet daily for 21 days starting on day 1 of cycle; subsequent courses repeated after 7-day tablet-free interval (duringwhich withdrawal bleeding occurs); for starting routines see under Dose above2. Dose 1 tablet daily for 28 days, starting on day 1 of cycle with first active tablet (withdrawal bleeding occurs when inactivetablets being taken); subsequent courses repeated without interval; for starting routines see under Dose above

BNFC 2011–2012 7.3.2 Progestogen-only contraceptives 4037.3.2 Progestogen-onlycontraceptives7.3.2.1 Oral progestogen-only contraceptives7.3.2.2 Parenteral progestogen-onlycontraceptives7.3.2.3 Intra-uterine progestogen-only deviceThe Faculty of Sexual and Reproductive Healthcarerecommends emergency contraception (see p. 408) ifone or more progestogen-only contraceptive tablets aremissed or taken more than 3 hours (12 hours forCerazette c ) late and unprotected intercourse hasoccurred before 2 further tablets have been correctlytaken.7.3.2.1 Oral progestogen-onlycontraceptivesOral progestogen-only preparations may offer a suitablealternative when oestrogens are contra-indicated(including those patients with venous thrombosis or apast history or predisposition to venous thrombosis),but have a higher failure rate than combined preparations.They are suitable for heavy smokers, and for thosewith hypertension, valvular heart disease, diabetes mellitus,and migraine. Menstrual irregularities (oligomenorrhoea,menorrhagia) are more common but tend toresolve on long-term treatment.Interactions Effectiveness of oral progestogen-onlypreparations is not affected by antibacterials that do notinduce liver enzymes. The efficacy of oral progestogenonlypreparations is, however, reduced by enzyme-inducingdrugs and an alternative contraceptive method,unaffected by the interacting drug, is recommendedduring treatment with an enzyme-inducing drug andfor at least 4 weeks afterwards—see p. 398 and Appendix1 (progestogens). For a short course of an enzymeinducingdrug, if a change in contraceptive method isundesirable or inappropriate, the progestogen-only oralmethod may be continued in combination with additionalcontraceptive precautions (e.g. condom) for theduration of treatment with the enzyme-inducing drugand for 4 weeks after stopping.Surgery All progestogen-only contraceptives (includingthose given by injection) are suitable for use as analternative to combined oral contraceptives beforemajor elective surgery, before all surgery to the legs,or before surgery which involves prolonged immobilisationof a lower limb.Starting routine One tablet daily, on a continuousbasis, starting on day 1 of cycle and taken at the sametime each day (if delayed by longer than 3 hours (12hours for Cerazette c ) contraceptive protection may belost). Additional contraceptive precautions are notnecessary when initiating treatment.Changing from a combined oral contraceptive Start onthe day following completion of the combined oralcontraceptive course without a break (or in the case ofED tablets omitting the inactive ones).After childbirth Start any time after 3 weeks postpartum(increased risk of breakthrough bleeding if startedearlier).Missed pill The following advice is now recommendedby family planning organisations:‘If you forget a pill, take it as soon as you remember andcarry on with the next pill at the right time. If the pill wasmore than 3 hours (12 hours for Cerazette c ) overdue you arenot protected. Continue normal pill-taking but you must alsouse another method, such as the condom, for the next 2days.’Diarrhoea and vomiting Vomiting and persistent,severe diarrhoea can interfere with the absorption oforal progestogen-only contraceptives. If vomitingoccurs within 2 hours of taking an oral progestogenonlycontraceptive, another pill should be taken as soonas possible. If a replacement pill is not taken within 3hours (12 hours for Cerazette c ) of the normal time fortaking the progestogen-only pill, or in cases of persistentvomiting or very severe diarrhoea, additional precautionsshould be used during illness and for 2 days afterrecovery (see also under Missed pill above).ORAL PROGESTOGEN-ONLYCONTRACEPTIVES(Progestogen-only pill, ‘POP’)Cautions arterial disease; sex-steroid dependent cancer;past ectopic pregnancy; malabsorption syndromes;active trophoblastic disease (until return tonormal of urine- and plasma-gonadotrophin concentration)—seekspecialist advice; systemic lupuserythematosus with positive (or unknown) antiphospholipidantibodies; functional ovarian cysts;history of jaundice in pregnancy; interactions: seenotes above and Appendix 1 (progestogens)Other conditions The product literature advises caution inpatients with history of thromboembolism, hypertension,diabetes mellitus and migraine; evidence for caution in theseconditions is unsatisfactoryContra-indications undiagnosed vaginal bleeding;severe arterial disease; acute porphyria (section9.8.2); history of breast cancer but can be used after 5years if no evidence of disease and non-hormonalcontraceptive methods unacceptableHepatic impairment caution in active liver disease;and recurrent cholestatic jaundice, avoid in livertumourPregnancy not known to be harmfulBreast-feeding progestogen-only contraceptives donot affect lactation; see also After Childbirth aboveSide-effects menstrual irregularities (see also notesabove); nausea, vomiting, headache, dizziness, breastdiscomfort, depression, skin disorders, disturbance ofappetite, weight changes, changes in libidoBreast cancer There is a small increase in the risk of havingbreast cancer diagnosed in women using, or who haverecently used, a progestogen-only contraceptive pill; thisrelative risk may be due to an earlier diagnosis. The mostimportant risk factor appears to be the age at which thecontraceptive is stopped rather than the duration of use; therisk disappears gradually during the 10 years after stoppingand there is no excess risk by 10 years. A possible smallincrease in the risk of breast cancer should be weighedagainst the benefitsLicensed use consult product literature for thelicensing status of individual preparations7 Obstetrics, gynaecology, and urinary-tract disorders

404 7.3.2 Progestogen-only contraceptives BNFC 2011–20127 Obstetrics, gynaecology, and urinary-tract disordersIndication and doseContraception. By mouth1 tablet daily at same time each day, starting onday 1 of cycle then continuously; if administrationdelayed for 3 hours (12 hours for Cerazette c ) ormore it should be regarded as a ‘missed pill’, seenotes aboveCerazette c (Organon) ATablets, f/c, desogestrel 75 micrograms, net price 3 28-tab pack = £8.68The Scottish Medicines Consortium has advised (September2003) that Cerazette c should be restricted for use in womenwho cannot tolerate oestrogen-containing contraceptives orin whom such preparations are contra-indicatedFemulen c (Pharmacia) ATablets, etynodiol diacetate 500 micrograms, netprice 3 28-tab pack = £3.31Micronor c (Janssen) ATablets, norethisterone 350 micrograms, net price 3 28-tab pack = £1.66Norgeston c (Bayer Schering) ATablets, s/c, levonorgestrel 30 micrograms, net price35-tab pack = 92pNoriday c (Pharmacia) ATablets, norethisterone 350 micrograms, net price 3 28-tab pack = £2.107.3.2.2 Parenteral progestogen-onlycontraceptivesMedroxyprogesterone acetate (Depo-Provera c )isalong-acting progestogen given by intramuscular injection;it is as effective as the combined oral preparationsbut because of its prolonged action it should never begiven without full counselling backed by the patientinformation leaflet. It may be used as a short-term orlong-term contraceptive for women who have beencounselled about the likelihood of menstrual disturbanceand the potential for a delay in return to fullfertility. Delayed return of fertility and irregular cyclesmay occur after discontinuation of treatment but there isno evidence of permanent infertility. Heavy bleeding hasbeen reported in patients given medroxyprogesteroneacetate in the immediate puerperium; delaying the firstinjection until 6 weeks after the birth may minimisebleeding problems. If the woman is not breast-feeding,the first injection may be given within 5 dayspostpartum (she should be warned that the risk ofheavy or prolonged bleeding may be increased). Themanufacturer advises that in women who are breastfeeding,the first dose should be delayed until 6 weeksafter the birth; however, evidence suggests no harmfuleffect to infant if given earlier. The benefits of usingmedroxyprogesterone acetate in breast-feeding womenoutweigh any risks.Reduction in bone mineral density and, rarely, osteoporosisand osteoporotic fractures have also beenreported with medroxyprogesterone acetate. The reductionin bone mineral density occurs in the first 2–3 yearsof use and then stabilises. See also below.. In adolescents, medroxyprogesterone acetate(Depo-Provera c ) should be used only whenother methods of contraception are inappropriate;. in all women, the benefits of using medroxyprogesteroneacetate beyond 2 years should beevaluated against the risks;. in women with risk factors for osteoporosis, amethod of contraception other than medroxyprogesteroneacetate should be considered.Norethisterone enantate (Noristerat c ) is a long-actingprogestogen given as an oily injection which providescontraception for 8 weeks; it is used as short-terminterim contraception e.g. before vasectomy becomeseffective.An etonogestrel-releasing implant (Nexplanon c ) isalso available. It is a highly effective long-actingcontraceptive, consisting of a single flexible rod that isinserted subdermally into the lower surface of the upperarm and provides contraception for up to 3 years. Themanufacturer advises that in heavier women, bloodetonogestrelconcentrations are lower and therefore theimplant may not provide effective contraception duringthe third year; they advise that earlier replacement maybe considered in such patients, however, evidence tosupport this recommendation is lacking. Local reactionssuch as bruising and itching can occur at the insertionsite. The contraceptive effect of etonogestrel is rapidlyreversed on removal of the implant. The doctor or nurseadministering (or removing) the system should be fullytrained in the technique and should provide fullcounselling reinforced by the patient informationleaflet.Implanon c , also an etonogestrel-releasing implant, hasbeen discontinued (October 2010), but some womenmay have the implant in place until 2013.The cautions, contra-indications, and side-effects of oralprogestogen-only contraceptives apply to parenteralprogestogen-only contraceptives, except that parenteralpreparations reliably inhibit ovulation and thereforeprotect against ectopic pregnancy and functionalovarian cysts.Interactions Effectiveness of parenteral progestogenonlycontraceptives is not affected by antibacterials thatdo not induce liver enzymes. The effectiveness of norethisteroneand medroxyprogesterone acetate intramuscularinjections is not affected by enzyme-inducingdrugs and they may be continued as normal duringcourses of these drugs. However, effectiveness of theetonogestrel-releasing implant may be reduced byenzyme-inducing drugs and an alternative contraceptivemethod, unaffected by the interacting drug, isrecommended during treatment with the enzyme-inducingdrug and for at least 4 weeks after stopping. For ashort course of an enzyme-inducing drug, if a change incontraceptive method is undesirable or inappropriate,the implant may be continued in combination withadditional contraceptive precautions (e.g. condom) forthe duration of treatment with the enzyme-inducingdrug and for 4 weeks after stopping it.

BNFC 2011–2012 7.3.2 Progestogen-only contraceptives 405PARENTERAL PROGESTOGEN-ONLYCONTRACEPTIVESCautions see notes above and under preparations;possible risk of breast cancer, see oral progestogenonlycontraceptives (section 7.3.2.1); history duringpregnancy of pruritus or of deterioration of otosclerosis,disturbances of lipid metabolism; interactions:see notes above and Appendix 1 (progestogens)Counselling Full counselling backed by patient informationleaflet required before administrationContra-indications see notes above; history of breastcancer but can be used after 5 years if no evidence ofdisease and non-hormonal contraceptive methodsunacceptableHepatic impairment see Oral Progestogen-onlyContraceptives, section 7.3.2.1Pregnancy not known to be harmful; for Implanon cor Nexplanon c if pregnancy occurs remove implantBreast-feeding progestogen-only contraceptives donot affect lactation; see also notes aboveSide-effects see notes above; injection-site reactionsCervical cancer Use of injectable progestogen-only contraceptivesis associated with a small increased risk of cervicalcancer; this increased risk may be similar to that seen withcombined oral contraceptives, see p. 399. The risk of cervicalcancer with other progestogen-only contraceptives is not yetknown.Licensed use consult product literature for thelicensing status of individual preparationsIndication and doseContraception see also notes above and underpreparations (roles vary according to preparation)For dose see under preparationsInjectable preparationsDepo-Provera c (Pfizer) AInjection (aqueous suspension), medroxyprogesteroneacetate 150 mg/mL, net price 1-mL prefilledsyringe = £6.01, 1-mL vial = £6.01. Counselling, seepatient information leafletDose. By deep intramuscular injection150 mg within first 5 days of cycle or within first 5 daysafter parturition (delay until 6 weeks after parturition ifbreast-feeding); for long-term contraception, repeatedevery 12 weeks (if interval greater than 12 weeks and 5days, rule out pregnancy before next injection and advisepatient to use additional contraceptive measures (e.g.barrier) for 14 days after the injection)Noristerat c (Bayer Schering) AInjection (oily), norethisterone enantate 200 mg/mL,net price 1-mL amp = £3.38. Counselling, see patientinformation leafletDose. By deep intramuscular injectionGiven very slowly into gluteal muscle, short-termcontraception, 200 mg within first 5 days of cycle orimmediately after parturition (duration 8 weeks); may berepeated once after 8 weeks (withhold breast-feeding forneonates with severe or persistent jaundice requiringmedical treatment)ImplantsNexplanon c (Organon) TAImplant, containing etonogestrel 68 mg in radiopaqueflexible rod, net price = £79.46. Counselling, seepatient information leafletDose. By subdermal implantationNo hormonal contraceptive use in previous month, 1implant inserted during first 5 days of cycle; postpartum,1 implant inserted 21–28 days after delivery; in breastfeedingmothers, 1 implant inserted after 28 days postpartum;abortion or miscarriage in the second trimester,1 implant inserted 21–28 days after abortion or miscarriage;abortion or miscarriage in first trimester, 1 implantinserted within 5 days; changing from other hormonalcontraceptive, consult product literature; remove implantwithin 3 years of insertion7.3.2.3 Intra-uterine progestogen-onlydeviceThe progestogen-only intra-uterine system, Mirena c ,releases levonorgestrel directly into the uterine cavity.It is used as a contraceptive, for the treatment ofprimary menorrhagia and for the prevention of endometrialhyperplasia during oestrogen replacementtherapy. This may therefore be a contraceptive methodof choice for women who have excessively heavymenses.The effects of the progestogen-only intra-uterine systemare mainly local and hormonal including prevention ofendometrial proliferation, thickening of cervical mucus,and suppression of ovulation in some women (in somecycles). In addition to the progestogenic activity, theintra-uterine system itself may contribute slightly to thecontraceptive effect. Return of fertility after removal israpid and appears to be complete.Advantages of the progestogen-only intra-uterine systemover copper intra-uterine devices are that theremay be an improvement in any dysmenorrhoea and areduction in blood loss; there is also evidence that thefrequency of pelvic inflammatory disease may bereduced (particularly in the youngest age groups whoare most at risk).In primary menorrhagia, menstrual bleeding is reducedsignificantly within 3–6 months of inserting the progestogen-onlyintra-uterine system, probably because itprevents endometrial proliferation. Another treatmentshould be considered if menorrhagia does not improvewithin this time (section 6.4.1.2).Cautions and contra-indications Generally thecautions and contra-indications for the progestogenonlyintra-uterine system are as for standard intrauterinedevices (section 7.3.4). Although the progestogen-onlyintra-uterine system produces little systemicprogestogenic activity, it is usually avoided for 5 yearsafter any evidence of breast cancer. However, the systemcan be considered for a woman in long-term remissionfrom breast cancer who has menorrhagia andrequires effective contraception. Since levonorgestrelis released close to the site of the main contraceptiveaction (on cervical mucus and endometrium) progestogenicside-effects and interactions are less likely; inparticular, enzyme-inducing drugs are unlikely to significantlyreduce the contraceptive effect of the progestogen-onlyintra-uterine system and additional contraceptiveprecautions are not required.7 Obstetrics, gynaecology, and urinary-tract disorders

406 7.3.3 Spermicidal contraceptives BNFC 2011–20127 Obstetrics, gynaecology, and urinary-tract disordersSide-effects Initially, changes in the pattern andduration of menstrual bleeding (spotting or prolongedbleeding) are common; endometrial disorders should beruled out before insertion and the patient should be fullycounselled (and provided with a patient informationleaflet). Improvement in progestogenic side-effects,such as mastalgia and in the bleeding pattern usuallyoccurs a few months after insertion and bleeding mayoften become very light or absent. Functional ovariancysts (usually asymptomatic) can occur and usuallyresolve spontaneously (ultrasound monitoring recommended).INTRA-UTERINE PROGESTOGEN-ONLY SYSTEMCautions see notes above; history of depression;advanced uterine atrophy; systemic lupus erythematosuswith positive (or unknown) antiphospholipidantibodies; not suitable for emergency contraception;interactions: see notes above and Appendix 1 (progestogens)Contra-indications see notes aboveHepatic impairment see Oral Progestogen-onlyContraceptives, section 7.3.2.1Pregnancy avoid; if pregnancy occurs remove systemBreast-feeding progestogen-only contraceptives donot affect lactationSide-effects see notes above; also abdominal pain,expulsion; peripheral oedema; depression (sometimessevere), nervousness; salpingitis, and pelvicinflammatory disease; pelvic pain, back pain; rarelyuterine perforation, hirsutism, hair loss, pruritus,migraine, rashLicensed use not licensed for use in women under18 yearsIndication and doseSee under preparationMirena c (Bayer Schering) AIntra-uterine system, T-shaped plastic frame(impregnated with barium sulphate and with threadsattached to base) with polydimethylsiloxane reservoirreleasing levonorgestrel 20 micrograms/24 hours, netprice = £85.66. Counselling, see patient informationleafletDoseContraception and menorrhagiaInsert into uterine cavity within 7 days of onset ofmenstruation, or any time if replacement, or any time ifreasonably certain the woman is not pregnant and thereis no risk of conception (additional precautions (e.g.barrier methods) necessary for next 7 days), or immediatelyafter first-trimester termination by curettage;postpartum insertions should be delayed until at least 4weeks after delivery; effective for 5 yearsNote When system is removed (and not immediatelyreplaced) and pregnancy is not desired, remove duringfirst few days of menstruation, otherwise additionalcontraceptive measures required for at least 7 daysbefore removalPrevention of endometrial hyperplasia during oestrogenreplacement therapyInsert during last days of menstruation or withdrawalbleeding or anytime if amenorrhoeic; effective for 4 years7.3.3 SpermicidalcontraceptivesSpermicidal contraceptives are useful additional safeguardsbut do not give adequate protection if used aloneunless fertility is already significantly diminished. Theyhave two components: a spermicide and a vehicle whichitself may have some inhibiting effect on sperm activity.They are suitable for use with barrier methods, such asdiaphragms or caps; however, spermicidal contraceptivesare not generally recommended for use withcondoms, as there is no evidence of any additionalprotection compared with non-spermicidal lubricants.Spermicidal contraceptives are not suitable for use inthose with or at high risk of sexually transmitted infections(including HIV); high frequency use of the spermicidenonoxinol ‘9’ has been associated with genitallesions, which may increase the risk of acquiring theseinfections.Products such as petroleum jelly (Vaseline c ), babyoil and oil-based vaginal and rectal preparations arelikely to damage condoms and contraceptivediaphragms made from latex rubber, and mayrender them less effective as a barrier method ofcontraception and as a protection from sexuallytransmitted infections (including HIV).Gygel c (Marlborough)Gel, nonoxinol ‘9’ 2%, net price 30 g = £4.25Excipients include hydroxybenzoates (parabens), propylene glycol,sorbic acidCondoms No evidence of harm to latex condoms and diaphragmsPregnancy toxicity in animal studiesBreast-feeding present in milk in animal studies7.3.4 Contraceptive devicesIntra-uterine devicesThe intra-uterine device (IUD) is a suitable contraceptivefor women of all ages irrespective of parity; however,it is less appropriate for those with an increasedrisk of pelvic inflammatory disease e.g. women under 25years (see below). The most effective intra-uterinedevices have at least 380 mm 2 of copper and havebanded copper on the arms.Smaller devices have been introduced to minimise sideeffects;these consist of a plastic carrier wound withcopper wire or fitted with copper bands; some also havea central core of silver to prevent fragmentation of thecopper.A frameless, copper-bearing intra-uterine device(GyneFix c ) is also available. It consists of a knotted,polypropylene thread with 6 copper sleeves; the deviceis anchored in the uterus by inserting the knot into theuterine fundus. The intra-uterine devices Multiload cCu250 and Multiload c Cu250 Short (Organon) havebeen discontinued, but some women may have thedevices in place until 2011.The timing and technique of fitting an intra-uterinedevice are critical for its subsequent performance. Thehealthcare professional inserting (or removing) thedevice should be fully trained in the technique and

BNFC 2011–2012 7.3.4 Contraceptive devices 407should provide full counselling, backed, where available,by the patient information leaflet. Devices shouldnot be fitted during the heavy days of the period; theyare best fitted after the end of menstruation and beforethe calculated time of implantation. The main excessrisk of infection occurs in the first 20 days after insertionand is believed to be related to existing carriage of asexually transmitted infection. Women under 25 yearsare at a higher risk of sexually transmitted infections,and pre-insertion screening (for chlamydia, and dependingon sexual history and local prevalence of disease,Neisseria gonorrhoeae) should be performed. If resultsare unavailable at the time of fitting an intra-uterinedevice for emergency contraception, appropriate prophylacticantibacterial cover should be given. Thewoman should be advised to attend as an emergencyif she experiences sustained pain during the next 20days.An intra-uterine device should not be removed in midcycleunless an additional contraceptive was used forthe previous 7 days. If removal is essential post-coitalcontraception should be considered.If an intra-uterine device fails and the woman wishes tocontinue to full-term the device should be removed inthe first trimester if possible.INTRA-UTERINE CONTRACEPTIVEDEVICESCautions see notes above; also anaemia, menorrhagia(progestogen intra-uterine system might be preferable,section 7.3.2.3), endometriosis, severe primarydysmenorrhoea, history of pelvic inflammatory disease,diabetes, fertility problems, nulliparity andyoung age, severely scarred uterus (including afterendometrial resection) or severe cervical stenosis;drug- or disease-induced immunosuppression (risk ofinfection—avoid if marked immunosuppression); epilepsy(risk of seizure at time of insertion); increasedrisk of expulsion if inserted before uterine involution;gynaecological examination before insertion, 6–8weeks after then annually but counsel women to seedoctor promptly in case of significant symptoms,especially pain; anticoagulant therapy (avoid if possible)Contra-indications severe anaemia, recent sexuallytransmitted infection (if not fully investigated andtreated), unexplained uterine bleeding, distorted orsmall uterine cavity, genital malignancy, active trophoblasticdisease (until return to normal of urineandplasma-gonadotrophin concentration), pelvicinflammatory disease, established or marked immunosuppression;copper devices: copper allergy,Wilson’s disease, medical diathermyPregnancy remove device; if pregnancy occurs,increased likelihood that it may be ectopicBreast-feeding not known to be harmfulSide-effects uterine or cervical perforation, displacement,expulsion; pelvic infection may be exacerbated,menorrhagia, dysmenorrhoea, allergy; on insertion:pain (alleviated by NSAID such as ibuprofen 30 minutesbefore insertion) and bleeding, occasionally epilepticseizure and vasovagal attackIndication and doseSee notes aboveCu-Safe c T300 (Williams) DIntra-uterine device, copper wire, wound on vertical stem ofT-shaped plastic carrier, surface area approx. 300 mm 2 ,impregnated with barium sulphate for radio-opacity, monofilamentthread attached to base of vertical stem; preloadedin inserter, net price = £9.11For uterine length over 5 cm; replacement every 5 years (see alsonotes above)Flexi-T 300 c (Durbin)Intra-uterine device, copper wire, wound on vertical stem ofT-shaped plastic carrier, surface area approx. 300 mm 2 ,impregnated with barium sulphate for radio-opacity, monofilamentthread attached to base of vertical stem; preloadedin inserter, net price = £9.47For uterine length over 5 cm; replacement every 5 years (see alsonotes above)Flexi-T c + 380 (Durbin)Intra-uterine device, copper wire, wound on vertical stem ofT-shaped plastic carrier with copper sleeve on each arm,total surface area approx. 380 mm 2 , impregnated with bariumsulphate for radio-opacity, monofilament threadattached to base of vertical stem; preloaded in inserter, netprice = £10.06For uterine length over 6 cm; replacement every 5 years (see alsonotes above)GyneFix c (Williams)Intra-uterine device, 6 copper sleeves with surface area of330 mm 2 on polypropylene thread, net price = £26.64Suitable for all uterine sizes; replacement every 5 yearsLoad c 375 (Durbin)Intra-uterine device, copper wire, wound on vertical stem ofU-shaped plastic carrier, surface area approx. 375 mm 2 ,impregnated with barium sulphate for radio-opacity, monofilamentthread attached to base of vertical stem; preloadedin inserter, net price = £8.52For uterine length over 7 cm; replacement every 5 years (see alsonotes above)Mini TT 380 c Slimline (Durbin)Intra-uterine device, copper wire, wound on vertical stem ofT-shaped plastic carrier with copper sleeves fitted flush on todistal portion of each horizontal arm, total surface areaapprox. 380 mm 2 , impregnated with barium sulphate forradio-opacity, thread attached to base of vertical stem; easyloadingsystem, no capsule, net price = £12.46For minimum uterine length 5 cm; replacement every 5 years (seealso notes above)Multiload c Cu375 (Organon)Intra-uterine device, as Load c 375, with copper surfacearea approx. 375 mm 2 and vertical stem length 3.5 cm, netprice = £9.24For uterine length 6–9 cm; replacement every 5 years (see alsonotes above)Multi-Safe c 375 (Williams)Intra-uterine device, copper wire, wound on vertical stem ofU-shaped plastic carrier, surface area approx. 375 mm 2 ,impregnated with barium sulphate for radio-opacity, monofilamentthread attached to base of vertical stem; preloadedin inserter, net price = £8.80For uterine length 6–9cm; replacement every 5 years (see alsonotes above)MultiSafe c 375 Short Stem (Williams) DIntra-uterine device, copper wire, wound on vertical stem ofU-shaped plastic carrier, surface area approx. 375 mm 2 ,impregnated with barium sulphate for radio-opacity, monofilamentthread attached to base of vertical stem; preloadedin inserter, net price = £8.80For uterine length 5–7cm; replacement every 5 years (see alsonotes above)7 Obstetrics, gynaecology, and urinary-tract disorders

408 7.3.5 Emergency contraception BNFC 2011–20127 Obstetrics, gynaecology, and urinary-tract disordersNeo-Safe c T380 (Williams)Intra-uterine device, copper wire, wound on vertical stem ofT-shaped plastic carrier, surface area approx. 380 mm 2 ,impregnated with barium sulphate for radio-opacity, threadsattached to base of vertical stem, net price = £13.80For uterine length 6.5–9 cm; replacement every 5 years (see alsonotes above)Nova-T c 380 (Bayer Schering)Intra-uterine device, copper wire with silver core, wound onvertical stem of T-shaped plastic carrier, surface area approx.380 mm 2 , impregnated with barium sulphate for radio-opacity,threads attached to base of vertical stem, net price =£12.97For uterine length 6.5–9 cm; replacement every 5 years (see alsonotes above)T-Safe c 380A Quickload (Williams)Intra-uterine device, copper wire, wound on vertical stem ofT-shaped plastic carrier with copper collar on the distalportion of each arm, total surface area approx. 380 mm 2 ,impregnated with barium sulphate for radio-opacity, threadsattached to base of vertical stem, net price = £10.29; availablewith a capsule loading device (T-Safe c CU 380AD),net price £10.29For uterine length 6.5–9 cm; replacement every 10 years (see alsonotes above)TT 380 c Slimline (Durbin)Intra-uterine device, copper wire, wound on vertical stem ofT-shaped plastic carrier, with copper sleeves fitted flush onto distal portion of each horizontal arm, total surface areaapprox. 380 mm 2 , impregnated with barium sulphate forradio-opacity, thread attached to base of vertical stem; easyloadingsystem, no capsule, net price = £12.46For uterine length 6.5–9 cm; replacement every 10 years (see alsonotes above)UT 380 Short c (Durbin)Intra-uterine device, copper wire, wound on vertical stem ofT-shaped plastic carrier, surface area approx. 380 mm 2 ,impregnated with barium sulphate for radio-opacity, threadattached to base of vertical stem; net price = £11.22For uterine length 5–7 cm; replacement every 5 years (see alsonotes above)UT 380 Standard c (Durbin)Intra-uterine device, copper wire, wound on vertical stem ofT-shaped plastic carrier, surface area approx. 380 mm 2 ,impregnated with barium sulphate for radio-opacity, threadattached to base of vertical stem; net price = £11.22For uterine length 6.5–9 cm; replacement every 5 years (see alsonotes above)Other contraceptive devicesRubber contraceptive capsType A Contraceptive PessaryOpaque rubber, sizes 1 (50 mm), 2 (55 mm), 3 (60 mm), 4(65 mm), 5 (75 mm), net price = £6.85Type B Contraceptive PessaryOpaque rubber, sizes 22 to 31 mm (rising in steps of 3 mm),net price = £8.46Type C Contraceptive PessaryOpaque rubber, sizes 1 to 3 (42, 48, and 54 mm), net price =£7.26Silicone contraceptive capsSilicone Contraceptive PessarySilicone, sizes 22, 26, and 30 mm, net price = £15.00Brands include FemCap cRubber contraceptive diaphragmsType A Diaphragm with Flat Metal SpringTransparent rubber with flat metal spring, sizes 55–95 mm(rising in steps of 5 mm), net price = £5.78Brands include Reflexions cType B Diaphragm with Coiled Metal SpringOpaque rubber with coiled metal spring, sizes 60–100 mm(rising in steps of 5 mm), net price = £6.79Type C Arcing Spring DiaphragmOpaque rubber with arcing spring, sizes 60–95 mm (rising insteps of 5 mm), net price = £7.72Silicone contraceptive diaphragmsType B Diaphragm with Coiled Metal SpringSilicone with coiled metal spring, sizes 60–90 mm (rising insteps of 5 mm), net price = £8.35Brands include Milex Omniflex cType C Arching Spring diaphragmSilicone with arcing spring, sizes 60–90 mm (rising in steps of5 mm), net price = £8.35Brands include Milex Arcing Style c , Ortho All-Flex c7.3.5 Emergency contraceptionHormonal methodsHormonal emergency contraceptives include levonorgestreland ulipristal; either drug should be taken assoon as possible after unprotected intercourse toincrease efficacy.Levonorgestrel is effective if taken within 72 hours (3days) of unprotected intercourse and may also be usedbetween 72 and 120 hours after unprotected intercourse[unlicensed use], but efficacy decreases with time. Ulipristal,a progesterone receptor modulator, is effective iftaken within 120 hours (5 days) of unprotected intercourse.Levonorgestrel is less effective than insertion of anintra-uterine device (see below). Ulipristal is as effectiveas levonorgestrel but it’s efficacy compared to an intrauterinedevice is not yet known.If vomiting occurs within 2 hours of taking levonorgestrelor within 3 hours of taking ulipristal, a replacementdose should be given. If an anti-emetic is requireddomperidone is preferred.When prescribing hormonal emergency contraceptionthe doctor should explain:. that the next period may be early or late;. that a barrier method of contraception needs to beused until the next period;. the need to return promptly if any lower abdominalpain occurs because this could signify an ectopicpregnancy (and also in 3 to 4 weeks if the subsequentmenstrual bleed is abnormally light, heavy orbrief, or is absent, or if she is otherwise concerned).Interactions The effectiveness of levonorgestrel, andpossibly ulipristal is reduced in women taking enzymeinducingdrugs (and possibly for 4 weeks after stopping);a copper intra-uterine device can be offered instead orthe dose of levonorgestrel should be increased to a totalof 3 mg taken as a single dose [unlicensed dose—advise

BNFC 2011–2012 7.4 Drugs for genito-urinary disorders 409women accordingly]. There is no need to increase thedose for emergency contraception if the patient is takingantibacterials that are not enzyme inducers.LEVONORGESTRELCautions see notes above; past ectopic pregnancy;severe malabsorption syndromes; active trophoblasticdisease (until return to normal of urine- and plasmagonadotrophinconcentration)—seek specialistadvice; interactions: see notes above and Appendix 1(progestogens)Contra-indications acute porphyria (section 9.8.2)Pregnancy not known to be harmfulBreast-feeding progestogen-only contraceptives donot affect lactationSide-effects menstrual irregularities (see also notesabove), nausea, low abdominal pain, fatigue, headache,dizziness, breast tenderness, vomitingLicensed use consult product literatureIndication and doseEmergency contraception. By mouth1.5 mg as a single dose as soon as possible aftercoitus (preferably within 12 hours but no later thanafter 72 hours)1Levonelle c One Step (Bayer Schering)Tablets, levonorgestrel 1.5 mg, net price 1-tab pack =£13.831. Can be sold to women over 16 years; when supplyingemergency contraception to the public, pharmacists shouldrefer to guidance issued by the Royal PharmaceuticalSocietyLevonelle c 1500 (Bayer Schering) ATablets, levonorgestrel 1.5 mg, net price 1-tab pack =£5.20ULIPRISTAL ACETATECautions see notes above; uncontrolled severeasthma; effectiveness of combined hormonal andprogestogen-only contraceptives may be reduced—additional precautions (barrier methods) required;repeated use within a menstrual cycle; interactions:see notes above and Appendix 1 (ulipristal)Hepatic impairment manufacturer advises avoid insevere impairment—no information availablePregnancy limited information availableBreast-feeding manufacturer advises avoid for atleast 36 hours—no information availableSide-effects gastro-intestinal disturbances (includingnausea, vomiting, diarrhoea, and abdominal pain);dizziness, fatigue, headache; menstrual irregularities(see notes above); back pain, muscle spasms; lesscommonly tremor, hot flushes, uterine spasm, breasttenderness, dry mouth, blurred vision, pruritus, andrashIndication and doseEmergency contraception. By mouth30 mg as a single dose as soon as possible aftercoitus, but no later than after 120 hoursellaOne c (HRA Pharma) TATablets, ulipristal acetate 30 mg, net price 1-tab pack= £16.95Intra-uterine deviceInsertion of an intra-uterine device is more effectivethan oral levonorgestrel for emergency contraception,see also notes above. A copper intra-uterine contraceptivedevice (section 7.3.4) can be inserted up to120 hours (5 days) after unprotected intercourse; sexuallytransmitted infections should be tested for andinsertion of the device should usually be covered byantibacterial prophylaxis (e.g. azithromycin 1 g as asingle dose). If intercourse has occurred more than 5days previously, the device can still be inserted up to 5days after the earliest likely calculated ovulation (i.e.within the minimum period before implantation),regardless of the number of episodes of unprotectedintercourse earlier in the cycle.7.4 Drugs for genito-urinarydisorders7.4.1 Drugs for urinary retention7.4.2 Drugs for urinary frequency, enuresis,and incontinence7.4.3 Drugs used in urological pain7.4.4 Bladder instillations and urologicalsurgery7.4.5 Drugs for erectile dysfunctionFor drugs used in the treatment of urinary-tract infectionssee section 5.1.13.7.4.1 Drugs for urinaryretentionAcute retention is painful and is treated by catheterisation.Chronic retention is painless and often long-standing.Clean intermittent catheterisation may be considered.After the cause has been established and treated, drugsmay be required to increase detrusor muscle tone.Alpha-blockers such as doxazosin and tamsulosin canbe used in some cases of dysfunctional voiding.Alpha-blockersThe selective alpha-blockers doxazosin and tamsulosincan be used to improve bladder emptying in childrenwith dysfunctional voiding where the post-void residualurine volume is significant; treatment should be underspecialist advice only. Alpha-blockers can reduce bloodpressure rapidly after the first dose and should beintroduced with caution.DOXAZOSINCautions see under Doxazosin (section 2.5.4)Contra-indications see under Doxazosin (section2.5.4)Hepatic impairment see under Doxazosin (section2.5.4)Pregnancy see under Doxazosin (section 2.5.4)7 Obstetrics, gynaecology, and urinary-tract disorders

410 7.4.2 Drugs for urinary frequency, enuresis, and incontinence BNFC 2011–20127 Obstetrics, gynaecology, and urinary-tract disordersBreast-feeding see under Doxazosin (section 2.5.4)Side-effects see under Doxazosin (section 2.5.4)Licensed use not licensed for use in childrenIndication and doseDysfunctional voiding (see notes above). By mouthChild 4–12 years initially 0.5 mg daily increasedat monthly intervals according to response; maximum2 mg dailyChild 12–18 years initially 1 mg daily, dose maybe doubled at intervals of 1 month according toresponse; usual maintenance 2–4 mg daily; max.8 mg dailyHypertension section 2.5.4PreparationsSection 2.5.4TAMSULOSIN HYDROCHLORIDECautions care with initial dose (postural hypotension);cataract surgery (risk of intra-operative floppy irissyndrome); interactions: Appendix 1 (alpha-blockers)Driving May affect performance of skilled tasks e.g. drivingContra-indications history of postural hypotensionHepatic impairment avoid in severe impairmentRenal impairment use with caution if estimatedglomerular filtration rate less than 10 mL/minute/1.73 m 2Side-effects dizziness, headache, asthenia; abnormalejaculation; less commonly nausea, vomiting, constipation,diarrhoea, palpitation, postural hypotension,syncope, rhinitis, rash, pruritus, and urticaria; veryrarely angioedema and priapism; also drowsiness,blurred vision, dry mouth, and oedema; also reportedintra-operative floppy iris syndromeLicensed use not licensed for use in childrenIndication and doseDysfunctional voiding (see notes above). By mouthChild 12–18 years 400 micrograms once dailyTamsulosin hydrochloride (Non-proprietary) ACapsules, m/r, tamsulosin hydrochloride 400 micrograms,net price 30-cap pack = £4.62. Label: 25,counselling, drivingBrands include Bazetham c MR, Contiflo c XL, Diffundox c XL,Pinexel c PR, Stronazon c MR, Tabphyn c MRFlomaxtra c XL (Astellas) ATablets, m/r, tamsulosin hydrochloride 400 micrograms,net price 30-tab pack = £10.47. Label: 25,counselling, driving7.4.2 Drugs for urinaryfrequency, enuresis, andincontinenceUrinary incontinenceAntimuscarinic drugs reduce symptoms of urgency andurge incontinence and increase bladder capacity; oxybutyninalso has a direct relaxant effect on urinarysmooth muscle. Oxybutynin can be considered firstfor children under 12 years. Side-effects limit the useof oxybutynin, but they may be reduced by starting at alower dose and then slowly titrating upwards; alternativelyoxybutynin can be given by intravesicular instillation.Tolterodine is also effective for urinary incontinence;it can be considered for children over 12 years,or for younger children who have failed to respond tooxybutynin. Modified-release preparations of oxybutyninand tolterodine are available; they may have fewerside-effects. Antimuscarinic treatment should bereviewed soon after it is commenced, and then atregular intervals; a response generally occurs within 6months but occasionally may take longer. Children withnocturnal enuresis may require specific additional measuresif night-time symptoms also need to be controlled(see p. 411).Cautions Antimuscarinic drugs should be used withcaution in autonomic neuropathy and in children susceptibleto angle-closure glaucoma. Antimuscarinicscan worsen hyperthyroidism, congestive heart failure,arrhythmias, and tachycardia. For interactions, seeAppendix 1 (antimuscarinics).Contra-indications Antimuscarinic drugs should beavoided in myasthenia gravis, significant bladder outflowobstruction or urinary retention, severe ulcerativecolitis, toxic megacolon, and in gastro-intestinalobstruction or intestinal atony.Side-effects Side-effects of antimuscarinic drugsinclude dry mouth, gastro-intestinal disturbancesincluding constipation, blurred vision, dry eyes, drowsiness,difficulty in micturition (less commonly urinaryretention), palpitation, and skin reactions (including dryskin, rash, and photosensitivity); also headache, diarrhoea,angioedema, arrhythmias, and tachycardia. Centralnervous system stimulation, such as restlessness,disorientation, hallucination, and convulsions mayoccur. Antimuscarinic drugs may reduce sweating leadingto heat sensations and fainting in hot environmentsor in patients with fever, and very rarely may precipitateangle-closure glaucoma.OXYBUTYNIN HYDROCHLORIDECautions see notes above; acute porphyria (section9.8.2)Contra-indications see notes aboveHepatic impairment manufacturer advises cautionRenal impairment manufacturer advises cautionPregnancy manufacturer advises avoid unless essential—toxicityin animal studiesBreast-feeding manufacturer advises avoid—presentin milk in animal studiesSide-effects see notes above; also dizziness; lesscommonly anorexia, facial flushing; rarely night terrorsLicensed use not licensed for use in children under 5years; intravesical instillation not licensed for use inchildrenIndication and doseUrinary frequency, urgency and incontinence,neurogenic bladder instability. By mouthChild 2–5 years 1.25–2.5 mg 2–3 times daily;

BNFC 2011–2012 7.4.2 Drugs for urinary frequency, enuresis, and incontinence 411Child 5–12 years 2.5–3 mg twice daily, increasedto 5 mg 2–3 times dailyChild 12–18 years 5 mg 2–3 times daily,increased if necessary to max. 5 mg 4 times daily. By intravesical instillationChild 2–18 years 5 mg 2–3 times dailyNocturnal enuresis associated with overactivebladder. By mouthChild 5–18 years 2.5–3 mg twice daily increasedto 5 mg 2–3 times daily (last dose before bedtime)Oxybutynin Hydrochloride (Non-proprietary) ATablets, oxybutynin hydrochloride 2.5 mg, net price56-tab pack = £6.58; 3 mg, 56-tab pack = £9.15; 5 mg,56-tab pack = £5.53, 84-tab pack = £12.50. Label: 3Intravesical instillation, oxybutynin (as hydrochloride)5 mg/30 mL.Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Cystrin c (Winthrop) ATablets, oxybutynin hydrochloride 5 mg (scored), netprice 84-tab pack = £21.99. Label: 3Ditropan c (Sanofi-Aventis) ATablets, both blue, scored, oxybutynin hydrochloride2.5 mg, net price 84-tab pack = £6.59; 5 mg, 84-tabpack = £12.82. Label: 3Modified releaseLyrinel c XL (Janssen) ATablets, m/r, oxybutynin hydrochloride 5 mg (yellow),net price 30-tab pack = £10.81; 10 mg (pink), 30-tab pack = £21.62. Label: 3, 25DoseNeurogenic bladder instability. By mouthChild 6–18 years initially 5 mg once daily adjustedaccording to response in steps of 5 mg at weekly intervals;max. 15 mg once dailyNote Children taking immediate-release oxybutynin may betransferred to the nearest equivalent daily dose of Lyrinel cXLTOLTERODINE TARTRATECautions see notes above; history of QT-interval prolongation;concomitant use with other drugs known toprolong QT intervalContra-indications see notes aboveHepatic impairment reduce dose; avoid Detrusitolc XLRenal impairment reduce dose if estimated glomerularfiltration rate less than 30 mL/minute/1.73 m 2 ;avoid Detrusitol c XL if estimated glomerular filtrationrate less than 30 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid—toxicity inanimal studiesBreast-feeding manufacturer advises avoid—noinformation availableSide-effects see notes above; also chest pain, peripheraloedema; sinusitis, bronchitis; paraesthesia,fatigue, vertigo, weight gain; flushing also reportedLicensed use not licensed for use in childrenIndication and doseUrinary frequency, urgency, incontinence. By mouthChild 2–18 years 1 mg once daily, increasedaccording to response; max. 2 mg twice dailyNocturnal enuresis associated with overactivebladder. By mouthChild 5–18 years 1 mg once daily at bedtime,increased according to response; max. 2 mg twicedailyDetrusitol c (Pharmacia) ATablets, f/c, tolterodine tartrate 1 mg, net price 56-tabpack = £29.03; 2 mg, 56-tab pack = £30.56Modified releaseDetrusitol c XL (Pharmacia) ACapsules, blue, m/r, tolterodine tartrate 4 mg, netprice 28-cap pack = £25.78. Label: 25Note Children stabilised on immediate-release tolteridone2 mg twice daily may be transferred to Detrusitol c XL 4 mgonce dailyNocturnal enuresisNocturnal enuresis is common in young children, butpersists in a small proportion by 10 years of age. Forchildren under 5 years, reassurance and advice on themanagement of nocturnal enuresis can be useful forsome families. Treatment may be considered in childrenover 5 years depending on their maturity and motivation,the frequency of nocturnal enuresis, and the needsof the child and their family.Initially, advice should be given on fluid intake, diet,toileting behaviour, and reward systems; for childrenwho do not respond to this advice, further treatmentmay be necessary. An enuresis alarm should be firstlinetreatment for motivated, well supported children;alarms have a lower relapse rate than drug treatmentwhen discontinued. Treatment should be reviewed after4 weeks, and, if there are early signs of response,continued until a minimum of 2 weeks’ uninterrupteddry nights have been achieved. If complete dryness isnot achieved after 3 months, only continue if the conditionis still improving and the child remains motivatedto use the alarm. If initial alarm treatment is unsuccessful,consider combination treatment with desmopressin(see below), or desmopressin alone if the alarm is nolonger appropriate or desirable.Desmopressin (section 6.5.2), an analogue of vasopressin,is given by oral or by sublingual administration;it should not be given intranasally for nocturnal enuresisdue to an increased incidence of side-effects. Desmopressinalone can be offered to children over 5 years ofage if an alarm is inappropriate or undesirable, or whenrapid or short-term results are the priority (for exampleto cover periods away from home); desmopressin alonecan also be used if there has been a partial response to acombination of desmopressin and an alarm followinginitial treatment with an alarm. Treatment should beassessed after 4 weeks and continued for 3 months ifthere are signs of response. Desmopressin should bewithdrawn at regular intervals (for 1 week every 3months) for full reassessment. Particular care is neededto avoid fluid overload by restricting fluid intake from7 Obstetrics, gynaecology, and urinary-tract disorders

412 7.4.3 Drugs used in urological pain BNFC 2011–20127 Obstetrics, gynaecology, and urinary-tract disorders1 hour before taking desmopressin until 8 hours after.When stopping treatment with desmopressin, gradualwithdrawal should be considered.Nocturnal enuresis associated with daytime symptoms(overactive bladder) can be managed with antimuscarinicdrugs (see Urinary incontinence, p. 410) incombination with desmopressin. Treatment should beprescribed only after specialist assessment and shouldbe continued for 3 months; the course can be repeated ifnecessary.The tricyclic antidepressant imipramine (section 4.3.1)may be considered for children who have not respondedto all other treatments and have undergone specialistassessment, however, behavioural disturbances canoccur and relapse is common after withdrawal. Treatmentshould not normally exceed 3 months unless aphysical examination is made and the child is fullyreassessed; toxicity following overdosage with tricyclicsis of particular concern.7.4.3 Drugs used in urologicalpainLidocaine gel is a useful topical application in urethralpain or to relieve the discomfort of catheterisation(section 15.2).Alkalinisation of urineAlkalinisation of urine can be undertaken with potassiumcitrate. The alkalinising action may relieve thediscomfort of cystitis caused by lower urinary tractinfections.POTASSIUM CITRATECautions cardiac disease; interactions: Appendix 1(potassium salts)Renal impairment close monitoring required—highrisk of hyperkalaemia; avoid in severe impairmentSide-effects hyperkalaemia on prolonged highdosage, mild diuresisIndication and doseRelief of discomfort in mild urinary-tract infections,alkalinisation of urine for dose see preparationsbelowPotassium Citrate Mixture BP(Potassium Citrate Oral Solution)Oral solution, potassium citrate 30%, citric acidmonohydrate 5% in a suitable vehicle with a lemonflavour. Extemporaneous preparations should berecently prepared according to the following formula:potassium citrate 3 g, citric acid monohydrate 500 mg,syrup 2.5 mL, quillaia tincture 0.1 mL, lemon spirit0.05 mL, double-strength chloroform water 3 mL,water to 10 mL. Contains about 28 mmol K + /10 mL.Label: 27Dose. By mouthChild 1–6 years 5 mL 3 times daily well diluted withwaterChild 6–18 years 10 mL 3 times daily well diluted withwaterNote Proprietary brands of potassium citrate are on sale tothe public for the relief of discomfort in mild urinary-tractinfections7.4.4 Bladder instillations andurological surgeryBladder infection Various solutions are available asirrigations or washouts.Aqueous chlorhexidine (section 13.11.2) can be used inthe management of common infections of the bladderbut it is ineffective against most Pseudomonas spp.Solutions containing chlorhexidine 1 in 5000 (0.02%)are used, but they may irritate the mucosa and causeburning and haematuria (in which case they should bediscontinued); sterile sodium chloride solution 0.9%(physiological saline) is usually adequate and is preferredas a mechanical irrigant.Dissolution of blood clots Clot retention is usuallytreated by irrigation with sterile sodium chloride solution0.9% but sterile sodium citrate solution forbladder irrigation 3% may also be helpful.Maintenance of indwelling urinarycathetersThe deposition which occurs in catheterised patients isusually chiefly composed of phosphate and to minimisethis the catheter (if latex) should be changed at least asoften as every 6 weeks. If the catheter is to be left forlonger periods a silicone catheter should be usedtogether with the appropriate use of catheter maintenancesolutions. Repeated blockage usually indicatesthat the catheter needs to be changed.CATHETER PATENCY SOLUTIONSChlorhexidine 0.02%Brands include Uro-Tainer Chlorhexidine c , 100-mLsachet = £2.60Sodium chloride 0.9%Brands include OptiFlo S c , 50- and 100-mL sachets =£3.20; Uriflex S c , 100-mL sachet = £2.40; UriflexSP c , with integral drug additive port, 100-mL sachet= £2.40; Uro-Tainer Sodium Chloride c , 50- and 100-mL sachets = £3.25; Uro-Tainer M c , with integraldrug additive port, 50- and 100-mL sachets = £2.90Solution GCitric acid 3.23%, magnesium oxide 0.38%, sodiumbicarbonate 0.7%, disodium edetate 0.01%. Brandsinclude OptiFlo G c , 50- and 100-mL sachets = £3.40;Uriflex G c , 100-mL sachet = £2.40; Uro-Tainer cTwin Suby G, 2 30-mL = £4.46Solution RCitric acid 6%, gluconolactone 0.6%, magnesiumcarbonate 2.8%, disodium edetate 0.01%. Brandsinclude OptiFlo R c , 50- and 100-mL sachets = £3.40;Uriflex R c , 100-mL sachet = £2.40; Uro-Tainer cTwin Solutio R, 2 30-mL = £4.46

BNFC 2011–2012 7.4.5 Drugs for erectile dysfunction 4137.4.5 Drugs for erectiledysfunctionThis section is not included in BNF for Children. Adolescentspresenting with erectile dysfunction should bereferred to a specialist.7 Obstetrics, gynaecology, and urinary-tract disorders

414 BNFC 2011–20128 Malignant disease andimmunosuppression8 Malignant disease and immunosuppression8.1 Cytotoxic drugs 4148.1.1 Alkylating drugs 4198.1.2 Cytotoxic antibiotics 4218.1.3 Antimetabolites 4238.1.4 Vinca alkaloids and etoposide 4268.1.5 Other antineoplastic drugs 4278.2 Drugs affecting the immuneresponse 4318.2.1 Antiproliferative immunosuppressants4318.2.2 Corticosteroids and otherimmunosuppressants 4338.2.3 Rituximab and alemtuzumab 4388.2.4 Other immunomodulating drugs 4398.3 Sex hormones and hormoneantagonists in malignant disease4418.1 Cytotoxic drugs8.1.1 Alkylating drugs8.1.2 Cytotoxic antibiotics8.1.3 Antimetabolites8.1.4 Vinca alkaloids and etoposide8.1.5 Other antineoplastic drugsThe management of childhood cancer is complex and isgenerally confined to specialist regional centres andsome associated shared-care units.Cytotoxic drugs have both anti-cancer activity and thepotential for damage to normal tissue. In children,chemotherapy is almost always started with curativeintent, but may be continued as palliation if the diseaseis refractory.Chemotherapy with a combination of two or morecytotoxic drugs aims to reduce the development ofresistance and to improve cytotoxic effect. Treatmentprotocols generally incorporate a series of treatmentcourses at defined intervals with clear criteria forstarting each course, such as adequate bone-marrowrecovery and renal or cardiac function. The principalcomponent of treatment for leukaemias in children iscytotoxic therapy, whereas solid tumours may be managedwith surgery or radiotherapy in addition tochemotherapy.Guidelines for handling cytotoxic drugs. Trained personnel should reconstitute cytotoxics;. Reconstitution should be carried out in designatedpharmacy areas;. Protective clothing (including gloves, gowns,and masks) should be worn;. The eyes should be protected and means of firstaid should be specified;. Pregnant staff should avoid exposure to cytotoxicdrugs (all females of child-bearing ageshould be informed of the reproductive hazard);. Use local procedures for dealing with spillagesand safe disposal of waste material, includingsyringes, containers, and absorbent material;. Staff exposure to cytotoxic drugs should bemonitored.Only medical or nursing staff who have received appropriatetraining should administer parenteral cytotoxics.In most instances central venous access will be requiredfor the intravenous administration of cytotoxics to children;care is required to avoid the risk of extravasation(see Side-effects of Cytotoxic Drugs and their Management).

BNFC 2011–2012 8.1 Cytotoxic drugs 415Intrathecal chemotherapyA Health Service Circular (HSC 2008/001) providesguidance on the introduction of safe practice in NHSTrusts where intrathecal chemotherapy is administered;written local guidance covering all aspects ofnational guidance should be available. Support fortraining programmes is also available.Copies, and further information may be obtainedfrom:Department of HealthPO Box 777London SE1 6XHFax: 01623 724524www.dh.gov.ukSafe system requirements for cytotoxic medicines:. Cytotoxic drugs for the treatment of cancer shouldbe given as part of a wider pathway of care that isco-ordinated by a multi-disciplinary team;. Cytotoxic drugs should be prescribed, dispensedand administered only in the context of a writtenprotocol or treatment plan;. Injectable cytotoxic drugs should only be dispensedif they are prepared for administration;. Oral cytotoxic medicines should be dispensed withclear directions for use.Risks of incorrect dosing of oral anti-cancermedicinesThe National Patient Safety Agency has advised(January 2008) that the prescribing and use of oralcytotoxic medicines should be carried out to thesame standard as parenteral cytotoxic therapy. Standardsto be followed to achieve this include:. non-specialists who prescribe or administer oralcytotoxic medication should have access towritten protocols and treatment plans, includingguidance on the monitoring and treatment oftoxicity. staff dispensing oral cytotoxic medicines shouldconfirm that the prescribed dose is appropriatefor the patient. Patients and their carers shouldhave written information that includes details ofthe intended oral anti-cancer regimen, the treatmentplan, and arrangements for monitoring,taken from the original protocol from the initiatinghospital. Staff dispensing oral cytotoxicmedicines should also have access to this information,and to advice from an experiencedcancer pharmacist in the initiating hospitalDosesDoses of cytotoxic drugs are determined using avariety of different methods including age, bodysurfacearea, or body-weight. Alternatively, dosesmay be fixed. Doses may be further adjusted followingconsideration of a patient’s neutrophil count,renal and hepatic function, and history of previousadverse effects to the cytotoxic drug. Doses mayalso differ depending on whether a drug is usedalone or in combination.Because of the complexity of dosage regimens in thetreatment of malignant disease, dose statementshave been omitted from many of the drug entriesin this chapter.Side-effects of cytotoxic drugs andtheir managementSide-effects common to most cytotoxic drugs are discussedbelow whilst side-effects characteristic of a particulardrug or class of drugs (e.g. neurotoxicity withvinca alkaloids) are mentioned in the appropriate sections.Manufacturers’ product literature, hospital-trustprotocols, and treatment protocols should be consultedfor full details of side-effects of individual drugs.Side-effects of cytotoxic drugs often do not occur at thetime of administration, but days or weeks later. It istherefore important that children, their carers, andhealthcare professionals can identify symptoms thatcause concern and can contact an expert for advice.Toxicities should be accurately recorded using a recognisedscoring system such as the Common ToxicityCriteria for Adverse Events (CTCAE) developed by theNational Cancer institute.Extravasation of intravenous drugs A number ofcytotoxic drugs will cause severe local tissue irritationand necrosis if leakage into the extravascular compartmentoccurs. For information on the prevention andmanagement of extravasation injury, see section 10.3.Gastro-intestinal effects Management of gastrointestinaleffects of cytotoxic drugs includes the use ofantacids, H 2 -receptor antagonists, and proton pumpinhibitors to protect the gastric mucosa, laxatives totreat constipation, and enteral and parenteral nutritionalsupport.Oral mucositis Good oral hygiene keeps the mouthclean and moist and helps to prevent mucositis; preventionis more effective than treatment of the complication.Good oral hygiene measures for children over 6months include brushing teeth with a soft small brushwith fluoride toothpaste 2–3 times daily, and rinsing themouth frequently. Daily fluoride supplements (section9.5.3) can be used on the advice of the child’s dentalteam. For children under 6 months or when it is notpossible to brush teeth, carers should be instructed howto clean the mouth using an oral sponge moistened withwater or with an antimicrobial solution such as dilutedchlorhexidine. Mucositis related to chemotherapy canbe extremely painful and may, in some circumstances,require opioid analgesia (section 4.7.2). Secondaryinfection with candida is frequent; treatment with asystemically absorbed antifungal, such as fluconazole(section 5.2), is effective.Nausea and vomiting Nausea and vomiting causeconsiderable distress to many children who receivechemotherapy, and to a lesser extent abdominal radiotherapy,and may lead to refusal of further treatment;prophylaxis of nausea and vomiting is therefore extremelyimportant. Symptoms may be acute (occurringwithin 24 hours of treatment), delayed (first occurringmore than 24 hours after treatment), or anticipatory(occurring prior to subsequent doses). Delayed andanticipatory symptoms are more difficult to controlthan acute symptoms and require different management.Susceptibility to nausea and vomiting may increase withrepeated exposure to the cytotoxic drug.Drugs may be divided according to their emetogenicpotential and some examples are given below, but the8 Malignant disease and immunosuppression

416 8.1 Cytotoxic drugs BNFC 2011–20128 Malignant disease and immunosuppressionsymptoms vary according to the dose, to other drugsadministered, and to the individual’s susceptibility toemetogenic stimuli.Mildly emetogenic treatment—fluorouracil, etoposide,low doses of methotrexate, the vinca alkaloids, andabdominal radiotherapy.Moderately emetogenic treatment—carboplatin, doxorubicin,intermediate and low doses of cyclophosphamide,mitoxantrone, and high doses of methotrexate.Highly emetogenic treatment—cisplatin, dacarbazine,and high doses of alkylating drugs.Anti-emetic drugs, when given regularly, help prevent orameliorate emesis associated with chemotherapy inchildren.Prevention of acute symptoms For patients at low riskof emesis, pretreatment with metoclopramide (or lesscommonly domperidone) continued for up to 24 hoursafter chemotherapy, is often effective (section 4.6); a5HT 3 -receptor antagonist (section 4.6) may also be ofbenefit.For patients at high risk of emesis or when other treatmentis inadequate, a 5HT 3 -receptor antagonist (section4.6) is often highly effective. The addition of dexamethasoneand other anti-emetics may also be required.Prevention of delayed symptoms Dexamethasone,given by mouth, is the drug of choice for preventingdelayed symptoms; it is used alone or with metoclopramide.The 5HT 3 -receptor antagonists may have arole in preventing uncontrolled symptoms.Prevention of anticipatory symptoms Good symptomcontrol is the best way to prevent anticipatory symptoms.Lorazepam can be helpful for its amnesiac, sedative,and anxiolytic effects.Bone-marrow suppression All cytotoxic drugsexcept vincristine and bleomycin cause bone-marrowdepression. This commonly occurs 7 to 10 days afteradministration, but is delayed for certain drugs, such asmelphalan. Peripheral blood counts must be checkedbefore each treatment. The duration and severity ofneutropenia can be reduced by the use of granulocytecolonystimulating factors (section 9.1.6); their useshould be reserved for children who have previouslyexperienced severe neutropenia.Infection in a child with neutropenia requires immediatebroad-spectrum antibacterial treatment that covers alllikely pathogens (Table 1, section 5.1). Appropriatebacteriological investigations should be conducted assoon as possible. All children should be investigated andtreated under the supervision of an appropriate oncologyor haematology specialist. Antifungal treatment(section 5.2) may be required in a child with prolongedneutropenia or fever lasting longer than 4–5 days.Chickenpox and measles can be particularly hazardousin immunocompromised children. Varicella–zosterimmunoglobulin (section 14.5.2) is indicated if thechild does not have immunity against varicella andhas had close contact with infectious chickenpox orherpes zoster. Antiviral prophylaxis (section 5.3.2.1)can be considered in addition to varicella–zosterimmunoglobulin or as an alternative if varicella–zosterimmunoglobulin is inappropriate. If an immunocompromisedchild has come into close contact with an infectiousindividual with measles, normal immunoglobulin(section 14.5.1) should be given.For advice on the use of live vaccines in individuals withimpaired immune response, see section 14.1.Alopecia Reversible hair loss is a common complication,although it varies in degree between drugs andindividual patients.Pregnancy and reproductive function Most cytotoxicdrugs are teratogenic and should not be administeredduring pregnancy, especially during the first trimester.Considerable caution is necessary if a pregnantwoman presents with cancer requiring chemotherapy,and specialist advice should always be sought.Contraceptive advice should be given to men andwomen before cytotoxic therapy begins (and shouldcover the duration of contraception required after therapyhas ended).Regimens that do not contain an alkylating drug mayhave less effect on fertility, but those with an alkylatingdrug carry the risk of causing permanent male sterility(there is no effect on potency). Pretreatment counsellingand consideration of sperm storage may be appropriate.Women are less severely affected, though the span ofreproductive life may be shortened by the onset of apremature menopause. No increase in fetal abnormalitiesor abortion rate has been recorded in patients whoremain fertile after cytotoxic chemotherapy.Long-term and delayed toxicity Cytotoxic drugsmay produce specific organ-related toxicity in children(e.g. cardiotoxicity with doxorubicin or nephrotoxicitywith cisplatin and ifosfamide). Manifestations of suchtoxicity may not appear for several months or evenyears after cancer treatment. Careful follow-up of survivorsof childhood cancer is therefore vital; national andlocal guidelines have been developed to facilitate this.Thromboembolism Venous thromboembolism canbe a complication of cancer itself, but chemotherapyincreases the risk.Tumour lysis syndrome Tumour lysis syndromeoccurs secondary to spontaneous or treatment relatedrapid destruction of malignant cells. Patients at risk oftumour lysis syndrome include those with non-Hodgkin’slymphoma (especially if high grade and bulkydisease), Burkitt’s lymphoma, acute lymphoblastic leukaemiaand acute myeloid leukaemia (particularly if highwhite blood cell counts or bulky disease), and occasionallythose with solid tumours. Pre-existing hyperuricaemia,dehydration and renal impairment are also predisposingfactors. Features, include hyperkalaemia,hyperuricaemia, and hyperphosphataemia with hypocalcaemia;renal damage and arrhythmias can follow.Early recognition of patients at risk, and initiation ofprophylaxis or therapy for tumour lysis syndrome, isessential.Drugs for cytotoxic-induced sideeffectsAnthracycline-induced cardiotoxicityThe anthracycline cytotoxic drugs are associated withdose-related, cumulative, and potentially life-threateningcardiotoxic side-effects.

BNFC 2011–2012 8.1 Cytotoxic drugs 417Dexrazoxane, an iron chelator, is licensed in adults forthe prevention of chronic cumulative cardiotoxicitycaused by doxorubicin or epirubicin treatment inadvanced or metastatic cancer patients who have previouslyreceived anthracycline therapy. In practice, dexrazoxaneis used for any patient receiving anthracyclinetherapy with evidence of subclinical cardiotoxicitythought to be secondary to anthracycline therapy, orfor those children at risk of anthracycline-induced cardiotoxicity.Children receiving dexrazoxane should continueto be monitored for cardiac toxicity. The myelosuppresiveeffects of dexrazoxane may be additive tothose of chemotherapy.DEXRAZOXANECautions see notes above; monitor full blood countHepatic impairment monitor liver functionRenal impairment use with caution—risk of accumulation;manufacturer of Cardioxane c advisesreduce dose by 50% if creatinine clearance less than40 mL/minute/1.73 m 2Pregnancy avoid unless essential (toxicity in animalstudies); ensure effective contraception during and for3 months after treatment in men and womenBreast-feeding discontinue breast-feedingSide-effects nausea, vomiting, dyspepsia, abdominalpain, diarrhoea, stomatitis, dry mouth, anorexia;dyspnoea; dizziness, syncope, asthenia, paraesthesia,tremor, fatigue, drowsiness; pyrexia; vaginalhaemorrhage; myalgia; blood disorders (includinganaemia, leucopenia, neutropenia, and thrombocytopenia);alopecia, pruritus; peripheral oedema, injection-sitereactions including phlebitis; also reportedsecondary malignanciesIndication and dosePrevention of anthracycline-induced cardiotoxicity(see notes above). By intravenous infusion, 30 minutes prior toanthracycline administration10–20 times the doxorubicin-equivalent dose(depending on treatment protocol) or 10 times theepirubicin-equivalent doseAdministration for intravenous infusion reconstituteeach vial with 25 mL Water for Injections then dilutecontents of each vial with 25–100 mL CompoundSodium Lactate; give over 15 minutesCardioxane c (Novartis) TAIntravenous infusion, powder for reconstitution,dexrazoxane (as hydrochloride), net price 500-mg vial= £156.57HyperuricaemiaHyperuricaemia, which may be present in high-gradelymphoma and leukaemia, can be markedly worsenedby chemotherapy and is associated with acute renalfailure.Allopurinol is used routinely in children at low tomoderate risk of hyperuricaemia. It should be started24 hours before treatment; patients should be adequatelyhydrated (consideration should be given toomitting phosphate and potassium from hydrationfluids). The dose of mercaptopurine or azathioprineshould be reduced if allopurinol is given concomitantly(see Appendix 1).Rasburicase is a recombinant urate oxidase used inchildren who are at high-risk of developing hyperuricaemia.It rapidly reduces plasma uric acid and may be ofparticular value in preventing complications followingtreatment of leukaemias or bulky lymphomas.ALLOPURINOLCautions ensure adequate fluid intake; for hyperuricaemiaassociated with cancer therapy, allopurinoltreatment should be started before cancer therapy;interactions: Appendix 1 (allopurinol)Hepatic impairment reduce dose, monitor hepaticfunctionRenal impairment manufacturer advises reduce doseor increase dose interval in severe impairment; adjustdose to maintain plasma-oxipurinol concentrationbelow 100 micromol/litrePregnancy toxicity not reported; manufactureradvises use only if no safer alternative and diseasecarries risk for mother or childBreast-feeding present in milk—not known to beharmfulSide-effects rashes (withdraw therapy; if rash mildre-introduce cautiously but discontinue immediatelyif recurrence—hypersensitivity reactions occur rarelyand include exfoliation, fever, lymphadenopathy,arthralgia, and eosinophilia resembling Stevens-Johnson or toxic epidermal necrolysis, vasculitis,hepatitis, renal impairment, and very rarely seizures);gastro-intestinal disorders; rarely malaise, headache,vertigo, drowsiness, visual and taste disturbances,hypertension, alopecia, hepatotoxicity, paraesthesiaand neuropathy, blood disorders (including leucopenia,thrombocytopenia, haemolytic anaemia andaplastic anaemia)Indication and doseProphylaxis of hyperuricaemia associated withcancer chemotherapy, prophylaxis of hyperuricaemicnephropathy, enzyme disorders causingincreased serum urate e.g. Lesch-Nyhansyndrome. By mouthChild 1 month–15 years 10–20 mg/kg daily(max. 400 mg daily), preferably after foodChild 15–18 years initially 100 mg daily,increased according to response; max. 900 mgdaily (doses over 300 mg daily given in divideddoses); preferably after foodAllopurinol (Non-proprietary) ATablets, allopurinol 100 mg, net price 28-tab pack =£1.18; 300 mg, 28-tab pack = £1.32. Label: 8, 21, 27Brands include Caplenal c , Cosuric c , Rimapurinol cZyloric c (Aspen) ATablets, allopurinol 100 mg, net price 100-tab pack =£10.19; 300 mg, 28-tab pack = £7.31. Label: 8, 21, 27Extemporaneous formulations available seeExtemporaneous Preparations, p. 6RASBURICASECautions monitor closely for hypersensitivity; atopicallergies; may interfere with test for uric acid—consultproduct literatureContra-indications G6PD deficiency (section 9.1.5)8 Malignant disease and immunosuppression

418 8.1 Cytotoxic drugs BNFC 2011–20128 Malignant disease and immunosuppressionPregnancy manufacturer advises avoid—no informationavailableBreast-feeding manufacturer advises avoid—noinformation availableSide-effects fever; nausea, vomiting; less frequentlydiarrhoea, headache, hypersensitivity reactions(including rash, bronchospasm and anaphylaxis);haemolytic anaemia, methaemoglobinaemiaLicensed use not licensed for use in childrenIndication and doseProphylaxis and treatment of acute hyperuricaemiawith initial chemotherapy for haematologicalmalignancy. By intravenous infusionConsult local treatment protocol for detailsFasturtec c (Sanofi-Aventis) AIntravenous infusion, powder for reconstitution,rasburicase, net price 1.5-mg vial (with solvent) =£57.88; 7.5-mg vial (with solvent) = £241.20Methotrexate-induced mucositis andmyelosuppressionFolinic acid (given as calcium folinate) is used tocounteract the folate-antagonist action of methotrexateand thus speed recovery from methotrexate-inducedmucositis or myelosuppression (‘folinic acid rescue’).The calcium salt of levofolinic acid, a single isomer offolinic acid, is also used following methotrexate administration.The dose of calcium levofolinate is generallyhalf that of calcium folinate.The disodium salts of folinic acid and levofolinic acidare also used for rescue therapy following methotrexateadministration.The efficacy of high dose methotrexate is enhanced bydelaying initiation of folinic acid for at least 24 hours,local protocols define the correct time. Folinic acid isnormally continued until the plasma-methotrexate concentrationfalls to 45–90 nanograms/mL (100–200 nanomol/litre).In the treatment of methotrexate overdose, folinateshould be administered immediately; other measuresto enhance the elimination of methotrexate are alsonecessary.Indication and doseSee under preparationCalcium folinate(Calcium leucovorin)Calcium Folinate (Non-proprietary) ATablets, scored, folinic acid (as calcium salt) 15 mg,net price 10-tab pack = £39.20, 30-tab pack = £85.74Brands include Refolinon cNote Not all strengths and pack sizes are available from allmanufacturersInjection, folinic acid (as calcium salt) 3 mg/mL, netprice 1-mL amp = £4.00, 10-mL amp = £4.62; 7.5 mg/mL, net price 2-mL amp = £7.80; 10 mg/mL, net price5-mL vial = £19.41, 10-mL vial = £35.09, 30-mL vial =£94.69, 35-mL vial = £90.98Brands include Refolinon cNote Not all strengths and pack sizes are available from allmanufacturersInjection, powder for reconstitution, folinic acid (ascalcium salt), net price 15-mg vial = £4.46; 30-mg vial= £8.36DoseReduction of methotrexate-induced toxicity. By mouth, by intravenous injection or byintravenous infusionSee notes above. Consult local treatment protocol fordetailsMethotrexate overdose. By intravenous injection or by intravenous infusionSee notes above. Consult local treatment protocol fordetailsMegaloblastic anaemia due to folate deficiency. By mouthChild up to 12 years 250 microgram/kg once dailyChild 12–18 years 15 mg once dailyMetabolic disorders leading to folate deficiency. By mouth or by intravenous infusionChild up to 18 years 15 mg once daily; larger doses maybe required in older childrenFOLINIC ACIDCautions avoid simultaneous administration ofmethotrexate; not indicated for pernicious anaemia orother megaloblastic anaemias due to vitamin B 12deficiency; interactions: Appendix 1 (folates)Safe PracticeIntrathecal injection contra-indicatedPregnancy not known to be harmful; benefit outweighsriskBreast-feeding presence in milk unknown but benefitoutweighs riskSide-effects rarely pyrexia after parenteral use; gastro-intestinaldisturbances, insomnia, agitation, anddepression after high dosesLicensed use consult product literature for licensingstatus of individual preparationsPrevention of megaloblastic anaemia associated withpyrimethamine and sulfadiazine treatment of congenitaltoxoplasmosis. By mouthNeonate 5 mg 3 times a week (increased up to 20 mg 3times a week if neutropenic)Child 1 month–1 year 10 mg 3 times a weekDisodium folinateSodiofolin c (Medac) AInjection, folinic acid (as disodium salt) 50 mg/mL,net price 2-mL vial = £35.09, 8-mL vial = £126.25, 18-mL vial = £284.07DoseAntidote to methotrexate. By intravenous injection or by intravenous infusionConsult local treatment protocols for details

BNFC 2011–2012 8.1.1 Alkylating drugs 419LEVOFOLINIC ACIDNote Levofolinic acid is an isomer of folinic acidCautions see Folinic acidSafe PracticeIntrathecal injection contra-indicatedPregnancy see Folinic acidBreast-feeding see Folinic acidSide-effects see Folinic acidIndication and doseReduction of methotrexate-induced toxicity. By intramuscular injection or by intravenousinjection or by intravenous infusionSee notes above. Consult local treatment protocolfor detailsMethotrexate overdose. By intramuscular injection or by intravenousinjection or by intravenous infusionSee notes above. Consult local treatment protocolfor detailsCalcium levofolinate(Calcium levoleucovorin)Calcium Levofolinate (Non-proprietary)Injection, levofolinic acid (as calcium salt) 10 mg/mL,net price 17.5-mL vial = £84.63Isovorin c (Wyeth) AInjection, levofolinic acid (as calcium salt) 10 mg/mL,net price 2.5-mL vial = £11.62, 17.5-mL vial = £81.33Disodium levofolinateLevofolinic Acid (Non-proprietary) AInjection, levofolinic acid (as disodium salt) 50 mg/mL, net price 1-mL vial = £24.70, 4-mL vial = £80.40Urothelial toxicityHaemorrhagic cystitis is a common manifestation ofurothelial toxicity which occurs with the oxazaphosphorines,cyclophosphamide and ifosfamide; it is causedby the metabolite acrolein. Adequate hydration is essentialto reduce the risk of urothelial toxicity. Mesna reactsspecifically with acrolein in the urinary tract, preventingtoxicity. Mesna is given for the same duration as cyclophosphamideor ifosfamide. It is generally given intravenously;the dose of mesna is equal to or greater thanthat of the oxazaphosphorine. For the role of nebulisedmesna as a mucolytic in cystic fibrosis, see section 3.7.MESNAContra-indications hypersensitivity to thiol-containingcompoundsPregnancy not known to be harmfulSide-effects nausea, vomiting, colic, diarrhoea, fatigue,headache, limb and joint pains, depression, irritability,rash, hypotension and tachycardia; rarelyhypersensitivity reactions (more common in patientswith auto-immune disorders)Licensed use not licensed for use in childrenIndication and doseUrothelial toxicity following oxazaphosphorinetherapy. By intravenous injection or by continuousintravenous infusionSee notes above. Consult local treatment protocolfor detailsMucolytic in cystic fibrosis section 3.7Mesna (Non-proprietary) ATablets, f/c, mesna 400 mg, net price 10-tab pack =£42.90; 600 mg, 10-tab pack = £61.10Injection, mesna 100 mg/mL, net price 4-mL amp =£3.95; 10-mL amp = £9.77Note For oral administration contents of ampoule are takenin a flavoured drink such as orange juice or cola which maybe stored in a refrigerator for up to 24 hours in a sealedcontainer8.1.1 Alkylating drugsExtensive experience is available with these drugs,which are among the most widely used in cancerchemotherapy. They act by damaging DNA, thus interferingwith cell replication. In addition to the side-effectscommon to many cytotoxic drugs (section 8.1), problemsassociated specifically with alkylating drugsinclude:. an adverse effect on gametogenesis which may bereversible, particularly in females; amenorrhoeamay also occur, which also may be reversible;. a marked increase in the incidence of secondarytumours and leukaemia, particularly when alkylatingdrugs are combined with extensive irradiation;. fluid retention with oedema and dilutional hyponatraemiain younger children; the risk of this complicationis higher in the first 2 days and also whengiven with concomitant vinca alkaloids;. urothelial toxicity with intravenous use; adequatehydration may reduce this risk; mesna (section 8.1)provides further protection against urotoxic effectsof cyclophosphamide and ifosfamide.BUSULFAN(Busulphan)Cautions see section 8.1 and notes above; monitor fullblood count regularly throughout treatment; monitorliver function; previous mediastinal or pulmonaryradiation therapy; avoid in acute porphyria (but seesection 9.8.2); interactions: Appendix 1 (busulfan)Hepatic impairment manufacturer advises monitorhepatic function—no information availablePregnancy avoid (teratogenic in animals); manufacturersadvise effective contraception during and for 6months after treatment in men or women; see alsoPregnancy and Reproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; alsohepatotoxicity (including hepatic veno-occlusive disease,hyperbilirubinaemia, jaundice, and fibrosis);cardiac tamponade in thalassaemia; pneumonia, skinhyperpigmentation; rarely progressive pulmonary8 Malignant disease and immunosuppression

420 8.1.1 Alkylating drugs BNFC 2011–20128 Malignant disease and immunosuppressionfibrosis, seizures, aplastic anaemia, visual disturbances,hypersensitivity reactions (including urticaria,erythema); very rarely myasthenia gravis, gynaecomastiaIndication and doseConditioning treatment before haematopoieticstem-cell transplantation. By mouth or by intravenous infusionConsult local treatment protocol for detailsMyleran c (GSK) ATablets, f/c, busulfan 2 mg, net price 25-tab pack =£5.20Busilvex c (Fabre) AConcentrate for intravenous infusion, busulfan6 mg/mL, net price 10-mL vial = £201.25BusulfanCapsules, busulfan 25 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, p. 809Extemporaneous formulations available seeExtemporaneous Preparations, p. 6CHLORAMBUCILCautions see section 8.1 and notes above; monitor fullblood count regularly throughout treatment;increased seizure risk in children with nephroticsyndrome or history of epilepsy; avoid in acute porphyria(but see section 9.8.2)Hepatic impairment manufacturer advises considerdose reduction in severe impairment—limited informationavailablePregnancy avoid; manufacturer advises effectivecontraception during treatment in men or women; seealso Pregnancy and Reproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; also lesscommonly skin rash (possible progression to Stevens-Johnson syndrome and toxic epidermal necrolysis);rarely seizures, hepatotoxicity and jaundice; veryrarely irreversible bone-marrow suppression, pulmonaryfibrosis, tremor, peripheral neuropathy, sterilecystitis, sterility in prepubertal and pubertal malesLicensed use not licensed for use in nephroticsyndromeIndication and doseHodgkin’s disease. By mouthConsult local treatment protocol for detailsNon-Hodgkin’s lymphoma. By mouthConsult local treatment protocol for detailsRelapsing steroid-sensitive nephroticsyndrome; initiated in specialist centres (seealso section 6.3.2, p. 371). By mouthChild 3 months–18 years 200 micrograms/kgonce daily for 8 weeksLeukeran c (GSK) ATablets, f/c, brown, chlorambucil 2 mg, net price 25-tab pack = £8.36Extemporaneous formulations available seeExtemporaneous Preparations, p. 6CYCLOPHOSPHAMIDECautions see section 8.1 and notes above; previous orconcurrent mediastinal irradiation—risk of cardiotoxicity;diabetes mellitus; avoid in acute porphyria(but see section 9.8.2); interactions: Appendix 1(cyclophosphamide)Contra-indications haemorrhagic cystitisHepatic impairment reduce dose—consult localtreatment protocol for detailsRenal impairment reduce dose—consult local treatmentprotocol for detailsPregnancy avoid; manufacturer advises effectivecontraception during and for at least 3 months aftertreatment in men or women; see also Pregnancy andReproductive Function, p. 416Breast-feeding discontinue breast-feeding during andfor 36 hours after stopping treatmentSide-effects see section 8.1 and notes above; alsoanorexia; pancreatitis; cardiotoxicity at high doses;interstitial pulmonary fibrosis; inappropriate secretionof anti-diuretic hormone, disturbances of carbohydratemetabolism; urothelial toxicity; pigmentation ofpalms, nails and soles; rarely hepatotoxicity and renaldysfunctionLicensed use not licensed for use in childrenIndication and doseAcute lymphoblastic leukaemia, non-Hodgkin’slymphoma, retinoblastoma, neuroblastoma,rhabdomyosarcoma, soft-tissue sarcomas,Ewing tumour, neuroectodermal tumours(including medulloblastoma), infant braintumours, ependymona, high-dose conditioningfor bone marrow transplantation, lupusnephritis. By mouth or by intravenous infusionConsult local treatment protocol for detailsSteroid-sensitive nephrotic syndrome see alsosection 6.3.2, p. 371. By mouthChild 3 months–18 years 2–3 mg/kg once dailyfor 8 weeks. By intravenous infusionChild 3 months–18 years 500 mg/m 2 once amonth for 6 monthsAdministration Consult local treatment protocol fordetailsCyclophosphamide (Non-proprietary) ATablets, s/c, cyclophosphamide (anhydrous) 50 mg,net price 100 = £20.20. Label: 25, 27Injection, powder for reconstitution, cyclophosphamide,net price 500-mg vial = £5.66; 1-g vial = £10.66Extemporaneous formulations available seeExtemporaneous Preparations, p. 6

BNFC 2011–2012 8.1.2 Cytotoxic antibiotics 421IFOSFAMIDECautions see section 8.1 and notes above; ensuresatisfactory electrolyte balance, and renal functionbefore each course (risk of tubular dysfunction, Fanconi’ssyndrome, or diabetes insipidus if renal toxicitynot treated promptly); avoid in acute porphyria (butsee section 9.8.2); interactions: Appendix 1 (ifosfamide)Contra-indications urinary tract obstruction; acuteinfection (including urinary-tract infection); urothelialdamageHepatic impairment avoidRenal impairment avoidPregnancy avoid (teratogenic and carcinogenic inanimals); manufacturer advises adequate contraceptionduring and for at least 6 months after treatmentin men or women; see also Pregnancy andReproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; alsodrowsiness, confusion, disorientation, restlessness,psychosis; urothelial toxicity causing haemorrhagiccystitis and dysuria, renal toxicity (see Cautionsabove); less commonly severe encephalopathy; rarelydiarrhoea, constipation, convulsions, anorexia; veryrarely jaundice, thrombophlebitis, syndrome of inappropriateantidiuretic hormone secretionIndication and doseRhabdomyosarcoma, soft-tissue sarcomas,Ewing tumour, germ cell tumour, osteogenicsarcoma. By intravenous infusionConsult local treatment protocol for detailsIfosfamide (Non-proprietary) AInjection, powder for reconstitution, ifosfamide, netprice 1-g vial = £43.53; 2-g vial = £88.62 (hosp. only)MELPHALANCautions see section 8.1 and notes above; monitor fullblood count before and throughout treatment; forhigh-dose intravenous administration establish adequatehydration (see notes above), consider use ofprophylactic anti-infective agents; haematopoieticstem cell transplantation essential for high dosetreatment (consult local treatment protocol fordetails); avoid in acute porphyria (but see section9.8.2); interactions: Appendix 1 (melphalan)Renal impairment reduce dose initially—consultproduct literaturePregnancy avoid; manufacturer advises adequatecontraception during treatment in men or women; seealso Pregnancy and Reproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes aboveLicensed use childhood neuroblastomaIndication and doseHigh intravenous dose with haematopoieticstem cell transplantation in the treatment ofchildhood neuroblastoma and some otheradvanced embryonal tumours. Intravenous infusionConsult local treatment protocol for detailsAlkeran c (GSK) AInjection, powder for reconstitution, melphalan50 mg (as hydrochloride). Net price 50-mg vial (withsolvent-diluent) = £33.138.1.2 Cytotoxic antibioticsCytotoxic antibiotics are widely used. Many act asradiomimetics and simultaneous use of radiotherapyshould be avoided because it may markedly increasetoxicity.Daunorubicin, doxorubicin, and epirubicin areanthracycline antibiotics. Mitoxantrone (mitozantrone)is an anthracycline derivative.All anthracycline antibiotics have been associated withvarying degrees of cardiac toxicity—this may be idiosyncraticand reversible, but is commonly related tototal cumulative dose and is irreversible. Cardiac functionshould be monitored before and at regular intervalsthroughout treatment and afterwards. Caution is necessarywith concomitant use of cardiotoxic drugs, or drugsthat reduce cardiac contractility. Anthracycline antibioticsshould not normally be used in children withleft ventricular dysfunction. Epirubicin and mitoxantroneare considered less toxic, and may be suitablefor children who have received high cumulative doses ofother anthracyclines. Dexrazoxane can be used toprevent chronic cumulative cardiotoxicity, see section8.1.BLEOMYCINCautions see section 8.1; ensure monitoring of pulmonaryfunction—investigate any shortness of breathbefore initiation; caution in handling—irritant to tissuesContra-indications acute pulmonary infection or significantlyreduced lung functionRenal impairment reduce dose—consult local treatmentprotocol for detailsPregnancy avoid (teratogenic and carcinogenic inanimal studies); see also Pregnancy and ReproductiveFunction, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1, less bone marrow suppression;anorexia; pulmonary toxicity e.g. pulmonaryfibrosis (usually dose-related and delayed); fever(directly following administration), fatigue; dermatologicaland mucous membrane toxicity, localised skinhyperpigmentation; rarely cardiorespiratory collapseand hyperpyrexiaLicensed use not licensed for use in childrenIndication and doseSome germ cell tumours, Hodgkin’s lymphoma. By intravenous infusionConsult local treatment protocol for detailsBleomycin (Non-proprietary) AInjection, powder for reconstitution, bleomycin (assulphate), net price 15 000-unit vial = £15.56Note To conform to the European Pharmacopoeia vialspreviously labelled as containing ‘15 units’ of bleomycin arenow labelled as containing 15 000 units. The amount ofbleomycin in the vial has not changed.Brands include Bleo-Kyowa c8 Malignant disease and immunosuppression

422 8.1.2 Cytotoxic antibiotics BNFC 2011–20128 Malignant disease and immunosuppressionDACTINOMYCIN(Actinomycin D)Cautions see section 8.1 and notes above; caution inhandling—irritant to tissuesHepatic impairment consider dose reduction if raisedserum bilirubin or biliary obstruction; consult localtreatment protocolsPregnancy avoid (teratogenic in animal studies); seealso Pregnancy and Reproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; lesscommonly cheilitis, dysphagia; fever, malaise,lethargy; anaemia, hypoglycaemia; myalgia; acne;rarely hepatotoxicity (possibly dose-related)Licensed use not licensed for use in children under12 yearsIndication and doseWilms’ tumour, childhood rhabdomyosarcomaand other soft tissue sarcomas, Ewing’s sarcoma. By intravenous injectionConsult local treatment protocol for detailsCosmegen Lyovac c (Ovation) AInjection, powder for reconstitution, dactinomycin,net price 500-microgram vial = £6.75DAUNORUBICINCautions see section 8.1 and notes above; caution inhandling—irritant to tissuesContra-indications myocardial insufficiency, recentmyocardial infarction, severe arrhythmia; previoustreatment with maximum cumulative doses of daunorubicinor other anthracyclineHepatic impairment reduce dose according to serumbilirubin concentration—consult local treatment protocolfor details; avoid in severe impairmentRenal impairment reduce dose—consult local treatmentprotocol for details; avoid in severe impairmentPregnancy avoid (teratogenic and carcinogenic inanimal studies), see also Pregnancy and ReproductiveFunction, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above, leucopenia,less commonly mucositis; cardiac toxicity(usually 1–6 months after initiation of therapy); fever;red urine discolourationLicensed use DaunoXome c not licensed for use inchildrenIndication and doseAcute myelogenous leukaemia, acute lymphocyticleukaemia. By intravenous infusionConsult local treatment protocol for detailsDaunorubicin (Non-proprietary) AInjection, powder for reconstitution, daunorubicin (ashydrochloride), net price 20-mg vial = £55.00Lipid formulationDaunoXome c (Gilead) AConcentrate for intravenous infusion, daunorubicinencapsulated in liposomes. For dilution before use, netprice 50-mg vial = £137.67DOXORUBICIN HYDROCHLORIDECautions see section 8.1 and notes above; caution inhandling—irritant to tissues; interactions: Appendix1 (doxorubicin)Contra-indications severe myocardial insufficiency,recent myocardial infarction, severe arrhythmia; previoustreatment with maximum cumulative doses ofdoxorubicin or other anthracyclineHepatic impairment reduce dose according to bilirubinconcentration—consult local treatment protocolfor details; avoid in severe impairmentPregnancy avoid (teratogenic and toxic in animalstudies); manufacturer of liposomal product adviseseffective contraception during and for at least 6months after treatment in men or women; see alsoPregnancy and Reproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; redurine discoloration; thrombophlebitis over injectionsite; less commonly bronchospasm, fever, amenorrhoea,and skin rashLicensed use not licensed for use in childrenIndication and dosePaediatric malignancies including Ewing’s sarcoma,osteogenic sarcoma, Wilms’ tumour,neuroblastoma, retinoblastoma, some livertumours, acute lymphoblastic leukaemia,Hodgkin’s lymphoma, non-Hodgkin’s lymphoma. By intravenous infusionConsult local treatment protocol for detailsDoxorubicin (Non-proprietary) AInjection, powder for reconstitution, doxorubicinhydrochloride, net price 10-mg vial = £18.72; 50-mgvial = £96.86Injection, doxorubicin hydrochloride 2 mg/mL, netprice 5-mL vial = £20.60, 25-mL vial = £103.00, 100-mL vial = £275.00EPIRUBICIN HYDROCHLORIDECautions see section 8.1 and notes above; caution inhandling—irritant to tissuesContra-indications severe myocardial insufficiency,recent myocardial infarction, severe arrhythmia,unstable angina, myocardiopathy; previous treatmentwith maximum cumulative doses of epirubicin orother anthracyclineHepatic impairment reduce dose according to bilirubinconcentration—consult local treatment protocolfor details; avoid in severe impairmentRenal impairment dose reduction may be necessaryin severe impairmentPregnancy avoid (carcinogenic in animal studies); seealso Pregnancy and Reproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; redurine discoloration; anaphylaxisLicensed use not licensed for use in childrenIndication and doseRecurrent acute lymphoblastic leukaemia,rhabdomyosarcoma, other soft tissue tumoursof childhood. Intravenous infusionConsult local treatment protocol for details

BNFC 2011–2012 8.1.3 Antimetabolites 423Epirubicin hydrochloride (Non-proprietary) AInjection, epirubicin hydrochloride 2 mg/mL, netprice 5-mL vial = £18.31, 25-mL vial = £92.13, 50-mLvial = £95.54, 100-mL vial = £306.20Injection, powder for reconstitution, epirubicinhydrochloride, net price 50-mg vial = £91.54Pharmorubicin c Solution for Injection (Pharmacia)AInjection, epirubicin hydrochloride 2 mg/mL, netprice 5-mL vial = £19.31, 25-mL vial = £96.54, 100-mLvial = £386.16MITOXANTRONE(Mitozantrone)Cautions see section 8.1 and notes aboveHepatic impairment use with caution—consult localtreatment protocolPregnancy avoid; effective contraception during andfor at least 6 months after treatment in men orwomen; see also Pregnancy and Reproductive Function,p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; transientblue-green discoloration of urine; less commonlygastro-intestinal bleeding, anorexia, allergic reactions,dyspnoea, fatigue, fever, amenorrhoea, and transientblue discoloration of skin and nailsLicensed use not licensed for use in childrenIndication and doseAcute myeloid leukaemia, recurrent acutelymphoblastic leukaemia. By intravenous infusionConsult local treatment protocol for detailsMitoxantrone (Non-proprietary) AConcentrate for intravenous infusion, mitoxantrone(as hydrochloride) 2 mg/mL, net price 10-mL vial =£100.00Onkotrone c (Baxter) AConcentrate for intravenous infusion, mitoxantrone(as hydrochloride) 2 mg/mL, net price 10-mL vial =£121.85, 12.5-mL vial = £152.33, 15-mL vial = £203.048.1.3 AntimetabolitesAntimetabolites are incorporated into new nuclearmaterial or they combine irreversibly with cellularenzymes and prevent normal cellular division.Cytarabine, fludarabine, mercaptopurine, methotrexate,and tioguanine are commonly used in paediatricchemotherapy.Methotrexate inhibits the enzyme dihydrofolate reductase,essential for the synthesis of purines and pyrimidines.It is given by mouth, intravenously, intramuscularly,or intrathecally. Methotrexate causesmyelosuppression, mucositis, and rarely pneumonitis.It is contra-indicated in significant renal impairmentbecause it is excreted primarily by the kidney. It is alsocontra-indicated in patients with severe hepatic impairment.It should also be avoided in the presence ofsignificant pleural effusion or ascites because it canaccumulate in these fluids, and its subsequent returnto the circulation may cause myelosuppression. Systemictoxicity may follow intrathecal administrationand blood counts should be carefully monitored. Folinicacid (section 8.1) following methotrexate administrationhelps to prevent methotrexate-induced mucositis andmyelosuppression.Cytarabine acts by interfering with pyrimidine synthesis.It is given subcutaneously, intravenously, orintrathecally. It is a potent myelosuppressant andrequires careful haematological monitoring. A liposomalformulation of cytarabine for intrathecal use is availablefor lymphomatous meningitis.Fludarabine is generally well tolerated but does causemyelosuppression, which may be cumulative.Fludarabine has a potent and prolonged immunosuppressiveeffect. Children treated with fludarabineare more prone to serious bacterial, opportunisticfungal, and viral infections, and prophylactic therapyis recommended in children at risk. To preventpotentially fatal transfusion-related graft-versushostreaction, only irradiated blood products shouldbe administered. Prescribers should consult specialistliterature when using highly immunosuppressivedrugs.Clofarabine is licensed for the treatment of acutelymphoblastic leukaemia in children who have relapsedor are refractory after receiving at least two previousregimens. It is given by intravenous infusion.Nelarabine is licensed for the treatment of T-cell acutelymphoblastic leukaemia and T-cell lymphoblasticlymphoma in children who have relapsed or who arerefractory after receiving at least two previous regimens.It is given by intravenous infusion. Neurotoxicityis common with nelarabine, and close monitoring forneurological events is strongly recommended—discontinuetreatment if neurotoxicity occurs.Mercaptopurine is used as maintenance therapy foracute lymphoblastic leukaemia and in the managementof ulcerative colitis and Crohn’s disease (section 1.5).Azathioprine, which is metabolised to mercaptopurine,is generally used as an immunosuppressant (section8.2.1 and section 10.1.3). The dose of both drugs shouldbe reduced if the child is receiving allopurinol since itinterferes with their metabolism. For the role of thiopurinemethyltransferase (TPMT) in the metabolism ofazathioprine see section 8.2.1.Tioguanine (thioguanine) is given by mouth for thetreatment of acute lymphoblastic leukaemia; it is givenat various stages of treatment in short-term cycles.Tioguanine has a lower incidence of gastro-intestinalside-effects than mercaptopurine. Long-term therapywith tioguanine is no longer recommended because ofthe high risk of liver toxicity.CLOFARABINECautions see section 8.1; cardiac diseaseHepatic impairment manufacturer advises caution inmild to moderate impairment; avoid in severeimpairmentRenal impairment manufacturer advises caution inmild to moderate impairment; avoid in severeimpairmentPregnancy manufacturer advises avoid (teratogenic inanimal studies); see also Pregnancy and ReproductiveFunction, p. 416Breast-feeding discontinue breast-feeding8 Malignant disease and immunosuppression

424 8.1.3 Antimetabolites BNFC 2011–20128 Malignant disease and immunosuppressionSide-effects see section 8.1; also diarrhoea, abdominalpain, jaundice; tachycardia, flushing, hypotension,pericardial effusion, oedema, haematoma;dyspnoea, cough; anxiety, agitation, dizziness, drowsiness,headache, paraesthesia, peripheral neuropathy,restlessness; haematuria; arthralgia, myalgia; rash,pruritus, hand-foot (desquamative) syndrome,increased sweating; pancreatitis also reportedLicensed use not licensed for use in children under 1yearIndication and doseRelapsed or refractory acute lymphoblasticleukaemia. By intravenous infusionConsult local treatment protocol for detailsEvoltra c (Genzyme) TAConcentrate for intravenous infusion, clofarabine1 mg/mL, net price 20-mL vial = £1153.20Electrolytes Na + 3.08 mmol/vialCYTARABINECautions see section 8.1 and notes above; interactions:Appendix 1 (cytarabine)Hepatic impairment reduce doseRenal impairment consult local treatment protocolsPregnancy avoid (teratogenic in animal studies); seealso Pregnancy and Reproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above;‘cytarabine syndrome’—6–12 hours after intravenousadministration—characterised by fever and malaise,myalgia, bone pain, maculopapular rash, and occasionallychest pain; less commonly conjunctivitis(consider prophylactic corticosteroid eye drops),neurotoxicity, renal and hepatic dysfunction, jaundice;rarely severe spinal cord toxicity following intrathecaladministrationLicensed use Depocyte c intrathecal injection notlicensed for use in childrenIndication and doseAcute lymphoblastic leukaemia, acute myeloidleukaemia, non-Hodgkin’s lymphoma. By intravenous injection, by intravenous infusion,or by subcutaneous injectionConsult local treatment protocol for detailsMeningeal leukaemia, meningeal neoplasms. By intrathecal injectionConsult local treatment protocol for detailsNote Based on weight or body-surface area, children maytolerate higher doses of cytarabine than adultsCytarabine (Non-proprietary) AInjection (for intravenous, subcutaneous or intrathecaluse), cytarabine 20 mg/mL, net price 5-mL vial =£4.00Injection (for intravenous or subcutaneous use),cytarabine 20 mg/mL, net price 5-mL vial = £3.90, 25-mL vial = £19.50Injection (for intravenous or subcutaneous use),cytarabine 100 mg/mL, net price 1-mL vial = £4.00; 5-mL vial = £20.00; 10-mL vial = £39.00; 20-mL vial =£77.50Lipid formulation for intrathecal useDepoCyte c (Napp) AIntrathecal injection, cytarabine encapsulated inliposomes, net price 50-mg vial = £1223.75FLUDARABINE PHOSPHATECautions see section 8.1 and notes above; monitor forsigns of haemolysis; monitor for neurological toxicity;worsening of existing and increased susceptibility toskin cancer; interactions: Appendix 1 (fludarabine)Contra-indications haemolytic anaemiaRenal impairment reduce dose by up to 50% ifcreatinine clearance 30–70 mL/minute/1.73 m 2 ;avoid if creatinine clearance less than 30 mL/minute/1.73 m 2Pregnancy avoid (embryotoxic and teratogenic inanimal studies); manufacturer advises effectivecontraception during and for at least 6 months aftertreatment in men or women; see also Pregnancy andReproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; alsodiarrhoea, anorexia; oedema; pneumonia, cough;peripheral neuropathy, visual disturbances; chills,fever, malaise, weakness; rash; less commonly gastrointestinalhaemorrhage, pulmonary toxicity (includingpulmonary infiltrates, pneumonitis, and fibrosis), andconfusion; rarely heart failure, arrhythmia, coma,seizures, agitation, myelodysplastic syndrome, acutemyeloid leukaemia, optic neuropathy, blindness, Stevens-Johnsonsyndrome, toxic epidermal necrolysis,skin cancer, and haemorrhagic cystitisLicensed use not licensed for use in childrenIndication and dosePoor prognosis or relapsed acute myeloidleukaemia, relapsed acute lymphoblastic leukaemia,conditioning before bone marrowtransplantation. By mouth, by intravenous injection, or byintravenous infusionConsult local treatment protocol for detailsFludarabine phosphate (Non-proprietary) AInjection, powder for reconstitution, fludarabinephosphate, net price 50-mg vial = £140.40Fludara c (Genzyme) ATablets, f/c, pink, fludarabine phosphate 10 mg, netprice 15-tab pack = £268.12, 20-tab pack = £350.70Injection, powder for reconstitution, fludarabinephosphate, net price 50-mg vial = £147.07MERCAPTOPURINE6-MercaptopurineCautions see section 8.1 and notes above; thiopurinemethyltransferase status (see section 8.2.1); monitorliver function—discontinue if jaundice develops;interactions: Appendix 1 (mercaptopurine)Hepatic impairment may need dose reductionRenal impairment manufacturer advises considerreducing dosePregnancy avoid (teratogenic); see also Pregnancyand Reproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; gastrointestinaleffects less common; hepatotoxicity (morefrequent at higher doses); rarely intestinal ulceration,

BNFC 2011–2012 8.1.3 Antimetabolites 425pancreatitis, fever, crystalluria with haematuria, rash,and hyperpigmentation; very rarely lymphomaLicensed use not licensed for use in children foracute lymphoblastic lymphoma or T-cell non-Hodgkins lymphomaIndication and doseAcute lymphoblastic leukaemia, lymphoblasticlymphomas. By mouthConsult local treatment protocol for detailsSevere ulcerative colitis and Crohn’s diseasesection 1.5.3Treatment of early stage Burkitt’s lymphoma,non-Hodgkin’s lymphoma, osteogenic sarcoma,some CNS tumours including infant braintumours, acute lymphoblastic leukaemia. By intravenous injection or infusionConsult local treatment protocol for detailsMeningeal leukaemia, treatment and preventionof CNS involvement of leukaemia. By intrathecal injectionConsult local treatment protocol for detailsSevere Crohn’s disease section 1.5.3Puri-Nethol c (GSK) ATablets, yellow, scored, mercaptopurine 50 mg, netprice 25-tab pack = £22.54MercaptopurineCapsules, mercaptopurine 10 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, p. 809Extemporaneous formulations available seeExtemporaneous Preparations, p. 6METHOTREXATECautions see section 8.1 and section 10.1.3; monitorrenal and hepatic function; peptic ulceration, ulcerativecolitis, diarrhoea, and ulcerative stomatitis;porphyria (section 9.8.2); interactions: Appendix 1(methotrexate)Hepatic impairment avoid in severe impairment—consult local treatment protocol for detailsRenal impairment reduce dose—risk of nephrotoxicityat high doses; avoid in severe impairmentPregnancy avoid (teratogenic; fertility may be reducedduring therapy but this may be reversible); manufactureradvises effective contraception during and for atleast 3 months after treatment in men or women; seealso Pregnancy and Reproductive Function, p. 416Breast-feeding discontinue breast-feeding—presentin milkSide-effects see section 8.1; also anorexia, abdominaldiscomfort, dyspepsia, gastro-intestinal ulcerationand bleeding, diarrhoea, toxic megacolon, hepatotoxicity(see Cautions above); hypotension, pericarditis,pericardial tamponade, thrombosis; pulmonaryoedema, pleuritic pain, pulmonary fibrosis, interstitialpneumonitis (see also Pulmonary Toxicity, p. 509);anaphylactic reactions, urticaria; dizziness, fatigue,chills, fever, drowsiness, malaise, headache, moodchanges, abnormal cranial sensations, neurotoxicity,confusion, psychosis, paraesthesia, cerebral oedema;precipitation of diabetes; menstrual disturbances,vaginitis, cystitis, reduced libido, impotence; haematuria,dysuria, renal failure; osteoporosis, arthralgia,myalgia, vasculitis; conjunctivitis, blepharitis, visualdisturbances; rash, pruritus, Stevens-Johnsonsyndrome, toxic epidermal necrolysis, photosensitivity,changes in nail and skin pigmentation, telangiectasia,acne, furunculosis, ecchymosis; injectionsitereactionsIndication and doseMaintenance and remission of acute lymphoblasticleukaemia, lymphoblastic lymphoma. By mouthConsult local treatment protocol for detailsRheumatic disease section 10.1.3Psoriasis section 13.5.3Methotrexate (Non-proprietary) AInjection, methotrexate (as sodium salt) 2.5 mg/mL,net price 2-mL vial = £1.68Injection, methotrexate (as sodium salt) 25 mg/mL,net price 2-mL vial = £3.00, 20-mL vial = £30.00Injection, methotrexate 100 mg/mL (not forintrathecal use), net price 10-mL vial = £78.33, 50-mLvial = £380.07Oral preparationsSection 10.1.3NELARABINECautions see section 8.1 and notes above; previous orconcurrent intrathecal chemotherapy or craniospinalirradiation (increased risk of neurotoxicity)Skilled tasks Drowsiness may affect performance of skilledtasks (e.g. cycling or driving)Pregnancy avoid (teratogenic in animal studies);manufacturer advises effective contraception duringand for at least 3 months after treatment in men andwomen; see also Pregnancy and Reproductive Function,p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; alsoconstipation, diarrhoea; confusion, seizures, drowsiness,peripheral neurological disorders, demyelination,hypoesthesia, paraesthesia, ataxia, tremor,headache, asthenia, fatigue; pyrexia; hypoglycaemia,electrolyte disturbances; arthralgia; benign andmalignant tumours also reportedIndication and doseT-cell acute lymphoblastic leukaemia, T-celllymphoblastic lymphoma. By intravenous infusionConsult local treatment protocol for detailsAtriance c (GSK) TAIntravenous infusion, nelarabine 5 mg/mL, net price50-mL vial = £222.00Electrolytes Na + 3.75 mmol/vialTIOGUANINE(Thioguanine)Cautions see section 8.1 and notes above; thiopurinemethyltransferase status (see section 8.2.1); monitor8 Malignant disease and immunosuppression

426 8.1.4 Vinca alkaloids and etoposide BNFC 2011–20128 Malignant disease and immunosuppressionliver function weekly—discontinue if liver toxicitydevelops; interactions: Appendix 1 (tioguanine)Hepatic impairment reduce doseRenal impairment reduce dosePregnancy avoid (teratogenicity reported when menreceiving tioguanine have fathered children); ensureeffective contraception during treatment in men orwomen; see also Pregnancy and Reproductive Function,p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1; also stomatitis andhepatotoxicity; rarely intestinal necrosis and perforationIndication and doseInfant acute lymphoblastic leukaemia. By mouthConsult local treatment protocol for detailsLanvis c (GSK) ATablets, yellow, scored, tioguanine 40 mg, net price25-tab pack = £54.49Extemporaneous formulations available seeExtemporaneous Preparations, p. 68.1.4 Vinca alkaloids andetoposideThe vinca alkaloids, vinblastine and vincristine areused to treat a variety of cancers including leukaemias,lymphomas, and some solid tumours.Neurotoxicity, usually as peripheral or autonomic neuropathy,occurs with all vinca alkaloids and is a limitingside-effect of vincristine; it occurs less often with vinblastine.Children with neurotoxicity commonly haveperipheral paraesthesia, loss of deep tendon reflexes,abdominal pain, and constipation; ototoxicity has beenreported. If symptoms of neurotoxicity are severe, dosesshould be reduced, but children generally tolerate vincristinebetter than adults. Motor weakness can alsooccur and dose reduction or discontinuation of therapymay be appropriate if motor weakness increases. Recoveryfrom neurotoxic effects is usually slow but complete.Myelosuppression is the dose-limiting side-effect of vinblastine;vincristine causes negligible myelosuppression.The vinca alkaloids may cause reversible alopecia. Theycause severe local irritation and care must be taken toavoid extravasation. Constipation is common with vinblastineand vincristine; prophylactic use of laxativesmay be considered.Safe PracticeVinblastine and vincristine are for intravenousadministration only. Inadvertent intrathecal administrationcan cause severe neurotoxicity, which isusually fatal.The National Patient Safety Agency has advised(August 2008) that teenage patients treated in anadolescent unit should receive their vinca alkaloiddose in a 50 mL minibag. Teenagers and childrentreated in a child unit may receive their vincaalkaloid dose in a syringe.Etoposide, usually given by slow intravenous infusion,is used to treat acute leukaemias, lymphomas, and somesolid tumours. Etoposide may also be given by mouthbut it is unpredictably absorbed.ETOPOSIDECautions see section 8.1 and notes above; interactions:Appendix 1 (etoposide)Hepatic impairment avoid in severe impairmentRenal impairment consider dose reduction—consultlocal treatment protocol for detailsPregnancy avoid (teratogenic in animal studies); seealso Pregnancy and Reproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1, dose limiting myelosuppression,mucositis more common if given withdoxorubicin; anaphylaxis associated with concentratedinfusions; hypotension associated with rapidinfusion; irritant to tissues if extravasatedLicensed use not licensed for use in childrenIndication and doseStage 4 neuroblastoma, germ-cell tumours,intracranial germ-cell tumours, rhabdomyosarcoma,soft-tissue sarcomas, neuroectodermaltumours (including medulloblastoma), relapsedHodgkin’s disease, non-Hodgkin’s lymphoma,Ewing tumour, acute lymphoblastic leukaemia,acute myeloid leukaemia. By mouth or by intravenous infusionConsult local treatment protocol for detailsEtoposide (Non-proprietary) AConcentrate for intravenous infusion, etoposide20 mg/mL, net price 5-mL vial = £12.15, 10-mL vial =£29.00, 25-mL vial = £60.75Brands include Eposin cEtopophos c (Bristol-Myers Squibb) AInjection, powder for reconstitution, etoposide (asphosphate), net price 100-mg vial = £26.17 (hosp.only)Vepesid c (Bristol-Myers Squibb) ACapsules, both pink, etoposide 50 mg, net price 20 =£99.82; 100 mg, 10-cap pack = £87.23 (hosp. only).Label: 23VINBLASTINE SULPHATECautions see section 8.1 and notes above; caution inhandling; interactions: Appendix 1 (vinblastine)Contra-indications see notes aboveSafe PracticeIntrathecal injection contra-indicatedHepatic impairment dose reduction may be necessary—consultlocal treatment protocol for detailsPregnancy avoid (limited experience suggests fetalharm; teratogenic in animal studies); see alsoPregnancy and Reproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; abdominalpain, constipation, leucopenia, muscle pain; lesscommonly peripheral neuropathy; rarely paralyticileus; irritant to tissues if extravasatedLicensed use licensed for use in children (age rangenot specified by manufacturer)

BNFC 2011–2012 8.1.5 Other antineoplastic drugs 427Indication and doseHodgkin’s disease and other lymphomas. By intravenous injectionConsult local treatment protocol for detailsVinblastine (Non-proprietary) AInjection, vinblastine sulphate 1 mg/mL, net price 10-mL vial = £13.09Velbe c (Genus) AInjection, powder for reconstitution, vinblastine sulphate,net price 10-mg amp = £14.15VINCRISTINE SULPHATECautions see section 8.1 and notes above; neuromusculardisease; ileus; caution in handling; interactions:Appendix 1 (vincristine)Contra-indications see notes aboveSafe PracticeIntrathecal injection contra-indicatedHepatic impairment dose reduction may be necessary—consultlocal treatment protocol for detailsPregnancy avoid (teratogenicity and fetal loss in animalstudies); see also Pregnancy and ReproductiveFunction, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; constipation(see notes above), diarrhoea, intestinal necrosis,paralytic ileus may occur in young children; doselimitingneuromuscular effects (see notes above);urinary retention, rarely convulsions followed bycoma; inappropriate secretion of antidiuretic hormone;irritant to tissues if extravasatedLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseAcute leukaemias, lymphomas, paediatric solidtumours. By intravenous injectionConsult local treatment protocol for detailsVincristine (Non-proprietary) AInjection, vincristine sulphate 1 mg/mL, net price 1-mL vial = £13.47; 2-mL vial = £26.66; 5-mL vial =£44.16Oncovin c (Genus) AInjection, vincristine sulphate 1 mg/mL, net price 1-mL vial = £14.18; 2-mL vial = £28.058.1.5 Other antineoplasticdrugsAmsacrineAmsacrine has an action and toxic effects similar tothose of doxorubicin (section 8.1.2) and is given intravenously.It is occasionally used in acute myeloid leukaemia.AMSACRINECautions see section 8.1 and notes above; considermonitoring cardiac function; monitor electrolytes(fatal arrhythmias possible if hypokalaemia); previoustreatment with anthracyclines; also caution in handling—irritantto skin and tissuesHepatic impairment manufacturer advises reduceinitial dose by 20–30%Renal impairment manufacturer advises reduce initialdose by 20–30%Pregnancy avoid (teratogenic and toxic in animalstudies); may reduce fertility; see also Pregnancy andReproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1; mucositis, phlebitis; lesscommonly diarrhoea, cardiotoxicity, haematuria,renal impairment, hepatotoxicity, skin rash; rarelyacute renal failure, grand mal seizuresLicensed use not licensed for use in childrenIndication and doseAcute myeloid leukaemia. By intravenous infusionConsult local treatment protocol for detailsAmsidine c (Goldshield) AConcentrate for intravenous infusion, amsacrine5 mg (as lactate)/mL, when reconstituted by mixingtwo solutions. Net price 1.5-mL (75-mg) amp with13.5-mL diluent vial = £54.08 (hosp. only)AsparaginaseAsparaginase is used almost exclusively in the treatmentof acute lymphoblastic leukaemia. Hypersensitivityreactions may occur and facilities for the managementof anaphylaxis should be available. A number ofdifferent preparations of asparaginase exist and only theproduct specified in the treatment protocol should beused.Crisantaspase is the enzyme asparaginase produced byErwinia chrysanthemi. Preparations of asparaginasederived from Escherichia coli are also available. Childrenwho are hypersensitive to asparaginase derivedfrom one organism may tolerate asparaginase derivedfrom another organism but cross-sensitivity occurs inabout 20–30% of individuals.CRISANTASPASECautions see section 8.1 and notes aboveContra-indications history of pancreatitis related toasparaginase therapyPregnancy avoid; see also Pregnancy and ReproductiveFunction, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1; also liver dysfunction,pancreatitis, diarrhoea; coagulation disorders;lethargy, drowsiness, confusion, dizziness, neurotoxicity,convulsions, headache; less commonly changesin blood lipids, anaphylaxis, hyperglycaemia; rarelyCNS depression; very rarely myalgia; abdominal painand hypertension also reported8 Malignant disease and immunosuppression

428 8.1.5 Other antineoplastic drugs BNFC 2011–20128 Malignant disease and immunosuppressionIndication and doseAcute lymphoblastic leukaemia, acute myeloidleukaemia, non-Hodgkin’s lymphoma. By intravenous, intramuscular or subcutaneousinjectionConsult local treatment protocol for detailsErwinase c (EUSA Pharma) AInjection, powder for reconstitution, crisantaspase,net price 10 000-unit vial = £301.70PreparationsPreparations of asparaginase derived from Escherichiacoli are available but they are not licensed, theyinclude: Medac c asparaginase, Elspar c asparaginase,and Oncaspar c pegaspargase.Dacarbazine and temozolomideDacarbazine is a component of a commonly usedcombination for Hodgkin’s disease (ABVD—doxorubicin[previously Adriamycin c ], bleomycin, vinblastine,and dacarbazine). It is given intravenously.Temozolomide is structurally related to dacarbazineand is used in children for second-line treatment ofmalignant glioma.DACARBAZINECautions see section 8.1; caution in handlingHepatic impairment dose reduction may be requiredin combined hepatic and renal impairment; avoid insevere impairmentRenal impairment dose reduction may be required incombined renal and hepatic impairment; avoid insevere impairmentPregnancy avoid (carcinogenic and teratogenic inanimal studies); ensure effective contraception duringand for at least 6 months after treatment in men orwomen; see also Pregnancy and Reproductive Function,p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1; also anorexia; less commonlyfacial flushing, confusion, headache, seizures,facial paraesthesia, influenza-like symptoms, blurredvision, renal impairment, rash; rarely diarrhoea,hepatotoxicity including liver necrosis and hepaticvein thrombosis, photosensitivity, irritant to skin andtissues, injection-site reactionsIndication and doseHodgkin’s disease, paediatric solid tumours. By intravenous injection or by intravenousinfusionConsult local treatment protocol for detailsDacarbazine (Non-proprietary) AInjection, powder for reconstitution, dacarbazine (ascitrate), net price 100-mg vial = £5.05; 200-mg vial =£7.16; 500-mg vial = £16.50; 600-mg vial = £22.50; 1-gvial = £31.80TEMOZOLOMIDECautions see section 8.1; interactions: Appendix 1(temozolomide)Hepatic impairment use with caution in severeimpairment—no information availableRenal impairment manufacturer advises caution—noinformation availablePregnancy avoid (teratogenic and embryotoxic inanimal studies); manufacturer advises adequatecontraception during treatment; men should avoidfathering a child during and for at least 6 months aftertreatment; see also Pregnancy and ReproductiveFunction, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1Indication and doseTreatment of malignant glioma. By mouthConsult local treatment protocol for detailsTemozolomide (Non-proprietary) ACapsules, temozolomide 5 mg, net price 5-cap pack =£13.58; 20 mg, 5-cap pack = £54.30; 100 mg, 5-cappack = £271.52; 140 mg, 5-cap pack = £380.18;180 mg, 5-cap pack = £488.74; 250 mg, 5-cap pack =£678.80. Label: 23, 25Brands include Temomedac cTemodal c (Schering-Plough) ACapsules, temozolomide 5 mg (green/white), netprice 5-cap pack = £16.29; 20 mg (yellow/white), 5-cap pack = £65.16; 100 mg (pink/white), 5-cap pack =£325.80; 140 mg (blue/white), 5-cap pack = £456.12;180 mg (orange/white), 5-cap pack = £586.44; 250 mg(white), 5-cap pack = £814.50. Label: 23, 25ImatinibImatinib, a tyrosine kinase inhibitor, has recently beenlicensed in children for the treatment of newly diagnosedPhiladelphia-chromosome-positive chronicmyeloid leukaemia when bone marrow transplantationis not considered first line treatment, and for Philadelphia-chromosome-positivechronic myeloid leukaemiain chronic phase after failure of interferon alfa, or inaccelerated phase, or in blast crisis.IMATINIBCautions see section 8.1; cardiac disease; monitor forfluid retention; monitor liver function (see alsoHepatic Impairment, below); interactions: Appendix1 (imatinib)Hepatic impairment start with minimum recommendeddose; reduce dose further if not tolerated;consult local treatment protocolRenal impairment start with minimum recommendeddose; reduce dose further if not tolerated; consultlocal treatment protocolPregnancy manufacturer advises avoid unless potentialbenefit outweighs risk; effective contraceptionrequired during treatment; see also Pregnancy andReproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1; also abdominal pain,appetite changes, constipation, diarrhoea, flatulence,gastro-oesophageal reflux, taste disturbance, weightchanges, dry mouth; oedema (including pulmonaryoedema, pleural effusion, and ascites), flushing,haemorrhage; cough, dyspnoea; dizziness, headache,insomnia, hypoaesthesia, paraesthesia, fatigue; influenza-likesymptoms; cramps, arthralgia; visual disturbances,lacrimation, conjunctivitis, dry eyes; epis-

BNFC 2011–2012 8.1.5 Other antineoplastic drugs 429taxis; dry skin, sweating, rash, pruritus, photosensitivity;less commonly gastric ulceration, pancreatitis,hepatic dysfunction (rarely hepatic failure, hepaticnecrosis), dysphagia, heart failure, tachycardia, palpitation,syncope, hypertension, hypotension, coldextremities, cough, acute respiratory failure, depression,drowsiness, anxiety, peripheral neuropathy, tremor,migraine, impaired memory, vertigo, gynaecomastia,menorrhagia, irregular menstruation, sexualdysfunction, electrolyte disturbances, renal failure,urinary frequency, gout, tinnitus, hearing loss; skinhyperpigmentation; rarely intestinal obstruction,gastro-intestinal perforation, inflammatory boweldisease, arrhythmia, atrial fibrillation, myocardialinfarction, angina, pulmonary fibrosis, pulmonaryhypertension, increased intracranial pressure, convulsions,confusion, haemolytic anaemia, rhabdomyolysis,myopathy, aseptic necrosis of bone, cataract,glaucoma, angioedema, exfoliative dermatitis,and Stevens-Johnson syndromeIndication and doseChronic phase and advanced phase chronicmyeloid leukaemia. By mouthConsult local treatment protocol for detailsGlivec c (Novartis) TATablets, f/c, imatinib (as mesilate) 100 mg (yellowbrown,scored), net price 60-tab pack = £802.04;400 mg (yellow), 30-tab pack = £1604.08. Label: 21, 27Counselling Tablets may be dispersed in water or applejuiceMitotaneMitotane is used in children for the symptomatic treatmentof advanced or inoperable adrenocortical carcinoma.It selectively inhibits the activity of the adrenalcortex, necessitating corticosteroid replacement therapy(section 6.3.1); the dose of glucocorticoid should beincreased in case of shock, trauma, or infection. Neuropsychologicalimpairment can occur, possibly secondaryto hypothyroidism, and growth retardation has alsobeen reported in children treated with mitotane.MITOTANECautions see notes above; risk of accumulation inoverweight patients; monitor plasma-mitotane concentration—consultproduct literature; avoid in acuteporphyria (section 9.8.2); interactions: Appendix 1(mitotane)Skilled tasks Central nervous system toxicity may affectperformance of skilled tasksCounselling Children and their carers should be warned tocontact doctor immediately if injury, infection, or illnessoccurs (because of the risk of acute adrenal insufficiency)Hepatic impairment manufacturer advises caution inmild to moderate impairment—monitoring of plasmamitotaneconcentration recommended; avoid insevere impairmentRenal impairment manufacturer advises caution inmild to moderate renal impairment—monitoring ofplasma-mitotane concentration recommended; avoidin severe impairmentPregnancy manufacturer advises avoid—women ofchild-bearing age should use effective contraceptionduring and after treatment; see also Pregnancy andReproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; alsogastro-intestinal disturbances (including nausea,vomiting, diarrhoea, epigastric discomfort), anorexia,liver disorders; hypercholesterolaemia, hypertriglyceridaemia;ataxia, confusion, asthenia, myasthenia,paraesthesia, drowsiness, neuropathy, cognitiveimpairment, movement disorder, dizziness, headache;gynaecomastia; prolonged bleeding time, leucopenia,thrombocytopenia, anaemia; rash; rarely hypersalivation,hypertension, postural hypotension, flushing,pyrexia, haematuria, proteinuria, haemorrhagic cystitis,hypouricaemia, visual disturbances and oculardisordersLicensed use not licensed for use in childrenIndication and doseSymptomatic treatment of advanced or inoperableadrenocortical carcinoma. By mouthConsult local treatment protocol for detailsLysodren c (HRA Pharma) ATablets, scored, mitotane 500 mg, net price 100-tabpack = £590.97. Label: 2, 10, 21, counselling, skilledtasks, adrenal suppressionPlatinum compoundsCarboplatin is used in the treatment of a variety ofpaediatric malignancies; it is given by intravenous infusion.Carboplatin can be given in an outpatient settingand is better tolerated than cisplatin; nausea and vomitingare less severe and nephrotoxicity, neurotoxicity,and ototoxicity are much less of a problem. Carboplatinis, however, more myelosuppressive than cisplatin.Cisplatin is of value in children with a variety ofmalignancies; it is given by intravenous infusion. Cisplatinrequires intensive intravenous hydration; routineuse of intravenous fluids containing potassium ormagnesium may also be required to help control hypokalaemiaand hypomagnesaemia. Treatment may becomplicated by severe nausea and vomiting; delayedvomiting may occur and is difficult to control. Cisplatinhas dose-related and potentially cumulative side-effectsincluding nephrotoxicity, neurotoxicity, and ototoxicity.Baseline testing of renal function and hearing isrequired; for children with pre-existing renal or hearingimpairment or marked bone-marrow suppression, considerationshould be given to withholding treatment orusing another drug.CARBOPLATINCautions see section 8.1 and notes above; considertherapeutic drug monitoring; interactions: Appendix1 (platinum compounds)Renal impairment reduce dose and monitor haematologicalparameters and renal function; avoid ifcreatinine clearance less than 20 mL/minute/1.73 m 2Pregnancy avoid (teratogenic and embryotoxic inanimal studies); see also Pregnancy and ReproductiveFunction, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes aboveLicensed use not licensed for use in children8 Malignant disease and immunosuppression

430 8.1.5 Other antineoplastic drugs BNFC 2011–20128 Malignant disease and immunosuppressionIndication and doseStage 4 neuroblastoma, germ cell tumours,low-grade gliomas (including astrocytomas),neuroectodermal tumours (including medulloblastoma),rhabdomyosarcoma (metastatic andnon-metastatic disease), soft-tissue sarcomas,retinoblastoma, high risk Wilms’ tumour, someliver tumours. By intravenous infusionConsult local treatment protocol for detailsCarboplatin (Non-proprietary) AInjection, carboplatin 10 mg/mL, net price 5-mL vial= £22.04, 15-mL vial = £56.92, 45-mL vial = £168.85,60-mL vial = £260.00CISPLATINCautions see section 8.1 and notes above; monitor fullblood count, renal function, audiology, and plasmaelectrolytes; interactions: Appendix 1 (platinumcompounds)Renal impairment avoid if possible—nephrotoxicPregnancy avoid (teratogenic and toxic in animalstudies); manufacturer advises effective contraceptionduring and for at least 3 months after treatment inmen or women; see also Pregnancy and ReproductiveFunction, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; alsoperipheral neuropathy; hypophosphataemia, hypocalcaemia,hyperuricaemia also reportedLicensed use not licensed for use in childrenIndication and doseOsteogenic sarcoma, stage 4 neuroblastoma,some liver tumours, infant brain tumours,intracranial germ-cell tumours. By intravenous infusionConsult local treatment protocol for detailsCisplatin (Non-proprietary) AInjection, cisplatin 1 mg/mL, net price 10-mL vial =£5.85, 50-mL vial = £24.50, 100-mL vial = £50.22Injection, powder for reconstitution, cisplatin, netprice 50-mg vial = £17.00ProcarbazineProcarbazine is most often used in Hodgkin’s disease. Itis given by mouth. It is a weak monoamine-oxidaseinhibitor and dietary restriction is rarely considerednecessary. Alcohol ingestion may cause a disulfiramlikereaction.PROCARBAZINECautions see section 8.1 and notes above; interactions:Appendix 1 (procarbazine)Hepatic impairment caution in mild to moderateimpairment; avoid in severe impairmentRenal impairment caution in mild to moderateimpairment; avoid in severe impairmentPregnancy avoid (teratogenic in animal studies andisolated reports in humans); see also Pregnancy andReproductive Function, p. 416Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; hypersensitivityrash (discontinue treatment)Indication and doseHodgkin’s lymphoma, gliomas. By mouthConsult local treatment protocol for detailsProcarbazine (Non-proprietary) ACapsules, ivory, procarbazine (as hydrochloride)50 mg, net price 50-cap pack = £199.60. Label: 4Extemporaneous formulations available seeExtemporaneous Preparations, p. 6TretinoinTretinoin is licensed for the induction of remission inacute promyelocytic leukaemia. It is used in previouslyuntreated children as well as in those who have relapsedafter standard chemotherapy or who are refractory to it.TRETINOINNote Tretinoin is the acid form of vitamin ACautions exclude pregnancy before starting treatment,see also Pregnancy below; monitor full bloodcount and coagulation profile, liver function, serumcalcium and plasma lipids before and during treatment;increased risk of thrombo-embolism during firstmonth of treatment; interactions: Appendix 1 (retinoids)Hepatic impairment reduce dose—consult localtreatment protocol for detailsRenal impairment reduce dose—consult local treatmentprotocol for detailsPregnancy teratogenic; effective contraception mustbe used for at least 1 month before oral treatment,during treatment and for at least 1 month after stopping(oral progestogen-only contraceptives not consideredeffective); see also Pregnancy and ReproductiveFunction, p. 416Breast-feeding discontinue breast-feedingSide-effects retinoic acid syndrome (fever, dyspnoea,acute respiratory distress, pulmonary infiltrates,pleural effusion, hyperleukocytosis, hypotension,oedema, weight gain, hepatic, renal and multi-organfailure) requires immediate treatment—consult productliterature; gastro-intestinal disturbances, pancreatitis;arrhythmias, flushing, oedema; headache,benign intracranial hypertension (children particularlysusceptible—consider dose reduction if intractableheadache), shivering, dizziness, confusion, anxiety,depression, insomnia, paraesthesia, visual and hearingdisturbances (children particularly susceptible tonervous system effects); raised liver enzymes, serumcreatinine and lipids; bone and chest pain, alopecia,erythema, rash, pruritus, sweating, dry skin andmucous membranes, cheilitis; thromboembolism,hypercalcaemia, and genital ulceration reportedIndication and doseAcute promyelocytic leukaemia. By mouthConsult treatment protocol for detailsVesanoid c (Roche) ACapsules, yellow/brown, tretinoin 10 mg, net price100-cap pack = £160.63. Label: 21, 25

BNFC 2011–2012 8.2 Drugs affecting the immune response 4318.2 Drugs affecting theimmune response8.2.1 Antiproliferative immunosuppressants8.2.2 Corticosteroids and otherimmunosuppressants8.2.3 Rituximab and alemtuzumab8.2.4 Other immunomodulating drugsImmunosuppressant therapyImmunosuppressants are used to suppress rejection inorgan transplant recipients and to treat a variety ofchronic inflammatory and autoimmune diseases. Solidorgan transplant patients are usually maintained on acalcineurin inhibitor (ciclosporin or tacrolimus), combinedwith an antiproliferative drug (azathioprine ormycophenolate mofetil) and a corticosteroid. Specialistmanagement is required and other immunomodulatorsmay be used to initiate treatment or to treat rejection.BioavailabilityDifferent formulations of the same immunosuppressantmay vary in bioavailability and to avoid reducedeffect or excessive side-effects, it is important not tochange formulation except on the advice of a transplantspecialist.Impaired immune responsiveness Infections in theimmunocompromised child can be severe and showatypical features. Specific local protocols should befollowed for the management of infection. Corticosteroidsmay suppress clinical signs of infection and allowdiseases such as septicaemia or tuberculosis to reach anadvanced stage before being recognised. Childrenshould be up-to-date with their childhood vaccinationsbefore initiation of immunosuppressant therapy (e.g.before transplantation); vaccination with varicella-zostervaccine (section 14.4) is also necessary during thisperiod—important: for advice on measles exposure,see section 14.5.1, and chickenpox (varicella) exposure,see section 14.5.2. For advice on the use of live vaccinesin individuals with impaired immune response, see section14.1. For general comments and warnings relatingto corticosteroids and immunosuppressants, see section6.3.2.Pregnancy Transplant patients immunosuppressedwith azathioprine should not discontinue it on becomingpregnant. However, there have been reports of prematurebirth and low birth-weight following exposure toazathioprine, particularly in combination with corticosteroids.Spontaneous abortion has been reported followingmaternal or paternal exposure. Azathioprine is teratogenicin animal studies.There is less experience of ciclosporin in pregnancy butit does not appear to be any more harmful than azathioprine.The use of these drugs during pregnancyneeds to be supervised in specialist units.8.2.1 AntiproliferativeimmunosuppressantsAzathioprine is widely used for transplant recipientsand it is also used to treat a number of auto-immuneconditions (see section 10.1.3), usually when corticosteroidtherapy alone provides inadequate control. It ismetabolised to mercaptopurine, and doses should bereduced to one quarter of the original dose when allopurinolis given concurrently. Blood tests and monitoringfor signs of myelosuppression are essential in longtermtreatment with azathioprine.Thiopurine methyltransferaseThe enzyme thiopurine methyltransferase (TPMT)metabolises thiopurine drugs (azathioprine,mercaptopurine, tioguanine); the risk of myelosuppressionis increased in patients with reduced activityof the enzyme, particularly for the few individualsin whom TPMT activity is undetectable. Considermeasuring TPMT activity before starting azathioprine,mercaptopurine, or tioguanine therapy.Patients with absent TPMT activity should notreceive thiopurine drugs; those with reducedTPMT activity may be treated under specialistsupervision.Mycophenolate mofetil is metabolised to mycophenolicacid which has a more selective mode of actionthan azathioprine. It is used in combination with acorticosteroid and either ciclosporin or tacrolimus forthe prophylaxis of acute rejection in transplant recipients.Compared with similar regimens incorporatingazathioprine, mycophenolate mofetil may reduce therisk of acute rejection episodes; the risk of opportunisticinfections (particularly due to tissue-invasive cytomegalovirus)and the occurrence of blood disorderssuch as leucopenia may be higher. Children may suffera high incidence of side-effects, particularly gastrointestinaleffects, calling for temporary reduction indose or interruption of treatment. Cases of pure redcell aplasia have been reported with mycophenolatemofetil; dose reduction or discontinuation of mycophenolatemofetil should be considered under specialistsupervision.NICE guidance (immunosuppressive therapyfor renal transplantation in children andadolescents)See p. 433Cyclophosphamide (section 8.1.1) is less commonlyprescribed as an immunosuppressant.AZATHIOPRINECautions thiopurine methyltransferase status (seenotes above); monitor for toxicity throughout treatment;monitor full blood count weekly (more frequentlywith higher doses or if severe hepatic or renalimpairment) for first 4 weeks (manufacturer advisesweekly monitoring for 8 weeks but evidence of practicalvalue unsatisfactory), thereafter reduce frequencyof monitoring to at least every 3 months;interactions: Appendix 1 (azathioprine)Bone marrow suppression Children and their carers shouldbe warned to report immediately any signs or symptoms of8 Malignant disease and immunosuppression

432 8.2.1 Antiproliferative immunosuppressants BNFC 2011–20128 Malignant disease and immunosuppressionbone marrow suppression e.g. inexplicable bruising orbleeding, infectionContra-indications hypersensitivity to mercaptopurineHepatic impairment reduce dose; monitor liver function;see also CautionsRenal impairment reduce dose; see also CautionsPregnancy see section 8.2; treatment should not normallybe initiated during pregnancyBreast-feeding present in milk in low concentration;no evidence of harm in small studies—use if potentialbenefit outweighs riskSide-effects hypersensitivity reactions (includingmalaise, dizziness, vomiting, diarrhoea, fever, rigors,myalgia, arthralgia, rash, hypotension and interstitialnephritis—calling for immediate withdrawal); doserelatedbone marrow suppression (see also Cautions);liver impairment, cholestatic jaundice, hair loss andincreased susceptibility to infections and colitis inpatients also receiving corticosteroids; nausea; rarelypancreatitis, pneumonitis, hepatic veno-occlusivedisease, lymphomaIndication and doseSuppression of transplant rejection. By mouth, or (if oral route not possible) byintravenous infusion (see also note below)Consult local treatment protocol for detailsChild 1 month–18 years maintenance, 1–3 mg/kg once daily, adjusted according to response; totaldaily dose may alternatively be given in 2 divideddosesSevere ulcerative colitis and Crohn’s diseasesection 1.5.3Systemic lupus erythematosus, vasculitis,auto-immune conditions when corticosteroidtherapy alone has proved inadequate section10.1.3Administration Consult local treatment protocol fordetailsFor intravenous injection, reconstitute 50 mg with 5–15 mL Water for Injections; give over at least 1 minuteFor intravenous infusion, reconstitute 50 mg with 5–15 mL Water for Injections; dilute requisite dose to aconcentration of 0.25–2.5 mg/mL in Glucose 5% orSodium Chloride 0.9%Note Intravenous injection is alkaline and very irritant.Intravenous route should therefore be used only if oral routenot feasible and discontinued as soon as oral route can betolerated. To reduce irritation flush line with infusion fluidAzathioprine (Non-proprietary) ATablets, azathioprine 25 mg, net price 28-tab pack =£6.67; 50 mg, 56-tab pack = £5.56. Label: 21Brands include Azamune cImuran c (Aspen) ATablets, both f/c, azathioprine 25 mg (orange), netprice 100-tab pack = £10.99; 50 mg (yellow), 100-tabpack = £7.99. Label: 21Injection, powder for reconstitution, azathioprine (assodium salt), net price 50-mg vial = £15.38Extemporaneous formulations available seeExtemporaneous Preparations, p. 6MYCOPHENOLATE MOFETILCautions full blood counts every week for 4 weeksthen twice a month for 2 months then every month inthe first year (consider interrupting treatment if neutropeniadevelops); active gastro-intestinal disease(risk of haemorrhage, ulceration and perforation);delayed graft function; increased susceptibility to skincancer (avoid exposure to strong sunlight); possibledecreased effectiveness of vaccination—avoid livevaccines; interactions: Appendix 1 (mycophenolatemofetil)Bone marrow suppression Children and their carers shouldbe warned to report immediately any signs or symptoms ofbone marrow suppression e.g. infection or inexplicablebruising or bleedingRenal impairment manufacturer advises considerdose reduction if estimated glomerular filtration rateless than 25 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid—congenitalmalformations reported; effective contraceptionrequired before treatment, during treatment, and for 6weeks after discontinuation of treatmentBreast-feeding manufacturer advises avoid—presentin milk in animal studiesSide-effects taste disturbance, gingival hyperplasia,nausea, constipation, flatulence, anorexia, weightloss, diarrhoea, vomiting, abdominal pain, gastrointestinalinflammation, ulceration, and bleeding,hepatitis, jaundice, pancreatitis, stomatitis, ileus,pleural effusion, oedema, tachycardia, hypertension,hypotension, vasodilatation, cough, dyspnoea,insomnia, agitation, confusion, depression, anxiety,convulsions, paraesthesia, myasthenic syndrome,tremor, dizziness, headache, influenza-like syndrome,infections, hyperglycaemia, renal impairment, malignancy(particularly of the skin), blood disorders(including leucopenia, anaemia, thrombocytopenia,pancytopenia, and red cell aplasia—see notes above),disturbances of electrolytes and blood lipids, arthralgia,alopecia, acne, skin hypertrophy, and rash; alsoreported intestinal villous atrophy, progressive multifocalleucoencephalopathy, interstitial lung disease,pulmonary fibrosisLicensed use not licensed for use in children under 2years for the prophylaxis of acute rejection in renaltransplantation; not licensed for use in children forthe prophylaxis of acute rejection in hepatic transplantationIndication and doseProphylaxis of acute rejection in renal transplantationin combination with a corticosteroidand ciclosporin. By mouthConsult local treatment protocol for detailsChild 1 month–18 years 600 mg/m 2 twice daily(max. 2 g daily)Prophylaxis of acute rejection in renal transplantationin combination with a corticosteroidand tacrolimus. By mouthConsult local treatment protocol for detailsChild 1 month–18 years 300 mg/m 2 twice daily(max. 2 g daily)

BNFC 2011–2012 8.2.2 Corticosteroids and other immunosuppressants 433Prophylaxis of acute rejection in hepatictransplantation in combination with a corticosteroidand ciclosporin or tacrolimus. By mouthConsult local treatment protocol for detailsChild 1 month–18 years 10 mg/kg twice daily,increased to 20 mg/kg twice daily (max. 2 g daily)Note Tablets and capsules not appropriate for dose titrationin children with body surface area less than 1.25 m 2Mycophenolate Mofetil (Non-proprietary) ACapsules, mycophenolate mofetil 250 mg, net price100-cap pack = £35.00Tablets, mycophenolate mofetil 500 mg, net price 50-tab pack = £31.50Brands include Arzip cCellCept c (Roche) ACapsules, blue/brown, mycophenolate mofetil250 mg, net price 100-cap pack = £82.26Tablets, lavender, mycophenolate mofetil 500 mg, netprice 50-tab pack = £82.26Oral suspension, mycophenolate mofetil 1 g/5 mLwhen reconstituted with water, net price 175 mL =£115.16Excipients include aspartame (section 9.4.1)8.2.2 Corticosteroids and otherimmunosuppressantsThe corticosteroids prednisolone and dexamethasoneare widely used in paediatric oncology; they have amarked antitumour effect. Dexamethasone is preferredfor acute lymphoblastic leukaemia whilst prednisolonemay be used for Hodgkin’s disease, non-Hodgkin’slymphoma, and B-cell lymphoma and leukaemia.Dexamethasone is the corticosteroid of choice in paediatricsupportive and palliative care. For children whoare not receiving a corticosteroid as a component oftheir chemotherapy, dexamethasone may be used toreduce raised intracranial pressure (see p. 19), or tohelp control emesis when combined with an appropriateanti-emetic (see p. 19). For more information on glucocorticoidtherapy, including the disadvantages of treatment,see section 6.3.2.The corticosteroids are also powerful immunosuppressants.They are used to prevent organ transplant rejection,and in high dose to treat rejection episodes.Ciclosporin (cyclosporin), a calcineurin inhibitor, is apotent immunosuppressant which is virtually non-myelotoxicbut markedly nephrotoxic. It may be used inorgan and tissue transplantation, for prevention of graftrejection following bone marrow, kidney, liver, pancreas,heart, lung, and heart-lung transplantation, and forprophylaxis and treatment of graft-versus-host disease.Ciclosporin also has a role in steroid-sensitive and steroid-resistantnephrotic syndrome; in corticosteroid-sensitivenephrotic syndrome it may be given with prednisolone(section 6.3).Tacrolimus is also a calcineurin inhibitor. Although notchemically related to ciclosporin it has a similar mode ofaction and side-effects.Sirolimus is a non-calcineurin inhibiting immunosuppressant.Basiliximab is a monoclonal antibody that prevents T-lymphocyte proliferation; it is used for prophylaxis ofacute rejection in allogeneic renal transplantation. It isgiven with ciclosporin and corticosteroid immunosuppressionregimens; its use should be confined to specialistcentres.Antithymocyte immunoglobulin (rabbit) is used forthe prophylaxis of organ rejection in renal and heartallograft recipients and for the treatment of corticosteroid-resistantallograft rejection in renal transplantation.Tolerability is increased by pretreatment with anintravenous corticosteroid and antihistamine; an antipyreticdrug such as paracetamol may also be beneficial.NICE guidanceImmunosuppressive therapy for renaltransplantation in children and adolescents(April 2006)NICE has recommended that for induction therapyin the prophylaxis of organ rejection, either basiliximabor daclizumab [discontinued] are options forcombining with a calcineurin inhibitor. For eachindividual, ciclosporin or tacrolimus is chosen asthe calcineurin inhibitor on the basis of side-effects.Mycophenolate mofetil is recommended as part ofan immunosuppressive regimen only if:. the calcineurin inhibitor is not tolerated, particularlyif nephrotoxicity endangers the transplantedkidney; or. there is very high risk of nephrotoxicity from thecalcineurin inhibitor, requiring a reduction in thedose of the calcineurin inhibitor or its avoidance.Mycophenolic acid is not recommended as part ofan immunosuppressive regimen for renal transplantationin children or adolescents.Sirolimus [not licensed for use in children] is recommendedas a component of immunosuppressiveregimen only if intolerance necessitates the withdrawalof a calcineurin inhibitor.These recommendations may not be consistent withthe marketing authorisation of some of the products.ANTITHYMOCYTEIMMUNOGLOBULIN (RABBIT)Cautions see notes above; monitor blood countContra-indications infectionPregnancy manufacturer advises use only if potentialbenefit outweighs risk—no information availableBreast-feeding manufacturer advises avoid—noinformation availableSide-effects nausea, vomiting, dysphagia, diarrhoea;hypotension; infusion-related reactions (includingcytokine release syndrome and anaphylaxis, see notesabove), serum sickness; fever, shivering, increasedsusceptibility to infection; increased susceptibility tomalignancy; lymphopenia, neutropenia, thrombocytopenia;myalgia; pruritus, rash8 Malignant disease and immunosuppression

434 8.2.2 Corticosteroids and other immunosuppressants BNFC 2011–20128 Malignant disease and immunosuppressionIndication and doseHeart transplantation. By intravenous infusion over at least 6 hoursChild 1 month–18 years 1–2.5 mg/kg daily for 3–5 days starting the day of transplantationNote To avoid excessive dosage in obese patients, calculatedose on the basis of ideal body weightRenal transplantation. By intravenous infusion over at least 6 hoursChild 1–18 years 1–1.5 mg/kg daily for 3–9 daysstarting the day of transplantationNote To avoid excessive dosage in obese patients, calculatedose on the basis of ideal body weightCorticosteroid-resistant renal graft rejection. By intravenous infusion over at least 6 hoursChild 1–18 years 1.5 mg/kg daily for 7–14 daysNote To avoid excessive dosage in obese patients, calculatedose on the basis of ideal body weightAdministration For continuous intravenous infusionreconstitute each vial with 5 mL water for injections toproduce a solution of 5 mg/mL; gently rotate to dissolve.Dilute requisite dose with Glucose 5% or SodiumChloride 0.9% to an approx. concentration of0.5 mg/mL; begin infusion immediately after dilution;give through an in-line filter (pore size 0.22 micron);incompatible with unfractionated heparin and hydrocortisonein glucose infusion—precipitation reportedThymoglobuline c (Genzyme) TAIntravenous infusion, powder for reconstitution,rabbit anti-human thymocyte immunoglobulin, netprice 25-mg vial = £158.77BASILIXIMABPregnancy manufacturer advises avoid—no informationavailable; adequate contraception must be usedduring treatment and for 16 weeks after last doseBreast-feeding manufacturer advises avoid—noinformation availableSide-effects severe hypersensitivity reactions andcytokine release syndrome reportedIndication and doseProphylaxis of acute rejection in allogeneicrenal transplantation used in combination withciclosporin and corticosteroid-containingimmunosuppression regimens. By intravenous injection or by intravenousinfusionConsult local treatment protocol for detailsChild over 1 year, body-weight under 35 kg10 mg within 2 hours before transplant surgery and10 mg 4 days after surgeryChild body-weight over 35 kg 20 mg within 2hours before transplant surgery and 20 mg 4 daysafter surgeryNote withhold second dose if severe hypersensitivity or graftloss occursAdministration For intravenous infusion, dilutereconstituted solution to a concentration notexceeding 400 micrograms/mL, with Glucose 5% orSodium Chloride 0.9%; give over 20–30 minutesSimulect c (Novartis) AInjection, powder for reconstitution, basiliximab, netprice 10-mg vial = £758.69, 20-mg vial = £842.38(both with water for injections). For intravenous infusionCICLOSPORIN(Cyclosporin)Cautions monitor kidney function—dose dependentincrease in serum creatinine and urea during first fewweeks may necessitate discontinuation (excluderejection of kidney transplant); monitor liver function(see also Hepatic Impairment below); monitor bloodpressure—discontinue if hypertension develops thatcannot be controlled by antihypertensives; hyperuricaemia;monitor serum potassium especially inrenal dysfunction (risk of hyperkalaemia); monitorserum magnesium; measure blood lipids beforetreatment and thereafter as appropriate; monitorwhole blood ciclosporin concentration (trough leveldependent on indication—consult local treatmentprotocol for details); use with tacrolimus specificallycontra-indicated; for patients other than transplantrecipients, preferably avoid other immunosuppressants(increased risk of infection and malignancies,including lymphoma and skin cancer); avoid excessiveexposure to UV light, including sunlight; interactions:Appendix 1 (ciclosporin)Additional cautions in nephrotic syndrome Contra-indicatedin uncontrolled hypertension, uncontrolled infections,and malignancy; in long-term management, perform renalbiopsies every 1–2 yearsAdditional cautions Atopic Dermatitis and Psoriasis, section13.5.3; Rheumatoid Arthritis, section 10.1.3Hepatic impairment dosage adjustment based onbilirubin and liver enzymes may be neededRenal impairment dose as in normal renal functionbut see Cautions above; in nephrotic syndromereduce dose by 25–50% if serum creatinine more than30% above baseline on more than one measurementPregnancy crosses placenta; see ImmunosuppressantTherapy, p. 431Breast-feeding present in milk—manufactureradvises avoidSide-effects anorexia, nausea, vomiting, abdominalpain, diarrhoea, gingival hyperplasia, hepatic dysfunction,hypertension, tremor, headache, paraesthesia,fatigue, renal dysfunction (renal structuralchanges on long-term administration; see also underCautions), hyperuricaemia, hyperkalaemia, hypomagnesaemia,hyperlipidaemia, hypercholesterolaemia,muscle cramps, myalgia, hypertrichosis; lesscommonly oedema, weight gain, signs of encephalopathy,anaemia, thrombocytopenia; rarely pancreatitis,motor polyneuropathy, menstrual disturbances,gynaecomastia, micro-angiopathic haemolytic anaemia,haemolytic uraemic syndrome, hyperglycaemia,muscle weakness, myopathy, visual disturbancessecondary to benign intracranial hypertension (discontinue);also reported with infusion anaphylaxisLicensed use not licensed for use in children under 3months

BNFC 2011–2012 8.2.2 Corticosteroids and other immunosuppressants 435Indication and dosePrevention of graft rejection following bonemarrow,kidney, liver, pancreas, heart, lung,and heart-lung transplantation, prophylaxisand treatment of graft-versus-host disease. By mouth or by intravenous infusionConsult local treatment protocols for detailsNephrotic syndrome see also section 6.3.2, p. 371. By mouthChild 1 month–18 years 3 mg/kg twice daily,increase if necessary in corticosteroid-resistantdisease; for maintenance reduce to lowest effectivedose according to whole blood-ciclosporinconcentrations, proteinuria, and renal functionRefractory ulcerative colitis section 1.5.3Severe psoriasis, severe eczema section 13.5.3ImportantPatients should be stabilised on a particular brand oforal ciclosporin because switching between formulationswithout close monitoring may lead to clinicallyimportant changes in blood-ciclosporin concentration.Prescribing and dispensing of ciclosporin should be bybrand name to avoid inadvertent switching. If it isnecessary to switch a patient to a different brand ofciclosporin, the patient should be monitored closelyfor changes in blood-ciclosporin concentration,serum-creatinine, blood pressure, and transplant function.Capimune c (Mylan) ACapsules, ciclosporin 25 mg (grey), net price 30-cappack = £13.80; 50 mg (white), 30-cap pack = £27.00;100 mg (grey), 30-cap pack = £51.50. Counselling,administrationExcipients include propylene glycol (see Excipients, p. 2)Note Contains ethanolCounselling Total daily dose should be taken in 2 divideddosesDeximune c (Dexcel) ACapsules, grey, ciclosporin 25 mg, net price 30-cappack = £13.94; 50 mg 30-cap pack = £27.31; 100 mg30-cap pack = £51.83. Counselling, administrationNote Contains ethyl lactate which is metabolised to ethanolCounselling Total daily dose should be taken in 2 divideddosesNeoral c (Novartis) ACapsules, ciclosporin 10 mg (yellow/white), net price60-cap pack = £18.48; 25 mg (blue/grey), 30-cap pack= £18.59; 50 mg (yellow/white), 30-cap pack =£36.41; 100 mg (blue/grey), 30-cap pack = £69.11.Counselling, administrationExcipients include propylene glycol (see Excipients, p. 2)Note Contains ethanolOral solution, yellow, sugar-free, ciclosporin 100 mg/mL, net price 50 mL = £103.55. Counselling, administrationExcipients include propylene glycol (see Excipients, p. 2)Note Contains ethanolCounselling Total daily dose should be taken in 2 divideddosesMix solution with orange juice (or squash) or apple juice (toimprove taste) or with water immediately before taking (andrinse with more to ensure total dose). Do not mix withgrapefruit juice. Keep medicine measure away from otherliquids (including water)Sandimmun c (Novartis) AConcentrate for intravenous infusion (oily), ciclosporin50 mg/mL. To be diluted before use, net price 1-mL amp = £1.94; 5-mL amp = £9.17Excipients include polyoxyl castor oil (risk of anaphylaxis, see Excipients,p. 2)Note Contains ethanolAdministration For intravenous infusion, dilute to a concentrationof 0.5–2.5 mg/mL with Glucose 5% or Sodium Chloride 0.9%;give over 2–6 hours; not to be used with PVC equipment; observepatient for signs of anaphylaxis for at least 30 minutes afterstarting infusion and at frequent intervals thereafterSIROLIMUSCautions monitor renal function when given withciclosporin; monitor whole blood-sirolimus troughconcentration (Afro-Caribbean patients may requirehigher doses); hyperlipidaemia (monitor lipids);monitor urine proteins; increased susceptibility toinfection (especially urinary-tract infection); increasedsusceptibility to lymphoma and other malignancies,particularly of the skin (limit exposure to UV light);interactions: Appendix 1 (sirolimus)Hepatic impairment monitor blood-sirolimus troughconcentration; dose reduction may be necessary,consult local treatment protocol for detailsPregnancy avoid unless essential—toxicity in animalstudies; effective contraception must be used duringtreatment and for 12 weeks after stoppingBreast-feeding discontinue breast-feedingSide-effects abdominal pain, constipation, nausea,diarrhoea, ascites, stomatitis, oedema, tachycardia,hypertension, hypercholesterolaemia, hypertriglyceridaemia,venous thromboembolism, pleural effusion,pneumonitis, headache, pyrexia, proteinuria, haemolyticuraemic syndrome, anaemia, thrombocytopenia,thrombotic thrombocytopenic purpura, leucopenia,neutropenia, hypokalaemia, hypophosphataemia,hyperglycaemia, lymphocele, arthralgia, osteonecrosis,epistaxis, acne, rash, impaired healing; less commonlypancreatitis, pulmonary embolism, pulmonaryhaemorrhage, pericardial effusion, nephroticsyndrome, pancytopenia; rarely interstitial lung disease,alveolar proteinosis, hepatic necrosis, lymphoedema,hypersensitivity reactions (including anaphylacticreactions, angiodema, exfoliative dermatitis,hypersensitivity vasculitis); also reported focal segmentalglomerulosclerosis, reversible impairment ofmale fertilityLicensed use not licensed for use in childrenIndication and doseSee NICE guidance, p. 433. By mouthConsult local treatment protocols for detailsRapamune c (Wyeth) ATablets, coated, sirolimus 0.5 mg (tan), net price 30-tab pack = £69.00; 1 mg (white), 30-tab pack = £86.49;2 mg (yellow), 30-tab pack = £172.98. Counselling,administrationImportant The 0.5-mg tablet is not bioequivalent to the 1-mg, 2-mg, and 5-mg tablets. Multiples of 0.5-mg tabletsshould not be used as a substitute for other tablet strengthsOral solution, sirolimus 1 mg/mL, net price 60 mL =£162.41. Counselling, administrationAdministration food may affect absorption (give at the same timewith respect to food). Mix solution with at least 60 mL water ororange juice in a glass or plastic container immediately beforetaking; refill container with at least 120 mL of water or orangejuice and drink immediately (to ensure total dose). Do not mixwith any other liquids8 Malignant disease and immunosuppression

436 8.2.2 Corticosteroids and other immunosuppressants BNFC 2011–20128 Malignant disease and immunosuppressionTACROLIMUSCautions monitor blood pressure, ECG (important:see cardiomyopathy below), fasting blood-glucoseconcentration, haematological and neurological(including visual) parameters, electrolytes, hepaticand renal function; monitor whole blood-tacrolimustrough concentration (especially during episodes ofdiarrhoea)—consult local treatment protocol fordetails; QT-interval prolongation; neurotoxicity;increased risk of infections, malignancies, and lymphoproliferativedisorders; avoid excessive exposureto UV light (including sunlight); pregnancy (excludebefore starting); interactions: Appendix 1 (tacrolimus)Skilled tasks May affect performance of skilled tasks (e.g.driving)Contra-indications hypersensitivity to macrolides;avoid concurrent administration with ciclosporin(care if patient has previously received ciclosporin)Hepatic impairment dose reduction may be necessaryin severe impairmentPregnancy avoid unless potential benefit outweighsrisk—risk of premature delivery, intra-uterine growthrestriction, and hyperkalaemia; toxicity in animalstudiesBreast-feeding avoid—present in milkSide-effects nausea, vomiting, diarrhoea, constipation,dyspepsia, flatulence, bloating, weight changes,anorexia, gastro-intestinal inflammation, ulceration,and perforation, hepatic dysfunction, jaundice,cholestasis, ascites, bile-duct abnormalities, oedema,tachycardia, hypertension, haemorrhage, thromboembolicand ischaemic events, dyspnoea, pleuraleffusion, parenchymal lung disorders, sleep disturbances,tremor, headache, peripheral neuropathy,mood changes, depression, confusion, anxiety, psychosis,seizures, paraesthesia, dizziness, renal impairment,renal failure, renal tubular necrosis, urinaryabnormalities, hyperglycaemia, electrolyte disturbances(including hyperkalaemia, hypokalaemia, andhyperuricaemia), blood disorders (including anaemia,leucopenia, pancytopenia, and thrombocytopenia),arthralgia, muscle cramp, visual disturbances, photophobia,tinnitus, impaired hearing, alopecia, sweating,acne; less commonly paralytic ileus, gastro-intestinalreflux disease, peritonitis, pancreatitis, heart failure,arrhythmia, cardiac arrest, cerebrovascular accident,cardiomyopathy (important: see Cardiomyopathybelow), palpitation, respiratory failure, coma, speechdisorder, amnesia, paralysis, influenza-like symptoms,encephalopathy, coagulation disorders, cataract,photosensitivity, hypoglycaemia, dysmenorrhoea,hypertonia, dermatitis; rarely pericardial effusion,respiratory distress syndrome, posterior reversibleencephalopathy syndrome, dehydration, thromboticthrombocytopenic purpura, blindness, toxic epidermalnecrolysis, hirsutism; very rarely myasthenia,haemorrhagic cystitis, Stevens Johnson syndromeCardiomyopathy Cardiomyopathy has been reported inchildren. Children should be monitored by echocardiographyfor hypertrophic changes—consider dose reduction or discontinuationif these occurLicensed use Advagraf c not licensed for use inchildrenIndication and doseSee under preparations and consult local treatmentprotocolsAtopic eczema (topical use) section 13.5.3ImportantAdoport c , Prograf c , Modigraf c , Vivadex c , andAdvagraf c (tacrolimus): serious medication errorsThere are 3 different oral formulations of tacrolimus:. Adoport c , Prograf c , and Vivadex c are immediate-releasecapsules taken twice daily, once in the morning and once inthe evening;. Modigraf c granules are used to prepare an immediatereleaseoral suspension which is taken twice daily, once inthe morning and once in the evening;. Advagraf c is a prolonged-release capsule that is takenonce daily in the morning.Switching between different oral formulations oftacrolimus requires careful therapeutic monitoring.Changes to oral tacrolimus therapy should be madeonly under the close supervision of a transplant specialist.Administration For continuous intravenous infusionover 24 hours, dilute to a concentration of 4–100 micrograms/mL with Glucose 5% or SodiumChloride 0.9%, to a total volume between 20–500 mL.Tacrolimus is incompatible with PVCAdoport c (Sandoz) ACapsules, tacrolimus (as monohydrate) 500 micrograms(white/ivory), net price 50-cap pack = £50.50;1 mg (white/brown), 50-cap pack = £65.52, 100-cappack = £131.02; 5 mg (white/orange), 50-cap pack =£242.05. Label: 23, counselling, skilled tasksDoseProphylaxis of graft rejection following liver transplantation,starting 12 hours after transplantation. By mouthNeonate initially 150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily, adjusted according to whole-blood concentrationProphylaxis of graft rejection following kidneytransplantation, starting within 24 hours of transplantation. By mouthNeonate initially 150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily, adjusted according to whole-blood concentrationNote A lower initial dose of 100 micrograms/kg twicedaily has been used in adolescents to prevent very high‘trough’ concentrationsProphylaxis of graft rejection following heart transplantationwithout antibody induction, starting within12 hours of transplantation. By mouthNeonate initially 150 micrograms/kg twice daily as soonas clinically possible (8–12 hours after discontinuation ofintravenous infusion), adjusted according to whole-bloodconcentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily as soon as clinically possible (8–12 hours afterdiscontinuation of intravenous infusion), adjustedaccording to whole-blood concentration

BNFC 2011–2012 8.2.2 Corticosteroids and other immunosuppressants 437Prophylaxis of graft rejection following heart transplantationfollowing antibody induction, startingwithin 5 days of transplantation. By mouthNeonate initially 50–150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 50–150 micrograms/kg twice daily, adjusted according to whole-blood concentrationAllograft rejection resistant to conventional immunosuppressivetherapy Consult local treatment protocolModigraf c (Astellas) TAGranules, tacrolimus (as monohydrate), 200 micrograms,net price 50-sachet pack = £71.30; 1 mg, 50-sachet pack = £356.65. Label: 13, 23, counselling,skilled tasksDoseProphylaxis of graft rejection following liver transplantation,starting 12 hours after transplantation. By mouthNeonate initially 150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily, adjusted according to whole-blood concentrationProphylaxis of graft rejection following kidneytransplantation, starting within 24 hours of transplantation. By mouthNeonate initially 150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily, adjusted according to whole-blood concentrationNote A lower initial dose of 100 micrograms/kg twicedaily has been used in adolescents to prevent very high‘trough’ concentrationsProphylaxis of graft rejection following heart transplantationwithout antibody induction starting within12 hours of transplantation. By mouthNeonate initially 150 micrograms/kg twice daily as soonas clinically possible (8–12 hours after discontinuingintravenous infusion), adjusted according to whole-bloodconcentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily as soon as clinically possible (8–12 hours afterdiscontinuing intravenous infusion), adjusted accordingto whole-blood concentrationProphylaxis of graft rejection following heart transplantationfollowing antibody induction startingwithin 5 days of transplantation. By mouthNeonate initially 50–150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 50–150 micrograms/kg twice daily, adjusted according to whole-blood concentrationAllograft rejection resistant to conventional immunosuppressivetherapy Consult local treatment protocolPrograf c (Astellas) ACapsules, tacrolimus (as monohydrate) 500 micrograms(yellow), net price 50-cap pack = £61.88; 1 mg(white), 50-cap pack = £80.28, 100-cap pack =£160.54; 5 mg (greyish-red), 50-cap pack = £296.58.Label: 23, counselling, skilled tasksConcentrate for intravenous infusion, tacrolimus5 mg/mL. To be diluted before use. Net price 1-mLamp = £58.46Excipients include polyoxyl castor oil (risk of anaphylaxis, see Excipients,p. 2)DoseProphylaxis of graft rejection following liver transplantation,starting 12 hours after transplantation. By mouthNeonate initially 150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily, adjusted according to whole-blood concentration. By continuous intravenous infusion (only if oral routeinappropriate)Neonate 50 micrograms/kg over 24 hours for up to 7days (then transfer to oral therapy), adjusted according towhole-blood concentrationChild 1 month–18 years 50 micrograms/kg over 24hours for up to 7 days (then transfer to oral therapy),adjusted according to whole-blood concentrationProphylaxis of graft rejection following kidneytransplantation, starting within 24 hours of transplantation. By mouthNeonate initially 150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily, adjusted according to whole-blood concentrationNote A lower initial dose of 100 micrograms/kg twicedaily has been used in adolescents to prevent very high‘trough’ concentrations. By continuous intravenous infusion (only if oral routeinappropriate)Neonate 75–100 micrograms/kg over 24 hours for up to7 days (then transfer to oral therapy), adjusted accordingto whole-blood concentrationChild 1 month–18 years 75–100 micrograms/kg over24 hours for up to 7 days (then transfer to oral therapy),adjusted according to whole-blood concentrationProphylaxis of graft rejection following heart transplantationwithout antibody induction, starting within12 hours of transplantation. By mouthNeonate initially 150 micrograms/kg twice daily as soonas clinically possible (8–12 hours after discontinuation ofintravenous infusion), adjusted according to whole-bloodconcentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily as soon as clinically possible (8–12 hours afterdiscontinuation of intravenous infusion), adjustedaccording to whole-blood concentration. By continuous intravenous infusionNeonate 30–50 micrograms/kg over 24 hours for up to 7days (then transfer to oral therapy), adjusted according towhole-blood concentrationChild 1 month–18 years 30–50 micrograms/kg over 24hours for up to 7 days (then transfer to oral therapy),adjusted according to whole-blood concentration8 Malignant disease and immunosuppression

438 8.2.3 Rituximab and alemtuzumab BNFC 2011–2012Prophylaxis of graft rejection following heart transplantationfollowing antibody induction, startingwithin 5 days of transplantation. By mouthNeonate initially 50–150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 50–150 micrograms/kg twice daily, adjusted according to whole-blood concentrationAllograft rejection resistant to conventional immunosuppressivetherapy Consult local treatment protocolModified releaseAdvagraf c is not licensed for use in childrenAdvagraf c (Astellas) ACapsules, m/r, tacrolimus (as monohydrate)500 micrograms (yellow/orange), net price 50-cappack = £35.79; 1 mg (white/orange), 50-cap pack =£71.59, 100-cap pack = £143.17; 3 mg (red/orange),50-cap pack = £214.76; 5 mg (red/orange), 50-cappack = £266.92. Label: 23, 25, counselling, skilledtasksExtemporaneous formulations available seeExtemporaneous Preparations, p. 68 Malignant disease and immunosuppressionVivadex c (Dexcel) ACapsules, tacrolimus 500 micrograms (ivory), netprice 50-cap pack = £46.41; 1 mg (white), 50-cap pack= £60.21, 100-cap pack = £120.41; 5 mg (red), 50-cappack = £222.44. Label: 23, counselling, skilled tasksDoseProphylaxis of graft rejection following liver transplantation,starting 12 hours after transplantation. By mouthNeonate initially 150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily, adjusted according to whole-blood concentrationProphylaxis of graft rejection following kidneytransplantation, starting within 24 hours of transplantation. By mouthNeonate initially 150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily, adjusted according to whole-blood concentrationNote A lower initial dose of 100 micrograms/kg twicedaily has been used in adolescents to prevent very high‘trough’ concentrationsProphylaxis of graft rejection following heart transplantationwithout antibody induction, starting within12 hours of transplantation. By mouthNeonate initially 150 micrograms/kg twice daily as soonas clinically possible (8–12 hours after discontinuation ofintravenous infusion), adjusted according to whole-bloodconcentrationChild 1 month–18 years initially 150 micrograms/kgtwice daily as soon as clinically possible (8–12 hours afterdiscontinuation of intravenous infusion), adjustedaccording to whole-blood concentrationProphylaxis of graft rejection following heart transplantationfollowing antibody induction, startingwithin 5 days of transplantation. By mouthNeonate initially 50–150 micrograms/kg twice daily,adjusted according to whole-blood concentrationChild 1 month–18 years initially 50–150 micrograms/kg twice daily, adjusted according to whole-blood concentrationAllograft rejection resistant to conventional immunosuppressivetherapy Consult local treatment protocol8.2.3 Rituximab andalemtuzumabRituximab, a monoclonal antibody which causes lysisof B lymphocytes, has been used as a component of thetreatment of post-transplantation lymphoproliferativedisease, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma,and severe cases of resistant immune modulateddisease including idiopathic thrombocytopenia purpura,haemolytic anaemia, and systemic lupus erythematosus.Full resuscitation facilities should be at hand and aswith other cytotoxics, treatment should be undertakenunder the close supervision of a specialist.Rituximab should be used with caution in childrenreceiving cardiotoxic chemotherapy or with a historyof cardiovascular disease; in adults exacerbation ofangina, arrhythmia, and heart failure have beenreported. Transient hypotension occurs frequently duringinfusion and antihypertensives may need to bewithheld for 12 hours before infusion. Progressive multifocalleucoencephalopathy (which is usually fatal orcauses severe disability) has been reported in associationwith rituximab; children treated with rituximabshould be monitored for cognitive, neurological, orpsychiatric signs and symptoms. If progressive multifocalleucoencephalopathy is suspected, suspend treatmentuntil it has been excluded.Infusion-related side-effects (including cytokine releasesyndrome) are reported commonly with rituximab andoccur predominantly during the first infusion; theyinclude fever and chills, nausea and vomiting, allergicreactions (such as rash, pruritus, angioedema, bronchospasmand dyspnoea), flushing and tumour pain. Childrenshould be given paracetamol and an antihistaminebefore each dose of rituximab to reduce these effects.Premedication with a corticosteroid should also beconsidered. The infusion may have to be stopped temporarilyand the infusion-related effects treated—consultproduct literature or local treatment protocol forappropriate management. Evidence of pulmonary infiltrationand features of tumour lysis syndrome should besought if infusion-related effects occur.Fatalities following severe cytokine release syndrome(characterised by severe dyspnoea) and associated withfeatures of tumour lysis syndrome have occurred 1–2hours after infusion of rituximab. Children with a hightumour burden as well as those with pulmonary insufficiencyor infiltration are at increased risk and should bemonitored very closely (and a slower rate of infusionconsidered).

BNFC 2011–2012 8.2.4 Other immunomodulating drugs 439Alemtuzumab, another monoclonal antibody thatcauses lysis of B and T lymphocytes, has been used inchildren for conditioning therapy before allogeneic bonemarrow transplantation. In common with rituximab, itcauses infusion-related side-effects including cytokinerelease syndrome (see above) and premedication withparacetamol, an antihistamine, and a corticosteroid isrecommended.ALEMTUZUMABCautions see notes above—for full details (includingmonitoring) consult product literature or local treatmentprotocolContra-indications for full details consult product literatureor local treatment protocolPregnancy avoid; manufacturer advises effectivecontraception during and for 6 months after treatmentin men or womenBreast-feeding manufacturer advises avoid breastfeedingduring treatment and for at least 4 weeks aftertreatmentSide-effects see notes above—for full details (includingmonitoring and management of side-effects)consult product literatureLicensed use not licensed for use in children under17 yearsIndication and doseSee notes above. By intravenous infusionConsult local treatment protocol for details8.2.4 Other immunomodulatingdrugsInterferon alfaInterferon alfa has shown some antitumour effect andmay have a role in inducing early regression of lifethreateningcorticosteroid-resistant haemangiomas ofinfancy. Interferon alfa preparations are also used inthe treatment of chronic hepatitis B, and chronic hepatitisC ideally in combination with ribavirin (section5.3.3). Interferon alfa should always be used under theclose supervision of a specialist. Side-effects are doserelated,but commonly include anorexia, nausea, influenza-likesymptoms, and lethargy. Ocular side-effectsand depression (including suicidal behaviour) have alsobeen reported. Myelosuppression may occur, particularlyaffecting granulocyte counts. Cardiovascular problems(hypotension, hypertension, and arrhythmias),nephrotoxicity and hepatotoxicity have been reportedand monitoring of hepatic function is recommended.Hypertriglyceridaemia, sometimes severe, has beenobserved; monitoring of lipid concentration is recommended.Other side-effects include hypersensitivityreactions, thyroid abnormalities, hyperglycaemia, alopecia,psoriasiform rash, confusion, coma and seizures,and reversible motor problems in young children.Rarely pulmonary infiltrates, pneumonitis, and pneumoniahave occurred; respiratory symptoms should beinvestigated and if pulmonary infiltrates are suspectedor lung function is impaired the discontinuation ofinterferon alfa should be considered.MabCampath c (Genzyme) AConcentrate for intravenous infusion, alemtuzumab30 mg/mL, net price 1-mL amp = £264.11RITUXIMABCautions see notes above—but for full details(including monitoring) consult product literature orlocal treatment protocolPregnancy avoid unless potential benefit to motheroutweighs risk of B-lymphocyte depletion in fetus—effective contraception (in both sexes) required duringand for 12 months after treatmentBreast-feeding avoid breast-feeding during and for 12months after treatmentSide-effects see notes above—but for full details(including monitoring and management of sideeffects)consult product literatureLicensed use not licensed for use in childrenIndication and doseSee notes above. By intravenous infusionConsult local treatment protocol for detailsMabThera c (Roche) AConcentrate for intravenous infusion, rituximab10 mg/mL, net price 10-mL vial = £174.63, 50-mL vial= £873.15INTERFERON ALFACautions consult product literature and local treatmentprotocol for details; interactions: Appendix 1(interferons)Contra-indications consult product literature andlocal treatment protocol for details; avoid injectionscontaining benzyl alcohol in neonates (see underpreparations below)Hepatic impairment close monitoring in mild tomoderate impairment; avoid if severeRenal impairment close monitoring required in mildto moderate impairment; avoid in severe impairmentPregnancy avoid unless potential benefit outweighsrisk (toxicity in animal studies); effective contraceptionrequired during treatment—consult productliteratureBreast-feeding unlikely to be harmfulSide-effects see notes above, consult product literatureand local treatment protocols for detailsLicensed use not licensed for use in children forchronic active hepatitis B; Roferon-A c not licensedfor use in childrenIndication and doseInduction of early regression of life-threateningcorticosteroid resistant haemangiomata ofinfancy. By subcutaneous injectionConsult local treatment protocol for detailsChronic active hepatitis B infection see underpreparations below8 Malignant disease and immunosuppression

440 8.2.4 Other immunomodulating drugs BNFC 2011–20128 Malignant disease and immunosuppressionChronic active hepatitis C infection see underpreparations belowIntronA c (Schering-Plough) AInjection, interferon alfa-2b (rbe) 10 million units/mL,net price 1-mL vial = £42.35, 2.5-mL vial = £105.95.For subcutaneous injection or intravenous infusionInjection pen, interferon alfa-2b (rbe), net price15 million units/mL, 1.5-mL cartridge = £76.28;25 million units/mL, 1.5-mL cartridge = £127.14;50 million units/mL, 1.5-mL cartridge = £254.28. Forsubcutaneous injectionNote Each 1.5-mL multidose cartridge delivers 6 doses of0.2 mL i.e. a total of 1.2 mLDoseChronic active hepatitis B. By subcutaneous injectionChild 2–18 years 5–10 million units/m 2 3 times weeklyChronic active hepatitis C (in combination with oralribavirin, see p. 328). By subcutaneous injectionChild 3–18 years 3 million units/m 2 3 times weeklyRoferon-A c (Roche) AInjection, interferon alfa-2a (rbe). Net price 6 millionunits/mL, 0.5-mL (3 million-unit) prefilled syringe =£14.20; 9 million units/mL, 0.5-mL (4.5 million-unit)prefilled syringe = £21.29; 12 million units/mL, 0.5-mL (6 million-unit) prefilled syringe = £28.37; 18 millionunits/mL, 0.5-mL (9 million-unit) prefilled syringe= £42.57; 30 million units/mL, 0.6-mL (18 millionunit)cartridge = £85.15, for use with Roferon pendevice. For subcutaneous injection (cartridges, vials,and prefilled syringes) and intramuscular injection(cartridges and vials)Excipients include benzyl alcohol (avoid in neonates, see Excipients,p. 2)DoseChronic active hepatitis B. By subcutaneous injectionChild 2–18 years 2.5–5 million units/m 2 3 times weekly;up to 10 million units/m 2 has been used 3 times weeklyRenal impairment manufacturer advises caution insevere impairment—risk of accumulationPregnancy manufacturers advise avoid unless potentialbenefit outweighs risk (toxicity in animal studies);effective contraception required during treatment—consult product literatureBreast-feeding manufacturer advises avoid—noinformation availableSide-effects nausea, vomiting; headache, fatigue,fever; myalgia, arthralgia; rash, injection-site reactions;rarely confusion and systemic lupus erythematosus;also reported, neutropenia, thrombocytopenia,and raised liver enzymesIndication and doseSee notes above and under Preparations belowImmukin c (Boehringer Ingelheim) AInjection, recombinant human interferon gamma-1b200 micrograms/mL, net price 0.5-mL vial = £66.67Dose. By subcutaneous injectionBody surface area 0.5 m 2 or less 1.5 micrograms/kg 3times a weekBody surface area greater than 0.5 m 2 50 micrograms/m 2 3 times a weekNot recommended for infant under 6 months withchronic granulomatous diseaseCanakinumabCanakinumab is a recombinant human monoclonalantibody that selectively inhibits interleukin-1betareceptor binding. It is licensed for the treatment ofcryopyrin-associated periodic syndromes, includingsevere forms of familial cold auto-inflammatorysyndrome (or familial cold urticaria), Muckle-Wellssyndrome, and neonatal-onset multisystem inflammatorydisease (also known as chronic infantile neurologicalcutaneous and articular syndrome). These are rareinherited auto-inflammatory disorders.Interferon gammaInterferon gamma-1b is used to reduce the frequencyof serious infection in chronic granulomatous diseaseand in severe malignant osteopetrosis.INTERFERON GAMMA-1b(Immune interferon)Cautions seizure disorders (including seizures associatedwith fever); cardiac disease (including ischaemia,congestive heart failure, and arrhythmias);monitor before and during treatment: haematologicaltests (including full blood count, differential white cellcount, and platelet count), blood chemistry tests(including renal and liver function tests) and urinalysis;avoid simultaneous administration of foreignproteins including immunological products (risk ofexaggerated immune response); interactions:Appendix 1 (interferons)Driving May impair ability to perform skilled tasks; effectsmay be enhanced by alcoholHepatic impairment manufacturer advises caution insevere impairment—risk of accumulationCANAKINUMABCautions history of recurrent infection or predispositionto infection; monitor neutrophil count beforestarting treatment, 1–2 months after starting treatment,and periodically thereafter; children shouldreceive all recommended vaccinations (includingpneumococcal and inactivated influenza vaccine)before starting treatment; avoid live vaccines unlesspotential benefit outweighs risk—consult product literaturefor further information and section 14.1,p. 599Tuberculosis Children should be evaluated for latent andactive tuberculosis before starting treatment and monitoredfor signs and symptoms of tuberculosis during and aftertreatmentContra-indications severe active infection (see alsoCautions); neutropenia; concomitant use with tumournecrosis factor inhibitors (possible increased risk ofinfections)Hepatic impairment no information availableRenal impairment limited information available butmanufacturer advises no dose adjustment requiredPregnancy manufacturer advises avoid unless potentialbenefit outweighs risk; effective contraception

BNFC 2011–2012 8.2.4 Other immunomodulating drugs 441required during treatment and for up to 3 months afterlast doseBreast-feeding consider if benefit outweighs risk—not known if present in human milkSide-effects vertigo, increased susceptibility to infection,injection-site reactionsIndication and doseCryopyrin-associated periodic syndromes. By subcutaneous injectionChild 4–18 yearsBody-weight 15–40 kg 2 mg/kg every 8 weeks. Ifclinical response not achieved 7 days after startingtreatment, a repeat dose of 2 mg/kg can be considered;if a full response is then achieved, subsequentdosing should be 4 mg/kg every 8 weeksBody-weight over 40 kg 150 mg every 8 weeks. Ifclinical response not achieved 7 days after startingtreatment, a repeat dose of 150 mg can be considered;if a full response is then achieved, subsequentdosing should be 300 mg every 8 weeksIlaris c (Novartis) TAInjection, powder for reconstitution, canakinumab,net price 150-mg vial = £9927.80Indication and doseSee notes above. By intravenous infusion (over 1 hour)Consult local treatment protocols for detailsMepact c (Takeda) TAIntravenous infusion, powder for reconstitution,mifamurtide, net price 4-mg vial = £2375.008.3 Sex hormones andhormone antagonists inmalignant diseaseClassification not used in BNF for Children.MifamurtideMifamurtide is licensed in children and adolescents forthe treatment of high-grade, resectable, non-metastaticosteosarcoma after complete surgical resection. It isused in combination with chemotherapy.MIFAMURTIDECautions asthma and chronic obstructive pulmonarydisease—consider prophylactic bronchodilator therapy;history of autoimmune, inflammatory, or collagendisease; monitor renal function, hepatic functionand clotting parameters; monitor patients withhistory of venous thrombosis, vasculitis, or unstablecardiovascular disorders for persistent or worseningsymptoms during administration—consult productliterature interactions: Appendix 1 (mifamurtide)Hepatic impairment use with caution—no informationavailableRenal impairment use with caution—no informationavailablePregnancy avoid; effective contraception requiredBreast-feeding avoid—no information availableSide-effects gastro-intestinal disturbances (includinganorexia, nausea, vomiting, diarrhoea, constipation,abdominal pain, dyspepsia); tachycardia, hypertension,palpitations, hypotension, phlebitis; oedema,respiratory disorders (including dyspnoea, epistaxis,cough, tachypnoea, haemoptysis, pleural effusion);confusion, depression, insomnia, headache, dizziness,paraesthesia, hypoaesthesia, tremor, drowsiness,anxiety; hypokalaemia, anaemia, leucopenia, thrombocytopenia,granulocytopenia; haematuria, dysuria,pollakiuria; musculoskeletal pain; blurred vision;vertigo, tinnitus, hearing loss; sweating, alopecia, rash,dry skin, flushing8 Malignant disease and immunosuppression

442 BNFC 2011–20129 Nutrition and blood9 Nutrition and blood9.1 Anaemias and some other blooddisorders 4429.1.1 Iron-deficiency anaemias 4429.1.1.1 Oral iron 4429.1.1.2 Parenteral iron 4449.1.2 Drugs used in megaloblasticanaemias 4459.1.3 Drugs used in hypoplastic,haemolytic, and renal anaemias 4479.1.4 Drugs used in platelet disorders 4539.1.5 G6PD deficiency 4549.1.6 Drugs used in neutropenia 4549.2 Fluids and electrolytes 4569.2.1 Oral preparations for fluid andelectrolyte imbalance 4579.2.1.1 Oral potassium 4579.2.1.2 Oral sodium and water 4589.2.1.3 Oral bicarbonate 4609.2.2 Parenteral preparations for fluidand electrolyte imbalance 4609.2.2.1 Electrolytes and water 4609.2.2.2 Plasma and plasma substitutes 4649.3 Intravenous nutrition 4669.4 Oral nutrition 4689.4.1 Foods for special diets 4689.4.2 Enteral nutrition 4699.5 Minerals 4719.5.1 Calcium and magnesium 4719.5.1.1 Calcium supplements 4719.5.1.2 Hypercalcaemia and hypercalciuria4739.5.1.3 Magnesium 4739.5.2 Phosphorus 4749.5.2.1 Phosphate supplements 4749.5.2.2 Phosphate-binding agents 4759.5.3 Fluoride 4769.5.4 Zinc 4789.6 Vitamins 4789.6.1 Vitamin A 4789.6.2 Vitamin B group 4799.6.3 Vitamin C 4819.6.4 Vitamin D 4829.6.5 Vitamin E 4859.6.6 Vitamin K 4869.6.7 Multivitamin preparations 4879.7 Bitters and tonics 4889.8 Metabolic disorders 4889.8.1 Drugs used in metabolic disorders4889.8.2 Acute porphyrias 4979.1 Anaemias and some otherblood disorders9.1.1 Iron-deficiency anaemias9.1.2 Drugs used in megaloblastic anaemias9.1.3 Drugs used in hypoplastic,haemolytic, and renal anaemias9.1.4 Drugs used in platelet disorders9.1.5 G6PD deficiency9.1.6 Drugs used in neutropeniaBefore initiating treatment for anaemia it is essential todetermine which type is present. Iron salts may beharmful and result in iron overload if given alone topatients with anaemias other than those due to irondeficiency.9.1.1 Iron-deficiency anaemias9.1.1.1 Oral iron9.1.1.2 Parenteral ironTreatment with an iron preparation is justified only inthe presence of a demonstrable iron-deficiency state.Before starting treatment, it is important to exclude anyserious underlying cause of the anaemia (e.g. gastrointestinalbleeding). The possibility of thalassaemiashould be considered in children of Mediterranean orIndian subcontinent descent.Prophylaxis with an iron preparation may be appropriatein those with a poor diet, malabsorption, menorrhagia,pregnancy, in haemodialysis patients, and in themanagement of low birth-weight infants such as pretermneonates.9.1.1.1 Oral ironIron salts should be given by mouth unless there aregood reasons for using another route.Ferrous salts show only marginal differences betweenone another in efficiency of absorption of iron. Haemoglobinregeneration rate is little affected by the type ofsalt used provided sufficient iron is given, and in mostpatients the speed of response is not critical. Choice ofpreparation is thus usually decided by formulation,palatability, incidence of side-effects, and cost.

BNFC 2011–2012 9.1.1 Iron-deficiency anaemias 443Treatment of iron-deficiency anaemia The oraldose of elemental iron to treat deficiency is 3–6 mg/kg(max. 200 mg) daily given in 2–3 divided doses. Ironsupplementation may also be required to produce anoptimum response to erythropoietins in iron-deficientchildren with chronic renal failure or in preterm neonates.(See also Prophylaxis of iron deficiency, below.)Prescribing Express the dose in terms of elemental iron andiron salt and select the most appropriate preparation; specifyboth the iron salt and formulation on the prescription. The ironcontent of artificial formula feeds should also be considered.Iron content of different iron saltsIron saltAmountContent offerrous ironFerrous fumarate 200 mg 65 mgFerrous gluconate 300 mg 35 mgFerrous sulphate 300 mg 60 mgFerrous sulphate, dried 200 mg 65 mgSodium feredetate 190 mg 27.5 mgTherapeutic response The haemoglobin concentrationshould rise by about 100–200 mg/100 mL (1–2 g/litre)per day or 2 g/100 mL (20 g/litre) over 3–4 weeks.When the haemoglobin is in the normal range, treatmentshould be continued for a further 3 months toreplenish the iron stores. Epithelial tissue changes suchas atrophic glossitis and koilonychia are usuallyimproved, but the response is often slow. The mostcommon reason for lack of response in children ispoor compliance; poor absorption is rare in children.Prophylaxis of iron deficiency In neonates, haemoglobinand haematocrit concentrations change rapidly.These changes are not due to iron deficiency and cannotbe corrected by iron supplementation. Similarly, neonatalanaemia resulting from repeated blood samplingdoes not respond to iron therapy.All babies, including preterm neonates, are born withsubstantial iron stores but these stores can becomedepleted unless dietary intake is adequate. All babiesrequire an iron intake of 400–700 nanograms daily tomaintain body stores. Iron in breast milk is wellabsorbed but that in artificial feeds or in cow’s milk isless so. Most artificial formula feeds are sufficientlyfortified with iron to prevent deficiency and their ironcontent should be taken into account when consideringfurther iron supplementation.Dose Prophylactic iron supplementation (elementaliron 5 mg daily) may be required in babies of lowbirth-weight who are solely breast-fed; supplementationis started 4–6 weeks after birth and continued untilmixed feeding is established.Infants with a poor diet may become anaemic in thesecond year of life, particularly if cow’s milk, rather thanfortified formula feed, is a major part of the diet.Compound preparations Some oral preparationscontain ascorbic acid to aid absorption of the iron,but the therapeutic advantage of such preparations isminimal and cost may be increased.There is no justification for the inclusion of other ingredients,such as the B group of vitamins, except folicacid for pregnant women, see p. 446.Side-effects Gastro-intestinal irritation can occur withiron salts. Nausea and epigastric pain are dose-related,but the relationship between dose and altered bowelhabit (constipation or diarrhoea) is less clear. Oral ironcan exacerbate diarrhoea in patients with inflammatorybowel disease.Iron preparations taken orally can be constipating andoccasionally lead to faecal impaction.If side-effects occur, the dose may be reduced; alternatively,another iron salt may be used, but an improvementin tolerance may simply be a result of a lowercontent of elemental iron. The incidence of side-effectsdue to ferrous sulphate is no greater than with other ironsalts when compared on the basis of equivalent amountsof elemental iron.Iron preparations are an important cause of accidentaloverdose in children and as little as 20 mg/kg of elementaliron can lead to symptoms of toxicity. For thetreatment of iron overdose, see Emergency Treatmentof Poisoning, p. 30.Counselling Although iron preparations are bestabsorbed on an empty stomach, they can be takenafter food to reduce gastro-intestinal side-effects; theymay discolour stools.FERROUS SULPHATECautions interactions: Appendix 1 (iron)Side-effects see notes aboveIndication and doseIron-deficiency anaemia, prophylaxis of irondeficiency see notes above and preparationsFerrous Sulphate (Non-proprietary)Tablets, coated, dried ferrous sulphate 200 mg (65 mgiron), net price 28-tab pack = £1.15DoseChild 6–18 years prophylactic, 1 tablet daily; therapeutic,1 tablet 2–3 times daily, see notes aboveIronorm c Drops (Wallace Mfg)Oral drops, ferrous sulphate 125 mg (25 mg iron)/mL,net price 15 mL = £4.95DoseChild 1 month–6 years prophylactic 0.3 mL daily, butsee notes aboveChild 6–18 years prophylactic 0.6 mL dailyFERROUS FUMARATECautions interactions: Appendix 1 (iron)Side-effects see notes aboveIndication and doseIron-deficiency anaemia, prophylaxis of irondeficiency see notes above and preparationsFersaday c (Goldshield)Tablets, brown, f/c, ferrous fumarate 322 mg (100 mgiron). Net price 28-tab pack = 79pDoseChild 12–18 years prophylactic, 1 tablet daily; therapeutic,1 tablet twice daily9 Nutrition and blood

444 9.1.1 Iron-deficiency anaemias BNFC 2011–20129 Nutrition and bloodFersamal c (Goldshield)Tablets, brown, ferrous fumarate 210 mg (68 mg iron),net price 100 = £1.44DoseChild 12–18 years prophylactic, 1 tablet 1–2 times daily;therapeutic, 1 tablet 2–3 times dailySyrup, brown, ferrous fumarate approx. 140 mg(45 mg iron)/5 mL. Net price 200 mL = £3.11DosePreterm neonate see notes aboveNeonate see notes aboveChild 1 month–12 years see notes aboveChild 12–18 years prophylactic, 5 mL twice daily;therapeutic, 10 mL twice dailyGalfer c (Thornton & Ross)Capsules, red/green, ferrous fumarate 305 mg(100 mg iron), net price 100 = £2.00DoseChild 12–18 years prophylactic, 1 capsule daily; therapeutic,1 capsule twice dailySyrup, brown, sugar-free ferrous fumarate 140 mg(45 mg iron)/5 mL. Net price 300 mL = £5.33DosePreterm neonate and body-weight up to 3 kg prophylactic,0.5 mL daily, see notes aboveNeonate prophylactic and therapeutic, 0.25 mL/kg twicedaily (total daily dose may alternatively be given in 3divided doses), see notes aboveChild 1 month–12 years prophylactic and therapeutic,0.25 mL/kg twice daily (total daily dose may alternativelybe given in 3 divided doses); max 20 mL daily, see notesaboveChild 12–18 years prophylactic, 10 mL once daily;therapeutic, 10 mL 1–2 times dailyFERROUS GLUCONATECautions interactions: Appendix 1 (iron)Side-effects see notes aboveIndication and doseIron-deficiency anaemia see notes above andpreparationpack = £6.06; D 1 30-mL dropper bottle for paediatricuse = £2.16. Counselling, use of dropperDoseNeonate (from dropper bottle) 1 drop (approx. 500 microgramsiron) per 450 g body-weight 3 times daily, seenotes aboveChild 1 month–2 years (from dropper bottle) 1 drop(approx. 500 micrograms iron) per 450 g body-weight 3times daily, see notes aboveChild 2–6 years therapeutic, 2.5 mL dailyChild 6–12 years therapeutic, 5 mL dailyChild 12–18 years prophylactic, 2.5 mL daily; therapeutic,5 mL 1–2 times daily (5 mL once daily if requiredduring second and third trimester of pregnancy)1. except 30 mL paediatric dropper bottle for prophylaxis andtreatment of iron deficiency in infants born prematurely;endorse prescription ‘SLS’SODIUM FEREDETATE(Sodium ironedetate)Cautions interactions: Appendix 1 (iron)Side-effects see notes aboveLicensed use not licensed for prophylaxis of irondeficiencyIndication and doseIron-deficiency anaemia, prophylaxis of irondeficiency see notes above and preparationSytron c (Archimedes)Elixir, sugar-free, sodium feredetate 190 mg equivalentto 27.5 mg of iron/5 mL. Net price 100 mL =£1.07DoseNeonate prophylactic, 1 mL daily, see notes above; therapeutic,up to 2.5 mL twice daily (smaller doses should beused initially), see notes aboveChild 1 month–1 year prophylactic, 1 mL daily, seenotes above; therapeutic, up to 2.5 mL twice daily(smaller doses should be used initially), see notes aboveChild 1–5 years therapeutic, 2.5 mL 3 times dailyChild 5–12 years therapeutic, 5 mL 3 times dailyChild 12–18 years therapeutic, 5 mL increasing graduallyto 10 mL 3 times dailyFerrous Gluconate (Non-proprietary)Tablets, red, coated, ferrous gluconate 300 mg (35 mgiron), net price 28 = £2.95DoseChild 6–12 years prophylactic and therapeutic, 1–3tablets dailyChild 12–18 years prophylactic, 2 tablets daily; therapeutic,4–6 tablets daily in divided dosesPOLYSACCHARIDE-IRON COMPLEXCautions interactions: Appendix 1 (iron)Side-effects see notes aboveIndication and doseIron-deficiency anaemia, prophylaxis of irondeficiency see notes above and preparationNiferex c (Tillomed)Elixir, brown, sugar-free, polysaccharide-iron complexequivalent to 100 mg of iron/5 mL. Net price 240-mL9.1.1.2 Parenteral ironIron can be administered parenterally as iron dextran,iron sucrose, or ferric carboxymaltose. Parenteral ironis generally reserved for use when oral therapy isunsuccessful because the child cannot tolerate oraliron, or does not take it reliably, or if there is continuingblood loss, or in malabsorption.Many children with chronic renal failure who are receivinghaemodialysis (and some who are receiving peritonealdialysis) also require iron by the intravenous routeon a regular basis (see also Erythropoietins, section9.1.3).With the exception of children with severe renal failurereceiving haemodialysis, parenteral iron does not producea faster haemoglobin response than oral ironprovided that the oral iron preparation is taken reliablyand is absorbed adequately.

BNFC 2011–2012 9.1.2 Drugs used in megaloblastic anaemias 445Anaphylactic reactions can occur with parenteral ironcomplexes; facilities for cardiopulmonary resuscitationmust be available. Depending on the preparation, asmall test dose may be required. If children complainof acute symptoms particularly nausea, back pain,breathlessness, or develop hypotension, the infusionshould be stopped.FERRIC CARBOXYMALTOSEA ferric carboxymaltose complex containing 5%(50 mg/mL) of ironCautions hypersensitivity can occur with parenteraliron and facilities for cardiopulmonary resuscitationmust be available; oral iron should not be givenconcomitantly; allergic disorders including asthmaand eczema; infection (discontinue if ongoing bacteraemia)Hepatic impairment use with caution; avoid in conditionswhere iron overload increases risk of impairmentPregnancy avoid in first trimester; crosses the placentain animal studies; may influence skeletaldevelopmentSide-effects gastro-intestinal disturbances; headache,dizziness; rash; injection-site reactions; less commonlyhypotension, flushing, chest pain, peripheral oedema,hypersensitivity reactions (including anaphylaxis),fatigue, paraesthesia, malaise, pyrexia, rigors, myalgia,arthralgia, back pain, pruritus, and urticaria; rarelydyspnoeaLicensed use not licensed for use in children under14 yearsIndication and doseIron-deficiency anaemia see notes above. By slow intravenous injection or by intravenousinfusionCalculated according to body-weight and irondeficit, consult product literatureFerinject c (Vifor) TAInjection, iron (as ferric carboxymaltose) 50 mg/mL,net price 2-mL vial = £21.75, 10-mL vial = £108.75Electrolytes Na + 0.24 mmol/mLIRON DEXTRANA complex of ferric hydroxide with sucrose containing5% (50 mg/mL) of ironCautions oral iron not to be given until 5 days after lastinjectionAnaphylaxis Anaphylactic reactions can occur with parenteraliron and a test dose is recommended before eachdose; the patient should be carefully observed for 60 minutesafter the first test dose and for 15 minutes after subsequenttest doses. Facilities for cardiopulmonary resuscitation mustbe available; risk of allergic reactions increased in immune orinflammatory conditionsContra-indications history of allergic disordersincluding asthma, and eczema; infection; activerheumatoid arthritisHepatic impairment avoid in severe impairmentRenal impairment avoid in acute renal failurePregnancy avoid in first trimesterSide-effects less commonly nausea, vomiting, abdominalpain, flushing, dyspnoea, anaphylactic reactions(see Anaphylaxis above), numbness, cramps, blurredvision, pruritus, and rash; rarely diarrhoea, chest pain,hypotension, angioedema, arrhythmias, tachycardia,dizziness, restlessness, fatigue, seizures, tremor,impaired consciousness, myalgia, arthralgia, sweating,and injection-site reactions; very rarely hypertension,palpitation, headache, paraesthesia, haemolysis,and transient deafnessLicensed use not licensed for use in children under14 yearsIndication and doseIron-deficiency anaemia see notes above. By slow intravenous injection or by intravenousinfusionCalculated according to body-weight and irondeficit, consult product literatureCosmoFer c (Vitaline) AInjection, iron (as iron dextran) 50 mg/mL, net price2-mL amp = £7.97; 10-mL amp = £39.85IRON SUCROSEA complex of ferric hydroxide with sucrose containing2% (20 mg/mL) of ironCautions oral iron therapy should not be given until 5days after last injection; infection (discontinue ifongoing bacteraemia)Anaphylaxis Anaphylactic reactions can occur with parenteraliron and a test dose is recommended before the firstdose; the patient should be carefully observed for 15 minutes.Facilities for cardiopulmonary resuscitation must beavailableContra-indications history of allergic disordersincluding asthma, eczema, and anaphylaxisHepatic impairment use with caution; avoid in conditionswhere iron overload increases risk of impairmentPregnancy avoid in first trimesterSide-effects taste disturbances; less commonlynausea, vomiting, abdominal pain, diarrhoea, hypotension,tachycardia, flushing, palpitation, chest pain,bronchospasm, dyspnoea, headache, dizziness, fever,myalgia, pruritus, rash, and injection-site reactions;rarely peripheral oedema, anaphylactic reactions (seeAnaphylaxis above), fatigue, asthenia, and paraesthesia;confusion, arthralgia, and increased sweatingalso reportedLicensed use not licensed for use in childrenIndication and doseIron-deficiency anaemia see notes above. By slow intravenous injection or by intravenousinfusionCalculated according to body-weight and irondeficit, consult product literatureVenofer c (Vifor) AInjection, iron (as iron sucrose) 20 mg/mL, net price5-mL vial = £9.359.1.2 Drugs used inmegaloblastic anaemiasMegaloblastic anaemias are rare in children; they mayresult from a lack of either vitamin B 12 or folate, and it isessential to establish in every case which deficiency ispresent and the underlying cause. In emergencies, whendelay might be dangerous, it is sometimes necessary to9 Nutrition and blood

446 9.1.2 Drugs used in megaloblastic anaemias BNFC 2011–20129 Nutrition and bloodadminister both substances after the bone marrow testwhile plasma assay results are awaited. Normally, however,appropriate treatment should not be instituteduntil the results of tests are available.Vitamin B 12 is used in the treatment of megaloblastosiscaused by prolonged nitrous oxide anaesthesia, whichinactivates the vitamin, and in the rare disorders ofcongenital transcobalamin II deficiency, methylmalonicacidaemia and homocystinuria (see section9.8.1).Vitamin B 12 should be given prophylactically after totalileal resection.Apart from dietary deficiency, all other causes of vitaminB 12 deficiency are attributable to malabsorption. Thereis little place for the use of low-dose vitamin B 12 orallyand none for vitamin B 12 intrinsic factor complexesgiven by mouth. Vitamin B 12 in large oral doses [unlicensed]may be effective.Hydroxocobalamin has completely replaced cyanocobalaminas the form of vitamin B 12 of choice fortherapy; it is retained in the body longer than cyanocobalaminand thus for maintenance therapy can begiven at intervals of up to 3 months. Treatment isgenerally initiated with frequent administration of intramuscularinjections to replenish the depleted bodystores. Thereafter, maintenance treatment, which isusually for life, can be instituted. There is no evidencethat doses larger than those recommended provide anyadditional benefit in vitamin B 12neuropathy.Folic acid has few indications for long-term therapysince most causes of folate deficiency are self-limiting orwill yield to a short course of treatment. It should not beused in undiagnosed megaloblastic anaemia unless vitaminB 12is administered concurrently otherwise neuropathymay be precipitated (see above).In folate-deficient megaloblastic anaemia (e.g. becauseof poor nutrition, pregnancy, or treatment with antiepileptics),daily folic acid supplementation for 4months brings about haematological remission andreplenishes body stores; higher doses may be necessaryin malabsorption states. In pregnancy, folic acid 5 mgdaily is continued to term.For prophylaxis in chronic haemolytic states, malabsorptionor in renal dialysis, folic acid is given dailyor sometimes weekly, depending on the diet and the rateof haemolysis.Folic acid is also used for the prevention of methotrexate-inducedside-effects in juvenile idiopathic arthritis(see also section 10.1.3, p. 508), severe Crohn’sdisease (see section 1.5.3, p. 54), and severe psoriasis(see section 13.5.3, p. 572).For prophylaxis in pregnancy, see Prevention of NeuralTube Defects below.Folic acid is actively excreted in breast milk and is wellabsorbed by the infant. It is also present in cow’s milkand artificial formula feeds but is heat labile. Serum andred cell folate concentrations fall after delivery andurinary losses are high, particularly in low birth-weightneonates. Although symptomatic deficiency is rare inthe absence of malabsorption or prolonged diarrhoea, itis common for neonatal units to give supplements offolic acid to all preterm neonates from 2 weeks of ageuntil full-term corrected age is reached, particularly ifheated breast milk is used without an artificial formulafortifier.Folinic acid is also effective in the treatment of folatedeficientmegaloblastic anaemia but it is normally onlyused in association with cytotoxic drugs (see section8.1); it is given as calcium folinate.Prevention of neural tube defects Folic acid supplementstaken before and during pregnancy can reducethe occurrence of neural tube defects. The risk of aneural tube defect occurring in a child should beassessed and folic acid given as follows:Women at a low risk of conceiving a child with aneural tube defect should be advised to take folicacid as a medicinal or food supplement at a dose of400 micrograms daily before conception and untilweek 12 of pregnancy. Women who have not beentaking folic acid and who suspect they are pregnantshould start at once and continue until week 12 ofpregnancy.Couples are at a high risk of conceiving a child witha neural tube defect if either partner has a neuraltube defect (or either partner has a family history ofneural tube defects), if they have had a previouspregnancy affected by a neural tube defect, or if thewoman has coeliac disease (or other malabsorptionstate), diabetes mellitus, sickle-cell anaemia, or istaking antiepileptic medicines (see also section4.8.1).Women in the high-risk group who wish to becomepregnant (or who are at risk of becoming pregnant)should be advised to take folic acid 5 mg daily andcontinue until week 12 of pregnancy (women withsickle-cell disease should continue taking their normaldose of folic acid 5 mg daily (or increase thedose to 5 mg daily) and continue this throughoutpregnancy).There is no justification for prescribing multipleingredientvitamin preparations containing vitaminB 12or folic acid.HYDROXOCOBALAMINCautions should not be given before diagnosis fullyestablished but see also notes above; interactionsAppendix 1 (hydroxocobalamin)Breast-feeding present in milk but not known to beharmfulSide-effects nausea, headache, dizziness; fever,hypersensitivity reactions (including rash and pruritus);injection-site reactions; hypokalaemia andthrombocytosis during initial treatment; chromaturiaLicensed use licensed for use in children (age notspecified by manufacturers); not licensed for use ininborn errors of metabolismIndication and doseMacrocytic anaemia without neurologicalinvolvement. By intramuscular injectionChild 1 month–18 years initially 250 micrograms–1mg 3 times a week for 2 weeks then250 micrograms once weekly until blood countnormal, then 1 mg every 3 months

BNFC 2011–2012 9.1.3 Drugs used in hypoplastic, haemolytic, renal anaemias 447Macrocytic anaemia with neurological involvement. By intramuscular injectionChild 1 month–18 years initially 1 mg on alternatedays until no further improvement, then 1 mgevery 2 monthsProphylaxis of macrocytic anaemias associatedwith vitamin B 12 deficiency. By intramuscular injectionChild 1 month–18 years 1 mg every 2–3 monthsLeber’s optic atrophy. By intramuscular injectionInitially 1 mg daily for 2 weeks, then 1 mg twiceweekly until no further improvement, thereafter1 mg every 1–3 monthsCongenital transcobalamin II deficiency. By intramuscular injectionNeonate 1 mg 3 times a week, reduce after 1 yearto 1 mg once weekly or as appropriateChild 1 month–18 years 1 mg 3 times a week,reduce after 1 year to 1 mg once weekly or asappropriateMethylmalonic acidaemia and homocystinuria. By intramuscular injectionChild 1 month–18 years initially 1 mg daily for 5–7 days, reduce according to response to maintenancedose of up to 1 mg once or twice weeklyMethylmalonic acidaemia, maintenance onceintramuscular response established. By mouthChild 1 month–18 years 5–10 mg once or twiceweeklyNote Some children do not respond to the oral routeCyanide poisoningSee Emergency Treatment of Poisoning, p. 32Hydroxocobalamin (Non-proprietary) AInjection, hydroxocobalamin 1 mg/mL. Net price 1-mL amp = 74pBrands include Cobalin-H c D, Neo-Cytamen c DInjection, hydroxocobalamin 2.5 mg/mL, 2 mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Administration For administration by mouth, injection solutionmay be given orally; it will not have prolonged effect via this routeNote The BP directs that when Vitamin B 12 injection isprescribed or demanded hydroxocobalamin injection shallbe dispensed or suppliedPowder available from specialist importing companiesIndication and doseFolate supplementation in neonates (see notesabove). By mouthNeonate 50 micrograms once daily or 500 microgramsonce weeklyMegaloblastic anaemia due to folate deficiency(see notes above). By mouthNeonate initially 500 micrograms/kg once dailyfor up to 4 monthsChild 1 month–1 year initially 500 micrograms/kg once daily (max. 5 mg) for up to 4 months; up to10 mg daily may be required in malabsorptionstatesChild 1–18 years 5 mg daily for 4 months (untilterm in pregnant women); up to 15 mg daily maybe required in malabsorption statesHaemolytic anaemia; metabolic disorders. By mouthChild 1 month–12 years 2.5–5 mg once dailyChild 12–18 years 5–10 mg once dailyProphylaxis of folate deficiency in dialysis. By mouthChild 1 month–12 years 250 microgram/kg(max. 10 mg) once dailyChild 12–18 years 5–10 mg once dailyPrevention of methotrexate side-effects injuvenile idiopathic arthritis. By mouthChild 2–18 years 1 mg daily or 5 mg once weekly,adjusted according to local guidelinesPrevention of methotrexate side-effects insevere Crohn’s disease or severe psoriasis. By mouthSee section 1.5.3 and section 13.5.3Prevention of neural tube defects. By mouthSee notes above1Folic Acid (Non-proprietary) ATablets, folic acid 400 micrograms, net price 90-tabpack = £2.37; 5 mg, 28-tab pack = £1.00Syrup, folic acid 2.5 mg/5 mL, net price 150 mL =£9.16; 400 micrograms/5 mL, 150 mL = £1.40Brands include Folicare c , Lexpec c (sugar-free)1. Can be sold to the public provided daily doses do not exceed500 micrograms9 Nutrition and bloodFOLIC ACIDCautions should never be given alone for vitamin B 12deficiency states (may precipitate subacute combineddegeneration of the spinal cord); interactions:Appendix 1 (folates)Side-effects rarely gastro-intestinal disturbancesLicensed use unlicensed for limiting methotrexatetoxicity9.1.3 Drugs used inhypoplastic, haemolytic,and renal anaemiasAnabolic steroids (see BNF, section 6.4.3), pyridoxine,antilymphocyte immunoglobulin, and various corticos-

448 9.1.3 Drugs used in hypoplastic, haemolytic, renal anaemias BNFC 2011–20129 Nutrition and bloodteroids are used in hypoplastic and haemolytic anaemias.Antilymphocyte immunoglobulin given intravenouslythrough a central line over 12–18 hours each day for 5days produces a response in about 50% of cases ofacquired aplastic anaemia; the response rate may beincreased when ciclosporin is given as well. Severereactions are common in the first 2 days and profoundimmunosuppression can occur; antilymphocyteimmunoglobulin should be given under specialist supervisionwith appropriate resuscitation facilities. Alternatively,oxymetholone tablets (available from ‘specialorder’manufacturers or specialist importing companies,see p. 809) may be used in aplastic anaemia at a dose of1–5 mg/kg daily for 3 to 6 months.It is unlikely that dietary deficit of pyridoxine (section9.6.2) produces clinically relevant haematologicaleffects. However, certain forms of sideroblastic anaemiarespond to pharmacological doses, possibly reflectingits role as a co-enzyme during haemoglobin synthesis.Pyridoxine is indicated in both idiopathic acquiredand hereditary sideroblastic anaemias. Although completecures have not been reported, some increase inhaemoglobin can occur with high doses. Reversiblesideroblastic anaemias respond to treatment of theunderlying cause but pyridoxine is indicated inpregnancy, haemolytic anaemias, or during isoniazidtreatment.Corticosteroids (section 6.3) have an important placein the management of haematological disorders includingautoimmune haemolytic anaemia, idiopathicthrombocytopenias (section 9.1.4) and neutropenias,and major transfusion reactions. They are also used inchemotherapy schedules for many types of lymphoma,lymphoid leukaemias, and paraproteinaemias, includingmultiple myeloma.ErythropoietinsEpoetins (recombinant human erythropoietins) areused to treat the anaemia associated with erythropoietindeficiency in chronic renal failure, see below.Epoetin beta is also used for the prevention of anaemiain preterm neonates of low birth-weight; a therapeuticresponse may take several weeks. Only unpreservedformulations should be used as other preparationsmay contain benzyl alcohol (see Excipients, p. 2).There is insufficient information to support the use oferythropoietins in children with leukaemia or in thosereceiving cancer chemotherapy.Darbepoetin is a glycosylated derivative of epoetin; itpersists longer in the body and can be administered lessfrequently than epoetin.Other factors, such as iron or folate deficiency, thatcontribute to the anaemia of chronic renal failure shouldbe corrected before treatment and monitored duringtherapy. Supplemental iron may improve the response inresistant patients and in preterm neonates (see section9.1.1.1). Aluminium toxicity, concurrent infection, orother inflammatory disease can impair the response toerythropoietin.Erythropoietins—haemoglobin concentrationIn chronic kidney disease, the use of erythropoietinscan be considered in a child with anaemia. The aimof treatment is to relieve symptoms of anaemia andto avoid the need for blood transfusion. The optimumhaemoglobin concentration is dependent onthe child’s age and factors such as symptoms, comorbidities,and patient preferences. The haemoglobinconcentration should not be increased beyondthat which provides adequate control of symptomsof anaemia. In adults, overcorrection of haemoglobinconcentration with erythropoietins in those withchronic kidney disease may increase the risk ofserious cardiovascular events and death; haemoglobinconcentrations higher than 12 g/100 mL shouldbe avoided in children.For MHRA/CHM advice relating to adults, see BNFsection 9.1.3.Pure red cell aplasiaThere have been very rare reports of pure red cellaplasia in patients treated with erythropoietins. Inpatients who develop a lack of efficacy with erythropoietintherapy and with a diagnosis of pure red cellaplasia, treatment with erythropoietins must be discontinuedand testing for erythropoietin antibodiesconsidered. Patients who develop pure red cell aplasiashould not be switched to another form oferythropoietin.DARBEPOETIN ALFACautions see EpoetinContra-indications see EpoetinHepatic impairment manufacturer advises cautionPregnancy no evidence of harm in animal studies—manufacturer advises cautionBreast-feeding manufacturer advises avoid—noinformation availableSide-effects see Epoetin; also, oedema, injection-sitepain; isolated reports of pure red cell aplasia particularlyfollowing subcutaneous administration inpatients with chronic renal failure (discontinue therapy)—seealso notes aboveIndication and doseSymptomatic anaemia associated with chronicrenal failure in children on dialysis (see alsonotes above). By intravenous or subcutaneous injectionChild 11–18 years initially 450 nanograms/kgonce weekly adjusted according to response byapprox. 25% at intervals of at least 4 weeks;maintenance dose, given once weekly or onceevery 2 weeksSymptomatic anaemia associated with chronicrenal failure in children not on dialysis (see alsonotes above). By intravenous or subcutaneous injectionChild 11–18 years by subcutaneous or intravenousinjection, initially 450 nanograms/kg onceweekly or by subcutaneous injection, initially750 nanograms/kg once every 2 weeks; adjustedaccording to response by approx. 25% at intervalsof at least 4 weeks; maintenance dose, given sub-

BNFC 2011–2012 9.1.3 Drugs used in hypoplastic, haemolytic, renal anaemias 449cutaneously or intravenously once weekly or subcutaneouslyonce every 2 weeks or subcutaneouslyonce every monthNote Subcutaneous route preferred in patients not onhaemodialysis. Reduce dose by approximately 25% if rise inhaemoglobin concentration exceeds 2 g/100 mL over 4weeks or if haemoglobin concentration exceeds 12 g/100 mL; if haemoglobin concentration continues to rise,despite dose reduction, suspend treatment until haemoglobinconcentration decreases and then restart at a doseapproximately 25% lower than the previous dose. Whenchanging route give same dose then adjust according toweekly or fortnightly haemoglobin measurements. Adjustdoses not more frequently than every 2 weeks duringmaintenance treatment.Aranesp c (Amgen) AInjection, prefilled syringe, darbepoetin alfa,25 micrograms/mL, net price 0.4 mL (10 micrograms)= £14.68; 40 micrograms/mL, 0.375 mL (15 micrograms)= £22.03, 0.5 mL (20 micrograms) = £29.37;100 micrograms/mL, 0.3 mL (30 micrograms) =£44.05, 0.4 mL (40 micrograms) = £58.73, 0.5 mL(50 micrograms) = £73.41; 200 micrograms/mL,0.3 mL (60 micrograms) = £88.09, 0.4 mL (80 micrograms)= £117.45, 0.5 mL (100 micrograms) =£146.81, 0.65 mL (130 micrograms) = £190.86;500 micrograms/mL, 0.3 mL (150 micrograms) =£220.22, 0.6 mL (300 micrograms) = £440.43, 1 mL(500 micrograms) = £734.05Injection (Aranesp c SureClick), prefilled disposableinjection device, darbepoetin alfa, 40 micrograms/mL, net price 0.5 mL (20 micrograms) = £29.36;100 micrograms/mL, net price 0.4 mL (40 micrograms)= £58.72; 200 micrograms/mL, net price0.3 mL (60 micrograms) = £88.09, 0.4 mL (80 micrograms)= £117.45, 0.5 mL (100 micrograms) =£146.81; 500 micrograms/mL, net price 0.3 mL(150 micrograms) = £220.22, 0.6 mL (300 micrograms)= £440.43, 1 mL (500 micrograms) = £734.05EPOETIN ALFA, BETA, and ZETA(Recombinant human erythropoietins)Note The prescriber must specify which epoetin is required,see also Biosimilar medicines, p. 2Cautions see notes above; also inadequately treated orpoorly controlled blood pressure (monitor closelyblood pressure, reticulocyte counts, haemoglobin, andelectrolytes), interrupt treatment if blood pressureuncontrolled; sudden stabbing migraine-like pain iswarning of hypertensive crisis; sickle-cell disease(lower target haemoglobin concentration may beappropriate); ischaemic vascular disease; thrombocytosis(monitor platelet count for first 8 weeks); epilepsy;malignant disease; increase in unfractionated orlow molecular weight heparin dose may be neededduring dialysisContra-indications pure red cell aplasia followingerythropoietin therapy (see also notes above);uncontrolled hypertension; avoid injections containingbenzyl alcohol in neonates (see under preparations,below)Hepatic impairment manufacturers advise caution inchronic hepatic failurePregnancy no evidence of harm; benefits probablyoutweigh risks of anaemia and blood transfusionBreast-feeding unlikely to be present in milk; effecton infant minimalSide-effects diarrhoea, nausea, vomiting; dosedependentincrease in blood pressure or aggravationof hypertension; in isolated patients with normal orlow blood pressure, hypertensive crisis withencephalopathy-like symptoms and generalised tonicclonicseizures requiring immediate medical attention;dose-dependent increase in platelet count (butthrombocytosis rare) regressing during treatment;influenza-like symptoms (may be reduced if intravenousinjection given over 5 minutes); cardiovascularevents; shunt thrombosis especially if tendency tohypotension or arteriovenous shunt complications;very rarely sudden loss of efficacy because of pure redcell aplasia, particularly following subcutaneousadministration in patients with chronic renal failure(discontinue erythropoietin therapy)—see also notesabove, hyperkalaemia, hypersensitivity reactions(including anaphylaxis and angioedema), skin reactions,injection-site reactions, and peripheral oedemaalso reportedLicensed use Eprex c 20 000–unit, 30 000–unit, and40 000–unit prefilled syringes not licensed for use inchildrenIndication and doseSee under preparations, belowEpoetin alfaBinocrit c (Sandoz) TAInjection, prefilled syringe, epoetin alfa, net price1000 units = £5.09; 2000 units = £10.18; 3000 units =£15.27; 4000 units = £20.36; 5000 units = £25.46;6000 units = £30.55; 8000 units = £40.73; 10 000 units= £50.91Note Biosimilar Medicine, p. 2DoseSymptomatic anaemia associated with chronic renalfailure in children on haemodialysis (see also notesabove). By intravenous injection over 1–5 minutesChild 1 month–18 years initially 50 units/kg 3 timesweekly adjusted according to response in steps of25 units/kg 3 times weekly at intervals of at least 4weeks; maintenance dose, body-weight under 10 kgusually 75–150 units/kg 3 times weekly, body-weight 10–30 kg usually 60–150 units/kg 3 times weekly, bodyweightover 30 kg usually 30–100 units/kg 3 timesweeklyNote Reduce dose by approximately 25 % if rise in haemoglobinconcentration exceeds 2 g/100 mL over 4 weeksor if haemoglobin concentration exceeds 12 g/100 mL; ifhaemoglobin concentration continues to rise, despite dosereduction, suspend treatment until haemoglobin concentrationdecreases and then restart at a dose approximately 25 %lower than the previous doseEprex c (Janssen) AInjection, prefilled syringe, epoetin alfa, net price1000 units = £5.53; 2000 units = £11.07; 3000 units =£16.60; 4000 units = £22.13; 5000 units = £27.66;6000 units = £33.19; 8000 units = £44.25; 10 000 units= £55.31; 20 000 units = £110.62; 30 000 units =£199.11; 40 000 units = £265.48. An auto-injectordevice is available for use with prefilled syringesDoseSymptomatic anaemia associated with chronic renalfailure in children on haemodialysis (see also notesabove). By intravenous injection over 1–5 minutesChild 1 month–18 years initially 50 units/kg 3 timesweekly adjusted according to response in steps of25 units/kg 3 times weekly at intervals of at least 49 Nutrition and blood

450 9.1.3 Drugs used in hypoplastic, haemolytic, renal anaemias BNFC 2011–20129 Nutrition and bloodweeks; maintenance dose, body-weight under 10 kgusually 75–150 units/kg 3 times weekly, body-weight 10–30 kg usually 60–150 units/kg 3 times weekly, bodyweight30–60 kg usually 30–100 units/kg 3 times weekly,body-weight over 60 kg usually 75–300 units/kg weekly(as a single dose or in divided doses)Note Reduce dose by approximately 25% if rise in haemoglobinconcentration exceeds 2 g/100 mL over 4 weeks or ifhaemoglobin concentration exceeds 12 g/100 mL; if haemoglobinconcentration continues to rise, despite dosereduction, suspend treatment until haemoglobin concentrationdecreases and then restart at a dose approximately 25%lower than the previous doseEpoetin betaNeoRecormon c (Roche) AInjection, prefilled syringe, epoetin beta, net price500 units = £3.75; 2000 units = £14.98; 3000 units =£22.47; 4000 units = £29.96; 5000 units = £37.47;6000 units = £44.94; 10 000 units = £70.14;20 000 units = £140.28; 30 000 units = £224.69Excipients include phenylalanine up to 300 micrograms/syringe (section9.4.1)DoseSymptomatic anaemia associated with chronic renalfailure (see also notes above). By subcutaneous injectionNeonate initially 20 units/kg 3 times weekly for 4 weeks,increased according to response at intervals of 4 weeks insteps of 20 units/kg 3 times weekly; total weekly dosemay be divided into daily doses; maintenance dose,initially reduce dose by half then adjust according toresponse at intervals of 1–2 weeks; total weekly maintenancedose may be given as a single dose or in 3 or 7divided doses; max. 720 units/kg weeklyChild 1 month–18 years initially 20 units/kg 3 timesweekly for 4 weeks, increased according to response atintervals of 4 weeks in steps of 20 units/kg 3 timesweekly; total weekly dose may be divided into dailydoses; maintenance dose, initially reduce dose by halfthen adjust according to response at intervals of 1–2weeks; total weekly maintenance dose may be given as asingle dose or in 3 or 7 divided doses; max. 720 units/kgweekly. By intravenous injection over 2 minutesNeonate initially 40 units/kg 3 times weekly for 4 weeks,increased according to response to 80 units/kg 3 timesweekly after 4 weeks, with further increases if needed atintervals of 4 weeks in steps of 20 units/kg 3 timesweekly; maintenance dose, initially reduce dose by halfthen adjust according to response at intervals of 1–2weeks; max. 720 units/kg weeklyChild 1 month–18 years initially 40 units/kg 3 timesweekly for 4 weeks, increased according to response to80 units/kg 3 times weekly after 4 weeks, with furtherincreases if needed at intervals of 4 weeks in steps of20 units/kg 3 times weekly; maintenance dose, initiallyreduce dose by half then adjust according to response atintervals of 1–2 weeks; max. 720 units/kg weeklyNote Subcutaneous route preferred in patients not onhaemodialysis. Reduce dose by approximately 25% if rise inhaemoglobin concentration exceeds 2 g/100 mL over 4weeks or if haemoglobin concentration approaches orexceeds 12 g/100 mL; if haemoglobin concentration continuesto rise, despite dose reduction, suspend treatmentuntil haemoglobin concentration decreases and then restartat a dose approximately 25% lower than the previous dose.Prevention of anaemias of prematurity in neonateswith birth-weight of 0.75–1.5 kg and gestational ageunder 34 weeks. By subcutaneous injection (of single-dose, unpreservedinjection)Neonate 250 units/kg 3 times weekly preferably startingwithin 3 days of birth and continued for 6 weeksMultidose injection, powder for reconstitution,epoetin beta, net price 50 000-unit vial = £374.48(with solvent)Excipients include phenylalanine up to 5 mg/vial (section 9.4.1), benzylalcohol (avoid in neonates, see Excipients p. 2)Note Avoid contact of reconstituted injection with glass; useonly plastic materialsDoseSymptomatic anaemia associated with chronic renalfailure (see also notes above). By subcutaneous injectionChild 3–18 years initially 20 units/kg 3 times weekly for4 weeks, increased according to response at intervals of 4weeks in steps of 20 units/kg 3 times weekly; total weeklydose may be divided into daily doses; maintenance dose,initially reduce dose by half then adjust according toresponse at intervals of 1–2 weeks; total weekly maintenancedose may be given as a single dose or in 3 or 7divided doses; max. 720 units/kg weekly. By intravenous injection over 2 minutesChild 3–18 years initially 40 units/kg 3 times weekly for4 weeks, increased according to response to 80 units/kg3 times weekly after 4 weeks, with further increases ifneeded at intervals of 4 weeks in steps of 20 units/kg 3times weekly; maintenance dose, initially reduce dose byhalf then adjust according to response at intervals of 1–2weeks; max. 720 units/kg weeklyNote Subcutaneous route preferred in patients not onhaemodialysis. Reduce dose by approximately 25% if rise inhaemoglobin concentration exceeds 2 g/100 mL over 4weeks or if haemoglobin concentration approaches orexceeds 12 g/100 mL; if haemoglobin concentration continuesto rise, despite dose reduction, suspend treatmentuntil haemoglobin concentration decreases and then restartat a dose approximately 25% lower than the previous dose.Epoetin zetaRetacrit c (Hospira) TAInjection, prefilled syringe, epoetin zeta, net price1000 units = £5.66; 2000 units = £11.31; 3000 units =£16.97; 4000 units = £22.63; 5000 units = £28.28;6000 units = £33.94; 8000 units = £45.25; 10 000 units= £56.57; 20 000 units = £203.64; 30 000 units =£305.46; 40 000 units = £407.27Excipients include phenylalanine up to 500 micrograms/syringe (section9.4.1)Note Biosimilar Medicine, p. 2DoseSymptomatic anaemia associated with chronic renalfailure in children on haemodialysis (see also notesabove). By intravenous injection over 1–5 minutesChild 1 month–18 years initially 50 units/kg 3 timesweekly adjusted according to response in steps of25 units/kg 3 times weekly at intervals of at least 4weeks; maintenance dose, body-weight under 10 kgusually 75–150 units/kg 3 times weekly, body-weight 10–30 kg usually 60–150 units/kg 3 times weekly, bodyweightover 30 kg usually 30–100 units/kg 3 timesweeklyNote Avoid increasing haemoglobin concentration at a rateexceeding 2 g/100 mL over 4 weeksSickle-cell diseaseSickle-cell disease is caused by a structural abnormalityof haemoglobin resulting in deformed, less flexible redblood cells. Acute complications in the more severeforms include sickle-cell crisis, where infarction of themicrovasculature and blood supply to organs results insevere pain. Sickle-cell crisis requires hospitalisation,intravenous fluids, analgesia (section 4.7), and treatmentof any concurrent infection. Chronic complica-

BNFC 2011–2012 9.1.3 Drugs used in hypoplastic, haemolytic, renal anaemias 451tions include skin ulceration, renal failure, and increasedsusceptibility to infection. Pneumococcal vaccine (section14.4), haemophilus influenzae type b vaccine (section14.4), an annual influenza vaccine (section 14.4),and prophylactic penicillin (Table 2, section 5.1) reducethe risk of infection. Hepatitis B vaccine (section 14.4)should be considered if the child is not immune.In most forms of sickle-cell disease, varying degrees ofhaemolytic anaemia are present accompanied byincreased erythropoiesis; this may increase folaterequirements and folate supplementation may be necessary(section 9.1.2).Hydroxycarbamide can reduce the frequency of crisesand the need for blood transfusions. Hydroxycarbamideshould be considered, in consultation with a specialistcentre, for children who have recurrent episodes ofacute pain (more than 3 admissions in the previous 12months, or who are very symptomatic in the community)or who have had 2 or more episodes of acute sicklechest syndrome in the last 2 years (or 1 episode requiringventilatory support). Beneficial effects of hydroxycarbamidemay not become evident for several months.Myelosuppression, and skin reactions are the mostcommon side-effects.HYDROXYCARBAMIDE(Hydroxyurea)Cautions see section 8.1 and notes above; also monitorrenal and hepatic function before and duringtreatment; monitor full blood count before treatment,then every 2 weeks for the first 2 months and thenevery 2 months thereafter (or every 2 weeks if onmax. dose); leg ulcers (review treatment if cutaneousvasculitic ulcerations develop); interactions: Appendix1 (hydroxycarbamide)Hepatic impairment manufacturer advises caution inmild to moderate impairment; avoid in severeimpairmentRenal impairment reduce initial dose by 50% if estimatedglomerular filtration rate less than 60 mL/minute/1.73 m 2 ; avoid if estimated glomerular filtrationrate less than 30 mL/minute/1.73 m 2Pregnancy avoid (teratogenic in animal studies);manufacturer advises effective contraception beforeand during treatment; see also section 8.1Breast-feeding discontinue breast-feedingSide-effects see section 8.1 and notes above; alsoheadache; less commonly dizziness, and rash; rarelyreduced sperm count and activity; fever, amenorrhoea,bleeding, and hypomagnesaemia also reportedIndication and doseSickle-cell disease (see notes above). By mouthChild 2–18 years initially 10–15 mg/kg oncedaily, increased every 12 weeks in steps of 5 mg/kg daily according to response; usual dose 15–30 mg/kg daily (max. 35 mg/kg daily)Iron overloadSevere tissue iron overload can occur in aplastic andother refractory anaemias, mainly as the result ofrepeated blood transfusions. It is a particular problemin refractory anaemias with hyperplastic bone marrow,especially thalassaemia major, where excessive ironabsorption from the gut and inappropriate iron therapycan add to the tissue siderosis.Iron overload associated with haemochromatosis canbe treated with repeated venesection. Venesection mayalso be used for patients who have received multipletransfusions and whose bone marrow has recovered.Where venesection is contra-indicated, and in thalassaemia,the long-term administration of the iron chelatingcompound desferrioxamine mesilate is useful.Subcutaneous infusions of desferrioxamine are givenover 8–12 hours, 3–7 times a week; the dose shouldreflect the degree of iron overload. The initial doseshould not exceed 30 mg/kg. For established overloadthe dose is usually between 20 and 50 mg/kg daily.Desferrioxamine (up to 2 g per unit of blood) may alsobe given at the time of blood transfusion, provided thatthe desferrioxamine is not added to the blood and is notgiven through the same line as the blood (but the twomay be given through the same cannula).Iron excretion induced by desferrioxamine is enhancedby ascorbic acid (vitamin C, section 9.6.3) 100–200 mgdaily by mouth; it should be given separately from foodsince it also enhances iron absorption. Ascorbic acidshould not be given to children with cardiac dysfunction;in children with normal cardiac function ascorbicacid should be introduced 1 month after starting desferrioxamine.Desferrioxamine infusion can be used to treat aluminiumoverload in dialysis patients; theoretically 100 mgof desferrioxamine binds with 4.1 mg of aluminium.Deferasirox, an oral iron chelator, is licensed for thetreatment of chronic iron overload in children over 6years with thalassaemia major who receive frequentblood transfusions (more than 7 mL/kg/month ofpacked blood cells). It is also licensed for chronic ironoverload when desferrioxamine is contra-indicated orinadequate in children with thalassaemia major whoreceive infrequent blood transfusions (less than 7 mL/kg/month of packed red blood cells), in children withother anaemias, and in children aged 2 to 5 years.The Scottish Medicines Consortium (p. 3) has advised(January 2007) that deferasirox is accepted forrestricted use within NHS Scotland for the treatmentof chronic iron overload associated with the treatmentof rare acquired or inherited anaemias requiring recurrentblood transfusions. It is not recommended forpatients with myelodysplastic syndromes.Deferiprone, an oral iron chelator, is licensed for thetreatment of iron overload in children over 6 years ofage with thalassaemia major in whom desferrioxamineis contra-indicated or is inadequate. Blood dyscrasias,particularly agranulocytosis, have been reported withdeferiprone.9 Nutrition and bloodSiklos c (Nordic) TATablets, scored, f/c, hydroxycarbamide 1 g, net price30-tab pack = £500.00Extemporaneous formulations available seeExtemporaneous Preparations, p. 6DEFERASIROXCautions eye and ear examinations required beforetreatment and annually during treatment; monitorbody-weight, height and sexual developmentannually; monitor serum-ferritin concentration

452 9.1.3 Drugs used in hypoplastic, haemolytic, renal anaemias BNFC 2011–20129 Nutrition and bloodmonthly; risk of gastro-intestinal ulceration andhaemorrhage; platelet count less than 50 10 9 /litre;consider treatment interruption if unexplained cytopeniaoccurs; not recommended in conditions whichmay reduce life expectancy (e.g. high-risk myelodysplasticsyndromes); history of liver cirrhosis; test liverfunction before treatment, then every 2 weeks duringthe first month, and then monthly; measure baselineserum-creatinine and monitor renal function weeklyduring the first month of treatment and monthlythereafter; test for proteinuria monthly; interactions:Appendix 1 (deferasirox)Hepatic impairment manufacturer advises caution—no information available; avoid in severe impairmentRenal impairment reduce dose by 10 mg/kg if serumcreatinineincreased above age-appropriate limits orestimated glomerular filtration rate less than 90 mL/minute/1.73 m 2 on 2 consecutive occasions—interrupttreatment if deterioration in renal function persistsafter dose reduction; avoid if estimated glomerularfiltration rate less than 60 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid unless essential—toxicityin animal studiesBreast-feeding manufacturer advises avoid—presentin milk in animal studiesSide-effects gastro-intestinal disturbances (includingulceration and fatal haemorrhage); headache; proteinuria;pruritus, rash; less commonly oedema, hepatitis,cholelithiasis, fatigue, anxiety, sleep disorder, dizziness,pyrexia, pharyngitis, glucosuria, renal tubulopathy,disturbances of hearing and vision (includinglens opacity and maculopathy), and skin pigmentation;hepatic failure, acute renal failure, blood disorders(including agranulocytosis, neutropenia, pancytopenia,and thrombocytopenia), hypersensitivityreactions (including anaphylaxis and angioedema),and alopecia also reportedLicensed use see notes aboveIndication and doseChronic iron overload. By mouthChild 2–18 years initially 10–30 mg/kg once dailyaccording to serum-ferritin concentration andamount of transfused blood (consult product literature);maintenance, adjust dose every 3–6months in steps of 5–10 mg/kg according toserum-ferritin concentration; usual max. 30 mg/kgdaily, but may be increased to max. 40 mg/kg dailyand reduced in steps of 5–10 mg/kg once controlachievedNote Dose should be rounded to nearest whole tabletsizeExjade c (Novartis) TADispersible tablets, deferasirox 125 mg, net price 28-tab pack = £117.60; 250 mg, 28-tab pack = £235.20;500 mg, 28-tab pack = £470.40. Label: 13, 22, counselling,administrationCounselling Tablets should be dispersed in water, orangejuice, or apple juice; if necessary, resuspend residue andswallowDEFERIPRONECautions monitor neutrophil count weekly and discontinuetreatment if neutropenia developsBlood disorders Patients or their carers should be told howto recognise signs of neutropenia and advised to seekimmediate medical attention if symptoms such as fever orsore throat developContra-indications history of agranulocytosis orrecurrent neutropeniaHepatic impairment manufacturer advises monitorliver function—interrupt treatment if persistent elevationin serum alanine aminotransferaseRenal impairment manufacturer advises caution—noinformation availablePregnancy manufacturer advises avoid beforeintended conception and during pregnancy—teratogenicand embryotoxic in animal studies; contraceptionadvised in girls of child-bearing potentialBreast-feeding manufacturer advises avoid—noinformation availableSide-effects gastro-intestinal disturbances (reducingdose and increasing gradually may improve tolerance),increased appetite; headache; red-brown urinediscoloration; neutropenia, agranulocytosis; zincdeficiency; arthropathyLicensed use see notes aboveIndication and doseIron overload in thalassaemia major. By mouthChild 6–18 years 25 mg/kg 3 times daily (max.100 mg/kg daily)Ferriprox c (Swedish Orphan) ATablets, f/c, scored, deferiprone 500 mg, net price100-tab pack = £152.39. Label: 14, counselling, blooddisordersOral solution, red, deferiprone 100 mg/mL, net price500 mL = £152.39. Label: 14, counselling, blood disordersDESFERRIOXAMINE MESILATE(Deferoxamine Mesilate)Cautions eye and ear examinations before treatmentand at 3-month intervals during treatment; monitorbody-weight and height in children at 3-month intervals—riskof growth restriction with excessive doses;aluminium-related encephalopathy (may exacerbateneurological dysfunction); interactions: Appendix 1(desferrioxamine)Renal impairment use with cautionPregnancy teratogenic in animal studies, manufactureradvises use only if potential benefit outweighsriskBreast-feeding manufacturer advises use only ifpotential benefit outweighs risk—no informationavailableSide-effects nausea, vomiting, abdominal pain,headache, pyrexia, growth retardation and bone disorders(see Cautions), arthralgia, myalgia, hearingdisturbances, injection-site reactions; rarely diarrhoea,hepatic impairment, hypotension (especiallywhen given too rapidly by intravenous injection),anaphylaxis, Yersinia and mucormycosis infections,blood dyscrasias (including thrombocytopenia andleucopenia), leg cramps, bone pain, visual disturbances(including lens opacity and retinopathy), rash;very rarely acute respiratory distress, neurologicaldisturbances (including dizziness, neuropathy, con-

BNFC 2011–2012 9.1.4 Drugs used in platelet disorders 453vulsions, and paraesthesia), renal impairment; musclespasms also reportedIndication and doseChronic iron overload see notes aboveAluminium overload in dialysis patients. By intravenous infusionChild 1 month–18 years 5 mg/kg once weeklyIron poisoningSee Emergency Treatment of Poisoning, p. 30Administration For intravenous or subcutaneousinfusion, reconstitute powder with Water for Injectionto a concentration of 100 mg/mL; dilute with Glucose5% or Sodium Chloride 0.9%. In haemodialysis orhaemofiltration administer over the last hour ofdialysis (may be given via the dialysis fistula). Intraperitoneal:may be added to dialysis fluid. In CAPDgive prior to the last exchange of the day.Note For full details and warnings relating to administration,consult product literatureDesferrioxamine mesilate (Non-proprietary) AInjection, powder for reconstitution, desferrioxaminemesilate, net price 500-mg vial = £4.26; 2-g vial =£17.05Desferal c (Novartis) AInjection, powder for reconstitution, desferrioxaminemesilate, net price 500-mg vial = £4.67, 2-g vial =£18.669.1.4 Drugs used in plateletdisordersIdiopathic thrombocytopenic purpura Acute idiopathicthrombocytopenic purpura is usually self-limitingin children. A corticosteroid, such as prednisolone(p. 376), is sometimes used if idiopathic thrombocytopenicpurpura does not resolve spontaneously or if it isassociated with severe cutaneous symptoms or mucousmembrane bleeding; corticosteroid treatment shouldnot be continued longer than 14 days regardless of theresponse.Immunoglobulin preparations (section 14.5) may beused in idiopathic thrombocytopenic purpura or wherea temporary rapid rise in platelets is needed, as inpregnancy or pre-operatively; they are often used inpreference to a corticosteroid. Anti-D immunoglobulinis licensed for the management of idiopathic thrombocytopenicpurpura.Other therapy that has been tried under specialist supervisionin refractory idiopathic thrombocytopenicpurpura includes azathioprine (section 8.2.1), cyclophosphamide(section 8.1.1), vincristine (section 8.1.4),and ciclosporin (section 8.2.2). Rituximab is also used inspecialist centres but experience of its use in children islimited. For patients with chronic severe thrombocytopeniarefractory to other therapy, tranexamic acid (section2.11) may be given to reduce the severity ofhaemorrhage.Splenectomy is considered in chronic thrombocytopenicpurpura if a satisfactory platelet count is notachieved with regular immunoglobulin infusions, ifthere is a relapse on withdrawing or reducing the doseof corticosteroid, and if other therapies are consideredinappropriate.Essential thrombocythaemia Anagrelide reducesplatelets in essential thrombocythaemia in patients atrisk of thrombo-haemorrhagic events who have notresponded adequately to other drugs or who cannottolerate other drugs.ANAGRELIDECautions cardiovascular disease—assess cardiacfunction before and during treatment; concomitantaspirin in patients at risk of haemorrhage; monitor fullblood count (monitor platelet count every 2 days for 1week, then weekly until maintenance dose established),liver function, serum creatinine, and urea;interactions: Appendix 1 (anagrelide)Skilled tasks Dizziness may affect performance of skilledtasks (e.g. driving)Hepatic impairment manufacturer advises caution inmild impairment; avoid in moderate to severeimpairmentRenal impairment manufacturer advises avoid ifestimated glomerular filtration rate less than 50 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid (toxicity inanimal studies)Breast-feeding manufacturer advises avoid—noinformation availableSide-effects gastro-intestinal disturbances; palpitation,tachycardia, fluid retention; headache, dizziness,fatigue; anaemia; rash; less commonly pancreatitis,gastro-intestinal haemorrhage, congestive heart failure,hypertension, arrhythmias, syncope, chest pain,dyspnoea, sleep disturbances, paraesthesia,hypoaesthesia, depression, nervousness, confusion,amnesia, fever, weight changes, impotence, blooddisorders, myalgia, arthralgia, epistaxis, dry mouth,alopecia, skin discoloration, and pruritus; rarely gastritis,colitis, postural hypotension, angina, myocardialinfarction, vasodilatation, pulmonary infiltrates,migraine, drowsiness, impaired coordination, dysarthria,asthenia, tinnitus, renal failure, nocturia, visualdisturbances, and gingival bleeding; allergic alveolitisand hepatitis also reportedLicensed use not licensed for use in childrenIndication and doseEssential thrombocythaemia in at-risk childrenwho have not responded adequately to othertherapy or who are intolerant of it (initiated underspecialist supervision). By mouthChild 7–18 years initially 500 micrograms dailyadjusted according to response in steps of500 micrograms daily at weekly intervals to max.10 mg daily (max. single dose 2.5 mg); usual doserange 1–3 mg daily in divided dosesXagrid c (Shire) TACapsules, anagrelide (as hydrochloride), 500 micrograms,net price 100–cap pack= £337.14. Counselling,skilled tasks, see above9 Nutrition and blood

454 9.1.5 G6PD deficiency BNFC 2011–20129 Nutrition and blood9.1.5 G6PD deficiencyGlucose 6-phosphate dehydrogenase (G6PD) deficiencyis highly prevalent in individuals originating from mostparts of Africa, from most parts of Asia, from Oceania,and from Southern Europe; it can also occur, rarely, inany other individuals. G6PD deficiency is more commonin males than it is in females.Individuals with G6PD deficiency are susceptible todeveloping acute haemolytic anaemia when they takea number of common drugs. They are also susceptibleto developing acute haemolytic anaemia when they eatfava beans (broad beans, Vicia faba); this is termedfavism and can be more severe in children or when thefresh fava beans are eaten raw.When prescribing drugs for children with G6PD deficiency,the following three points should be kept inmind:. G6PD deficiency is genetically heterogeneous; susceptibilityto the haemolytic risk from drugs varies;thus, a drug found to be safe in some G6PD-deficientindividuals may not be equally safe in others;. manufacturers do not routinely test drugs for theireffects in G6PD-deficient individuals;. the risk and severity of haemolysis is almost alwaysdose-related.The lists below should be read with these points in mind.Ideally, information about G6PD deficiency should beavailable before prescribing a drug listed below. However,in the absence of this information, the possibility ofhaemolysis should be considered, especially if the childbelongs to a group in which G6PD deficiency is common.A very few G6PD-deficient individuals with chronic nonspherocytichaemolytic anaemia have haemolysis evenin the absence of an exogenous trigger. These childrenmust be regarded as being at high risk of severe exacerbationof haemolysis following administration of any ofthe drugs listed below.Drugs with definite risk of haemolysis in mostG6PD-deficient individualsDapsone and other sulfones (higher doses fordermatitis herpetiformis more likely to cause problems)Methylthioninium chlorideNiridazole [not on UK market]NitrofurantoinPamaquin [not on UK market]Primaquine (30 mg weekly for 8 weeks has beenfound to be without undue harmful effects in Africanand Asian people, see section 5.4.1)Quinolones (including ciprofloxacin, moxifloxacin,nalidixic acid, norfloxacin, and ofloxacin)RasburicaseSulfonamides (including co-trimoxazole; some sulfonamides,e.g. sulfadiazine, have been tested andfound not to be haemolytic in many G6PD-deficientindividuals)Drugs with possible risk of haemolysis insome G6PD-deficient individualsAspirin (acceptable up to a dose of at least 1 g dailyin most G6PD-deficient individuals)Chloroquine (acceptable in acute malaria and malariachemoprophylaxis)Menadione, water-soluble derivatives (e.g.menadiol sodium phosphate)Probenecid [not on UK market]Quinidine (acceptable in acute malaria) [not on UKmarket]Quinine (acceptable in acute malaria)Note Naphthalene in mothballs also causes haemolysis inindividuals with G6PD-deficiency.9.1.6 Drugs used inneutropeniaRecombinant human granulocyte-colony stimulatingfactor (rhG-CSF) stimulates the production of neutrophilsand may reduce the duration of chemotherapyinducedneutropenia and thereby reduce the incidenceof associated sepsis; there is as yet no evidence that itimproves overall survival. Filgrastim (unglycosylatedrhG-CSF) and lenograstim (glycosylated rhG-CSF)have similar effects; both have been used in a varietyof clinical settings, including cytotoxic-induced neutropenia,and neutropenia following bone marrow transplantation,but they do not have any clear-cut routineindications. In congenital neutropenia filgrastim usuallyincreases the neutrophil count with an appropriateclinical response. Prolonged use may be associatedwith an increased risk of myeloid malignancy.Treatment with granulocyte-colony stimulating factorsshould only be prescribed by those experienced in theiruse.Neonatal neutropenia Filgrastim has been used totreat sepsis-induced neutropenia in preterm neonates.There is no clear evidence that granulocyte-colonystimulating factors improve survival or long-term outcomes.Cautions Granulocyte-colony stimulating factorsshould be used with caution in patients with pre-malignantor malignant myeloid conditions. Full blood counts(including differential white cell count and plateletcount) should be monitored. Treatment should be withdrawnin patients who develop signs of pulmonaryinfiltration. There have been reports of pulmonary infiltratesleading to acute respiratory distress syndrome—patients with a history of pulmonary infiltrates or pneumoniamay be at higher risk. Granulocyte-colony stimulatingfactors should be used with caution in childrenwith sickle-cell disease. Spleen size should be monitoredduring treatment as there is a risk of splenomegaly andrupture.

BNFC 2011–2012 9.1.6 Drugs used in neutropenia 455Pregnancy There have been reports of toxicityin animal studies and manufacturers advise not touse granulocyte-colony stimulating factors duringpregnancy unless the potential benefit outweighs therisk.Breast-feeding There is no evidence for the use ofgranulocyte-colony stimulating factors during breastfeedingand manufacturers advise avoiding use.Side-effects Side-effects of granulocyte-colony stimulatingfactors include gastro-intestinal disturbances,anorexia, headache, asthenia, fever, musculoskeletalpain, bone pain, rash, alopecia, injection-site reactions,thrombocytopenia, and leucocytosis. Less commonlychest pain can occur. Pulmonary side-effects, particularlyinterstitial pneumonia (see Cautions above), cutaneousvasculitis, and acute febrile neutrophilic dermatosishave rarely been reported.FILGRASTIM(Recombinant human granulocyte-colony stimulatingfactor, G-CSF)Cautions see notes above; also regular morphologicaland cytogenetic bone-marrow examinations recommendedin severe congenital neutropenia (possiblerisk of myelodysplastic syndromes or leukaemia);secondary acute myeloid leukaemia; osteoporoticbone disease (monitor bone density if given for morethan 6 months); interactions: Appendix 1 (filgrastim)Contra-indications severe congenital neutropenia(Kostman’s syndrome) with abnormal cytogeneticsPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also mucositis, splenicenlargement, hepatomegaly, transient hypotension,epistaxis, urinary abnormalities (including dysuria,proteinuria, and haematuria), osteoporosis, exacerbationof rheumatoid arthritis, anaemia, transientdecrease in blood glucose, pseudogout, and raiseduric acid; very rarely splenic ruptureLicensed use not licensed for treatment of glycogenstorage disease or neonatal neutropeniaIndication and doseCytotoxic-induced neutropenia. Preferably by subcutaneous injection or byintravenous infusion (over 30 minutes)Child 1 month–18 years 5 micrograms/kg dailystarted not less than 24 hours after cytotoxicchemotherapy, continued until neutrophil count innormal range, usually for up to 14 days (up to 38days in acute myeloid leukaemia)Myeloablative therapy followed by bone-marrowtransplantation. By intravenous infusion over 30 minutes orover 24 hours or by subcutaneous infusion over24 hoursChild 1 month–18 years 10 micrograms/kg daily,started not less than 24 hours following cytotoxicchemotherapy (and within 24 hours of bone-marrowinfusion), then adjusted according to absoluteneutrophil count (consult product literature andlocal protocol)Mobilisation of peripheral blood progenitorcells for autologous infusion, used alone. By subcutaneous injection or by subcutaneousinfusion over 24 hoursChild 1 month–18 years 10 micrograms/kg dailyfor 5–7 daysMobilisation of peripheral blood progenitorcells for autologous infusion following adjunctivemyelosuppressive chemotherapy (toimprove yield). By subcutaneous injectionChild 1 month–18 years 5 micrograms/kg daily,started the day after completion of chemotherapyand continued until neutrophil count in normalrange; for timing of leucopheresis consult productliteratureMobilisation of peripheral blood progenitorcells in normal donors for allogeneic infusion. By subcutaneous injectionChild over 16 years 10 micrograms/kg daily for4–5 days; for timing of leucopheresis consult productliteratureSevere chronic neutropenia. By subcutaneous injectionChild 1 month–18 years in severe congenitalneutropenia, initially 12 micrograms/kg daily insingle or divided doses (initially 5 micrograms/kgdaily in idiopathic or cyclic neutropenia), adjustedaccording to response (consult product literatureand local protocol)Persistent neutropenia in HIV infection. By subcutaneous injectionChild 1 month–18 years initially 1 microgram/kgdaily, increased as necessary until absolute neutrophilcount in normal range (usual max. 4 micrograms/kgdaily), then adjusted to maintainabsolute neutrophil count in normal range (consultproduct literature)Neonatal neutropenia. By subcutaneous injectionNeonate 10 micrograms/kg daily, discontinue ifwhite cell count exceeds 50 10 9 /litreGlycogen storage disease type 1b. By subcutaneous injection5 micrograms/kg daily, adjusted as necessaryAdministration For subcutaneous or intravenousinfusion, dilute with Glucose 5% to a concentration ofnot less than 15 micrograms/mL; to dilute to a concentrationof 2–15 micrograms/mL, add albuminsolution (human albumin solution) to produce a finalalbumin solution of 2 mg/mL; not compatible withSodium Chloride solutionsNeupogen c (Amgen) AInjection, filgrastim 30 million units (300 micrograms)/mL;net price 1-mL vial = £58.56Injection (Singleject c ), filgrastim 60 million units(600 micrograms)/mL, net price 0.5-mL prefilledsyringe = £58.56; 96 million units (960 micrograms)/mL, 0.5-mL prefilled syringe = £93.409 Nutrition and blood

456 9.2 Fluids and electrolytes BNFC 2011–2012Nivestim c (Hospira) TAInjection, prefilled syringe, filgrastim, net price12 million-units (120 micrograms)/0.2 mL = £36.00;30 million-units (300 micrograms)/0.5 mL = £58.00;48 million-units (480 micrograms)/0.5 mL = £93.00Note Biosimilar medicine, p. 2Ratiograstim c (Ratiopharm UK) TAInjection, prefilled syringe, filgrastim, net price30 million-units (300 micrograms)/0.5 mL = £62.26;48 million-units (480 micrograms)/0.8 mL = £99.29Note Biosimilar medicine, p. 2Tevagrastim c (TEVA UK) TAInjection, prefilled syringe, filgrastim, net price30 million-units (300 micrograms)/0.5 mL = £62.25;48 million-units (480 micrograms)/0.8 mL = £99.29Note Biosimilar medicine, p. 2chemotherapy and continued until neutrophilcount in acceptable range; for timing of leucopheresisconsult product literatureAdministration for intravenous infusion, dilutereconstituted solution to a concentration of not lessthan 2 micrograms/mL (Granocyte-13) or 2.5 micrograms/mL(Granocyte-34) with Sodium Chloride0.9%Granocyte c (Chugai) AInjection, powder for reconstitution, lenograstim, netprice 13.4 million-unit (105-microgram) vial = £40.11;33.6 million-unit (263-microgram) vial = £62.54 (bothwith 1-mL prefilled syringe water for injections)Excipients include phenylalanine (section 9.4.1)Zarzio c (Sandoz) TAInjection, prefilled syringe, filgrastim, net price30 million-units (300 micrograms)/0.5 mL = £59.00;48 million-units (480 micrograms)/0.5 mL = £94.00Note Biosimilar medicine, p. 29 Nutrition and bloodLENOGRASTIM(Recombinant human granulocyte-colony stimulatingfactor, rHuG-CSF)Cautions see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also splenic rupture andtoxic epidermal necrolysisLicensed use not licensed for use in children forcytotoxic-induced neutropenia, mobilisation ofperipheral blood progenitor cells (monotherapy oradjunctive therapy), or following peripheral stemcells transplantationIndication and doseFollowing peripheral stem cells or bone-marrowtransplantation. By intravenous infusion over 30 minutes or bysubcutaneous injectionChild 2–18 years 150 micrograms/m 2 dailystarted the day after transplantation, continueduntil neutrophil count stable in acceptable range(max. 28 days)Cytotoxic-induced neutropenia. By subcutaneous injectionChild 2–18 years 150 micrograms/m 2 dailystarted the day after completion of chemotherapy,continued until neutrophil count stable in acceptablerange (max. 28 days)Mobilisation of peripheral blood progenitorcells, used alone. By subcutaneous injectionChild 2–18 years 10 micrograms/kg daily for 4–6days (5–6 days in healthy donors)Mobilisation of peripheral blood progenitorcells following adjunctive myelosuppressivechemotherapy (to improve yield). By subcutaneous injectionChild 2–18 years 150 micrograms/m 2 daily,started 1–5 days after completion of9.2 Fluids and electrolytes9.2.1 Oral preparations for fluid andelectrolyte imbalance9.2.2 Parenteral preparations for fluid andelectrolyte imbalanceThe following tables give a selection of useful electrolytevalues:Electrolyte concentrations—intravenousfluidsMillimoles per litreIntravenous infusion Na + K + HCO 3 Cl Ca 2þNormal plasma values 142 4.5 26 103 2.5Sodium Chloride 0.9% 150 — — 150 —Compound Sodium 131 5 29 111 2Lactate (Hartmann’s)Sodium Chloride0.45% and Glucose5%75 — — 75 —Potassium Chloride0.15% and Glucose5%Potassium Chloride0.15% and SodiumChloride 0.9%Potassium Chloride0.3% and Glucose 5%Potassium Chloride0.3% and SodiumChloride 0.9%— 20 — 20 —150 20 — 170 —— 40 — 40 —150 40 — 190 —To correct metabolic acidosisSodium Bicarbonate1.26%150 — 150 — —Sodium Bicarbonate 1000 — 1000 — —8.4% for cardiac arrestSodium Lactate (m/6) 167 — 167 — —

BNFC 2011–2012 9.2.1 Oral preparations for fluid and electrolyte imbalance 457Electrolyte content—gastro-intestinalsecretionsType ofMillimoles per litrefluidH + Na + K + HCO 3 ClGastric 40–60 20–80 5–20 — 100–150Biliary — 120–140 5–15 30–50 80–120Pancreatic — 120–140 5–15 70–110 40–80Smallbowel— 120–140 5–15 20–40 90–130Faeces, vomit, or aspiration should be saved and analysedwhere possible if abnormal losses are suspected; where thisis impracticable the approximations above may be helpful inplanning replacement therapy9.2.1 Oral preparations for fluidand electrolyte imbalance9.2.1.1 Oral potassium9.2.1.2 Oral sodium and water9.2.1.3 Oral bicarbonateSodium and potassium salts, which may be given bymouth to prevent deficiencies or to treat establisheddeficiencies of mild or moderate degree, are discussedin this section. Oral preparations for removing excesspotassium and preparations for oral rehydration therapyare also included here. Oral bicarbonate, for metabolicacidosis, is also described in this section.For reference to calcium, magnesium, and phosphate,see section 9.5.9.2.1.1 Oral potassiumCompensation for potassium loss is especially necessary:. in children in whom secondary hyperaldosteronismoccurs, e.g. renal artery stenosis, renal tubule disorder,the nephrotic syndrome, and severe heartfailure;. in children with excessive losses of potassium in thefaeces, e.g. chronic diarrhoea associated with intestinalmalabsorption or laxative abuse;. in those taking digoxin or anti-arrhythmic drugs,where potassium depletion may induce arrhythmias.Measures to compensate for potassium loss may berequired during long-term administration of drugsknown to induce potassium loss (e.g. corticosteroids).Potassium supplements are seldom required with thesmall doses of diuretics given to treat hypertension;potassium-sparing diuretics (rather than potassiumsupplements) are recommended for prevention of hypokalaemiadue to diuretics such as furosemide or thethiazides when these are given to eliminate oedema.Dosage If potassium salts are used for the preventionof hypokalaemia, then doses of potassium chloride 1–2 mmol/kg (usual max. 50 mmol potassium) daily bymouth are suitable in patients taking a normal diet.Smaller doses must be used if there is renal insufficiencyto reduce the risk of hyperkalaemia. Potassium saltscause nausea and vomiting and poor compliance is amajor limitation to their effectiveness (small divideddoses may minimise gastric irritation); when appropriate,potassium-sparing diuretics are preferable (see alsoabove). Regular monitoring of plasma-potassium concentrationis essential in those taking potassium supplements.When there is established potassium depletionlarger doses may be necessary, the quantity dependingon the severity of any continuing potassium loss (monitoringof plasma-potassium concentration and specialistadvice would be required). Potassium depletion isfrequently associated with chloride depletion and withmetabolic alkalosis, and these disorders require correction.Administration Potassium salts are preferably givenas a liquid (or effervescent) preparation, rather thanmodified-release tablets; they should be given as thechloride (the use of effervescent potassium tablets BPC1968 should be restricted to hyperchloraemic states,section 9.2.1.3). Potassium chloride solutions suitablefor use by mouth in neonates are available from ‘specialorder’manufacturers or specialist importing companies,see p. 809; they should be used with care because theyare hypertonic and can damage the gastric mucosa.Salt substitutes A number of salt substitutes which containsignificant amounts of potassium chloride are readily availableas health food products (e.g. LoSalt c and Ruthmol c ). Theseshould not be used by patients with renal failure as potassiumintoxication may result.POTASSIUM CHLORIDECautions see notes above; cardiac disease; withmodified-release preparations, intestinal stricture,history of peptic ulcer, hiatus hernia; interactions:Appendix 1 (potassium salts)Contra-indications plasma-potassium concentrationabove 5 mmol/litreRenal impairment close monitoring required— risk ofhyperkalaemia; avoid in severe impairmentSide-effects nausea, vomiting, abdominal pain, diarrhoea,flatulence; with modified-release preparations,gastro-intestinal obstruction, ulceration, and bleedingalso reportedIndication and dosePotassium depletion. By mouthNeonate 0.5–1 mmol/kg K + twice daily (total dailydose may alternatively be given in 3 divideddoses), adjusted according to plasma-potassiumconcentrationChild 1 month–18 years 0.5–1 mmol/kg K +twice daily (total daily dose may alternatively begiven in 3 divided doses), adjusted according toplasma-potassium concentrationNote Do not confuse Effervescent Potassium Tablets BPC1968 (section 9.2.1.3) with effervescent potassium chloridetablets. Effervescent Potassium Tablets BPC 1968 do notcontain chloride ions and their use should be restricted tohyperchloraemic states (section 9.2.1.3).Kay-Cee-L c (Geistlich)Syrup, sugar-free, red, potassium chloride 7.5%(1 mmol/mL each of K + and Cl ), net price 500 mL =£4.07. Label: 219 Nutrition and blood

458 9.2.1 Oral preparations for fluid and electrolyte imbalance BNFC 2011–20129 Nutrition and bloodSando-K c (HK Pharma)Tablets, effervescent, potassium bicarbonate andchloride equivalent to potassium 470 mg (12 mmol ofK + ) and chloride 285 mg (8 mmol of Cl ), net price 20= £1.53. Label: 13, 21Modified-release preparationsAvoid unless effervescent tablets or liquid preparationsinappropriateSlow-K c (Alliance) UTablets, m/r, orange, s/c, potassium chloride 600 mg(8 mmol each of K + and Cl ), net price 100 = £2.14.Label: 25, 27, counselling, swallow whole with fluidduring meals while sitting or standingManagement of hyperkalaemiaAcute severe hyperkalaemia calls for urgent treatmentwith intravenous infusion of soluble insulin (0.3–0.6 units/kg/hour in neonates and 0.05–0.2 units/kg/hour in children over 1 month) with glucose 0.5–1 g/kg/hour (5–10 mL/kg of glucose 10%; 2.5–5 mL/kg ofglucose 20% via a central venous catheter may also beconsidered). If insulin cannot be used, salbutamol (section3.1.1.1) can be given by intravenous injection, but ithas a slower onset of action and may be less effective forreducing plasma-potassium concentration.Calcium gluconate (section 9.5.1.1) is given by slowintravenous injection to manage cardiac excitabilitycaused by hyperkalaemia.The correction of causal or compounding acidosis withsodium bicarbonate infusion (section 9.2.2.1) shouldbe considered (important: preparations of sodiumbicarbonate and calcium salts should not be administeredin the same line— risk of precipitation). Intravenousfurosemide can also be given but is less effectivein children with renal impairment. Drugsexacerbating hyperkalaemia should be reviewed andstopped as appropriate; dialysis may occasionally berequired.Ion-exchange resins may be used to remove excesspotassium in mild hyperkalaemia or in moderate hyperkalaemiawhen there are no ECG changes. Calciumpolystyrene sulphonate is preferred unless plasma-calciumconcentrations are high.POLYSTYRENE SULPHONATE RESINSCautions impaction of resin with excessive dosage orinadequate dilution; monitor for electrolyte disturbances(stop if plasma-potassium concentrationbelow 5 mmol/litre); sodium-containing resin incongestive heart failure, hypertension, and oedema;interactions: Appendix 1 (polystyrene sulphonateresins)Contra-indications obstructive bowel disease; neonateswith reduced gut motility; calcium-containingresin in hyperparathyroidism, multiple myeloma, sarcoidosis,or metastatic carcinomaRenal impairment use sodium-containing resin withcautionPregnancy manufacturers advise use only if potentialbenefit outweighs risk—no information availableBreast-feeding manufacturers advise use only ifpotential benefit outweighs risk—no informationavailableSide-effects faecal impaction following rectal administration,gastro-intestinal concretions following oraladministration, intestinal necrosis reported with concomitantuse of sorbitol, gastric irritation, anorexia,nausea, vomiting, constipation (discontinue treatment—avoidmagnesium-containing laxatives), diarrhoea,hypomagnesaemia; gastro-intestinal obstruction,ulceration, necrosis, and ischaemic colitis alsoreported; with calcium-containing resin, hypercalcaemia(including in dialysed patients and occasionallythose with renal impairment); with sodium containingresin, sodium retention, hypocalcaemiaIndication and doseHyperkalaemia associated with anuria orsevere oliguria, and in dialysis patients. By mouthChild 1 month–18 years 125–250 mg/kg (max.15 g) 3–4 times daily. By rectumNeonate 125–250 mg/kg repeated as necessaryevery 6–8 hours. Irrigate colon to remove resinafter 6–12 hoursChild 1 month—18 years 125–250 mg/kgrepeated as necessary every 6–8 hours. Irrigatecolon to remove resin after 6–12 hoursAdministration By mouth: administer in water or as apaste—do not give with fruit squash, which has a highpotassium content.By rectum: mix 1 g of resin with 5–10 mL of amethylcellulose solution. Water may be used butretention is more difficult.Calcium Resonium c (Sanofi-Aventis)Powder, buff, calcium polystyrene sulphonate, netprice 300 g = £68.47. Label: 13Resonium A c (Sanofi-Aventis)Powder, buff, sodium polystyrene sulphonate, netprice 454 g = £67.50. Label: 139.2.1.2 Oral sodium and waterSodium chloride is indicated in states of sodium depletion.In preterm neonates in the first few weeks of lifeand in chronic conditions associated with mild or moderatedegrees of sodium depletion, e.g. in salt-losingbowel or renal disease, oral supplements of sodiumchloride (section 9.2.1.3) may be sufficient. Sodiumchloride solutions suitable for use by mouth in neonatesare available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809; they should beused with care because they are hypertonic. Supplementationwith sodium chloride may be required toreplace losses in children with cystic fibrosis particularlyin warm weather.SODIUM CHLORIDEIndication and doseSee also section 9.2.2

BNFC 2011–2012 9.2.1 Oral preparations for fluid and electrolyte imbalance 459Sodium supplementation in neonates. By mouthPreterm neonate 2 mmol/100 mL of formula feedor 3–4 mmol/100 mL of breast milk, consult dieticianSodium replacement. By mouthChild 1 month–18 years according to requirements,generally 1–2 mmol/kg daily in divideddoses, higher doses may be needed in severedepletionChronic renal loss. By mouthChild 1 month–18 years 1–2 mmol/kg daily individed doses, adjusted according to requirementsSlow Sodium c (HK Pharma)Tablets, m/r, sodium chloride 600 mg (approx.10 mmol each of Na + and Cl ). Net price 100-tab pack= £6.05. Label: 25Capsules available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Extemporaneous formulations available seeExtemporaneous Preparations, p. 6Oral rehydration therapy (ORT)Diarrhoea in children is usually self-limiting, however, inchildren under 6 months of age, and more particularly inthose under 3 months, symptoms of dehydration may beless obvious and there is a risk of rapid and severedeterioration. Intestinal absorption of sodium and wateris enhanced by glucose (and other carbohydrates).Replacement of fluid and electrolytes lost through diarrhoeacan therefore be achieved by giving solutionscontaining sodium, potassium, and glucose or anothercarbohydrate such as rice starch.Oral rehydration solutions should:. enhance the absorption of water and electrolytes;. replace the electrolyte deficit adequately and safely;. contain an alkalinising agent to counter acidosis;. be slightly hypo-osmolar (about 250 mmol/litre) toprevent the possible induction of osmotic diarrhoea;. be simple to use in hospital and at home;. be palatable and acceptable, especially to children;. be readily available.It is the policy of the World Health Organization (WHO)to promote a single oral rehydration solution but to useit flexibly (e.g. by giving extra water between drinks oforal rehydration solution to moderately dehydratedinfants).Oral rehydration solutions used in the UK are lower insodium (50–60 mmol/litre) than the WHO formulationsince, in general, patients suffer less severe sodium loss.Rehydration should be rapid over 3 to 4 hours (except inhypernatraemic dehydration in which case rehydrationshould occur more slowly over 12 hours). The patientshould be reassessed after initial rehydration and if stilldehydrated rapid fluid replacement should continue.Once rehydration is complete further dehydration isprevented by encouraging the patient to drink normalvolumes of an appropriate fluid and by replacing continuinglosses with an oral rehydration solution; ininfants, breast-feeding or formula feeds should beoffered between oral rehydration drinks.For intravenous rehydration see section 9.2.2.ORAL REHYDRATION SALTS (ORS)Licensed use Dioralyte c Relief not licensed for usein children under 3 monthsIndication and doseFluid and electrolyte loss in diarrhoea see notesabove. By mouthChild 1 month–1 year 1–1½ times usual feedvolumeChild 1–12 years 200 mL after every loosemotionChild 12–18 years 200–400 mL after every loosemotionUK formulationsNote After reconstitution any unused solution should be discardedno later than 1 hour after preparation unless stored in arefrigerator when it may be kept for up to 24 hours.Dioralyte c (Sanofi-Aventis)Oral powder, sodium chloride 470 mg, potassiumchloride 300 mg, disodium hydrogen citrate 530 mg,glucose 3.56 g/sachet, net price 6-sachet pack =£2.25, 20-sachet pack (black currant- or citrus-flavouredor natural) = £6.72Note Reconstitute 1 sachet with 200 mL of water (freshlyboiled and cooled for infants); 5 sachets reconstituted with1 litre of water provide Na + 60 mmol, K + 20 mmol, Cl60 mmol, citrate 10 mmol, and glucose 90 mmolDioralyte c Relief (Sanofi-Aventis)Oral powder, sodium chloride 350 mg, potassiumchloride 300 mg, sodium citrate 580 mg, cooked ricepowder 6 g/sachet, net price 6-sachet pack (apricot-,black currant- or raspberry-flavoured) = £2.50, 20-sachet pack (apricot-flavoured) = £7.13Note Reconstitute 1 sachet with 200 mL of water (freshlyboiled and cooled for infants); 5 sachets when reconstitutedwith 1 litre of water provide Na + 60 mmol, K + 20 mmol, Cl50 mmol and citrate 10 mmol; contains aspartame (section9.4.1)Electrolade c (Actavis)Oral powder, sodium chloride 236 mg, potassiumchloride 300 mg, sodium bicarbonate 500 mg, anhydrousglucose 4 g/sachet (banana-, black currant-,lemon and lime-, or orange-flavoured). Net price 6-sachet (plain or multiflavoured) pack = £1.33, 20-sachet (single- or multiflavoured) pack = £4.99Note Reconstitute 1 sachet with 200 mL of water (freshlyboiled and cooled for infants); 5 sachets when reconstitutedwith 1 litre of water provide Na + 50 mmol, K + 20 mmol, Cl40 mmol, HCO 3 30 mmol, and glucose 111 mmolWHO formulationOral Rehydration Salts (Non-proprietary)Oral powder, sodium chloride 2.6 g, potassiumchloride 1.5 g, sodium citrate 2.9 g, anhydrous glucose13.5 g. To be dissolved in sufficient water to produce1 litre (providing Na + 75 mmol, K + 20 mmol, Cl –65 mmol, citrate 10 mmol, glucose 75 mmol/litre)Note Recommended by the WHO and the United NationsChildren’s Fund but not commonly used in the UK9 Nutrition and blood

460 9.2.2 Parenteral preparations for fluid & electrolyte imbalance BNFC 2011–20129.2.1.3 Oral bicarbonateSodium bicarbonate is given by mouth for chronicacidotic states such as uraemic acidosis or renal tubularacidosis. The dose for correction of metabolic acidosis isnot predictable and the response must be assessed. Forsevere metabolic acidosis, sodium bicarbonate can begiven intravenously (section 9.2.2).Sodium supplements may increase blood pressure orcause fluid retention and pulmonary oedema in those atrisk; hypokalaemia may be exacerbated.Sodium bicarbonate may affect the stability or absorptionof other drugs if administered at the same time. Ifpossible, allow 1–2 hours before administering otherdrugs orally.Where hyperchloraemic acidosis is associated withpotassium deficiency, as in some renal tubular andgastro-intestinal disorders it may be appropriate togive oral potassium bicarbonate, although acute orsevere deficiency should be managed by intravenoustherapy.Potassium Tablets, Effervescent (Non-proprietary)Effervescent tablets, potassium bicarbonate 500 mg,potassium acid tartrate 300 mg, each tablet providing6.5 mmol of K + . To be dissolved in water beforeadministration. Net price 56 = £33.38. Label: 13, 21Note These tablets do not contain chloride; for effervescenttablets containing potassium and chloride, see under PotassiumChloride, section 9.2.1.19.2.2 Parenteral preparationsfor fluid and electrolyteimbalance9.2.2.1 Electrolytes and water9.2.2.2 Plasma and plasma substitutes9 Nutrition and bloodSODIUM BICARBONATECautions see notes above; avoid in respiratory acidosis;interactions: Appendix 1 (antacids)Indication and doseRenal acidosis (see also notes above). By mouthNeonate initially 1–2 mmol/kg daily in divideddoses, adjusted according to responseChild 1 month–18 years initially 1–2 mmol/kgdaily in divided doses, adjusted according toresponseMetabolic acidosis section 9.2.2.1Renal hyperkalaemia section 9.2.2.1Sodium Bicarbonate (Non-proprietary)Capsules, sodium bicarbonate 500 mg (approx.6 mmol each of Na + and HCO –3 ), net price 56-cappack = £5.16Tablets, sodium bicarbonate 600 mg, net price 100-tab pack = £2.48Important Oral solutions of sodium bicarbonate are requiredoccasionally; these need to be obtained from ‘special-order’manufacturers or specialist importing companies, see p. 809,and the strength of sodium bicarbonate should be stated onthe prescriptionPOTASSIUM BICARBONATECautions cardiac disease, interactions: Appendix 1(potassium salts)Contra-indications hypochloraemia; plasma-potassiumconcentration above 5 mmol/litreRenal impairment close monitoring required—highrisk of hyperkalaemia; avoid in severe impairmentSide-effects nausea, vomiting, abdominal pain, diarrhoea,and flatulence9.2.2.1 Electrolytes and waterSolutions of electrolytes are given intravenously, to meetnormal fluid and electrolyte requirements or to replenishsubstantial deficits or continuing losses when it is notpossible or desirable to use the oral route. When intravenousadministration is not possible, fluid (as sodiumchloride 0.9% or glucose 5%) can also be given subcutaneouslyby hypodermoclysis.In an individual patient the nature and severity of theelectrolyte imbalance must be assessed from the historyand clinical and biochemical examination. Sodium,potassium, chloride, magnesium, phosphate, and waterdepletion can occur singly and in combination with orwithout disturbances of acid-base balance; for referenceto the use of magnesium and phosphates, see section9.5.Isotonic solutions may be infused safely into a peripheralvein. Solutions more concentrated than plasma, forexample 15% glucose, are best given through an indwellingcatheter positioned in a large vein.Maintenance fluid requirements in children are usuallyderived from the relationship that exists betweenbody-weight and metabolic rate; the figures in thetable below may be used as a guide outside the neonatalperiod. The glucose requirement is that needed tominimise gluconeogenesis from amino acids obtainedas substrate from muscle breakdown. Maintenancefluids are intended only to provide hydration for ashort period until enteral or parenteral nutrition canbe established.It is usual to meet these requirements by using astandard solution of sodium chloride and glucose. Solutionscontaining 20 mmol/litre of potassium chloridemeet usual potassium requirements when given in thesuggested volumes; adjustments may be needed if thereis an inability to excrete fluids or electrolytes, excessiverenal loss or continuing extra-renal losses. The exactrequirements depend upon the nature of the clinicalsituation and types of losses incurred; see Caution ondilutional hyponatraemia below.

BNFC 2011–2012 9.2.2 Parenteral preparations for fluid & electrolyte imbalance 461Fluid requirements for children over 1month:BodyweightUnder10 kg24-hour fluid requirement100 mL/kg10–20 kg 100 mL/kg for the first 10 kg+ 50 mL/kg for each 1 kg body-weight over10 kgOver 20 kg100 mL/kg for the first 10 kg+ 50 mL/kg for each 1 kg body-weightbetween 10–20 kg+ 20 mL/kg for each 1 kg body-weight over20 kg(max. 2 litres in females, 2.5 litres in males)Important The baseline fluid requirements shown in thetable above should be adjusted to take account of factorsthat reduce water loss (e.g. increased antidiuretic hormone,renal failure, hypothermia, and high ambient humidity) orincrease water loss (e.g. pyrexia or burns).Caution During parenteral hydration, fluids and electrolytesshould be monitored closely and any disturbancecorrected by slow infusion of an appropriatesolution. The volume of fluid infused should take intoaccount the possibility of reduced fluid loss owing toincreased antidiuretic hormone and factors such asrenal failure, hypothermia, and high humidity.Dilutional hyponatraemia is a rare but potentially fatalrisk of parenteral hydration. It may be caused by inappropriateuse of hypotonic fluids such as sodium chloride0.18% and glucose 4% intravenous infusion, especiallyin the postoperative period when antidiuretichormone secretion is increased. Dilutional hyponatraemiais characterized by a rapid fall in plasma-sodiumconcentration leading to cerebral oedema and seizures;any child with severe hyponatraemia or rapidly changingplasma-sodium concentration should be referredurgently to a paediatric high dependency facility.Safe practiceSodium chloride 0.18% and glucose 4% intravenousinfusion fluid should not generally be used for fluidreplacement in children because of the risk of hyponatraemia;availability of this infusion should berestricted to critical care and specialist wards, suchas renal, liver, and cardiac units. Local guidelines onintravenous fluids should be consulted.Replacement therapy: initial intravenous replacementfluid is generally required if the child is over 10%dehydrated, or if 5–10% dehydrated and oral or enteralrehydration is not tolerated or possible. Oral rehydrationis adequate, if tolerated, in the majority of those lessthan 10% dehydrated. Subsequent fluid and electrolyterequirements are determined by clinical assessment offluid balance.Neonates Neonates lose water through the skin andnose, particularly if preterm or if the skin is damaged.The basic fluid requirement for a term baby in averageambient humidity is 40–60 mL/kg/day plus urinarylosses. Preterm babies have very high transepidermallosses particularly in the first few days of life; they mayneed more fluid replacement than full term babies andup to 180 mL/kg/day may be required. Local guidelinesfor fluid management in the neonatal period should beconsulted.Intravenous sodiumIntravenous sodium chloride in isotonic (0.9%) solutionprovides the most important extracellular ions innear physiological concentrations and is indicated insodium depletion. It may be given for initial treatment ofacute fluid loss and to replace ongoing gastro-intestinallosses from the upper gastro-intestinal tract. Intravenoussodium chloride is commonly given as a componentof maintenance and replacement therapy, usuallyin combination with other electrolytes and glucose,see notes above. Sodium chloride solutions should beused cautiously in renal insufficiency, cardiac failure,cardio-respiratory diseases, hepatic cirrhosis and inchildren receiving glucocorticoids. Hyponatraemiawith serious consequences may occur if maintenanceand replacement fluids do not meet sodium requirements(see Caution, dilutional hyponatraemia, above).Chronic hyponatraemia should ideally be corrected byfluid restriction. However, if sodium chloride is required,the deficit should be corrected slowly to avoid the risk ofosmotic demyelination syndrome; the rise in plasmasodiumconcentration should be no more than10 mmol/litre in 24 hours.Sodium chloride and glucose solutions are indicatedwhen there is combined water and sodium depletion.A1:1 mixture of isotonic sodium chloride and 5% glucoseallows some of the water (free of sodium) to enter bodycells which suffer most from dehydration while thesodium salt with a volume of water determined by thenormal plasma Na + remains extracellular. Maintenancefluid should accurately reflect daily requirements andclose monitoring is required to avoid fluid and electrolyteimbalance. Illness or injury increase the secretion ofanti-diuretic hormone and therefore the ability toexcrete excess water may be impaired. Injudicious useof hypotonic solutions such as sodium chloride 0.18%and glucose 4% may also cause dilutional hyponatraemiaespecially in children (see Caution on dilutionalhyponatraemia, above); if necessary, guidance should besought from a clinician experienced in the managementof fluid and electrolytes.Combined sodium, potassium, chloride, and waterdepletion may occur, for example, with severe diarrhoeaor persistent vomiting; replacement is carried out withsodium chloride intravenous infusion 0.9% and glucoseintravenous infusion 5% with potassium as appropriate.Compound sodium lactate (Hartmann’s solution) canbe used instead of isotonic sodium chloride solutionduring or after surgery, or in the initial management ofthe injured or wounded.Neonates The sodium requirement for most healthyneonates is 3 mmol/kg daily. Preterm neonates, particularlybelow 30 weeks gestation, may require up to6 mmol/kg daily. Hyponatraemia may be caused byexcessive renal loss of sodium; it may also be dilutionaland restriction of fluid intake may be appropriate. Sodiumsupplementation is likely to be required if the serumsodium concentration is significantly reduced.Hypernatraemia may also occur, most often due todehydration (e.g. breast milk insufficiency). Severe9 Nutrition and blood

462 9.2.2 Parenteral preparations for fluid & electrolyte imbalance BNFC 2011–20129 Nutrition and bloodhypernatraemia and hyponatraemia can cause fits andrarely brain damage. Sodium in drug preparations,delivered via continuous infusions, or in infusions tomaintain the patency of intravascular or umbilical lines,can result in significant amounts of sodium being delivered,(e.g. 1 mL/hour of 0.9% sodium chloride infusedover 24 hours is equivalent to 3.6 mmol/day of sodium).SODIUM CHLORIDECautions restrict intake in impaired renal function,cardiac failure, hypertension, peripheral and pulmonaryoedema, toxaemia of pregnancy; see also notesaboveSide-effects administration of large doses may giverise to sodium accumulation and oedemaIndication and doseElectrolyte imbalance see notes above, also section9.2.1.2Sodium Chloride (Non-proprietary) AIntravenous infusion, usual strength sodium chloride0.9% (9 g, 150 mmol each of Na + and Cl /litre), thisstrength being supplied when normal saline forinjection is requested. Net price 2-mL amp = 32p; 5-mL amp = 38p; 10-mL amp = 52p; 20-mL amp =£1.04; 50-mL amp = £3.63In hospitals, 500- and 1000-mL packs, and sometimes other sizes,are availableNote The term ‘normal saline’ should not be used todescribe sodium chloride intravenous infusion 0.9%; theterm ‘physiological saline’ is acceptable but it is preferable togive the composition (i.e. sodium chloride intravenous infusion0.9%).With other ingredientsNote See above for warning on hyponatraemiaSodium Chloride and Glucose (Non-proprietary) AIntravenous infusion, sodium chloride 0.18% (Na +and Cl – each 30 mmol/litre), glucose 4%In hospitals, usually 500-mL packs and sometimes other sizes areavailableIntravenous infusion, sodium chloride 0.45% (Na +and Cl – each 75 mmol/litre), glucose 5%In hospitals, usually 500-mL packs and sometimes other sizes areavailableIntravenous infusion, sodium chloride 0.9% (Na +and Cl – each 150 mmol/litre), glucose 5%In hospitals, usually 500-mL packs and sometimes other sizes areavailableRinger’s Solution (Non-proprietary) ACalcium chloride (dihydrate) 322 micrograms, potassiumchloride 300 micrograms, sodium chloride8.6 mg/mL, providing the following ions (in mmol/litre), Ca 2þ 2.2, K + 4, Na + 147, Cl 156In hospitals, 500- and 1000-mL packs, and sometimes other sizes,are availableSodium Lactate, Compound (Non-proprietary) A(Hartmann’s Solution; Ringer-Lactate Solution)Intravenous infusion, sodium chloride 0.6%, sodiumlactate 0.32%, potassium chloride 0.04%, calciumchloride 0.027% (containing Na + 131 mmol, K +5 mmol, Ca 2þ 2 mmol, HCO 3 (as lactate) 29 mmol,Cl 111 mmol/litre)In hospitals, 500- and 1000-mL packs, and sometimes other sizes,are availableIntravenous glucoseGlucose solutions are used mainly to replace waterdeficit and should not be given alone except whenthere is no significant loss of electrolytes; prolongedadministration of glucose solutions without electrolytescan lead to hyponatraemia and other electrolyte disturbances.Water depletion (dehydration) tends to occurwhen losses are not matched by a comparable intake, asmay occur in coma or dysphagia.Water loss rarely exceeds electrolyte losses but this canoccur in fevers, hyperthyroidism, and in uncommonwater-losing renal states such as diabetes insipidus orhypercalcaemia. The volume of glucose solution neededto replace deficits varies with the severity of the disorder;the rate of infusion should be adjusted to returnthe plasma-sodium concentration to normal over 48hours.Glucose solutions are also used to correct and preventhypoglycaemia and to provide a source of energy inthose too ill to be fed adequately by mouth; glucosesolutions are a key component of parenteral nutrition(section 9.3).Glucose solutions are given with insulin for the emergencymanagement of hyperkalaemia (see p. 458).They are also given, after correction of hyperglycaemia,during treatment of diabetic ketoacidosis, when theymust be accompanied by continuous insulin infusion(section 6.1.3).Injections containing more than 10% glucose can beirritant and should be given into a central venous line;however, solutions containing up to 12.5% can beadministered for a short period into a peripheral line.GLUCOSE(Dextrose Monohydrate)Note Glucose BP is the monohydrate but Glucose IntravenousInfusion BP is a sterile solution of anhydrous glucoseor glucose monohydrate, potency being expressed in termsof anhydrous glucoseSide-effects glucose injections especially if hypertonicmay have a low pH and may cause venousirritation and thrombophlebitisIndication and doseFluid replacement see notes aboveProvision of energy section 9.3Hypoglycaemia section 6.1.4Glucose (Non-proprietary) AIntravenous infusion, glucose or anhydrous glucose(potency expressed in terms of anhydrous glucose),usual strengths 5% (50 mg/mL), 10% (100 mg/mL),and 20% (200 mg/mL); 20% solution, net price 20-mLamp = £2.04; 50% solution 1 , 20-mL amp = 95 p, 50-mL vial = £2.13In hospitals, 500- and 1000-mL packs, and sometimes other sizesand strengths, are available; also available Minijet c Glucose, 50%in 50-mL disposable syringe 11. A restriction does not apply where administration is forsaving life in emergency

BNFC 2011–2012 9.2.2 Parenteral preparations for fluid & electrolyte imbalance 463Intravenous potassiumPotassium chloride and sodium chloride intravenousinfusion is the initial treatment for the correction ofsevere hypokalaemia and when sufficient potassiumcannot be taken by mouth. Ready-mixed infusion solutionsshould be used when possible (see under SafePractice below); for peripheral intravenous infusion,the concentration of potassium should not usuallyexceed 40 mmol/litre. Potassium infusions should begiven slowly over at least 2–3 hours and at a rate notexceeding 0.2 mmol/kg/hour with specialist advice andECG monitoring in difficult cases. Higher concentrationsof potassium chloride or faster infusion rates maybe given in very severe depletion, but require specialistadvice.Repeated measurements of plasma-potassium concentrationare necessary to determine whether furtherinfusions are required and to avoid the developmentof hyperkalaemia, which is especially likely in renalimpairment.Initial potassium replacement therapy should notinvolve glucose infusions, because glucose may causea further decrease in the plasma-potassium concentration.Safe PracticePotassium overdose can be fatal. Ready-mixed infusionsolutions containing potassium should be used.Exceptionally, if potassium chloride concentrate isused for preparing an infusion, the infusion solutionshould be thoroughly mixed. Local policies onavoiding inadvertent use of potassium chloride concentrateshould be followed.POTASSIUM CHLORIDECautions for peripheral intravenous infusion the concentrationof solution should not usually exceed 3 g(40 mmol)/litre; specialist advice and ECG monitoring(see notes above); interactions: Appendix 1(potassium salts)Contra-indications plasma-potassium concentrationabove 5 mmol/litreRenal impairment close monitoring required—highrisk of hyperkalaemia; avoid in severe impairmentSide-effects rapid infusion toxic to heartIndication and doseElectrolyte imbalance see also oral potassiumsupplements, section 9.2.1.1. By slow intravenous infusionDepending on the deficit or the daily maintenancerequirements, see also notes aboveNeonate 1–2 mmol/kg dailyChild 1 month–18 years 1–2 mmol/kg dailyAdministration see notes abovePotassium Chloride and Glucose (Non-proprietary)AIntravenous infusion, usual strengths potassiumchloride 0.3% (3 g, 40 mmol each of K + and Cl /litre)or 0.15% (1.5 g, 20 mmol each of K + and Cl /litre)with 5% of anhydrous glucoseIn hospitals, 500- and 1000-mL packs, and sometimes other sizes,are availablePotassium Chloride and Sodium Chloride (Non-proprietary)AIntravenous infusion, usual strength potassiumchloride 0.15% (1.5 g/litre) with sodium chloride 0.9%(9 g/litre), containing K + 20 mmol, Na + 150 mmol,and Cl 170 mmol/litreIn hospitals, 500- and 1000-mL packs, and sometimes other sizes,are availablePotassium Chloride, Sodium Chloride, and Glucose(Non-proprietary) AIntravenous infusion, sodium chloride 0.45% (4.5 g,Na + 75 mmol/litre) with 5% of anhydrous glucose andusually sufficient potassium chloride to provide K +10–40 mmol/litre (to be specified by the prescriber)In hospitals, 500- and 1000-mL packs, and sometimes other sizesare availablePotassium Chloride (Non-proprietary) ASterile concentrate, potassium chloride 15%(150 mg, approximately 2 mmol each of K + and Cl /mL). Net price 10-mL amp = 48pSolutions containing 10 and 20% of potassium chloride are alsoavailable in both 5- and 10-mL ampoulesImportant Must be diluted with not less than 50 times itsvolume of Sodium Chloride 0.9% or other suitable diluentand mixed well; see Safe Practice, aboveBicarbonate and trometamolSodium bicarbonate is used to control severe metabolicacidosis (pH < 7.1) particularly that caused by lossof bicarbonate (as in renal tubular acidosis or fromexcessive gastro-intestinal losses). Mild metabolic acidosisassociated with volume depletion should first bemanaged by appropriate fluid replacement because acidosisusually resolves as tissue and renal perfusion arerestored. In more severe metabolic acidosis or when theacidosis remains unresponsive to correction of anoxiaor hypovolaemia, sodium bicarbonate (1.26%) can beinfused over 3–4 hours with plasma-pH and electrolytemonitoring. In severe shock (section 2.7.1), for examplein cardiac arrest, metabolic acidosis can develop withoutsodium depletion; in these circumstances sodiumbicarbonate is best given intravenously as a smallvolume of hypertonic solution, such as 8.4%; plasmapH and electrolytes should be monitored. For chronicacidotic states, sodium bicarbonate can be given bymouth (section 9.2.1.3).Trometamol (tris(hydroxymethyl)aminomethane,THAM), an organic buffer, corrects metabolic acidosisby causing an increase in urinary pH and an osmoticdiuresis. It is indicated when sodium bicarbonate isunsuitable as in carbon dioxide retention, hypernatraemia,or renal impairment. Respiratory support may berequired because trometamol induces respiratorydepression. It is also used during cardiac bypass surgeryand, very rarely, in cardiac arrest.SODIUM BICARBONATEIndication and doseMetabolic acidosis see also notes above. By slow intravenous injection of a strongsolution (up to 8.4%), or by continuous intravenousinfusion of a weaker solution (usually1.26%)An amount appropriate to the body base deficit9 Nutrition and blood

464 9.2.2 Parenteral preparations for fluid & electrolyte imbalance BNFC 2011–20129 Nutrition and bloodRenal hyperkalaemia. By slow intravenous injectionNeonate 1 mmol/kg dailyChild 1 month–18 years 1 mmol/kg dailyRenal acidosis section 9.2.1.3Sodium Bicarbonate AIntravenous infusion, usual strength sodium bicarbonate1.26% (12.6 g, 150 mmol each of Na + andHCO 3/litre); various other strengths availableIn hospitals, 500- and 1000-mL packs, and sometimes other sizes,are availableAdministration For peripheral infusion dilute 8.4% solutionat least 1 in 10; for central line infusion dilute 1 in 5 withGlucose 5% or 10% or Sodium Chloride 0.9%. Extravasationcan cause severe tissue damageMinijet c Sodium Bicarbonate (UCB Pharma) AIntravenous injection, sodium bicarbonate in disposablesyringe, net price 4.2%, 10 mL = £11.03; 8.4%,10 mL = £11.10, 50 mL = £12.15TROMETAMOL(Tris(hydroxymethyl)aminomethane, THAM)Cautions see notes above; extravasation can causesevere tissue damageContra-indications anuria; chronic respiratory acidosisRenal impairment use with caution, may causehyperkalaemiaPregnancy limited information available, hypoglycaemiamay harm fetusBreast-feeding no information availableSide-effects respiratory depression; hypoglycaemia;hyperkalaemia in renal impairment; liver necrosisreported following administration via umbilical vein inneonatesLicensed use unlicensed preparationIndication and doseMetabolic acidosis. By intravenous infusionAn amount appropriate to the body base deficitPreparationsAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809WaterWater for Injections A Net price 1-mL amp = 18p;2-mL amp = 20p; 5-mL amp = 36p; 10-mL amp = 37p,10-ml vial = £1.40; 20-mL amp = 92p; 50-mL amp =£1.91; 100-mL vial= £2.019.2.2.2 Plasma and plasma substitutesAlbumin solutions, prepared from whole blood, containsoluble proteins and electrolytes but no clottingfactors, blood group antibodies, or plasma cholinesterases;they may be given without regard to the recipient’sblood group.Albumin is usually used after the acute phase of illnessto correct a plasma-volume deficit; hypoalbuminaemiaitself is not an appropriate indication. The use ofalbumin solutions in acute plasma or blood loss maybe wasteful; plasma substitutes are more appropriate.Concentrated albumin solutions may also be used toobtain a diuresis in hypoalbuminaemic patients (e.g. innephrotic syndrome).Recent evidence does not support the previous viewthat the use of albumin increases mortality.Plasma and plasma substitutes are often used in veryill children whose condition is unstable. Therefore,close monitoring is required and fluid and electrolytetherapy should be adjusted according to the child’scondition at all times.ALBUMIN SOLUTION(Human Albumin Solution)A solution containing protein derived from plasma,serum, or normal placentas; at least 95% of theprotein is albumin. The solution may be isotonic(containing 3.5–5% protein) or concentrated (containing15–25% protein).Cautions history of cardiac or circulatory disease(administer slowly to avoid rapid rise in blood pressureand cardiac failure, and monitor cardiovascularand respiratory function); increased capillary permeability;correct dehydration when administering concentratedsolutionContra-indications cardiac failure; severe anaemiaSide-effects hypersensitivity reactions (includinganaphylaxis) with nausea, vomiting, increased salivation,fever, tachycardia, hypotension and chillsreportedIndication and doseSee notes above and under preparations, belowIsotonic solutionsIndications: acute or sub-acute loss of plasma volumee.g. in burns, pancreatitis, trauma, and complicationsof surgery; plasma exchangeAvailable as: Human Albumin Solution 4.5% (50-,100-, 250- and 400-mL bottles—Baxter); HumanAlbumin Solution 5% (250- and 500-mL bottles—Baxter); Albunorm c 5% (100-, 250-, and 500-mLbottles—Octapharma); Octalbin c 5% (100- and 250-mL bottles—Octapharma); Zenalb c 4.5% (50-, 100-,250-, and 500-mL bottles—BPL)Concentrated solutions (20%)Indications: severe hypoalbuminaemia associatedwith low plasma volume and generalised oedemawhere salt and water restriction with plasma volumeexpansion are required; adjunct in the treatment ofhyperbilirubinaemia by exchange transfusion in thenewborn; paracentesis of large volume ascites associatedwith portal hypertensionAvailable as: Human Albumin Solution 20% (50- and100-mL vials—Baxter); Albunorm c 20% (50- and100-mL bottles—Octapharma); Flexbumin c 20% (50-and 100-mL bags—Baxter); Octalbin c 20% (50- and100-mL bottles—Octapharma); Zenalb c 20% (50-and 100-mL bottles—BPL)

BNFC 2011–2012 9.2.2 Parenteral preparations for fluid & electrolyte imbalance 465Plasma substitutesGelatin and the etherified starches (pentastarch andtetrastarch) are macromolecular substances which aremetabolised slowly; they may be used at the outset toexpand and maintain blood volume in shock arisingfrom conditions such as burns or septicaemia. Plasmasubstitutes may be used as an immediate short-termmeasure to treat haemorrhage until blood is available.They are rarely needed when shock is due to sodiumand water depletion because, in these circumstances,the shock responds to water and electrolyte repletion;see also section 2.7.1 for the management of shock.Plasma substitutes should not be used to maintainplasma volume in conditions such as burns or peritonitiswhere there is loss of plasma protein, water, and electrolytesover periods of several days or weeks. In thesesituations, plasma or plasma protein fractions containinglarge amounts of albumin should be given.Large volumes of some plasma substitutes can increasethe risk of bleeding through depletion of coagulationfactors.Plasma and plasma substitutes are often used in veryill children whose condition is unstable. Therefore,close monitoring is required and fluid and electrolytetherapy should be adjusted according to the child’scondition at all times.The use of plasma substitutes in children requiresspecialist supervision due to the risk of fluid overload;use is best restricted to an intensive caresetting.Cautions Plasma substitutes should be used withcaution in cardiac disease, liver disease, or renal impairment;urine output should be monitored. Care should betaken to avoid haematocrit concentration from fallingbelow 25–30% and the child should be monitored forhypersensitivity reactions.Side-effects Hypersensitivity reactions may occurincluding, rarely, severe anaphylactic reactions. Transientincrease in bleeding time may occur.GELATINNote The gelatin is partially degradedCautions see notes abovePregnancy manufacturer of Geloplasma c advisesavoid at the end of pregnancySide-effects see notes aboveIndication and doseLow blood volume in hypovolaemic shock,burns and cardiopulmonary bypass. By intravenous infusionInitially 10–20 mL/kg of a 3.5–4% solution (seenotes above)Gelofusine c (Braun) AIntravenous infusion, succinylated gelatin (modifiedfluid gelatin, average molecular weight 30 000) 40 g(4%), Na + 154 mmol, Cl 124 mmol/litre, net price500-mL Ecobag c = £5.15; 1-litre Ecobag c = £9.67Contains traces of calciumGeloplasma c (Fresenius Kabi) AIntravenous infusion, partially hydrolysed and succinylatedgelatin (modified liquid gelatin) (as anhydrousgelatin) 30 g (3%), Na + 150 mmol, K + 5 mmol,Mg 2þ 1.5 mmol, Cl 100 mmol, lactate 30 mmol/litre,net price 500-mL bag = £5.05Isoplex c (Beacon) AIntravenous infusion, succinylated gelatin (modifiedfluid gelatin, average molecular weight 30 000) 40 g(4%), Na + 145 mmol, K + 4 mmol, Mg 2þ 0.9 mmol, Cl105 mmol, lactate 25 mmol/litre, net price 500-mLbag = £7.53; 1-litre bag = £14.54Volplex c (Beacon) AIntravenous infusion, succinylated gelatin (modifiedfluid gelatin, average molecular weight 30 000) 40 g(4%), Na + 154 mmol, Cl 125 mmol/litre, net price500-mL bag = £4.70; 1-litre bag = £9.09ETHERIFIED STARCHA starch composed of more than 90% of amylopectinthat has been etherified with hydroxyethyl groups; theterms tetrastarch and pentastarch reflect the degreeof etherificationCautions see notes aboveRenal impairment use with caution in mild to moderateimpairment; avoid in severe impairmentSide-effects see notes above; also pruritus, raisedserum amylaseIndication and doseLow blood volume. By intravenous infusionAccording to the child’s condition (see notesabove)PentastarchHAES-steril c (Fresenius Kabi) AIntravenous infusion, pentastarch (weight averagemolecular weight 200 000) 10% in sodium chlorideintravenous infusion 0.9%, net price, 500 mL = £16.50Hemohes c (Braun) AIntravenous infusion, pentastarch (weight averagemolecular weight 200 000), net price (both in sodiumchloride intravenous infusion 0.9%) 6%, 500 mL =£12.50; 10%, 500 mL = £16.50TetrastarchTetraspan c (Braun) AIntravenous infusion, hydroxyethyl starch (weightaverage molecular weight 130 000) 6% in sodiumchloride 0.625%, containing Na + 140 mmol, K +4 mmol, Mg 2þ 1 mmol, Cl 118 mmol, Ca 2þ 2.5 mmol,acetate 24 mmol, malate 5 mmol/litre, net price 500-mL bag = £13.50Volulyte c (Fresenius Kabi) AIntravenous infusion, hydroxyethyl starch (weightaverage molecular weight 130 000) 6% in sodiumchloride intravenous infusion 0.6%, containing Na +137 mmol, K + 4 mmol, Mg 2þ 1.5 mmol, Cl 110 mmol,acetate 34 mmol/litre, net price 500-mL bag = £13.509 Nutrition and blood

466 9.3 Intravenous nutrition BNFC 2011–20129 Nutrition and bloodVoluven c (Fresenius Kabi) AIntravenous infusion, hydroxyethyl starch (weightaverage molecular weight 130 000) 6% in sodiumchloride intravenous infusion 0.9%, net price 500-mLbag = £12.50Hypertonic solutionHyperHAES c (Fresenius Kabi) AIntravenous infusion, hydroxyethyl starch (weightaverage molecular weight 200 000) 6% in sodiumchloride intravenous infusion 7.2%, net price 250-mLbag = £28.00Cautions see notes above; also diabetes9.3 Intravenous nutritionWhen adequate feeding through the alimentary tract isnot possible, nutrients may be given by intravenousinfusion. This may be in addition to oral or enteraltube feeding—supplemental parenteral nutrition, ormay be the sole source of nutrition—total parenteralnutrition (TPN). Complete enteral starvation is undesirableand total parenteral nutrition is a last resort.Indications for parenteral nutrition include prematurity;severe or prolonged disorders of the gastro-intestinaltract; preparation of undernourished patients for surgery,chemotherapy, or radiation therapy; major surgery,trauma, or burns; prolonged coma or inability to eat;and some patients with renal or hepatic failure. Thecomposition of proprietary preparations used in childrenis given in the table Proprietary Infusion Fluids forParenteral Feeding, p. 467.Parenteral nutrition requires the use of a solution containingamino acids, glucose, lipids, electrolytes, traceelements, and vitamins. This is now commonly providedby the pharmacy in the form of an amino-acid, glucose,electrolyte bag, and a separate lipid infusion or, in olderchildren a single ‘all-in-one’ bag. If the patient is able totake small amounts by mouth, vitamins may be givenorally.The nutrition solution is infused through a centralvenous catheter inserted under full surgical precautions.Alternatively, infusion through a peripheral vein may beused for supplementary as well as total parenteralnutrition, depending on the availability of peripheralveins; factors prolonging cannula life and preventingthrombophlebitis include the use of soft polyurethanepaediatric cannulas and use of nutritional solutions oflow osmolality and neutral pH. Nutritional fluids shouldbe given by a dedicated intravenous line; if not possible,compatibility with any drugs or fluids should be checkedas precipitation of components may occur. Extravasationof parenteral nutrition solution can cause severetissue damage and injury; the infusion site should beregularly monitored.Before starting intravenous nutrition the patient shouldbe clinically stable and renal function and acid-basestatus should be assessed. Appropriate biochemicaltests should have been carried out beforehand andserious deficits corrected. Nutritional and electrolytestatus must be monitored throughout treatment. Thenutritional components of parenteral nutrition regimensare usually increased gradually over a number of days toprevent metabolic complications and to allow metabolicadaptation to the infused nutrients. The solutions areusually infused over 24 hours but this may be graduallyreduced if long-term nutrition is required. Home parenteralnutrition is usually infused over 12 hours overnight.Complications of long-term parenteral nutrition includegall bladder sludging, gall stones, cholestasis and abnormalliver function tests. For details of the prevention andmanagement of parenteral nutrition complications, specialistliterature should be consulted.Protein (nitrogen) is given as mixtures of essential andnon-essential synthetic L-amino acids. Ideally, all essentialamino acids should be included with a wide varietyof non-essential ones to provide sufficient nitrogentogether with electrolytes (see also section 9.2.2). Solutionsvary in their composition of amino acids; theyoften contain an energy source (usually glucose) andelectrolytes. Solutions for use in neonates and childrenunder 1 year of age are based on the amino acid profileof umbilical cord blood (Primene c ) or breast milk(Vaminolact c ) and contain amino acids that areessential in this age group; these amino acids may notbe present in sufficient quantities in preparationsdesigned for older children and adults.Energy requirements must be met if amino acids are tobe utilised for tissue maintenance. An appropriateenergy to protein ratio is essential and requirementswill vary depending on the child’s age and condition. Amixture of carbohydrate and fat energy sources (usually30–50% as fat) gives better utilisation of amino acidsthan glucose alone.Glucose is the preferred source of carbohydrate, butfrequent monitoring of blood glucose is required particularlyduring initiation and build-up of the regimen;insulin may be necessary. Glucose above a concentrationof 12.5% must be infused through a central venouscatheter to avoid thrombosis; the maximum concentrationof glucose that should normally be infused in fluidrestricted children is 20–25%.In parenteral nutrition regimens, it is necessary toprovide adequate phosphate in order to allow phosphorylationof glucose and to prevent hypophosphataemia.Neonates, particularly preterm neonates, andyoung children also require phosphorus and calciumto ensure adequate bone mineralisation. The compatibilityand solubility of calcium and phosphorus salts iscomplex and unpredictable; precipitation is a risk andspecialist pharmacy advice should be sought.Fat (lipid) emulsions have the advantages of a highenergy to fluid volume ratio, neutral pH, and iso-osmolaritywith plasma, and provide essential fatty acids.Several days of adaptation may be required to attainmaximal utilisation. Reactions include occasional febrileepisodes (usually only with 20% emulsions) and rareanaphylactic responses. Interference with biochemicalmeasurements such as those for blood gases and calciummay occur if samples are taken before fat has beencleared. Regular monitoring of plasma cholesterol andtriglyceride is necessary to ensure clearance from theplasma, particularly in conditions where fat metabolismmay be disturbed e.g. infection. Emulsions containing20% or 30% fat should be used in neonates as they arecleared more efficiently. Additives should not bemixed with fat emulsions unless compatibility isknown.

BNFC 2011–2012 9.3 Intravenous nutrition 467Proprietary Infusion Fluids for Parenteral FeedingPreparationClinOleic 20% (Baxter)Net price 100 mL = £6.28; 250 mL= £10.08; 500 mL = £13.88Nitrogeng/litre1;2 EnergykJ/litreElectrolytes mmol/litreK + Mg 2þ Na + Acet ClGlamin (Fresenius Kabi)22.4 62Net price 250 mL = £14.58; 500 mL= £27.20Intralipid 10% (Fresenius Kabi)Net price 100 mL = £4.70; 500 mL= £10.30Intralipid 20% (Fresenius Kabi)Net price 100 mL = £7.05; 250 mL= £11.60; 500 mL = £15.45Intralipid 30% (Fresenius Kabi)Net price 333 mL = £17.30Lipofundin MCT/LCT 10% (Braun)Net price 100 mL = £7.70; 500 mL= £12.90Lipofundin MCT/LCT 20% (Braun)Net price 100 mL = £12.51; 250 mL= £11.30; 500 mL = £19.18Other components/litre8360 purified olive and soya oil200 g, glycerol 22.5 g, eggphosphatides 12 g4600 soya oil 100 g, glycerol22 g, purified egg phospholipids12 g, phosphate15 mmol8400 soya oil 200 g, glycerol22 g, purified egg phospholipids12 g, phosphate15 mmol12600 soya oil 300 g, glycerol16.7 g, purified egg phospholipids12 g, phosphate15 mmol4430 soya oil 50 g, mediumchain triglycerides 50 g8000 soya oil 100 g, mediumchain triglycerides 100 g3 Primene 10% (Baxter)15 19Net price 100 mL = £5.78, 250 mL= £7.92Synthamin 9 (Baxter)9.1 60 5 70 100 70 acid phosphate 30 mmolNet price 500 mL = £6.66; 1000 mL= £12.34Synthamin 9 EF (electrolyte-free) 9.1 44 22(Baxter)Net price 500 mL = £6.66; 1000 mL= £12.34Vamin 9 Glucose (Fresenius Kabi) 9.4 1700 20 1.5 50 50 Ca 2þ 2.5 mmol, anhydrousNet price 100 mL = £3.80; 500 mLglucose 100 g= £7.70; 1000 mL = £13.40Vaminolact (Fresenius Kabi) 9.3Net price 100 mL = £4.35; 500 mL= £10.001. Note. 1000 kcal = 4200 kJ; 1000 kJ= 238.8 kcal. All entries are A2. Excludes protein- or amino acid-derived energy3. For use in neonates and children only9 Nutrition and bloodElectrolytes are usually provided as the chloride salts ofpotassium and sodium. Acetate salts can be used toreduce the amount of chloride infused; hyperchloraemicacidosis or hypochloraemic alkalosis can occur in pretermneonates or children with renal impairment.Administration. Because of the complex requirementsrelating to parenteral nutrition full detailsrelating to administration have been omitted. In allcases specialist pharmacy advice, product literatureand other specialist literature should be consulted.Supplementary preparationsCompatibility with the infusion solution must beascertained before adding supplementary preparations.Addiphos c (Fresenius Kabi) ASolution, sterile, phosphate 40 mmol, K + 30 mmol,Na + 30 mmol/20 mL. For addition to Vamin c solutionsand glucose intravenous infusions. Net price 20-mL vial = £1.53

468 9.4 Oral nutrition BNFC 2011–20129 Nutrition and bloodAdditrace c (Fresenius Kabi) ASolution, trace elements for addition to Vamin csolutions and glucose intravenous infusions, traces ofFe 3þ , Zn 2þ , Mn 2þ , Cu 2þ , Cr 3þ , Se 4þ , Mo 6þ ,F,I . Forchildren over 40 kg. Net price 10-mL amp = £2.31Cernevit c (Baxter) ASolution, dl-alpha tocopherol 11.2 units, ascorbicacid 125 mg, biotin 69 micrograms, colecalciferol220 units, cyanocobalamin 6 micrograms, folic acid414 micrograms, glycine 250 mg, nicotinamide 46 mg,pantothenic acid (as dexpanthenol) 17.25 mg, pyridoxinehydrochloride 5.5 mg, retinol (as palmitate)3500 units, riboflavin (as dihydrated sodium phosphate)4.14 mg, thiamine (as cocarboxylase tetrahydrate)3.51 mg. Dissolve in 5 mL water for injections.Net price per vial = £4.64Decan c (Baxter) ASolution, trace elements for addition to infusionsolutions, Fe 2þ , Zn 2þ , Cu 2þ , Mn 2þ ,F, Co 2þ I , Se 4þ ,Mo 6þ , Cr 3þ . For children over 40 kg. Net price 40-mLvial = £2.00Dipeptiven c (Fresenius Kabi) ASolution, N(2)-L-alanyl-L-glutamine 200 mg/mL(providing L-alanine 82 mg, L-glutamine 134.6 mg).For addition to infusion solutions containing aminoacids. Net price 50 mL = £16.40, 100 mL = £30.50DoseAmino acid supplement for hypercatabolic or hypermetabolicstates300–400 mg/kg daily; max. 400 mg/kg daily, dose not toexceed 20% of total amino acid intakeGlycophos c Sterile Concentrate (Fresenius Kabi) ASolution, sterile, phosphate 20 mmol, Na + 40 mmol/20 mL. For addition to Vamin c and Vaminolact csolutions, and glucose intravenous infusions. Netprice 20-mL vial = £4.60Peditrace c (Fresenius Kabi) ASolution, trace elements for addition toVaminolact c , Vamin c 14 Electrolyte-Free solutionsand glucose intravenous infusions, traces of Zn 2þ ,Cu 2þ , Mn 2þ , Se 4þ ,F,I . For use in neonates (whenkidney function established, usually second day oflife), infants, and children. Net price 10-mL vial =£4.18Cautions reduced biliary excretion especially in cholestatic liverdisease or in markedly reduced urinary excretion (careful biochemicalmonitoring required); total parenteral nutrition exceeding1 month (measure serum manganese concentration and checkliver function before commencing treatment and regularly duringtreatment)—discontinue if manganese concentration raised or ifcholestasis developsSolivito N c (Fresenius Kabi) ASolution, powder for reconstitution, biotin 60 micrograms,cyanocobalamin 5 micrograms, folic acid400 micrograms, glycine 300 mg, nicotinamide 40 mg,pyridoxine hydrochloride 4.9 mg, riboflavin sodiumphosphate 4.9 mg, sodium ascorbate 113 mg, sodiumpantothenate 16.5 mg, thiamine mononitrate 3.1 mg.Dissolve in water for injections or glucose intravenousinfusion for adding to glucose intravenous infusion orIntralipid c ; dissolve in Vitlipid N c or Intralipid c foradding to Intralipid c only. Net price per vial = £2.32Vitlipid N c (Fresenius Kabi) AEmulsion, adult, vitamin A 330 units, ergocalciferol20 units, dl-alpha tocopherol 1 unit, phytomenadione15 micrograms/mL. For addition to Intralipid c . Foradults and children over 11 years. Net price 10-mLamp = £2.32Emulsion, infant, vitamin A 230 units, ergocalciferol40 units, dl-alpha tocopherol 0.7 unit, phytomenadione20 micrograms/mL. For addition to Intralipid c .Net price 10-mL amp = £2.329.4 Oral nutrition9.4.1 Foods for special diets9.4.2 Enteral nutrition9.4.1 Foods for special dietsThese are preparations that have been modified toeliminate a particular constituent from a food or thatare nutrient mixtures formulated as food substitutes forchildren who either cannot tolerate or cannot metabolisecertain common constituents of food.Coeliac disease Intolerance to gluten in coeliacdisease is managed by completely eliminating glutenfrom the diet. A range of gluten-free products is availablefor prescription—see Appendix 2 (p. 777).Phenylketonuria Phenylketonuria (hyperphenylalaninaemia,PKU), which results from the inability to metabolisephenylalanine, is managed by restricting dietaryintake of phenylalanine to a small amount sufficient fortissue building and repair.Aspartame (used as a sweetener in some foods andmedicines) contributes to the phenylalanine intake andmay affect control of phenylketonuria. If alternatives areunavailable, children with phenylketonuria should notbe denied access to appropriate medication; the amountof aspartame consumed can be taken in to account inthe management of the condition. Where the presenceof aspartame in a preparation is specified in the productliterature, aspartame is listed as an excipient in therelevant product entry in BNF for Children; the childor carer should be informed of this.For further information on special dietary products usedin the management of metabolic diseases, see Appendix2.Some rare forms of phenylketonuria are caused by adeficiency of tetrahydrobiopterin. Treatment involvesoral supplementation of tetrahydrobiopterin; in somesevere cases, the addition of the neurotransmitter precursors,levodopa (section 4.9.1) and 5-hydroxytryptophan,is also necessary.Sapropterin, a synthetic form of tetrahydrobiopterin, islicensed as an adjunct to dietary restriction of phenylalaninein the management of patients with phenylketonuriaand tetrahydrobiopterin deficiency.

BNFC 2011–2012 9.4.2 Enteral nutrition 469TETRAHYDROBIOPTERINRenal impairment use with caution—accumulationof metabolitesPregnancy crosses the placenta; use only if benefitoutweighs riskBreast-feeding present in milk, effects unknownSide-effects diarrhoea, urinary frequency, disturbedsleepLicensed use not licensedIndication and doseMonotherapy in tetrahydrobiopterin-sensitivephenylketonuria (specialist use only). By mouthChild 1 month–18 years 10 mg/kg twice daily(total daily dose may alternatively be given in 3divided doses), adjusted according to responseIn combination with neurotransmitter precursorsfor tetrahydrobiopterin-sensitive phenylketonuria(specialist use only). By mouthChild 1 month–2 years initially 250–750 micrograms/kg4 times daily (total daily dose mayalternatively be given in 3 divided doses), adjustedaccording to response; max. 7 mg/kg dailyChild 2–18 years initially 250–750 micrograms/kg 4 times daily (total daily dose may alternativelybe given in 3 divided doses), adjusted according toresponse; usual max. 10 mg/kg dailyTetrahydrobiopterin (Non-proprietary)Tablets, tetrahydrobiopterin 10 mg and 50 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809SAPROPTERIN DIHYDROCHLORIDENote Sapropterin is a synthetic form of tetrahydrobiopterinCautions monitor blood-phenylalanine concentrationbefore and after first week of treatment—if unsatisfactoryresponse increase dose at weekly intervals tomax. dose and monitor blood-phenylalanine concentrationweekly; discontinue treatment if unsatisfactoryresponse after 1 month; monitor blood-phenylalanineand tyrosine concentrations 1–2 weeks after doseadjustment and during treatment; history of convulsionsHepatic impairment manufacturer advises caution—no information availableRenal impairment manufacturer advises caution—noinformation availablePregnancy manufacturer advises caution—consideronly if strict dietary management inadequateBreast-feeding manufacturer advises avoid—noinformation availableSide-effects diarrhoea, vomiting, abdominal pain;nasal congestion, cough, pharyngolaryngeal pain;headacheIndication and dosePhenylketonuria (specialist use only). By mouthChild 4–18 years initially 10 mg/kg once daily,preferably in the morning, adjusted according toresponse; usual dose 5–20 mg/kg dailyTetrahydrobiopterin deficiency (specialist useonly). By mouthNeonate initially 2–5 mg/kg once daily, preferablyin the morning, adjusted according to response;max. 20 mg/kg daily; total daily dose may alternativelybe given in 2–3 divided dosesChild 1 month–18 years initially 2–5 mg/kg oncedaily, preferably in the morning, adjusted accordingto response; max. 20 mg/kg daily; total dailydose may alternatively be given in 2–3 divideddosesKuvan c (Merck Serono) TADispersible tablets, sapropterin dihydrochloride100 mg, net price 30-tab pack = £597.22, 120-tab pack= £2388.88. Label: 13, 21, counselling, tablets shouldbe dissolved in water and taken within 20 minutes9.4.2 Enteral nutritionChildren have higher nutrient requirements per kgbody-weight, different metabolic rates, and physiologicalresponses compared to adults. They have lownutritional stores and are particularly vulnerable togrowth and nutritional problems during critical periodsof development. Major illness, operations, or traumaimpose increased metabolic demands and can rapidlyexhaust nutritional reserves.Every effort should be made to optimise oral food intakebefore beginning enteral tube feeding; this may includechange of posture, special seating, feeding equipment,oral desensitisation, food texture changes, thickening ofliquids, increasing energy density of food, treatment ofreflux or oesophagitis, as well as using age-specificnutritional supplements.Enteral tube feeding has a role in both short-termrehabilitation and long-term nutritional managementin paediatrics. It can be used as supportive therapy, inwhich the enteral feed supplies a proportion of therequired nutrients, or as primary therapy, in which theenteral feed delivers all the necessary nutrients. Mostchildren receiving tube feeds should also be encouragedto take oral food and drink. Tube feeding should beconsidered in the following situations:. unsafe swallowing and risk of aspiration;. inability to consume at least 60% of energy needsby mouth;. total feeding time of more than 4 hours per day;. weight loss or no weight gain for a period of 3months (less for younger children and infants);. weight for height (or length) less than 2nd percentilefor age and sex.Most feeds for enteral use (Appendix 2) contain proteinderived from cows’ milk or soya. Elemental feeds containingprotein hydrolysates or free amino acids can beused for children who have diminished ability to breakdown protein, for example in inflammatory bowel diseaseor pancreatic insufficiency.9 Nutrition and blood

470 9.4.2 Enteral nutrition BNFC 2011–20129 Nutrition and bloodEven when nutritionally complete feeds are given, waterand electrolyte balance should be monitored. Haematologicaland biochemical parameters should also bemonitored, particularly in the clinically unstable child.Extra minerals (e.g. magnesium and zinc) may beneeded in patients where gastro-intestinal secretionsare being lost. Additional vitamins may also be needed.Feeds containing vitamin K may affect the INR inchildren receiving warfarin—see interactions: Appendix1 (vitamins).Choosing the best formula for children depends onseveral factors including: nutritional requirements, gastro-intestinalfunction, underlying disease, nutrientrestrictions, age, and feed characteristics (nutritionalcomposition, viscosity, osmolality, availability andcost). Children have specific dietary requirements andin many situations liquid feeds prepared for adults aretotally unsuitable and should not be given. Expertadvice from a dietician should be sought before prescribingenteral feeds for a child.Infant formula feeds Child 0–12 months. Terminfants with normal gastro-intestinal function are giveneither breast milk or normal infant formula during thefirst year of life. The average intake is between 150 mLand 200 mL/kg/day. Infant milk formulas are based onwhey- or casein-dominant protein, lactose with or withoutmaltodextrin, amylose, vegetable oil and milk fat.The composition of all normal and soya infant formulashave to meet The Infant Formula and Follow-on FormulaRegulations (England and Wales) 2007, whichenact the European Community Regulations 2006/141/EC; the composition of other enteral and specialistfeeds has to meet the Commission Directive (1999/21/EC) on Dietary Foods for Special Medical Purposes.A high-energy feed (Appendix 2, p. 750), which contains9–11% of energy derived from protein can be used forinfants who fail to grow adequately. Alternatively,energy supplements (Appendix 2, p. 771) may beadded to normal infant formula to achieve a higherenergy content (but this will reduce the protein toenergy ratio) or the normal infant formula concentrationmay be increased slightly. Care should be taken not topresent an osmotic load of more than 500 milliosmols/kg water to the normal functioning gut, otherwiseosmotic diarrhoea will result. Concentrating or supplementingfeeds should not be attempted without theadvice of a paediatric dietician.Enteral feeds Child 1–6 years (body–weight 8–20 kg). Ready-to-use feeds (Appendix 2, p. 750) basedon caseinates, maltodextrin and vegetable oils (with orwithout added medium chain triglyceride (MCT) oil orfibre) are well tolerated and effective in improvingnutritional status in this age group. Although originallydesigned for children 1–6 years (body–weight 8–20 kg),some products have ACBS approval for use in childrenweighing up to 30 kg (approx. 10 years of age). Enteralfeeds formulated for children 1–6 years are low in sodiumand potassium; electrolyte intake and biochemicalstatus should be monitored. Older children in this agerange taking small feed volumes may need to be givenadditional micronutrients. Fibre-enriched feeds may behelpful for children with chronic constipation or diarrhoea.Child 7–12 years (body-weight 21–45 kg). Dependingon age, weight, clinical condition and nutritionalrequirements, ready-to-use feeds (Appendix 2, p. 750)formulated for 7–12 year olds may be given at appropriaterates.Child over 12 years (body-weight over 45 kg). Asthere are no standard enteral feeds formulated for thisage group, adult formulations are used. The intake ofprotein, electrolytes, vitamins, and trace mineralsshould be carefully assessed and monitored.Note Adult feeds containing more than 6 g/100 mL protein or2 g/100 mL fibre should be used with caution and expertadvice.Specialised formula It is essential that any infantwho is intolerant of breast milk or normal infant formula,or whose condition requires nutrient-specificadaptation, is prescribed an adequate volume of anutritionally complete replacement formula (see Appendix2, p. 763). In the first 4 months of life, a volume of150–200 mL/kg/day is recommended. After 6 months,should the formula still be required, a volume of600 mL/day should be maintained, in addition to solidfood.Products for cow’s milk protein intolerance or lactoseintolerance. There are a number of infant formulasformulated for cow’s milk protein intolerance or lactoseintolerance; these feeds may contain a residual amountof lactose (less than 1 g/100 mL formula)—sometimesdescribed as clinically lactose-free or ‘lactose-free’ bymanufacturers. If the total daily intake of these formulasis low, it may be necessary to supplement with calcium,and a vitamin and mineral supplement.Soya-based infant formulas have a high phytoestrogencontent and this may be a long-term reproductive healthrisk. The Chief Medical Officer has advised that soyabasedinfant formulas should not be used as the firstchoice for the management of infants with proven cow’smilk sensitivity, lactose intolerance, galactokinase deficiencyand galactosaemia. Most UK paediatricians withexpertise in inherited metabolic disease still advocatesoya-based formulations for infants with galactosaemiaas there are concerns about the residual lactose contentof low lactose formulas and protein hydrolysates basedon cow’s milk protein.Low lactose infant formulations, based on whole cow’smilk protein, are unsuitable for children with cow’s milkprotein intolerance. Liquid soya milks purchased fromsupermarkets and health food stores are not nutritionallycomplete and should never be used for infants under1 year of age.Protein hydrolysate formulas. Non-milk, peptidebasedfeeds containing hydrolysates of casein, whey,meat and soya protein, are suitable for infants withdisaccharide or whole protein intolerance. The totaldaily intake of electrolytes, vitamins and mineralsshould be carefully assessed and modified to meet thechild’s nutritional requirements; these feeds have a highosmolality when given at recommended dilution andneed gradual and careful introduction.Elemental (amino acid based formula). Specially formulatedelemental feeds containing essential and nonessentialamino acids are available for use in infants andchildren under 6 years with proven whole protein intolerance.Adult elemental formula may be used for chil-

BNFC 2011–2012 9.5 Minerals 471dren over 6 years; the intake of electrolytes, vitaminsand minerals should be carefully assessed and modifiedto meet nutritional requirements. These feeds have ahigh osmolality when given at the recommended concentrationand therefore need gradual and careful introduction.Modular feeds. Modular feeds (see Specialised Formulasfor Specific Clinical Conditions, p. 768) are based onindividual protein, fat, carbohydrate, vitamin and mineralcomponents or modules which can be combined tomeet the specific needs of a child. Modular feeds areused when nutritionally complete specialised formulaare not tolerated, or if the fluid and nutrient requirementschange e.g. in gastro-intestinal, renal or liverdisease. The main advantage of modular feeds is theirflexibility; disadvantages include their complexity andpreparation difficulties. Modular feeds should not beused without the supervision of a paediatric dietician.Specialised formula. Highly specialised formulas aredesigned to meet the specific requirements in variousclinical conditions such as renal and liver diseases.When using these formulas, both the biochemical statusof the child and their growth parameters need to bemonitored.Feed thickeners Carob based thickeners (Appendix2, p. 777) may be used to thicken feeds for infants under1 year with significant gastro-oesophageal reflux.Breast-fed infants can be given the thickener mixed toa paste with water or breast-milk prior to feeds.Pre-thickened formula Milk-protein- or casein-dominantinfant formula, which contains small quantities ofpre-gelatinized starch, is recommended primarily forinfants with mild gastro-oesophageal reflux. Pre-thickenedformula is prepared in the same way as normalinfant formula and flows through a standard teat. Thefeeds do not thicken on standing but thicken in thestomach when exposed to acid pH.Starched based thickeners can be used to thickenliquids and feeds for children over 1 year of age withdysphagia.Dietary supplements for oral use (Appendix 2,p. 756) Three types of prescribable fortified dietarysupplements are available: fortified milk and non-milktasting (juice-style) drinks, and fortified milk-basedsemi-solid preparations. The recommended daily quantityis age-dependent. The following is a useful guide: 1–2 years, 200 kcal (840 kJ); 3–5 years, 400 kcal (1680 kJ);6–11 years, 600 kcal (2520 kJ); and over 12 years,800 kcal (3360 kJ). Supplements containing 1.5 kcal/mL are high in protein and should not be used forchildren under 3 years of age. Many supplements arehigh in sugar or maltodextrin; care should be taken toprevent prolonged contact with teeth. Ideally supplementsshould be administered after meals or at bedtimeso as not to affect appetite.Products for metabolic diseases There is a largerange of disease-specific infant formulas and aminoacid-based supplements available for use in childrenwith metabolic diseases (see under specific metabolicdiseases, Appendix 2, p. 781). Some of these formulasare nutritionally incomplete and supplementation withvitamins and other nutrients may be necessary. Many ofthe product names are similar; to prevent metaboliccomplications in children who cannot tolerate specificamino acids it is important to ensure the correct supplementis supplied.Preparations (Borderline substances) See Appendix2.9.5 Minerals9.5.1 Calcium and magnesium9.5.2 Phosphorus9.5.3 Fluoride9.5.4 ZincSee section 9.1.1 for iron salts.9.5.1 Calcium and magnesium9.5.1.1 Calcium supplements9.5.1.2 Hypercalcaemia and hypercalciuria9.5.1.3 Magnesium9.5.1.1 Calcium supplementsCalcium supplements are usually only required wheredietary calcium intake is deficient. This dietary requirementvaries with age and is relatively greater in childhood,pregnancy, and lactation, due to an increaseddemand. Hypocalcaemia may be caused by vitamin Ddeficiency (section 9.6.4), impaired metabolism, a failureof secretion (hypoparathyroidism), or resistance toparathyroid hormone (pseudohypoparathyroidism).Mild asymptomatic hypocalcaemia may be managedwith oral calcium supplements. Severe symptomatichypocalcaemia requires an intravenous infusion of calciumgluconate 10% over 5 to 10 minutes, repeating thedose if symptoms persist; in exceptional cases it may benecessary to maintain a continuous calcium infusionover a day or more. Calcium chloride injection is alsoavailable, but is more irritant; care should be taken toprevent extravasation.For the role of calcium gluconate in temporarily reducingthe toxic effects of hyperkalaemia, see p. 458.Persistent hypocalcaemia requires oral calcium supplementsand either a vitamin D analogue (alfacalcidol orcalcitriol) for hypoparathyroidism and pseudohypoparathyroidismor natural vitamin D (calciferol) if due tovitamin D deficiency (section 9.6.4). It is important tomonitor plasma and urinary calcium during long-termmaintenance therapy.Neonates Hypocalcaemia is common in the first fewdays of life, particularly following birth asphyxia orrespiratory distress. Late onset at 4–10 days after birthmay be secondary to vitamin D deficiency, hypoparathyroidismor hypomagnesaemia and may be associatedwith seizures.9 Nutrition and blood

472 9.5.1 Calcium and magnesium BNFC 2011–20129 Nutrition and bloodCALCIUM SALTSCautions see notes above; sarcoidosis; history ofnephrolithiasis; avoid calcium chloride in respiratoryacidosis or respiratory failure; interactions: Appendix1 (antacids, calcium salts)Contra-indications conditions associated with hypercalcaemiaand hypercalciuria (e.g. some forms ofmalignant disease); see also Calcium Gluconateinjection, belowRenal impairment use with caution; risk of hypercalcaemiaand renal calculiSide-effects gastro-intestinal disturbances, constipation;bradycardia, arrhythmias; with injection, peripheralvasodilatation, fall in blood pressure, injectionsitereactions, severe tissue damage with extravasationIndication and doseSee notes above; calcium deficiency. By mouthNeonate 0.25 mmol/kg 4 times a day, adjusted toresponseChild 1 month–4 years 0.25 mmol/kg 4 times aday, adjusted to responseChild 5–12 years 0.2 mmol/kg 4 times a day,adjusted to responseChild 12–18 years 10 mmol 4 times a day,adjusted to responseAcute hypocalcaemia, urgent correction;hyperkalaemia (prevention of arrhythmias). By slow intravenous injection over 5–10 minutesNeonate 0.11 mmol/kg (0.5 mL/kg of calciumgluconate 10%) as a single dose. [Some units use adose of 0.46 mmol/kg (2 mL/kg calcium gluconate10%) for hypocalcaemia in line with US practice]Child 1 month–18 years 0.11 mmol/kg (0.5 mL/kg calcium gluconate 10%), max 4.5 mmol (20 mLcalcium gluconate 10%)Calcium Lactate (Non-proprietary)Tablets, calcium lactate 300 mg (calcium 39 mg orCa 2þ 1 mmol), net price 84 = £2.92Adcal c (ProStrakan)Chewable tablets, fruit flavour, calcium carbonate1.5 g (calcium 600 mg or Ca 2þ 15 mmol), net price100-tab pack = £7.25. Label: 24Cacit c (Warner Chilcott)Tablets, effervescent, pink, calcium carbonate 1.25 g,providing calcium citrate when dispersed in water(calcium 500 mg or Ca 2þ 12.5 mmol), net price 76-tabpack = £11.81. Label: 13Calcichew c (Shire)Tablets (chewable), orange flavour, calcium carbonate1.25 g (calcium 500 mg or Ca 2þ 12.5 mmol), netprice 100-tab pack = £9.33. Label: 24Forte tablets (chewable), orange flavour, scored,calcium carbonate 2.5 g (calcium 1 g or Ca 2þ25 mmol), net price 60-tab pack = £13.16. Label: 24Excipients include aspartame (section 9.4.1)Calcium-500 (Martindale)Tablets, pink, f/c, calcium carbonate 1.25 g (calcium500 mg or Ca 2þ 12.5 mmol), net price 100-tab pack =£9.46. Label: 25Calcium-Sandoz c (Alliance)Syrup, orange flavour, calcium glubionate 1.09 g,calcium lactobionate 727 mg (calcium 108.3 mg orCa 2þ 2.7 mmol)/5 mL, net price 300 mL = £4.07Sandocal c (Novartis Consumer Health)Sandocal 400 tablets, effervescent, orange flavour,calcium lactate gluconate 930 mg, calcium carbonate700 mg, providing calcium 400 mg (Ca 2þ 10 mmol),net price 5 20-tab pack = £6.87. Label: 13Excipients include aspartame (section 9.4.1)Sandocal 1000 tablets, effervescent, orange flavour,calcium lactate gluconate 2.263 g, calcium carbonate1.75 g, providing 1 g calcium (Ca 2þ 25 mmol), net price3 10-tab pack = £6.17. Label: 13Excipients include aspartame (section 9.4.1)Acute hypocalcaemia, maintenance. By continuous intravenous infusionNeonate 0.5 mmol/kg daily over 24 hours,adjusted to response, use oral route as soon aspossible due to risk of extravasationChild 1 month–2 years 1 mmol/kg daily (usualmax 8.8 mmol) over 24 hours, use oral route assoon as possible due to risk of extravasationChild 2–18 years 8.8 mmol over 24 hours, useoral route as soon as possible due to risk ofextravasationOral preparationsCalcium Gluconate (Non-proprietary)Effervescent tablets, calcium gluconate 1 g (calcium89 mg or Ca 2þ 2.23 mmol), net price 28-tab pack =£14.83. Label: 13Note Each tablet usually contains 4.46 mmol Na +Parenteral preparationsCalcium Gluconate (Non-proprietary) AInjection, calcium gluconate 10% (calcium 8.4 mg orCa 2þ 226 micromol)/mL. Net price 10-mL amp = 60pAdministration For intravenous infusion dilute to at least45 micromol/mL with Glucose 5% or Sodium Chloride 0.9%.Maximum administration rate 45 micromol/kg/hour (or in neonatesmax. 22 micromol/kg/hour). May be given more concentratedvia a central venous catheter. May be used undiluted (10%calcium gluconate) in emergencies. Avoid extravasation; shouldnot be given by intramuscular injection. Incompatible with sodiumbicarbonate and phosphate solutions.Note The MHRA has advised that repeated or prolongedadministration of calcium gluconate injection packaged in10 mL glass containers is contra-indicated in children under18 years and in patients with renal impairment owing to therisk of aluminium accumulation; in these patients the use ofcalcium gluconate injection packaged in plastic containers isrecommendedCalcium Chloride (Non-proprietary) AInjection, calcium chloride dihydrate 10% (calcium27.3 mg or Ca 2þ 680 micromol/mL), net price 10-mLdisposable syringe = £5.10Brands include Minijet c Calcium Chloride 10%

BNFC 2011–2012 9.5.1 Calcium and magnesium 473Injection, calcium chloride dihydrate 13.4% (calcium36 mg or Ca 2þ 910 micromol/mL), net price 10–mLamp = £14.94With vitamin DSection 9.6.49.5.1.2 Hypercalcaemia andhypercalciuriaSevere hypercalcaemia Severe hypercalcaemia callsfor urgent treatment before detailed investigation of thecause. Dehydration should be corrected first with intravenousinfusion of sodium chloride 0.9%. Drugs (suchas thiazides and vitamin D compounds) which promotehypercalcaemia, should be discontinued and dietarycalcium should be restricted.If severe hypercalcaemia persists drugs which inhibitmobilisation of calcium from the skeleton may berequired. The bisphosphonates are useful anddisodium pamidronate (section 6.6.2) is probably themost effective.Corticosteroids (section 6.3) are widely given, but mayonly be useful where hypercalcaemia is due to sarcoidosisor vitamin D intoxication; they often take severaldays to achieve the desired effect.Calcitonin (section 6.6.1) is relatively non-toxic, but itseffect can wear off after a few days despite continueduse; it is rarely effective where bisphosphonates havefailed to reduce serum calcium adequately.After treatment of severe hypercalcaemia the underlyingcause must be established. Further treatment isgoverned by the same principles as for initial therapy.Salt and water depletion and drugs promoting hypercalcaemiashould be avoided; oral administration of abisphosphonate may be useful. Parathyroidectomy maybe indicated for hyperparathyroidism.Hypercalciuria Hypercalciuria should be investigatedfor an underlying cause, which should be treated. Reducingdietary calcium intake may be beneficial but severerestriction of calcium intake has not proved beneficialand may even be harmful.9.5.1.3 MagnesiumMagnesium is an essential constituent of many enzymesystems, particularly those involved in energy generation;the largest stores are in the skeleton.Magnesium salts are not well absorbed from the gastrointestinaltract, which explains the use of magnesiumsulphate (section 1.6.4) as an osmotic laxative.Magnesium is excreted mainly by the kidneys and istherefore retained in renal failure, but significant hypermagnesaemia(causing muscle weakness and arrhythmias)is rare.Hypomagnesaemia Since magnesium is secreted inlarge amounts in the gastro-intestinal fluid, excessivelosses in diarrhoea, stoma or fistula are the most commoncauses of hypomagnesaemia; deficiency may alsooccur as a result of treatment with certain drugs. Hypomagnesaemiaoften causes secondary hypocalcaemia(with which it may be confused), particularly in neonates,and also hypokalaemia and hyponatraemia.Symptomatic hypomagnesaemia is associated with adeficit of 0.5–1 mmol/kg. Magnesium is given initiallyby intravenous infusion or by intramuscular injection ofmagnesium sulphate; the intramuscular injection ispainful. Plasma magnesium concentration should bemeasured to determine the rate and duration of infusionand the dose should be reduced in renal impairment. Toprevent recurrence of the deficit, magnesium may begiven by mouth in divided doses. For maintenance (e.g.in intravenous nutrition), parenteral doses of magnesiumare of the order of 0.2–0.4 mmol/kg (usual max.20 mmol) Mg 2þ daily.Arrhythmias Magnesium sulphate has also beenrecommended for the emergency treatment of seriousarrhythmias, especially in the presence of hypokalaemia(when hypomagnesaemia may also be present) andwhen salvos of rapid ventricular tachycardia show thecharacteristic twisting wave front known as torsade depointes (see also section 2.3.1).MAGNESIUM SULPHATECautions see notes above; in severe hypomagnesaemiaadminister initially via controlled infusiondevice (preferably syringe pump); monitor bloodpressure, respiratory rate, urinary output and for signsof overdosage (loss of patellar reflexes, weakness,nausea, sensation of warmth, flushing, drowsiness,double vision, and slurred speech); interactions:Appendix 1 (magnesium, parenteral)Hepatic impairment avoid in hepatic coma if risk ofrenal failureRenal impairment avoid or reduce dose; increasedrisk of toxicityPregnancy sufficient may cross the placenta inmothers treated with high doses e.g. in pre-eclampsia,causing hypotonia and respiratory depression innewbornsSide-effects generally associated with hypermagnesaemia,nausea, vomiting, thirst, flushing of skin,hypotension, arrhythmias, coma, respiratory depression,drowsiness, confusion, loss of tendon reflexes,muscle weaknessIndication and doseNeonatal hypocalcaemia. By deep intramuscular injection or intravenousinfusionNeonate 0.4 mmol/kg Mg 2þ (100 mg/kg magnesiumsulphate) 12 hourly for 2–3 dosesHypomagnesaemia. By intravenous injection over at least 10 minutesNeonate 0.4 mmol/kg Mg 2þ (100 mg/kg magnesiumsulphate) 6–12 hourly as necessary9 Nutrition and blood

474 9.5.2 Phosphorus BNFC 2011–20129 Nutrition and bloodChild 1 month–12 years 0.2 mmol/kg Mg 2þ(50 mg/kg magnesium sulphate) 12 hourly asnecessaryChild 12–18 years 4 mmol Mg 2þ (1 g magnesiumsulphate) 12 hourly as necessaryTorsade de pointes (consult local guidelines). By intravenous injection over 10–15 minutesChild 1 month–18 years 0.1–0.2 mmol/kg (25–50 mg/kg magnesium sulphate); max. 8 mmol (2 gmagnesium sulphate); dose repeated once ifnecessaryPersistent pulmonary hypertension section 2.5.1Severe acute asthma section 3.1Administration Dilute to 10% (100 mg in 1 mL) withGlucose 5 or 10%, Sodium Chloride 0.45 or 0.9% orGlucose and Sodium Chloride combinations. Up to20% solution may be given in fluid restriction. Rate ofadministration should not exceed 10 mg/kg/minuteof magnesium sulphateNote Magnesium sulphate 1 g equivalent to Mg 2þ approx.4 mmolMagnesium Sulphate (Non-proprietary) AInjection, magnesium sulphate 20% (Mg 2þ approx.0.8 mmol/mL), net price 20-mL (4-g) amp = £2.75;50% (Mg 2þ approx. 2 mmol/mL), 2-mL (1-g) amp =£2.39, 4-mL (2-g) prefilled syringe = £7.39; 5-mL (2.5-g) amp = £3.00, 10-mL (5-g) amp = 69p; 10-mL (5-g)prefilled syringe = £4.95Brands include Minijet c Magnesium Sulphate 50%MAGNESIUM-L-ASPARTATECautions see under Magnesium SulphateRenal impairment avoid or reduce dose; increasedrisk of toxicitySide-effects see under Magnesium Sulphate; alsodiarrhoeaLicensed use classified as a Food for Special MedicalPurposes for use in children over 2 yearsIndication and doseHypomagnesaemia. By mouthChild 1 month–2 years initially 0.2 mmol/kg ofMg 2þ 3 times daily dissolved in water, doseadjusted as requiredChild 2–10 years half a sachet (5 mmol Mg 2þ )daily dissolved in 100 mL of water, dose adjustedas requiredChild 10–18 years one sachet (10 mmol Mg 2þ )daily dissolved in 200 mL of water, dose adjustedas requiredMagnaspartate c (KoRa)Oral powder, magnesium-L-aspartate 6.5 g (10 mmolMg 2þ )/sachet, net price 10-sachet pack = £7.95Excipients include sucroseMAGNESIUM GLYCEROPHOSPHATECautions see under Magnesium SulphateRenal impairment avoid or reduce dose; increasedrisk of toxicitySide-effects see under Magnesium Sulphate; alsodiarrhoeaLicensed use not licensedIndication and doseHypomagnesaemia. By mouthChild 1 month–12 years initially 0.2 mmol/kgMg 2þ 3 times daily, dose adjusted as requiredChild 12–18 years initially 4–8 mmol Mg 2þ 3times daily, dose adjusted as requiredAdministration tablets may be dispersed in waterMagnesium Glycerophosphate (Non-proprietary)Tablets, magnesium glycerophosphate 1 g (approximatelymagnesium 97 mg or Mg 2þ 4 mmol)Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Liquid, magnesium glycerophosphate 250 mg/mL(approximately magnesium 24.25 mg or Mg 2þ1 mmol/mL)Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Extemporaneous formulations available seeExtemporaneous Preparations, p. 69.5.2 Phosphorus9.5.2.1 Phosphate supplements9.5.2.2 Phosphate-binding agents9.5.2.1 Phosphate supplementsOral phosphate supplements may be required in additionto vitamin D in children with hypophosphataemicvitamin D-resistant rickets (section 9.6.4). Diarrhoea is acommon side-effect and should prompt a reduction indosage.Phosphate infusion is occasionally needed in phosphatedeficiency arising from use of parenteral nutrition deficientin phosphate supplements; phosphate depletionalso occurs in severe diabetic ketoacidosis. It is difficultto provide detailed guidelines for the treatment of severehypophosphatemia because the extent of total bodydeficits and response to therapy are difficult to predict.High doses of phosphate may result in a transient serumelevation followed by redistribution into intracellularcompartments or bone tissue; excessive doses maycause hypocalcaemia and metastatic calcification. It isessential to monitor plasma concentrations of calcium,phosphate, potassium and other electrolytes. It isrecommended that severe hypophosphataemia be treatedintravenously as large doses of oral phosphate maycause diarrhoea; intestinal absorption may be unreliableand dose adjustment may be necessary.

BNFC 2011–2012 9.5.2 Phosphorus 475Phosphate is not the first choice for the treatment ofhypercalcaemia because of the risk of precipitation ofcalcium phosphate in the kidney and other tissues. Ifused, the child should be well hydrated and electrolytesmonitored.Neonates Phosphate deficiency may occur in verylow-birthweight infants and may compromise bonegrowth if not corrected. Parenterally fed infants maybe at risk of phosphate deficiency due to the limitedsolubility of phosphate. Some units routinely supplementexpressed breast milk with phosphate, althoughthe effect on the osmolality of the milk should beconsidered.PHOSPHATECautions see notes above, also cardiac disease, diabetesmellitus, dehydration; avoid extravasation withparenteral forms, severe tissue necrosis; sodium andpotassium concentrations of preparationsRenal impairment reduce dose; monitor closelySide-effects nausea, diarrhoea; hypotension, oedema;hypocalcaemia; acute renal failure; phlebitis; tissuenecrosis on extravasationIndication and doseHypophosphataemia, including hypophosphataemicrickets and osteomalacia (see notes above). By mouthNeonate 1 mmol/kg daily in 1–2 divided doses, oras a supplement in breast milkChild 1 month–5 years 2–3 mmol/kg (max.48 mmol) phosphate daily in 2–4 divided doses,adjusted as necessaryChild 5–18 years 2–3 mmol/kg (max. 97 mmol)phosphate daily in 2–4 divided doses, adjusted asnecessaryAdministration Caution, solubility in breast milk is limitedto 1.2 mmol in 100 mL if calcium also added, contactpharmacy department for details. By intravenous infusion (see administrationbelow and seek specialist advice)Neonate 1 mmol/kg phosphate daily, adjusted asnecessaryChild 1 month–2 years 0.7 mmol/kg phosphatedaily, adjusted as necessaryChild 2–18 years 0.4 mmol/kg phosphate daily,adjusted as necessaryAdministration (see also Important, below) Diluteinjection with Sodium Chloride 0.9% or 0.45% or Glucose5% or 10%. Administration rate of phosphate should notexceed 0.05 mmol/kg/hour. In emergencies in intensivecare faster rates may be used—seek specialist adviceImportantSome phosphate injection preparations also containpotassium. For peripheral intravenous administrationthe concentration of potassium should not usuallyexceed 40 mmol/litre. The infusion solution shouldbe thoroughly mixed. Local policies on avoidinginadvertent use of potassium concentrate should befollowed. The potassium content of some phosphatepreparations may also limit the rate at which they maybe administered, see section 9.2.2.1.OralPhosphate-Sandoz c (HK Pharma)Tablets, effervescent, anhydrous sodium acid phosphate1.936 g, sodium bicarbonate 350 mg, potassiumbicarbonate 315 mg, equivalent to phosphorus 500 mg(phosphate 16.1 mmol), sodium 468.8 mg (Na +20.4 mmol), potassium 123 mg (K + 3.1 mmol). Netprice 20 = £3.29. Label: 13Extemporaneous formulations available seeExtemporaneous Preparations, p. 6Various strengths and salts available, caution electrolyteloadInjectionPhosphates (Fresenius Kabi) AIntravenous infusion, phosphates (providing phosphate100 mmol/litre, potassium 19 mmol/litre, sodium162 mmol/litre), net price 500 mL (Polyfusor c )=£3.75.Potassium acid phosphate (Non-proprietary) AInjection, 13.6% (1 mmol/mL phosphate, 1 mmol/mL potassium) 10 mL ampouleNote See also Important, aboveDipotassium hydrogen phosphate (Non-proprietary)AInjection, 17.42% (1 mmol/mL phosphate and2 mmol/mL potassium) 10 mL ampouleNote See also Important, aboveDisodium hydrogen phosphate (Non-proprietary) AInjection, 17.42% (0.6 mmol/mL phosphate and1.2 mmol/mL sodium) 10 mL ampoule9.5.2.2 Phosphate-binding agentsCalcium-containing preparations are used as phosphate-bindingagents in the management of hyperphosphataemiacomplicating renal failure. Aluminiumcontainingpreparations are rarely used as phosphatebindingagents and can cause aluminium accumulation.Sevelamer hydrochloride is licensed for the treatmentof hyperphosphataemia in adults on haemodialysis orperitoneal dialysis. Although experience is limited inchildren sevelamer may be useful when hypercalcaemiaprevents the use of calcium carbonate.ALUMINIUM HYDROXIDECautions see notes above; interactions: Appendix 1(antacids)Side-effects constipation; hyperaluminaemiaAlu-Cap c (Meda)Capsules, green/red, dried aluminium hydroxide475 mg (low Na + ), net price 120-cap pack = £3.75DoseHyperphosphataemia. By mouthChild 5–12 years 1–2 capsules 3–4 times daily, adjustedas necessaryChild 12–18 years 1–5 capsules 3–4 times daily,adjusted as necessary9 Nutrition and blood

476 9.5.3 Fluoride BNFC 2011–20129 Nutrition and bloodCALCIUM SALTSCautions interactions: Appendix 1 (antacids, calciumsalts)Contra-indications hypercalcaemia, hypercalciuriaSide-effects hypercalcaemiaIndication and dosePhosphate binding in renal failure and hyperphosphataemia. By mouthChild 1 month–1 year 120 mg calcium carbonate3–4 times daily with feeds, adjusted as necessaryChild 1–6 years 300 mg calcium carbonate 3–4times daily prior to or with meals, adjusted asnecessaryChild 6–12 years 600 mg calcium carbonate 3–4times daily prior to or with meals, adjusted asnecessaryChild 12–18 years 1.25 g calcium carbonate 3–4times daily prior to or with meals, adjusted asnecessaryAdcal c Section 9.5.1.1Calcichew c Section 9.5.1.1Calcium-500 Section 9.5.1.1Phosex c (Vitaline)Tablets, yellow, scored, calcium acetate 1 g (calcium250 mg or Ca 2þ 6.2 mmol), net price 180-tab pack =£19.79. Counselling, do not chew, with mealsDosePhosphate-binding agent (with meals) in renal failure,according to the requirements of the patientExtemporaneous formulations available seeExtemporaneous Preparations, p. 6SEVELAMER HYDROCHLORIDECautions gastro-intestinal disorders; interactions:Appendix 1 (sevelamer)Contra-indications bowel obstructionPregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding manufacturer advises use only ifpotential benefit outweighs riskSide-effects nausea, vomiting, abdominal pain, constipation,diarrhoea, dyspepsia, flatulence; very rarelyintestinal obstruction; also reported intestinal perforation,ileus, diverticulitis, pruritus, and rashLicensed use not licensed for use in children under18 yearsIndication and doseHyperphosphataemia in patients on haemodialysisor peritoneal dialysis. By mouthChild 12–18 years initially 0.8–1.6 g 3 times dailywith meals, then adjusted according to plasmaphosphateconcentrationRenagel c (Genzyme) ATablets, f/c, sevelamer hydrochloride 800 mg, netprice 180-tab pack = £117.97. Label: 25, counselling,with mealsExcipients include propylene glycol (see Excipients, p. 2)9.5.3 FluorideAvailability of adequate fluoride confers significantresistance to dental caries. It is now considered thatthe topical action of fluoride on enamel and plaque ismore important than the systemic effect.When the fluoride content of drinking water is less than700 micrograms per litre (0.7 parts per million), dailyadministration of fluoride tablets or drops provide suitablesupplementation. Systemic fluoride supplementsshould not be prescribed without reference to the fluoridecontent of the local water supply. Infants need notreceive fluoride supplements until the age of 6 months.Dentifrices which incorporate sodium fluoride or monofluorophosphateare also a convenient source of fluoride.Individuals who are either particularly caries prone ormedically compromised may be given additional protectionby use of fluoride rinses or by application offluoride gels. Rinses may be used daily or weekly; dailyuse of a less concentrated rinse is more effective thanweekly use of a more concentrated one. High-strengthgels must be applied regularly under professional supervision;extreme caution is necessary to prevent the childfrom swallowing any excess. Less concentrated gels areavailable for home use. Varnishes are also available andare particularly valuable for young or disabled childrensince they adhere to the teeth and set in the presence ofmoisture.Fluoride mouthwash, oral drops, tablets, and toothpasteare prescribable on form FP10D (GP14 in Scotland,WP10D in Wales; for details see preparations below).There are also arrangements for health authorities tosupply fluoride tablets in the course of pre-school dentalschemes, and they may also be supplied in school dentalschemes.Fluoride gels are not prescribable on form FP10D (GP14in Scotland, WP10D in Wales).FLUORIDESNote Sodium fluoride 2.2 mg provides approx. 1 mg fluorideionContra-indications not for areas where drinking wateris fluoridatedSide-effects occasional white flecks on teeth withrecommended doses; rarely yellowish-brown discolorationif recommended doses are exceededIndication and doseProphylaxis of dental caries—see notes aboveNote Dose expressed as fluoride ion (F ):Water content less than F 300 micrograms/litre (0.3parts per million). By mouthChild 6 months–3 years F 250 micrograms daily

BNFC 2011–2012 9.5.3 Fluoride 477Child 3–6 years F 500 micrograms dailyChild 6 years and over F1 mg dailyWater content between F 300 and 700 micrograms/litre(0.3–0.7 parts per million)Child 3–6 years FChild 6 years and over F250 micrograms daily500 micrograms dailyWater content above F 700 micrograms/litre (0.7parts per million), supplements not advisedNote These doses reflect the recommendations of the BritishDental Association, the British Society of Paediatric Dentistryand the British Association for the Study of CommunityDentistry (Br Dent J 1997; 182: 6–7)MouthwashesRinse mouth for 1 minute and spit outCounselling Avoid eating, drinking, or rinsing mouth for 15minutes after useDuraphat c (Colgate-Palmolive)Weekly dental rinse (= mouthwash), blue, sodiumfluoride 0.2%. Net price 150 mL = £2.13. Counselling,see aboveDoseChild 6 years and over for weekly use, rinse with 10 mLDental prescribing on NHS May be prescribed as SodiumFluoride Mouthwash 0.2%TabletsCounselling Tablets should be sucked or dissolved in themouth and taken preferably in the eveningThere are arrangements for health authorities to supply fluoridetablets in the course of pre-school dental schemes, andthey may also be supplied in school dental schemes.En-De-Kay c (Manx)Fluotabs 3–6 years, orange-flavoured, scored, sodiumfluoride 1.1 mg (F 500 micrograms), net price200-tab pack = £2.38Dental prescribing on NHS May be prescribed as SodiumFluoride TabletsFluotabs 6+ years, orange-flavoured, scored, sodiumfluoride 2.2 mg (F 1 mg), net price 200-tab pack =£2.38Dental prescribing on NHS May be prescribed as SodiumFluoride TabletsFluor-a-day c (Dental Health)Tablets, buff, sodium fluoride 1.1 mg (F 500 micrograms),net price 200-tab pack = £2.54; 2.2 mg (F1 mg), 200-tab pack = £2.54Dental prescribing on NHS May be prescribed as SodiumFluoride TabletsFluoriGard c (Colgate-Palmolive)Tablets 0.5, purple, grape-flavoured, scored, sodiumfluoride 1.1 mg (F 500 micrograms), net price 200-tab pack = £1.91Dental prescribing on NHS May be prescribed as SodiumFluoride TabletsTablets 1.0, orange, orange-flavoured, scored, sodiumfluoride 2.2 mg (F 1 mg), net price 200-tab pack= £1.91Dental prescribing on NHS May be prescribed as SodiumFluoride TabletsEn-De-Kay c (Manx)Daily fluoride mouthrinse (= mouthwash), blue,sodium fluoride 0.05%. Net price 250 mL = £1.51DoseChild 6 years and over for daily use, rinse with 10 mLDental prescribing on NHS May be prescribed as SodiumFluoride Mouthwash 0.05%Fluorinse A (= mouthwash), red, sodium fluoride2%. Net price 100 mL = £4.97. Counselling, see aboveDoseChild 8 years and over for daily use, dilute 5 drops to10 mL of water; for weekly use, dilute 20 drops to 10 mLDental prescribing on NHS May be prescribed as SodiumFluoride Mouthwash 2%FluoriGard c (Colgate-Palmolive)Daily dental rinse (= mouthwash), blue, sodiumfluoride 0.05%. Net price 500 mL = £2.61. Counselling,see aboveDoseChild 6 years and over for daily use, rinse with 10 mLDental prescribing on NHS May be prescribed as SodiumFluoride Mouthwash 0.05%GelsFluoriGard c (Colgate-Palmolive)Gel-Kam (= gel), stannous fluoride 0.4% in glycerolbasis. Net price 100 mL = £2.63. Counselling, seebelowDoseChild over 3 years for daily use, using a toothbrush,apply on to all tooth surfacesCounselling Swish between teeth for 1 minute before spittingout. Avoid eating, drinking, or rinsing mouth for at least30 minutes after use9 Nutrition and bloodOral dropsNote Fluoride supplements not considered necessary below 6months of age (see notes above)En-De-Kay c (Manx)Fluodrops c (= paediatric drops), sugar-free, sodiumfluoride 550 micrograms (F 250 micrograms)/0.15 mL. Net price 60 mL = £2.38Dental prescribing on NHS Corresponds to Sodium FluorideOral Drops DPF 0.37% equivalent to sodium fluoride80 micrograms (F 36 micrograms)/dropToothpastesDuraphat c (Colgate-Palmolive) ADuraphat c ‘2800 ppm’ toothpaste, sodium fluoride0.619%. Net price 75 mL = £3.26. Counselling, seebelowDoseChild over 10 years apply 1 cm twice daily using atoothbrushCounselling Brush teeth for 1 minute before spitting out.Avoid drinking or rinsing mouth for 30 minutes after useDental prescribing on NHS May be prescribed as SodiumFluoride Toothpaste 0.619%

478 9.5.4 Zinc BNFC 2011–20129 Nutrition and bloodDuraphat c ‘5000 ppm’ toothpaste, sodium fluoride1.1%. Net price 51 g = £6.50. Counselling, see belowDoseChild over 16 years apply 2 cm 3 times daily after mealsusing a toothbrushCounselling Brush teeth for 3 minutes before spitting outDental prescribing on NHS May be prescribed as SodiumFluoride Toothpaste 1.1%9.5.4 ZincZinc supplements should not be given unless there isgood evidence of deficiency (hypoproteinaemia spuriouslylowers plasma-zinc concentration) or in zinclosingconditions. Zinc deficiency can occur as a resultof inadequate diet or malabsorption; excessive loss ofzinc can occur in trauma, burns, and protein-losingconditions. A zinc supplement is given until clinicalimprovement occurs, but it may need to be continuedin severe malabsorption, metabolic disease, or in zinclosingstates. Zinc is used in the treatment of Wilson’sdisease (section 9.8.1) and acrodermatitis enteropathica,a rare inherited abnormality of zinc absorption.Parenteral nutrition regimens usually include traceamounts of zinc (section 9.3). If necessary, further zinccan be added to some intravenous feeding regimens.ZINC SULPHATECautions interactions: Appendix 1 (zinc)Renal impairment accumulation may occur in acuterenal failurePregnancy crosses placenta; risk theoretically minimal,but no information availableBreast-feeding present in milk; risk theoreticallyminimal, but no information availableSide-effects abdominal pain, dyspepsia, nausea,vomiting, diarrhoea, gastric irritation, gastritis; irritability,headache, lethargyLicensed use Solvazinc c not licensed for use inacrodermatitis enteropathicaSolvazinc c (Galen)Effervescent tablets, zinc sulphate monohydrate125 mg (45 mg zinc), net price 30 = £4.32. Label: 13,21DoseZinc deficiency (see notes above). By mouthNeonate 1 mg/kg elemental zinc dailyChild under 10 kg half a tablet daily in water after food,adjusted as necessaryChild 10–30 kg half a tablet 1–3 times daily in waterafter food, adjusted as necessaryChild over 30 kg 1 tablet 1–3 times daily in water afterfood, adjusted as necessaryAcrodermatitis enteropathica. By mouthNeonate 0.5–1 mg/kg elemental zinc twice daily (totaldaily dose may alternatively be given in 3 divided doses),adjusted as necessaryChild 1 month–18 years 0.5–1 mg/kg elemental zinctwice daily (total daily dose may alternatively be given in3 divided doses), adjusted as necessary9.6 Vitamins9.6.1 Vitamin A9.6.2 Vitamin B group9.6.3 Vitamin C9.6.4 Vitamin D9.6.5 Vitamin E9.6.6 Vitamin K9.6.7 Multivitamin preparationsVitamins are used for the prevention and treatment ofspecific deficiency states or where the diet is known tobe inadequate; they may be prescribed in the NHS toprevent or treat deficiency but not as dietary supplements.Except for iron-deficiency anaemia, a primaryvitamin or mineral deficiency due to simple dietaryinadequacy is rare in the developed world. Some childrenmay be at risk of developing deficiencies becauseof an inadequate intake, impaired vitamin synthesis ormalabsorption in disease states such as cystic fibrosisand Crohn’s disease.The use of vitamins as general ‘pick-me-ups’ is ofunproven value and the ‘fad’ for mega-vitamin therapywith water-soluble vitamins, such as ascorbic acid andpyridoxine, is unscientific and can be harmful. Manyvitamin supplements are described as ‘multivitamin’ butfew contain the whole range of essential vitamins andmany contain relatively high amounts of vitamins A andD. Care should be taken to ensure the correct dose is notexceeded.Dietary reference values for vitamins are available in theDepartment of Health publication:Dietary Reference Values for Food Energy and Nutrients forthe United Kingdom: Report of the Panel on Dietary ReferenceValues of the Committee on Medical Aspects of FoodPolicy. Report on Health and Social Subjects 41. London:HMSO, 1991Dental patients It is unjustifiable to treat stomatitis orglossitis with mixtures of vitamin preparations; thisdelays diagnosis and correct treatment.Most patients who develop a nutritional deficiencydespite an adequate intake of vitamins have malabsorptionand if this is suspected the patient should bereferred to a medical practitioner.9.6.1 Vitamin ADeficiency of vitamin A (retinol) is associated withocular defects (particularly xerophthalmia) and anincreased susceptibility to infections, but deficiency israre in the UK (even in disorders of fat absorption).Vitamin A supplementation may be required in childrenwith liver disease, particularly cholestatic liver disease,due to the malabsorption of fat soluble vitamins. Inthose with complete biliary obstruction an intramusculardose once a month may be appropriate.Treatment is sometimes initiated with very high dosesof vitamin A and the child should be monitored closely;very high doses are associated with acute toxicity.

BNFC 2011–2012 9.6.2 Vitamin B group 479Preterm neonates have low plasma concentrations ofvitamin A and are usually given vitamin A supplements,often as part of an oral multivitamin preparation (section9.6.7) once enteral feeding has been established.Massive overdose can cause rough skin, dry hair, anenlarged liver, and a raised erythrocyte sedimentationrate and raised serum calcium and serum alkalinephosphatase concentrations.Pregnancy In view of evidence suggesting that highlevels of vitamin A may cause birth defects, women whoare (or may become) pregnant are advised not to takevitamin A supplements (including tablets and fish-liveroil drops), except on the advice of a doctor or anantenatal clinic; nor should they eat liver or productssuch as liver paté or liver sausage.VITAMIN A(Retinol)Cautions see notes above; interactions: Appendix 1(vitamins)Pregnancy excessive doses can be teratogenic; seealso notes aboveBreast-feeding toxicity likely if mother taking highdosesSide-effects see notes aboveLicensed use preparations containing only vitaminA are not licensedIndication and doseSee also notes aboveVitamin A deficiency. By mouthNeonate 5000 units dailyChild 1 month–1 year 5000 units daily with orafter foodChild 1–18 years 10 000 units daily with or afterfoodNote Higher doses may be used initially for treatment ofsevere deficiencyPrevention of deficiency in complete biliaryobstruction. By intramuscular injectionNeonate 50 000 units once a monthChild 1 month–1 year 50 000 units once a monthArovit c (Non-proprietary)Oral solution, vitamin A 150 000 units/mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Aquasol-A c (Non-proprietary)Injection, vitamin A (as palmitate) 50 000 units/mL,2-mL ampAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809VITAMINS A and DCautions see notes above and section 9.6.4; prolongedexcessive ingestion of vitamins A and D can lead tohypervitaminosis; interactions: Appendix 1 (vitamins)Pregnancy see notes aboveSide-effects see notes above and section 9.6.4Licensed use not licensed in children under 6months of ageIndication and doseSee notes above and section 9.6.4Prevention of vitamin A and D deficiency seeindividual preparations for dose informationVitamins A and DVitamins A and D (Non-proprietary)Capsules, vitamin A 4000 units, vitamin D 400 units.Net price 84 = £3.44Note May be difficult to obtainDoseChild 1–18 years 1 capsule dailyVitamins A, C and DHealthy Start Children’s Vitamin Drops (Non-proprietary)Oral drops, vitamin A 5000 units, vitamin D2000 units, ascorbic acid 150 mg/mLAvailable free of charge to children under 4 years in families on theHealthy Start Scheme, or alternatively may be available direct tothe public—further information for healthcare professionals canbe accessed at http://tinyurl.com/3yckebe. Beneficiaries cancontact their midwife or health visitor for further information onwhere to obtain supplies.DosePrevention of vitamin deficiency. By mouthChild 1 month–5 years 5 drops daily (5 drops containvitamin A approx. 700 units, vitamin D approx. 300 units,ascorbic acid approx. 20 mg)Note Healthy Start Vitamins for women (containing ascorbicacid, vitamin D, and folic acid) are also available free ofcharge to women on the Healthy Start Scheme duringpregnancy and until their baby is one year old, or alternativelymay be available direct to the public—further informationfor healthcare professionals can be accessed athttp://tinyurl.com/3yckebe. Beneficiaries can contact theirmidwife or health visitor for further information on where toobtain supplies.9.6.2 Vitamin B groupDeficiency of the B vitamins, other than vitamin B 12(section 9.1.2), is rare in the UK and is usually treated bypreparations containing thiamine (B 1 ), and riboflavin(B 2 ). Other members (or substances traditionally classifiedas members) of the vitamin B complex such asaminobenzoic acid, biotin, choline, inositol, and pantothenicacid or panthenol may be included in vitamin Bpreparations, but there is no evidence of their value assupplements; however, they can be used in the managementof certain metabolic disorders (section 9.8.1).Anaphylaxis has been reported with parenteral B vitamins(see MHRA/CHM advice, below).As with other vitamins of the B group, pyridoxine (B 6 )deficiency is rare, but it may occur during isoniazidtherapy (section 5.1.9) or penicillamine treatment inWilson’s disease (section 9.8.1) and is characterised byperipheral neuritis. High doses of pyridoxine are givenin some metabolic disorders, such as hyperoxaluria,cystathioninuria and homocystinuria; folic acid supplementationmay also be beneficial in these disorders9 Nutrition and blood

480 9.6.2 Vitamin B group BNFC 2011–20129 Nutrition and blood(section 9.1.2). Pyridoxine is also used in sideroblasticanaemia (section 9.1.3). Rarely, seizures in the neonatalperiod or during infancy respond to pyridoxine treatment;pyridoxine should be tried in all cases of earlyonsetintractable seizures and status epilepticus. Pyridoxinehas been tried for a wide variety of other disorders,but there is little sound evidence to support theclaims of efficacy, and overdosage induces toxic effects.A number of mitochondrial disorders may respond totreatment with certain B vitamins but these disordersrequire specialist management. Thiamine is used in thetreatment of maple syrup urine disease, mitochondrialrespiratory chain defects and, together with riboflavin,in the treatment of congenital lactic acidosis; riboflavinis also used in glutaric acidaemias and cytochromeoxidase deficiencies; biotin (section 9.8.1) is used incarboxylase defects.Folic acid and vitamin B 12 are used in the treatment ofmegaloblastic anaemia (section 9.1.2). Folinic acid(available as calcium folinate) is used in associationwith cytotoxic therapy (section 8.1).RIBOFLAVIN(Riboflavine, vitamin B 2 )Cautions see notes abovePregnancy crosses the placenta but no adverse effectsreported, information at high doses limitedBreast-feeding present in breast milk but no adverseeffects reported, information at high doses limitedSide-effects bright yellow urineLicensed use not licensed in childrenIndication and doseSee also notes aboveMetabolic diseases. By mouthNeonate 50 mg 1–2 times daily, adjusted accordingto responseChild 1 month–18 years 50–100 mg 1–2 timesdaily, adjusted according to response, up to 400 mgdaily has been usedRiboflavin (Non-proprietary)Tablets, 10 mg, 50 mg and 100 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Oral vitamin B complex preparationsSee belowExtemporaneous formulations available seeExtemporaneous Preparations, p. 6THIAMINE(Vitamin B 1 )Cautions anaphylactic shock may occasionally followinjection (see MHRA/CHM advice below)MHRA/CHM advice (September 2007)Although potentially serious allergic adverse reactionsmay rarely occur during, or shortly after, parenteraladministration, the CHM has recommended that:1. This should not preclude the use of parenteralthiamine in patients where this route of administrationis required, particularly in patients atrisk of Wernicke-Korsakoff syndrome wheretreatment with thiamine is essential;2. Intravenous administration should be by infusionover 30 minutes;3. Facilities for treating anaphylaxis (including resuscitationfacilities) should be available whenparenteral thiamine is administered.Breast-feeding severely thiamine-deficient mothersshould avoid breast-feeding as toxic methyl-glyoxalpresent in milkSide-effects hypersensitivity reactions to injectionLicensed use not licensed in childrenIndication and doseSee also notes aboveMaple syrup urine disease. By mouthNeonate 5 mg/kg daily, adjusted as necessaryChild 1 month–18 years 5 mg/kg daily, adjustedas necessaryMetabolic disorders including congenital lacticacidosis. By mouth or by intravenous infusion over 30minutesNeonate 50–200 mg once daily (total dose mayalternatively be given in 2–3 divided doses),adjusted as necessaryChild 1 month–18 years 100–300 mg once daily(total dose may alternatively be given in 2–3divided doses), adjusted as necessary; up to 2 gdaily may be necessaryThiamine (Non-proprietary)Tablets, thiamine hydrochloride 50 mg, net price 100= £5.19; 100 mg, 100 = £8.04Brands include Benerva c DInjection, 50 mg/mL, 2-mL vial; 100 mg/mL, 2-mLvialInjection (intramuscular), 100 mg/mL, 5-mL vialAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Note Some preparations may contain phenol as a preservativeOral vitamin B complex preparationsSee belowPYRIDOXINE HYDROCHLORIDE(Vitamin B 6 )Cautions see notes above; risk of cardiovascular collapsewith intravenous injection—resuscitation facilitiesmust be available, monitor closely; interactions:Appendix 1 (vitamins)Side-effects sensory neuropathy reported with highdoses given for extended periodsLicensed use not licensed for use in children

BNFC 2011–2012 9.6.3 Vitamin C 481Indication and doseSee also notes aboveMetabolic diseases including cystathioninuriaand homocystinuria. By mouthNeonate 50–100 mg 1–2 times dailyChild 1 month–18 years 50–250 mg 1–2 timesdailyTreatment of isoniazid-induced neuropathy. By mouthNeonate 5–10 mg dailyChild 1 month–12 years 10–20 mg 2–3 timesdailyChild 12–18 years 30–50 mg 2–3 times dailyPrevention of isoniazid-induced neuropathy. By mouthNeonate 5 mg dailyChild 1 month–12 years 5–10 mg dailyChild 12–18 years 10 mg dailyPrevention of penicillamine-induced neuropathyin Wilson’s disease (see notes above). By mouthChild 1–12 years 5–10 mg dailyChild 12–18 years 10 mg dailyPyridoxine-dependent seizures. By intravenous injection or by mouthNeonate initial test dose 50–100 mg by intravenousinjection, may be repeated; if responsivefollowed by an oral maintenance dose of 50–100 mg once daily, adjusted as necessaryChild 1 month–12 years initial test dose 50–100 mg daily; if responsive followed by an oraldose of 20–50 mg 1–2 times daily, adjusted asnecessary; doses up to 30 mg/kg or 1 g daily havebeen usedPyridoxine (Non-proprietary)Tablets, pyridoxine hydrochloride 10 mg, net price500 = £8.53; 20 mg, 500 = £8.53; 50 mg, 28 = £1.52Injection, 25 mg/mL, 2 mL vialAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Extemporaneous formulations available seeExtemporaneous Preparations, p. 6Oral vitamin B complex preparationsNote Other multivitamin preparations are in section 9.6.7.Vitamin B Tablets, Compound UTablets, nicotinamide 15 mg, riboflavin 1 mg, thiaminehydrochloride 1 mg, net price 28 = £1.00Vitamin B Tablets, Compound, Strong UTablets, brown, f/c or s/c, nicotinamide 20 mg,pyridoxine hydrochloride 2 mg, riboflavin 2 mg, thiaminehydrochloride 5 mg. Net price 28-tab pack =£2.30Vigranon B c (Wallace Mfg) DUSyrup, thiamine hydrochloride 5 mg, riboflavin 2 mg,nicotinamide 20 mg, pyridoxine hydrochloride 2 mg,panthenol 3 mg/5 mL. Net price 150 mL = £2.41DoseTreatment of deficiency. By mouthChild 1 month–1 year 5 mL 3 times dailyChild 1–12 years 10 mL 3 times dailyChild 12–18 years 10–15mL 3 times dailyProphylaxis of deficiency. By mouthChild 1 month–1 year 5 mL once dailyChild 1–12 years 5 mL twice dailyChild 12–18 years 5 mL 3 times daily9.6.3 Vitamin C(Ascorbic acid)Vitamin C therapy is essential in scurvy, but less floridmanifestations of vitamin C deficiency have beenreported. Vitamin C is used to enhance the excretionof iron one month after starting desferrioxamine therapy(section 9.1.3); it is given separately from food as it alsoenhances iron absorption. Vitamin C is also used in thetreatment of some inherited metabolic disorders, particularlymitochondrial disorders; specialist managementof these conditions is required.Severe scurvy causes gingival swelling and bleedingmargins as well as petechiae on the skin. This is, however,exceedingly rare and a child with these signs ismore likely to have leukaemia. Investigation should notbe delayed by a trial period of vitamin treatment.Claims that vitamin C ameliorates colds or promoteswound healing have not been proved.ASCORBIC ACID(Vitamin C)Cautions interactions: Appendix 1 (vitamins)Contra-indications hyperoxaluriaSide-effects nausea, diarrhoea; headache, fatigue;hyperoxaluriaLicensed use not licensed for metabolic disordersIndication and doseTreatment of scurvy. By mouthChild 1 month–4 years 125–250 mg daily in 1–2divided dosesChild 4–12 years 250–500 mg daily in 1–2divided dosesChild 12–18 years 500 mg–1 g daily in 1–2divided dosesAdjunct to desferrioxamine (see notes above). By mouthChild 1 month–18 years 100–200 mg daily 1 hourbefore food9 Nutrition and blood

482 9.6.4 Vitamin D BNFC 2011–20129 Nutrition and bloodMetabolic disorders (tyrosinaemia type III; transienttyrosinaemia of the newborn; glutathionesynthase deficiency; Hawkinsinuria). By mouthNeonate 50–200 mg daily, adjusted as necessaryChild 1 month–18 years 200–400 mg daily in 1–2divided doses, adjusted as necessary; up to 1 gdaily may be requiredAscorbic Acid (Non-proprietary)Tablets, ascorbic acid 50 mg, net price 28 = £1.79;100 mg, 28 = £1.42; 200 mg, 28 = £1.42; 500 mg (label:24), 28 = £2.34Excipients may include aspartameBrands include Redoxon c DInjection, ascorbic acid 100 mg/mL, net price 5-mLamp = £4.39Excipients include metabisulphite9.6.4 Vitamin DNote The term Vitamin D is used for a range of compoundsincluding ergocalciferol (calciferol, vitamin D 2 ), colecalciferol(vitamin D 3 ), dihydrotachysterol, alfacalcidol (1a-hydroxycholecalciferol),and calcitriol (1,25-dihydroxycholecalciferol).Asymptomatic vitamin D deficiency is common in theUnited Kingdom; symptomatic deficiency may occur incertain ethnic groups, particularly as rickets or hypocalcaemia,and rarely in association with malabsorption.The amount of vitamin D required in infancy is relatedto the stores built up in-utero and subsequent exposureto sunlight. The amount of vitamin D in breast milkvaries and some breast-fed babies, particularly if pretermor born to vitamin D deficient mothers, maybecome deficient. Most formula milk and supplementfeeds contain adequate vitamin D to prevent deficiency.Simple, nutritional vitamin D deficiency can be preventedby oral supplementation of 400 units of ergocalciferol(calciferol, vitamin D 2 ) or colecalciferol (vitaminD 3 ) daily, using multi-vitamin drops (section 9.6.7),preparations of vitamins A and D (section 9.6.1), manufactured‘special’ solutions, or as calcium and ergocalciferoltablets (although the calcium and other vitaminsin supplements are unnecessary); excessivesupplementation may cause hypercalcaemia.Inadequate bone mineralisation can be caused by adeficiency, or a lack of action of vitamin D or its activemetabolite. In childhood this causes bowing and distortionof bones (rickets). In nutritional vitamin D deficiencyrickets, initial high doses of ergocalciferol orcolecalciferol should be reduced to supplementaldoses after 8–12 weeks, as there is a significant risk ofhypercalcaemia (see caution below). However, calciumsupplements are recommended if there is hypocalcaemiaor evidence of a poor dietary calcium intake. Asingle large dose of ergocalciferol or colecalciferol canalso be effective for the treatment of nutritional vitaminD deficiency rickets.Poor bone mineralisation in neonates and young childrenmay also be due to inadequate intake of phosphateor calcium particularly during long-term parenteralnutrition—supplementation with phosphate (section9.5.2.1) or calcium (section 9.5.1.1) may be required.Hypophosphataemic rickets occurs due to abnormalphosphate excretion; treatment with high doses of oralphosphate (section 9.5.2.1), and hydroxylated (activated)forms of vitamin D allow bone mineralisationand optimise growth.Nutritional deficiency of vitamin D is best treated withcolecalciferol or ergocalciferol. Preparations containingcalcium and colecalciferol are also occasionally used inchildren where there is evidence of combined calciumand vitamin D deficiency. Vitamin D deficiency causedby intestinal malabsorption or chronic liver diseaseusually requires vitamin D in pharmacological doses,such as ergocalciferol in doses of up to 40 000 unitsdaily; the hypocalcaemia of hypoparathyroidism oftenrequires higher doses in order to achieve normocalcaemiaand alfacalcidol is generally preferred.Vitamin D supplementation is often given in combinationwith calcium supplements for persistent hypocalcaemiain neonates, and in chronic renal disease.Vitamin D requires hydroxylation, by the kidney andliver, to its active form therefore the hydroxylated derivativesalfacalcidol or calcitriol should be prescribed ifpatients with severe liver or renal impairment requirevitamin D therapy. Alfacalcidol is generally preferred inchildren as there is more experience of its use andappropriate formulations are available. Calcitriol is unlicensedfor use in children and is generally reserved forthose with severe liver disease.Important. All patients receiving pharmacologicaldoses of vitamin D or its analogues should have theirplasma-calcium concentration checked at intervals(initially once or twice weekly) and whenever nauseaor vomiting occur.ERGOCALCIFEROL(Calciferol, Vitamin D 2 )Cautions see notes above; monitor plasma-calciumconcentration in patients receiving high doses and inrenal impairment; interactions: Appendix 1 (vitamins)Contra-indications hypercalcaemia; metastatic calcificationPregnancy high doses teratogenic in animals buttherapeutic doses unlikely to be harmfulBreast-feeding caution with high doses as may causehypercalcaemia in infant—monitor serum-calciumconcentrationSide-effects symptoms of overdosage include anorexia,lassitude, nausea and vomiting, diarrhoea,constipation, weight loss, polyuria, sweating, headache,thirst, vertigo, and raised concentrations ofcalcium and phosphate in plasma and urineLicensed use Calcium and Ergocalciferol tablets notlicensed for use in children under 6 yearsIndication and doseSee also notes aboveNutritional vitamin-D deficiency rickets. By mouthChild 1–6 months 3000 units daily, adjusted asnecessaryChild 6 months–12 years 6000 units daily,adjusted as necessaryChild 12–18 years 10 000 units daily, adjusted asnecessary

BNFC 2011–2012 9.6.4 Vitamin D 483Nutritional or physiological supplement; preventionof rickets. By mouthNeonate 400 units dailyChild 1 month–18 years 400–600 units dailyVitamin D deficiency in intestinal malabsorptionor in chronic liver disease. By mouth or by intramuscular injectionChild 1–12 years 10 000–25 000 units daily,adjusted as necessaryChild 12–18 years 10 000–40 000 units daily,adjusted as necessaryPharmacological strengths(see notes above)The BP directs that when calciferol is prescribed or demanded,colecalciferol or ergocalciferol should be dispensed or suppliedErgocalciferol (Non-proprietary)Tablets, ergocalciferol 250 micrograms (10 000 units),net price 100 = £21.99; 1.25 mg (50 000 units), 100 =£30.34Note May be difficult to obtainImportant When the strength of the tablets ordered orprescribed is not clear, the intention of the prescriber orpurchaser with respect to the strength (expressed in microgramsor milligrams per tablet) should be ascertained.Injection A, ergocalciferol, 7.5 mg (300 000 units)/mL in oil, net price 1-mL amp = £8.50, 2-mL amp =£9.85Note Other formulations of ergocalciferol are available from‘special-order’ manufacturers or specialist importing companies,see p. 809Daily supplementsNote There is no plain vitamin D tablet available for treatingsimple deficiency (see notes above). Alternatives include vitaminscapsules (section 9.6.7), preparations of vitamins A and D(section 9.6.1), and calcium and ergocalciferol tablets (seebelow).For prescribing information on calcium, see section 9.5.1Calcium and Ergocalciferol (Non-proprietary)(Calcium and Vitamin D)Tablets, calcium lactate 300 mg, calcium phosphate150 mg (calcium 97 mg or Ca 2þ 2.4 mmol), ergocalciferol10 micrograms (400 units). Net price 28-tab pack= £7.10. Counselling, crush before administration ormay be chewedHypophosphataemic rickets; persistent hypocalcaemiadue to hypoparathyroidism or pseudohypoparathyroidism. By mouth or by intravenous injectionChild 1 month–12 years 25–50 nanograms/kg(max. 1 microgram) once daily, adjusted as necessaryChild 12–18 years 1 microgram once daily,adjusted as necessaryPersistent neonatal hypocalcaemia. By mouth or by intravenous injectionNeonate 50–100 nanograms/kg once daily,adjusted as necessary (up to 2 micrograms/kgdaily may be needed in resistant cases)Prevention of vitamin D deficiency in renal orcholestatic liver disease. By mouth or by intravenous injectionNeonate 20 nanograms/kg once daily, adjusted asnecessaryChild 1 month–12 years, body-weight under20 kg 15–30 nanograms/kg (max. 500 nanograms)once daily; body-weight over 20 kg 250–500 nanograms once daily, adjusted as necessaryChild 12–18 years 250–500 nanograms oncedaily, adjusted as necessaryAlfacalcidol (Non-proprietary) ACapsules, alfacalcidol 250 nanograms, net price 30-cap pack = £5.94; 500 nanograms 30-cap pack =£11.64; 1 microgram 30-cap pack = £15.91One-Alpha c (LEO) ACapsules, alfacalcidol 250 nanograms (white), netprice 30-cap pack = £3.37; 500 nanograms (red), 30-cap pack = £6.27; 1 microgram (brown), 30-cap pack= £8.75Excipients include sesame oilOral drops, sugar-free, alfacalcidol 2 micrograms/mL(1 drop contains approx. 100 nanograms), net price10 mL = £22.49Excipients include alcoholNote The concentration of alfacalcidol in One-Alpha c dropsis 10 times greater than that of the former preparation One-Alpha c solution.Injection, alfacalcidol 2 micrograms/mL, net price0.5-mL amp = £2.16, 1-mL amp = £4.11Excipients include alcohol, propylene glycol (caution in neonates, see,p. 2)Note Shake ampoule for at least 5 seconds before use9 Nutrition and bloodALFACALCIDOL(1a-Hydroxycholecalciferol)Cautions see under Ergocalciferol; also nephrolithiasisContra-indications see under ErgocalciferolPregnancy see under ErgocalciferolBreast-feeding see under ErgocalciferolSide-effects see under Ergocalciferol; also rarelynephrocalcinosis, pruritus, rash, and urticariaIndication and doseSee also notes aboveCALCITRIOL(1,25-Dihydroxycholecalciferol)Cautions see under Ergocalciferol; monitor plasmacalcium, phosphate, and creatinine during dosagetitrationContra-indications see under ErgocalciferolPregnancy see under ErgocalciferolBreast-feeding see under ErgocalciferolSide-effects see under ErgocalciferolLicensed use not licensed for use in childrenIndication and doseSee also notes above

484 9.6.4 Vitamin D BNFC 2011–20129 Nutrition and bloodVitamin D dependent rickets; hypophosphataemicrickets; persistent hypocalcaemia due tohypoparathyroidism or pseudo-hypoparathyroidism(limited experience). By mouthChild 1 month–12 years initially 15 nanograms/kg (max. 250 nanograms) once daily, increased ifnecessary in steps of 5 nanograms/kg daily (max.250 nanograms) every 2–4 weeksChild 12–18 years initially 250 nanograms oncedaily increased if necessary in steps of 5 nanograms/kgdaily (max. 250 nanograms step) every2–4 weeks; usual dose 0.5–1 microgram dailyHypocalcaemia in dialysis patients (limitedexperience). By intravenous injectionChild 12–18 years initially 250–500 nanograms(approx. 10 nanograms/kg) 3 times a week,increased if necessary in steps of 2–5 nanograms/kg every 2–4 weeks; usual dose 0.5–3 micrograms3 times a weekAdministration For administration by mouth, injectionsolution may be given orally or contents ofcapsule administered by oral syringe; capsules containapprox. 0.168 mL of fluidFor administration by intravenous injection, injectionmay be given via catheter after dialysisCalcitriol (Non-proprietary) ACapsules, calcitriol 250 nanograms, net price 30-cappack = £18.04, 100-cap pack = £19.15; 500 nanograms,30-cap pack =£32.25, 100-cap pack = £25.76Rocaltrol c (Roche) ACapsules, calcitriol 250 nanograms (red/white), netprice 100 = £18.04; 500 nanograms (red), 100 =£32.25Calcijex c (Abbott) AInjection, calcitriol 1 microgram/mL, net price 1-mLamp = £5.14; 2 micrograms/mL, 1-mL amp = £10.28COLECALCIFEROL(Cholecalciferol, vitamin D 3)Cautions see under ErgocalciferolContra-indications see under ErgocalciferolPregnancy see under ErgocalciferolBreast-feeding see under ErgocalciferolSide-effects see under ErgocalciferolLicensed use Sandocal c + D 600 not licensed foruse in children under 2 years; Adcal-D3 c ,Calceos c , and Sandocal c + D 1200 not licensedfor use in children under 12 years; Cacit c D3,Calcichew-D 3cForte, Calcichew-D 3c500 mg/400 unit, and Kalcipos-D c not licensed for use inchildren (age range not specified by manufacturers);Calfovit D3 c and Natecal D3 c not licensed for usein children under 18 yearsIndication and doseSee under Ergocalciferol and notes above—alternativeto Ergocalciferol, see also PharmacologicalStrengthsColecalciferolVarious formulations available from ‘special-order’manufacturers or specialist importing companies, seep. 809With calciumFor prescribing information on calcium, see section9.5.1Adcal-D c 3 (ProStrakan)Tablets (chewable), lemon or tutti-frutti flavour, calciumcarbonate 1.5 g (calcium 600 mg or Ca 2þ15 mmol), colecalciferol 10 micrograms (400 units),net price 56-tab pack = £3.89, 112-tab pack = £7.78.Label: 24Dissolve (effervescent tablets), lemon flavour, calciumcarbonate 1.5 g (calcium 600 mg or Ca 2þ15 mmol), colecalciferol 10 micrograms (400 units),net price 56-tab pack = £4.99. Label: 13Cacit c D3 (Warner Chilcott)Granules, effervescent, lemon flavour, calcium carbonate1.25 g (calcium 500 mg or Ca 2þ 12.5 mmol),colecalciferol 11 micrograms (440 units)/sachet, netprice 30-sachet pack = £4.06. Label: 13Calceos c (Galen)Tablets (chewable), lemon flavour, calcium carbonate1.25 g (calcium 500 mg or Ca 2þ 12.5 mmol), colecalciferol10 micrograms (400 units), net price 60-tabpack = £3.62. Label: 24Calcichew-D c 3 (Shire)Calcichew-D c3 tablets (chewable), orange flavour,calcium carbonate 1.25 g (calcium 500 mg or Ca 2þ12.5 mmol), colecalciferol 5 micrograms (200 units),net price 100-tab pack = £7.68. Label: 24Excipients include aspartame (section 9.4.1)Calcichew-D c3 Forte tablets (chewable), lemonflavour, calcium carbonate 1.25 g (calcium 500 mg orCa 2þ 12.5 mmol), colecalciferol 10 micrograms(400 units), net price 100-tab pack = £7.21. Label: 24Excipients include aspartame (section 9.4.1)Calcichew-D c3 500 mg/400 unit caplets, f/c, lemonflavour, calcium carbonate providing calcium 500 mg(Ca 2þ 12.5 mmol), colecalciferol 10 micrograms(400 units), net price 100-tab pack = £7.57Excipients include propylene glycol (see Excipients ,p. 2)Calfovit D3 c (Menarini)Powder, lemon flavour, calcium phosphate 3.1 g(calcium 1.2 g or Ca 2þ 30 mmol), colecalciferol20 micrograms (800 units), net price 30-sachet pack =£4.32. Label: 13, 21Kalcipos-D c (Meda) ATablets (chewable), calcium carbonate providingcalcium 500 mg (Ca 2þ 12.5 mmol), colecalciferol20 micrograms (800 units), net price 30-tab pack =£4.21. Label: 24Natecal D3 c (Chiesi)Tablets (chewable), (aniseed, peppermint, andmolasses flavour), calcium carbonate 1.5 g (calcium600 mg or Ca 2þ 15 mmol), colecalciferol 10 micrograms(400 units), net price 60-tab pack = £3.63.Label: 24Excipients include aspartame (section 9.4.1)Sandocal c +D (Novartis Consumer Health)Sandocal c +D 600 tablets, effervescent, orangeflavour, calcium lactate gluconate 1.36 g, calciumcarbonate 1.05 g, providing calcium 600 mg (Ca 2þ

BNFC 2011–2012 9.6.5 Vitamin E 48515 mmol), colecalciferol concentrate 4 mg, providingcolecalciferol 10 micrograms (400 units), net price 60-tab pack = £5.35, 100-tab pack = £8.75. Label: 13Excipients include aspartame (section 9.4.1)Sandocal c +D 1200 tablets, effervescent, orangeflavour, calcium lactate gluconate 2.72 g, calciumcarbonate 2.1 g, providing calcium 1200 mg (Ca 2þ30 mmol), colecalciferol concentrate 8 mg, providingcolecalciferol 20 micrograms (800 units), net price 30-tab pack = £4.32. Label: 13Excipients include aspartame (section 9.4.1)Extemporaneous formulations available seeExtemporaneous Preparations, p. 69.6.5 Vitamin E(Tocopherols)The daily requirement of vitamin E has not been welldefined. Vitamin E supplements are given to childrenwith fat malabsorption such as in cystic fibrosis andcholestatic liver disease. In children with abetalipoproteinaemiaabnormally low vitamin E concentrationsmay occur in association with neuromuscular problems;this usually responds to high doses of vitamin E. Someneonatal units still administer a single intramusculardose of vitamin E at birth to preterm neonates to reducethe risk of complications; no trials of long-term outcomehave been carried out. The intramuscular route shouldalso be considered in children with severe liver diseasewhen response to oral therapy is inadequate.Vitamin E has been tried for various other conditionsbut there is little scientific evidence of its value.ALPHA TOCOPHERYL ACETATECautions predisposition to thrombosis; increased riskof necrotising enterocolitis in preterm neonates (seeadministration); interactions: Appendix 1 (vitamins)Pregnancy no evidence of safety of high dosesBreast-feeding excreted in milk, minimal riskalthough caution with large dosesSide-effects diarrhoea and abdominal pain, particularlywith high dosesIndication and doseVitamin E deficiency. By mouthNeonate 10 mg/kg once dailyChild 1 month–18 years 2–10 mg/kg daily, up to20 mg/kg has been usedMalabsorption in cystic fibrosis. By mouth (with food and pancreatic enzymes)Child 1 month–1 year 50 mg once daily, adjustedas necessaryChild 1–12 years 100 mg once daily, adjusted asnecessaryChild 12–18 years 100–200 mg once daily,adjusted as necessaryVitamin E deficiency in cholestasis and severeliver disease. By mouthNeonate 10 mg/kg dailyChild 1 month–12 years initially 100 mg daily,adjusted according to response; up to 200 mg/kgdaily may be requiredChild 12–18 years initially 200 mg daily, adjustedaccording to response; up to 200 mg/kg daily maybe required. By intramuscular injectionNeonate 10 mg/kg once a monthChild 1 month–18 years 10 mg/kg (max. 100 mg)once a monthMalabsorption in abetalipoproteinaemia. By mouthNeonate 100 mg/kg once dailyChild 1 month–18 years 50–100 mg/kg oncedailyVitamin E Suspension (Non-proprietary)Suspension, alpha tocopheryl acetate 100 mg/mL.Net price 100 mL = £30.35Excipients include sucroseAdministration consider dilution in neonates due to highosmolality (see Cautions)Note Tablets containing tocopheryl acetate are available from‘special-order’ manufacturers or specialist importing companies,see p. 809Vitamin E InjectionInjection tocopheryl acetate 50 mg/mL, 2-mLampouleAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809ALPHA TOCOPHEROLCautions predisposition to thrombosis; interactions:Appendix 1 (vitamins)Contra-indications preterm neonatesHepatic impairment manufacturer advises cautionand monitor closely—no information availableRenal impairment manufacturer advises caution andmonitor closely; risk of renal toxicity due to polyethyleneglycol contentPregnancy manufacturer advises caution; no evidenceof harm in animal studiesBreast-feeding manufacturer advises use only ifpotential benefit outweighs risk—no informationavailableSide-effects diarrhoea; less commonly asthenia,headache, pruritus, disturbances in serum-potassiumand serum-sodium concentrations, alopecia, and rashVedrop c (Orphan Europe) TAOral solution, yellow, D-alpha tocopherol (as tocofersolan)50 mg/mL, net price 20 mL = £54.55, 60 mL= £163.65 (all with oral syringe)Note Tocofersolan is a water-soluble form of D-alpha tocopherolDoseVitamin E deficiency because of malabsorption incongenital or hereditary chronic cholestasis. By mouthNeonate 17 mg/kg daily, adjusted as necessaryChild 1 month–18 years 17 mg/kg daily, adjusted asnecessary9 Nutrition and blood

486 9.6.6 Vitamin K BNFC 2011–20129 Nutrition and blood9.6.6 Vitamin KVitamin K is necessary for the production of bloodclotting factors and proteins necessary for the normalcalcification of bone.Because vitamin K is fat soluble, children with fat malabsorption,especially in biliary obstruction or hepaticdisease, may become deficient. For oral administrationto prevent vitamin K deficiency in malabsorption syndromes,a water-soluble synthetic vitamin K derivative,menadiol sodium phosphate (see Contra-indicationsbelow) can be used if supplementation with phytomenadioneby mouth has been insufficient.Oral coumarin anticoagulants act by interfering withvitamin K metabolism in the hepatic cells and theireffects can be antagonised by giving vitamin K; foradvice on the use of vitamin K in haemorrhage, seesection 2.8.2.Vitamin K deficiency bleeding Neonates are relativelydeficient in vitamin K and those who do notreceive supplements are at risk of serious bleeding,including intracranial bleeding. The Chief Medical Officerand the Chief Nursing Officer have recommendedthat all newborn babies should receive vitamin K toprevent vitamin K deficiency bleeding (previouslytermed haemorrhagic disease of the newborn). Localprotocols may vary and an appropriate regimen shouldbe selected after discussion with parents in the antenatalperiod.Vitamin K (as phytomenadione) 1 mg may be given by asingle intramuscular injection at birth; this preventsvitamin K deficiency bleeding in virtually all babies;preterm neonates may be given 400 micrograms/kg(max. 1 mg). The intravenous route may be used inpreterm neonates of very low birth-weight if intramuscularinjection is not possible; however, it may notprovide the prolonged protection of the intramuscularinjection; any babies receiving intravenous vitamin Kshould be given subsequent oral doses.Alternatively, in healthy babies who are not at particularrisk of bleeding disorders, vitamin K may be given bymouth, and arrangements must be in place to ensure theappropriate regimen is followed. Two doses of a colloidal(mixed micelle) preparation of phytomenadione2 mg should be given in the first week, the first dosebeing given at birth and the second at 4–7 days. Forexclusively breast-fed babies, a third dose of phytomenadione2 mg is given at 1 month of age; the thirddose is omitted in formula-fed babies because formulafeeds contain adequate vitamin K. An alternative regimenis to give one dose of phytomenadione 1 mg bymouth at birth (using the contents of a phytomenadionecapsule, see preparation below) to protect from the riskof vitamin K deficiency bleeding in the first week; forexclusively breast-fed babies, further doses of phytomenadione1 mg are given by mouth (using the contentsof a phytomenadione capsule) at weekly intervals for 12weeks.For the treatment of vitamin K deficiency bleeding,intravenous phytomenadione is used, see Phytomenadionebelow.MENADIOL SODIUM PHOSPHATECautions G6PD deficiency (section 9.1.5) and vitaminE deficiency (risk of haemolysis); interactions:Appendix 1 (vitamins)Contra-indications neonates and infantsPregnancy avoid in late pregnancy and labour unlessbenefit outweighs risk of neonatal haemolytic anaemia,hyperbilirubinaemia, and kernicterus in neonateIndication and doseSee notes aboveSupplementation in vitamin K malabsorption. By mouthChild 1–12 years 5–10 mg daily, adjusted asnecessaryChild 12–18 years 10–20 mg daily, adjusted asnecessaryMenadiol Phosphate (Non-proprietary)Tablets, menadiol sodium phosphate equivalent to10 mg of menadiol phosphate, net price 100-tab pack= £58.39Extemporaneous formulations available seeExtemporaneous Preparations, p. 6PHYTOMENADIONE(Vitamin K 1 )Cautions intravenous injections should be given veryslowly—risk of vascular collapse (see also below);interactions: Appendix 1 (vitamins)Pregnancy use if potential benefit outweighs riskBreast-feeding present in milk, but see notes aboveIndication and doseNeonatal prophylaxis of vitamin-K deficiencybleeding see notes aboveNeonatal hypoprothrombinaemia or vitamin-Kdeficiency bleeding. By intravenous injectionNeonate 1 mg repeated 8 hourly if necessaryNeonatal biliary atresia and liver disease. By mouthNeonate 1 mg dailyReversal of coumarin anticoagulation whencontinued anticoagulation required or if nosignificant bleeding (see also section 2.8.2)—seekspecialist advice. By intravenous injectionChild 1 month–18 years 15–30 micrograms/kg(max. 1 mg) as a single dose, repeated as necessaryReversal of coumarin anticoagulation whenanticoagulation not required or if significantbleeding; treatment of haemorrhage associatedwith vitamin-K deficiency (see also section2.8.2)—seek specialist advice. By intravenous injectionChild 1 month–18 years 250–300 micrograms/kg (max. 10 mg) as a single dose

BNFC 2011–2012 9.6.7 Multivitamin preparations 487Neokay c (Neoceuticals) ACapsules, brown, phytomenadione 1 mg in an oilybasis, net price 12-cap pack = £3.95; 100-cap pack =£34.00Note The contents of one capsule should be administered bycutting the narrow tubular tip off and squeezing the liquidcontents into the mouth; if the baby spits out the dose or issick within three hours of administration a replacement doseshould be givenDoseNeonatal prophylaxis of vitamin-K deficiency bleedingsee notes aboveColloidal formulationKonakion c MM (Roche) AInjection, phytomenadione 10 mg/mL in a mixedmicelles vehicle. Net price 1-mL amp = 38pExcipients include glycocholic acid 54.6 mg/amp, lecithinCautions reduce dose in liver impairment (glycocholic acid maydisplace bilirubin); reports of anaphylactoid reactionsAdministration Konakion c MM may be administered by slowintravenous injection or by intravenous infusion in glucose 5%;not for intramuscular injectionKonakion c MM Paediatric (Roche) TAInjection, phytomenadione 10 mg/mL in a mixedmicelles vehicle, net price 0.2-mL amp = 95pExcipients include glycocholic acid 10.9 mg/amp, lecithinCautions parenteral administration in premature infants bodyweightless than 2.5 kg (increased risk of kernicterus)Administration Konakion c MM Paediatric may be administeredby mouth or by intramuscular injection or by intravenousinjection. For intravenous injection, may be diluted with Glucose5% if necessary9.6.7 MultivitaminpreparationsMultivitamin supplements are used in children withvitamin deficiencies and also in malabsorption conditionssuch as cystic fibrosis or liver disease. To avoidpotential toxicity, the content of all vitamin preparations,particularly vitamin A, should be considered whenused together with other supplements. Supplementationis not required if nutrient enriched feeds are used;consult a dietician for further advice.MULTIVITAMIN PREPARATIONSCautions see individual vitamins; vitamin A concentrationof preparations variesContra-indications see individual vitaminsSide-effects see individual vitaminsLicensed use Dalivit c not licensed for use inchildren under 6 weeksIndication and doseSee under preparations belowVitaminsCapsules, ascorbic acid 15 mg, nicotinamide 7.5 mg,riboflavin 500 micrograms, thiamine hydrochloride1 mg, vitamin A 2500 units, vitamin D 300 units, netprice 28-cap pack = £1.50DosePrevention of deficiency. By mouthChild 1–12 years 1 capsule dailyChild 12–18 years 2 capsules dailyCystic fibrosis: prevention of deficiency. By mouthChild 1–18 years 2–3 capsules dailyAbidec c (Chefaro UK)Drops, vitamins A, B group, C, and D. Net price 25 mL(with dropper) = £2.20Note Contains 1333 units of vitamin A (as palmitate) per 0.6 mLdoseExcipients include arachis (peanut) oil and sucroseDosePrevention of deficiency. By mouthPreterm neonate 0.6 mL dailyNeonate 0.3 mL dailyChild 1 month–1 year 0.3 mL dailyChild 1–18 years 0.6 mL dailyCystic fibrosis: prevention of deficiency. By mouthChild 1 month–1 year 0.6 mL dailyChild 1–18 years 1.2 mL dailyDalivit c (LPC)Oral drops, vitamins A, B group, C, and D, net price25 mL = £2.98, 50 mL = £4.85Note Contains 5000 units of vitamin A (as palmitate) per 0.6 mLdoseExcipients include sucroseDosePrevention of deficiency. By mouthNeonate (including preterm) 0.3 mL dailyChild 1 month–1 year 0.3 mL dailyChild 1–18 years 0.6 mL dailyCystic fibrosis: prevention of deficiency. By mouthChild 1 month–1 year 0.6 mL dailyChild 1–18 years 1 mL dailyVitamin and mineral supplements andadjuncts to synthetic dietsForceval c (Alliance)Capsules, brown/red, vitamins (ascorbic acid 60 mg,biotin 100 micrograms, cyanocobalamin 3 micrograms,folic acid 400 micrograms, nicotinamide18 mg, pantothenic acid 4 mg, pyridoxine 2 mg, riboflavin1.6 mg, thiamine 1.2 mg, vitamin A 2500 units,vitamin D 2400 units, vitamin E 10 mg, minerals andtrace elements (calcium 100 mg, chromium200 micrograms, copper 2 mg, iodine 140 micrograms,iron 12 mg, magnesium 30 mg, manganese3 mg, molybdenum 250 micrograms, phosphorus77 mg, potassium 4 mg, selenium 50 micrograms, zinc15 mg), net price 15-cap pack = £2.83, 30-cap pack =£5.19, 90-cap pack = £12.53. Label: 25DoseVitamin and mineral deficiency and as adjunct insynthetic dietsChild 12–18 years 1 capsule daily one hour after a mealJunior capsules, brown, vitamins (ascorbic acid25 mg, biotin 50 micrograms, cyanocobalamin9 Nutrition and blood

488 9.8 Metabolic disorders BNFC 2011–20129 Nutrition and blood2 micrograms, folic acid 100 micrograms, nicotinamide7.5 mg, pantothenic acid 2 mg, pyridoxine1 mg, riboflavin 1 mg, thiamine 1.5 mg, vitamin A1250 units, vitamin D 2 200 units, vitamin E 5 mg, vitaminK 1 25 micrograms), minerals and trace elements(chromium 50 micrograms, copper 1 mg, iodine75 micrograms, iron 5 mg, magnesium 1 mg, manganese1.25 mg, molybdenum 50 micrograms, selenium25 micrograms, zinc 5 mg), net price 30-cap pack =£3.52, 60-cap pack = £6.69DoseVitamin and mineral deficiency and as adjunct insynthetic dietsChild 5–12 years 2 junior capsules dailyKetovite c (Paines & Byrne)Tablets A, yellow, ascorbic acid 16.6 mg, riboflavin1 mg, thiamine hydrochloride 1 mg, pyridoxinehydrochloride 330 micrograms, nicotinamide 3.3 mg,calcium pantothenate 1.16 mg, alpha tocopherylacetate 5 mg, inositol 50 mg, biotin 170 micrograms,folic acid 250 micrograms, acetomenaphthone500 micrograms, net price 100-tab pack = £4.17DosePrevention of vitamin deficiency in disorders ofcarbohydrate or amino-acid metabolism and adjunctin restricted, specialised, or synthetic dietsChild 1 month—18 years 1 tablet 3 times daily; doseadjusted according to condition, diet, or age; use withKetovite c Liquid for complete vitamin supplementationAdministration may be crushed immediately before useLiquid, pink, sugar-free, vitamin A 2500 units, ergocalciferol400 units, choline chloride 150 mg, cyanocobalamin12.5 micrograms/5 mL, net price 150-mLpack = £2.70DosePrevention of vitamin deficiency in disorders ofcarbohydrate or amino-acid metabolism and adjunctin restricted, specialised, or synthetic dietsChild 1 month—18 years 5 mL daily; dose adjustedaccording to condition, diet, or age; use with Ketovite cTablets for complete vitamin supplementationAdministration may be mixed with milk, cereal, or fruit juice9.8.1 Drugs used in metabolicdisordersMetabolic disorders should be managed under the guidanceof a specialist. As many preparations are unlicensedand may be difficult to obtain, arrangements forcontinued prescribing and supply should be made inprimary care.General advice on the use of medicines in metabolicdisorders can be obtained from:Alder Hey Children’s HospitalMedicines Information CentreTel: (0151) 252 5381andGreat Ormond Street Hospital for ChildrenPharmacyTel: (020) 7405 9200Wilson’s diseasePenicillamine is used in Wilson’s disease (hepatolenticulardegeneration) to aid the elimination of copperions; it is also used for cystinuria. Children who arehypersensitive to penicillin may react rarely to penicillamine.Trientine is used for the treatment of Wilson’s diseaseonly, in patients intolerant of penicillamine; it is not analternative to penicillamine in other diseases such ascystinuria. Penicillamine-induced systemic lupuserythematosus may not resolve on transfer to trientine.Zinc prevents the absorption of copper in Wilson’sdisease. Symptomatic patients should be treated initiallywith a chelating agent because zinc has a slow onset ofaction. When transferring from chelating treatment tozinc maintenance therapy, chelating treatment shouldbe co-administered for 2–3 weeks until zinc produces itsmaximal effect.9.7 Bitters and tonicsClassification not included in BNF for Children.9.8 Metabolic disorders9.8.1 Drugs used in metabolic disorders9.8.2 Acute porphyriasThis section covers drugs used in metabolic disordersand not readily classified elsewhere.PENICILLAMINECautions concomitant nephrotoxic drugs (increasedrisk of toxicity); monitor urine for proteinuria; monitorblood and platelet count regularly (see below); neurologicalinvolvement in Wilson’s disease; interactions:Appendix 1 (penicillamine)Blood counts and urine tests Consider withdrawal if plateletcount falls below 120 000/mm 3 or white blood cellsbelow 2500/mm 3 or if 3 successive falls within referencerange (can restart at reduced dose when counts return towithin reference range but permanent withdrawal necessaryif recurrence of leucopenia or thrombocytopenia)Counselling Warn child and carer to tell doctor immediatelyif sore throat, fever, infection, non-specific illness, unexplainedbleeding and bruising, purpura, mouth ulcers, orrashes developContra-indications lupus erythematosusRenal impairment reduce dose and monitor renalfunction or avoid—consult product literaturePregnancy fetal abnormalities reported rarely; avoid ifpossibleBreast-feeding manufacturer advises avoid unlesspotential benefit outweighs risk—no informationavailable

BNFC 2011–2012 9.8.1 Drugs used in metabolic disorders 489Side-effects initially nausea, anorexia, fever, and skinreactions; taste loss (mineral supplements notrecommended); blood disorders including thrombocytopenia,leucopenia, agranulocytosis and aplasticanaemia; proteinuria, rarely haematuria (withdrawimmediately and seek specialist advice); haemolyticanaemia, pancreatitis, cholestatic jaundice, nephroticsyndrome, lupus erythematosus-like syndrome,myasthenia gravis-like syndrome, neuropathy (especiallyif neurological involvement in Wilson’s disease—prophylacticpyridoxine recommended, seesection 9.6.2, polymyositis (rarely with cardiac involvement),dermatomyositis, mouth ulcers, stomatitis,alopecia, bronchiolitis and pneumonitis, pemphigus,Goodpasture’s syndrome, and Stevens-Johnsonsyndrome also reported; male and female breastenlargement reported; in non-rheumatoid conditionsrheumatoid arthritis-like syndrome also reported; laterashes (consider withdrawing treatment)Indication and doseWilson’s disease. By mouthChild 1 month–12 years 2.5 mg/kg twice dailybefore food, increased at 1–2 week intervals to10 mg/kg twice dailyChild 12–18 years 0.75–1 g twice daily beforefood, max. 2 g daily for 1 year; usual maintenancedose 0.75–1 g dailyCystinuria. By mouthChild 1 month–12 years 5–10 mg/kg twice dailybefore food, adjusted to maintain urinary cystinebelow 200 mg/litre; maintain adequate fluid intakeChild 12–18 years 0.5–1.5 g twice daily beforefood, adjusted to maintain urinary cystine below200 mg/litre; maintain adequate fluid intakePenicillamine (Non-proprietary) ATablets, penicillamine 125 mg, net price 56-tab pack= £16.66; 250 mg, 56-tab pack = £25.00. Label: 6, 22,counselling, blood disorder symptoms (see above)Distamine c (Alliance) ATablets, all f/c, penicillamine 125 mg, net price 100 =£10.34; 250 mg, 100 = £17.78. Label: 6, 22, counselling,blood disorder symptoms (see above)TRIENTINE DIHYDROCHLORIDECautions see notes above; interactions: Appendix 1(trientine)Pregnancy teratogenic in animal studies—use only ifbenefit outweighs risk; monitor maternal and neonatalserum-copper concentrationsSide-effects nausea, rash; very rarely anaemia; duodenitisand colitis also reportedIndication and doseWilson’s disease in patients intolerant ofpenicillamine. By mouthChild 2–12 years 0.6–1.5 g daily in 2–4 divideddoses before food, adjusted according to response;reduce dose and increase frequency if nausea is aproblemChild 12–18 years 1.2–2.4 g daily in 2–4 divideddoses before food, adjusted according to response;reduce dose and increase frequency if nausea is aproblemTrientine Dihydrochloride (Univar) ACapsules, trientine dihydrochloride 300 mg. Label: 6,22ZINC ACETATECautions portal hypertension (risk of hepatic decompensationwhen switching from chelating agent);monitor full blood count and serum cholesterol;interactions: Appendix 1 (zinc)Pregnancy usual dose 25 mg 3 times daily adjustedaccording to plasma-copper concentration andurinary copper excretionBreast-feeding manufacturer advises avoid; presentin milk—may cause zinc-induced copper deficiency ininfantSide-effects gastric irritation (usually transient; maybe reduced if first dose taken mid-morning or with alittle protein); less commonly sideroblastic anaemiaand leucopeniaIndication and doseWilson’s diseaseNote dose expressed as elemental zinc. By mouthChild 1–6 years 25 mg twice dailyChild 6–16 years body-weight under 57 kg, 25 mg3 times daily; body-weight 57 kg or over, 50 mg 3times dailyChild 16–18 years 50 mg 3 times dailyWilzin c (Orphan Europe) ACapsules, zinc (as acetate) 25 mg (blue), net price250-cap pack = £132.00; 50 mg (orange), 250-cappack = £242.00. Label: 23Administration capsules may be opened and the contents mixedwith waterCarnitine deficiencyCarnitine is available for the management of primarycarnitine deficiency due to inborn errors of metabolism,or of secondary deficiency in haemodialysis patients.Carnitine is also used in the treatment of some organicacidaemias; however, use in fatty acid oxidation iscontroversial.CARNITINECautions diabetes mellitus; monitoring of free andacyl carnitine in blood and urine recommendedRenal impairment accumulation of metabolites mayoccur with chronic oral administration in severeimpairmentPregnancy appropriate to use; no evidence of teratogenicityin animal studiesSide-effects nausea, vomiting, abdominal pain, diarrhoea,fishy body odour; side-effects may be doserelated—monitortolerance during first week and afterany dose increase9 Nutrition and blood

490 9.8.1 Drugs used in metabolic disorders BNFC 2011–20129 Nutrition and bloodLicensed use not licensed for use by intravenousinfusion; tablets, chewable tablets, and oral liquid(10%) not licensed in children under 12 years;paediatric oral solution (30%) not licensed in childrenover 12 years; not licensed for use in organicacidaemiasIndication and dosePrimary deficiency and organic acidaemias. By mouthNeonate 50 mg/kg twice daily, higher doses up to200 mg/kg daily occasionally requiredChild 1 month–18 years 50 mg/kg twice daily,higher doses up to 200 mg/kg daily occasionallyrequired; usual max. 3 g daily. By intravenous infusionNeonate initially 100 mg/kg over 30 minutes followedby a continuous infusion of 4 mg/kg/hourChild 1 month–18 years initially 100 mg/kg over30 minutes followed by a continuous infusion of4 mg/kg/hour. By slow intravenous injection over 2–3 minutesNeonate up to 100 mg/kg/daily in 2–4 divideddosesChild 1 month–18 years up to 100 mg/kg/dailyin 2–4 divided dosesSecondary deficiency in dialysis patients. By slow intravenous injection over 2–3 minutesChild 1 month–18 years 20 mg/kg after eachdialysis session, adjusted according to plasmacarnitineconcentration. By mouth(maintenance therapy if benefit gained from firstintravenous course)Child 1 month–18 years 1 g dailyAdministration for intravenous infusion, dilute injectionwith Sodium Chloride 0.9% or Glucose 5% or 10%.Carnitor c (Sigma-Tau) ATablets, L-carnitine 330 mg, net price 90-tab pack =£103.95Chewable tablets, L-carnitine 1 g, net price 10-tabpack = £35.00Oral liquid, L-carnitine 100 mg/mL (10%), net price10 10-mL (1-g) single-dose bottle = £35.00Paediatric oral solution, L-carnitine 300 mg/mL(30%), net price 20 mL = £21.00Injection, L-carnitine 200 mg/mL, net price 5-mLamp = £11.90Fabry’s diseaseAgalsidase alfa and agalsidase beta, enzymes producedby recombinant DNA technology, are licensedfor long-term enzyme replacement therapy in Fabry’sdisease (a lysosomal storage disorder caused by deficiencyof alpha-galactosidase A).AGALSIDASE ALFA and BETACautions interactions: Appendix 1 (agalsidase alfaand beta)Infusion-related reactions Infusion-related reactions verycommon; manage by slowing the infusion rate or interruptingthe infusion, or minimise by pre-treatment with an antihistamine,antipyretic, or corticosteroid—consult productliteraturePregnancy use with cautionBreast-feeding use with caution—no informationavailableSide-effects gastro-intestinal disturbances, taste disturbances;tachycardia, bradycardia, palpitation,hypertension, hypotension, chest pain, oedema,flushing; dyspnoea, cough, rhinorrhoea; headache,fatigue, dizziness, asthenia, paraesthesia, syncope,neuropathic pain, tremor, sleep disturbances; influenza-likesymptoms, nasopharyngitis; muscle spasms,myalgia, arthralgia; eye irritation; tinnitus; hypersensitivityreactions, angioedema, pruritus, urticaria,rash, acne; less commonly cold extremities, parosmia,ear pain and swelling, skin discoloration, and injection-sitereactionsIndication and doseFabry’s disease (specialist use only)see under preparationsFabrazyme c (Genzyme) AIntravenous infusion, powder for reconstitution,agalsidase beta, net price 5-mg vial = £315.08; 35-mgvial = £2196.59DoseFabry’s disease (specialist use only). By intravenous infusionChild 8–18 years 1 mg/kg every 2 weeksAdministration for intravenous infusion, reconstitute initiallywith Water for Injections (5 mg in 1.1 mL, 35 mg in 7.2 mL) toproduce a solution containing 5 mg/mL; dilute with SodiumChloride 0.9% (for doses less than 35 mg dilute with at least50 mL; doses 35–70 mg dilute with at least 100 mL; doses 70–100 mg dilute with at least 250 mL; doses greater than 100 mgdilute with 500 mL) and give through an in-line low proteinbinding0.2 micron filter at an initial rate of no more than 15 mg/hour; for subsequent infusions, infusion rate may be increasedgradually once tolerance has been establishedReplagal c (Shire HGT) AConcentrate for intravenous infusion, agalsidasealfa 1 mg/mL, net price 1-mL vial = £356.85; 3.5-mLvial = £1068.64DoseFabry’s disease (specialist use only). By intravenous infusionChild 7–18 years 200 micrograms/kg every 2 weeksAdministration for intravenous infusion, dilute requisite dosewith 100 mL Sodium Chloride 0.9% and give over 40 minutesusing an in-line filter; use within 3 hours of dilutionGaucher’s diseaseImiglucerase, an enzyme produced by recombinantDNA technology, is administered as enzyme replacementtherapy in Gaucher’s disease, a familial disorderaffecting principally the liver, spleen, bone marrow, andlymph nodes.Velaglucerase alfa, an enzyme produced by recombinantDNA technology, is administered as enzyme replacementtherapy for the treatment of type I Gaucher’sdisease.

BNFC 2011–2012 9.8.1 Drugs used in metabolic disorders 491Miglustat, an inhibitor of glucosylceramide synthase, islicensed in adults for the treatment of mild to moderatetype I Gaucher’s disease in patients for whom imigluceraseis unsuitable; it is given by mouth.IMIGLUCERASECautions monitor for imiglucerase antibodies; whenstabilised, monitor all parameters and response totreatment at intervals of 6–12 monthsPregnancy manufacturer advises use with caution—limited information availableBreast-feeding no information availableSide-effects hypersensitivity reactions (includingurticaria, angioedema, cyanosis, hypotension, flushing,tachycardia, paraesthesia, backache); less commonlynausea, vomiting, diarrhoea, abdominalcramps, fatigue, headache, dizziness, fever, arthralgia,injection-site reactionsIndication and doseGaucher’s disease type I (specialist use only). By intravenous infusionNeonate initially 60 units/kg once every 2 weeks,adjusted according to response; doses as low as30 units/kg once every 2 weeks may be appropriateChild 1 month–18 years initially 60 units/kgonce every 2 weeks, adjusted according toresponse; doses as low as 30 units/kg once every 2weeks may be appropriateGaucher’s disease type III (specialist use only). By intravenous infusionNeonate 60–120 units/kg once every 2 weeks,adjusted according to responseChild 1 month–18 years 60–120 units/kg onceevery 2 weeks, adjusted according to responseAdministration For intravenous infusion, initiallyreconstitute with Water for Injections (200 units in5.1 mL, 400 units in 10.2 mL) to a concentration of40 units/mL; dilute requisite dose with SodiumChloride 0.9% to a final volume of 100–200 mL; giveinitial dose at a rate not exceeding 0.5 units/kg/minute, subsequent doses to be given at a rate notexceeding 1 unit/kg/minute; administer within 3hours of reconstitutionCerezyme c (Genzyme) AIntravenous infusion, powder for reconstitution,imiglucerase, net price 200-unit vial = £535.65; 400-unit vial = £1071.29Electrolytes Na + 0.62 mmol/200-unit vial, 1.24 mmol/400-unit vialVELAGLUCERASE ALFACautions monitor immunoglobulin G (IgG) antibodyconcentration in severe infusion-related reactions or ifthere is a lack or loss of effect with velaglucerase alfaInfusion-related reactions Infusion-related reactions verycommon; manage by slowing the infusion rate, or interruptingthe infusion, or minimise by pre-treatment with anantihistamine, antipyretic, or corticosteroid—consult productliteraturePregnancy manufacturer advises use with caution—limited information availableBreast-feeding manufacturer advises use with caution—noinformation availableSide-effects nausea, abdominal pain, tachycardia,hypertension, hypotension, flushing, headache, dizziness,malaise, pyrexia, arthralgia, bone pain, backpain, hypersensitivity reactions, rash, urticariaIndication and doseGaucher’s disease type I (specialist use only). By intravenous infusionChild 4–18 years 60 units/kg once every 2weeks; adjusted according to response to 15–60 units/kg once every 2 weeksAdministration for intravenous infusion, reconstituteeach 400-unit vial with 4.3 mL water for injections;dilute requisite dose in 100 mL Sodium Chloride 0.9%and give over 60 minutes through a 0.22 micron filter;start infusion within 24 hours of reconstitutionVPRIV c (Shire HGT) TAIntravenous infusion, powder for reconstitution,velaglucerase alfa, net price 400-unit vial = £1410.20Electrolytes Na + 0.53 mmol/400-unit vialMucopolysaccharidosisLaronidase, an enzyme produced by recombinant DNAtechnology, is licensed for long-term replacement therapyin the treatment of non-neurological manifestationsof mucopolysaccharidosis I, a lysosomal storage disordercaused by deficiency of alpha-L-iduronidase.Idursulfase, an enzyme produced by recombinant DNAtechnology, is licensed for long-term replacement therapyin mucopolysaccharidosis II (Hunter syndrome), alysosomal storage disorder caused by deficiency ofiduronate-2-sulfatase.Galsulfase, a recombinant form of human N-acetylgalactosamine-4-sulfatase,is licensed for long-term replacementtherapy in mucopolysaccharidosis VI (Maroteaux-Lamysyndrome).Infusion-related reactions Infusion-related reactionsoften occur with administration of laronidase,idursulfase, and galsulfase; they can be managed byslowing the infusion rate or interrupting the infusion,and can be minimised by pre-treatment with an antihistamineand an antipyretic. Recurrent infusion-relatedreactions may require pre-treatment with a corticosteroid—consultproduct literature for details.GALSULFASECautions respiratory disease; acute febrile or respiratoryillness (consider delaying treatment)Infusion-related reactions See notes abovePregnancy manufacturer advises avoid unless essentialBreast-feeding manufacturer advises avoid—noinformation availableSide-effects abdominal pain, umbilical hernia, gastroenteritis;chest pain, hypertension; dyspnoea,apnoea, nasal congestion; rigors, malaise, areflexia;pharyngitis; conjunctivitis, corneal opacity; ear pain;facial oedema9 Nutrition and blood

492 9.8.1 Drugs used in metabolic disorders BNFC 2011–2012Indication and doseMucopolysaccharidosis VI (specialist use only). By intravenous infusionChild 5–18 years 1 mg/kg once weeklyAdministration for intravenous infusion, dilute requisitedose with Sodium Chloride 0.9% to a final volumeof 250 mL and mix gently; infuse through a 0.2 micronin-line filter; give approx. 2.5% of the total volumeover 1 hour, then infuse remaining volume over next 3hours; if body-weight under 20 kg and at risk of fluidoverload, dilute requisite dose in 100 mL SodiumChloride 0.9% and give over at least 4 hoursNaglazyme c (BioMarin) TAConcentrate for intravenous infusion, galsulfase1 mg/mL, net price 5-mL vial = £982.00Indication and doseNon-neurological manifestations of mucopolysaccharidosisI (specialist use only). By intravenous infusionChild 1 month–18 years 100 units/kg onceweeklyAdministration for intravenous infusion, dilute withSodium Chloride 0.9%; body-weight under 20 kg,dilute to 100 mL, body-weight over 20 kg dilute to250 mL; give through in-line filter (0.22 micron) initiallyat a rate of 2 units/kg/hour then increase graduallyevery 15 minutes to max. 43 units/kg/hourAldurazyme (Genzyme) AConcentrate for intravenous infusion, laronidase100 units/mL, net price 5-mL vial = £444.70Electrolytes Na + 1.29 mmol /5-mL vial9 Nutrition and bloodIDURSULFASECautions severe respiratory disease; acute febrilerespiratory illness (consider delaying treatment)Infusion-related reactions See notes aboveContra-indications women of child-bearing potentialPregnancy manufacturer advises avoidBreast-feeding manufacturer advises avoid—presentin milk in animal studiesSide-effects gastro-intestinal disturbances, swollentongue; arrhythmia, tachycardia, chest pain, cyanosis,peripheral oedema, hypertension, hypotension,flushing; bronchospasm, hypoxia, cough, wheezing,tachypnoea, dyspnoea; headache, dizziness, tremor;pyrexia; arthralgia; facial oedema, urticaria, pruritus,rash, infusion-site swelling, erythema; pulmonaryembolism and anaphylaxis also reportedIndication and doseMucopolysaccharidosis II (specialist use only). By intravenous infusionChild 5–18 years 500 micrograms/kg onceweeklyAdministration for intravenous infusion, dilute requisitedose in 100 mL Sodium Chloride 0.9% and mixgently (do not shake); give over 3 hours (graduallyreduced to 1 hour if no infusion-related reactions)Elaprase c (Shire HGT) TAConcentrate for intravenous infusion, idursulfase2 mg/mL, net price 3-mL vial = £1985.00LARONIDASECautions monitor immunoglobulin G (IgG) antibodyconcentration; interactions: Appendix 1 (laronidase)Infusion-related reactions See notes abovePregnancy manufacturer advises avoid unless essential—noinformation availableBreast-feeding manufacturer advises avoid—noinformation availableSide-effects nausea, vomiting, diarrhoea, abdominalpain; cold extremities, pallor, flushing, tachycardia,blood pressure changes; dyspnoea, cough, angioedema,anaphylaxis; headache, paraesthesia, dizziness,fatigue, restlessness; influenza-like symptoms;musculoskeletal pain, pain in extremities; rash, pruritus,urticaria, alopecia, infusion-site reactions;bronchospasm and respiratory arrest also reportedNephropathic cystinosisMercaptamine is available for the treatment of nephropathiccystinosis. The oral dose is increased over severalweeks to avoid intolerance. Mercaptamine has avery unpleasant taste and smell, which can affect compliance.All patients receiving mercaptamine should be registered(contact local specialist centre for details).Mercaptamine eye drops are used in the management ofocular symptoms arising from the deposition of cystinecrystals in the eye.Safe PracticeMercaptamine has been confused with mercaptopurine;care must be taken to ensure the correctdrug is prescribed and dispensed.MERCAPTAMINE(Cysteamine)Cautions leucocyte-cystine concentration and haematologicalmonitoring required—consult productliterature; dose of phosphate supplement may need tobe adjusted if transferring from phosphocysteamine tomercaptamineContra-indications hypersensitivity to penicillaminePregnancy avoid—teratogenic and toxic in animalstudiesBreast-feeding avoidSide-effects breath and body odour, nausea, vomiting,diarrhoea, anorexia, abdominal pain, gastroenteritis,dyspepsia, encephalopathy, headache, malaise,fever, rash; less commonly gastro-intestinal ulcer,seizures, hallucinations, nervousness, leucopenia,nephrotic syndromeLicensed use eye drops not licensedIndication and doseNephropathic cystinosis (specialist use only). By mouthNeonate initially one-sixth to one-quarter of theexpected maintenance dose, increased graduallyover 4–6 weeks; maintenance, 1.3 g/m 2 (approx.50 mg/kg) daily in 4 divided doses

BNFC 2011–2012 9.8.1 Drugs used in metabolic disorders 493Child 1 month–12 years or under 50 kg initiallyone-sixth to one-quarter of the expected maintenancedose, increased gradually over 4–6 weeks;maintenance, 1.3 g/m 2 (approx. 50 mg/kg) daily in4 divided dosesChild 12–18 years or over 50 kg initially onesixthto one-quarter of the expected maintenancedose, increased gradually over 4–6 weeks; maintenance,2 g daily in 4 divided dosesCystagon c (Orphan Europe) ACapsules, mercaptamine (as bitartrate) 50 mg, netprice 100-cap pack = £70.00; 150 mg, 100-cap pack =£190.00. Label: 21Note For child under 6 years at risk of aspiration, capsulescan be opened and contents sprinkled on food (at a temperaturesuitable for eating); avoid adding to acidic drinks(e.g. orange juice)Eye dropsMercaptamine (Non-proprietary)Eye drops, mercaptamine 0.11%, 10 mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Pompe diseaseAlglucosidase alfa, an enzyme produced by recombinantDNA technology, is licensed for long-term replacementtherapy in Pompe disease, a lysosomal storagedisorder caused by deficiency of acid alpha-glucosidase.ALGLUCOSIDASE ALFACautions cardiac and respiratory dysfunction—monitorclosely; monitor immunoglobulin G (IgG) antibodyconcentrationInfusion-related reactions Infusion-related reactions verycommon, calling for use of antihistamine, antipyretic, orcorticosteroid; consult product literature for detailsPregnancy toxicity in animal studies, but treatmentshould not be withheldBreast-feeding manufacturer advises avoid—noinformation availableSide-effects nausea, vomiting, diarrhoea; flushing,tachycardia, blood pressure changes, cold extremities,cyanosis, facial oedema, chest discomfort; cough,tachypnoea, bronchospasm; headache, agitation, tremor,irritability, restlessness, paraesthesia, dizziness,fatigue; pyrexia; antibody formation; myalgia, musclespasms; sweating, rash, pruritus, urticaria, injectionsitereactions; hypersensitivity reactions (includinganaphylaxis); severe skin reactions (including ulcerativeand necrotising skin lesions) also reportedIndication and dosePompe disease (specialist use only). By intravenous infusionNeonate 20 mg/kg every 2 weeksChild 1 month –18 years 20 mg/kg every 2weeksAdministration For intravenous infusion, reconstitute50 mg with 10.3 mL Water for Injections to produce5 mg/mL solution; gently rotate vial without shaking;dilute requisite dose with Sodium Chloride 0.9% togive a final concentration of 0.5–4 mg/mL; givethrough a low protein-binding in-line filter(0.2 micron) at an initial rate of 1 mg/kg/hourincreased by 2 mg/kg/hour every 30 minutes to max.7 mg/kg/hourMyozyme c (Genzyme) TAIntravenous infusion, powder for reconstitution,alglucosidase alfa, net price 50-mg vial = £356.06Urea cycle disordersSodium benzoate and sodium phenylbutyrate areused in the management of urea cycle disorders. Both,either singly or in combination, are indicated as adjunctivetherapy in all patients with neonatal-onset diseaseand in those with late-onset disease who have a historyof hyperammonaemic encephalopathy. Sodium benzoateis also used in non-ketotic hyperglycinaemia.Gastro-intestinal side-effects of sodium benzoate orsodium phenylbutyrate may be reduced by giving smallerdoses more frequently. The preparations containsignificant amounts of sodium; therefore, they shouldbe used with caution in children with congestive heartfailure, renal insufficiency and clinical conditions involvingsodium retention with oedema.The long-term management of urea cycle disordersincludes oral maintenance treatment with sodium benzoateand sodium phenylbutyrate combined with a lowprotein diet and other drugs such as arginine or citrulline,depending on the specific disorder.Carglumic acid is licensed for the treatment of hyperammonaemiadue to N-acetylglutamate synthase deficiency.ARGININECautions monitor plasma pH and chlorideContra-indications not to be used in the treatment ofarginase deficiencyPregnancy no information availableBreast-feeding no information availableSide-effects intravenous injection only: nausea,vomiting; flushing, hypotension; headache, numbness;hyperchloraemic metabolic acidosis; irritation atinjection-siteLicensed use injection and tablets not licensed inchildren; powder licensed for urea cycle disorders inchildrenIndication and doseAcute hyperammonaemia in carbamylphosphatesynthetase deficiency, ornithine carbamyltransferase deficiency (specialist use only). By intravenous infusionNeonate initially 200 mg/kg over 90 minutes followedby 8 mg/kg/hourChild 1 month–18 years initially 200 mg/kg over90 minutes followed by 8 mg/kg/hour9 Nutrition and blood

494 9.8.1 Drugs used in metabolic disorders BNFC 2011–20129 Nutrition and bloodMaintenance treatment of hyperammonaemiain carbamylphosphate synthetase deficiency,ornithine carbamyl transferase deficiency (specialistuse only). By mouthNeonate 100 mg/kg daily in 3–4 divided dosesChild 1 month–18 years 100 mg/kg daily in 3–4divided dosesAcute hyperammonaemia in citrullinaemia,arginosuccinic aciduria (specialist use only). By intravenous infusionNeonate initially 600 mg/kg over 90 minutes followedby 25 mg/kg/hourChild 1 month–18 years initially 600 mg/kg over90 minutes followed by 25 mg/kg/hourMaintenance treatment of hyperammonaemiain citrullinaemia, arginosuccinic aciduria (specialistuse only). By mouthNeonate 100–175 mg/kg 3–4 times daily, withfood, adjusted according to responseChild 1 month–18 years 100–175 mg/kg 3–4times daily, with food, adjusted according toresponseL-Arginine (Non-proprietary)Tablets, L-arginine (as hydrochloride) 500 mg,Oral solution, L-arginine 100 mg/mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Powder, L-arginine (as hydrochloride), net price 100 g= £12.27Prescribe as a borderline substance (ACBS). For use as a supplementin urea cycle disorders other than arginase deficiency, suchas hyperammonaemia types I and II, citrullinaemia, arginosuccinicaciduria, and deficiency of N-acetyl glutamate synthetaseInjection, L-arginine (as hydrochloride) 500 mg/mL,10-mL ampoules; 100 mg/mL, 200-mL ampAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Note Other strengths may be available from ‘special-order’manufacturers or specialist importing companies, see p. 809Administration dilute to a concentration of 20 mg/mL withSodium Chloride 0.9% or 0.45%, or Glucose 5% or 10%; max.concentration 100 mg/mL; may be given orallyCARGLUMIC ACIDPregnancy manufacturer advises avoid unless essential—noinformation availableBreast-feeding manufacturer advises avoid—presentin milk in animal studiesSide-effects sweatingIndication and doseHyperammonaemia due to N-acetyl glutamatesynthase deficiency (initiated under specialistsupervision). By mouthNeonate initially 50–125 mg/kg twice dailyimmediately before feeds, adjusted according toplasma-ammonia concentration; maintenance 5–50 mg/kg twice daily; total daily dose may alternativelybe given in 3–4 divided dosesChild 1 month–18 years initially 50–125 mg/kgtwice daily immediately before food, adjustedaccording to plasma-ammonia concentration;maintenance 5–50 mg/kg twice daily; total dailydose may alternatively be given in 3–4 divideddosesCarbaglu c (Orphan Europe) ADispersible tablets, carglumic acid 200 mg, net price5-tab pack = £299.00, 60-tab pack = £3499.00. Label:13CITRULLINEPregnancy no information availableBreast-feeding no information availableIndication and doseCarbamyl phosphate synthase deficiency,ornithine carbamyl transferase deficiency. By mouthNeonate 150 mg/kg daily in 3–4 divided doses,adjusted according to responseChild 1 month–18 years 150 mg/kg daily in 3–4divided doses, adjusted according to responseCitrulline Powder (Non-proprietary)Powder, L-citrulline 100 gAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Administration May be mixed with drinks or taken as a pasteSODIUM BENZOATECautions see notes above; neonates (risk of kernicterusand increased side-effects); interactions:Appendix 1 (sodium benzoate)Renal impairment see notes abovePregnancy no information availableBreast-feeding no information availableSide-effects nausea, vomiting, anorexia; irritability,lethargy, comaLicensed use not licensed for use in childrenIndication and doseAcute hyperammonaemia due to urea cycledisorders (specialist use only). By intravenous infusionNeonate initially 250 mg/kg over 90 minutes followedby 20 mg/kg/hour, adjusted according toresponseChild 1 month–18 years initially 250 mg/kg over90 minutes followed by 20 mg/kg/hour, adjustedaccording to responseMaintenance treatment of hyperammonaemiadue to urea cycle disorders; non-ketotichyperglycinaemia (specialist use only). By mouthNeonate 50–150 mg/kg 3–4 times daily, with food,adjusted according to responseChild 1 month–18 years 50–150 mg/kg 3–4times daily, with food, adjusted according toresponse

BNFC 2011–2012 9.8.1 Drugs used in metabolic disorders 495Administration for administration by mouth, oralsolution or powder may be administered in fruitdrinks; less soluble in acidic drinksSodium Benzoate (Non-proprietary) ATablets, sodium benzoate 500 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Capsules, sodium benzoate 50 mg; 250 mg; 400 mg;500 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Oral solution, sodium benzoate 100 mg/mL;200 mg/mL; 300 mg/mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809PowderAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Injection, sodium benzoate 200 mg/mL, 5-mL ampNote Contains Na + 1.4 mmol /mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Administration for intravenous infusion, dilute to a concentrationof 20 mg/mL with Sodium Chloride 0.9% or 0.45%, or Glucose 5%or 10%; max. concentration 50 mg/mLSODIUM PHENYLBUTYRATECautions see notes above; congestive heart failure;interactions: Appendix 1 (sodium phenylbutyrate)Hepatic impairment manufacturer advises use withcautionRenal impairment manufacturer advises use withcaution; see also notes abovePregnancy avoid—toxicity in animal studies; manufactureradvises adequate contraception in women ofchild-bearing potentialBreast-feeding manufacturer advises avoid—noinformation availableSide-effects amenorrhoea and irregular menstrualcycles, decreased appetite, body odour, taste disturbances;less commonly nausea, vomiting, abdominalpain, peptic ulcer, pancreatitis, rectal bleeding,arrhythmia, oedema, syncope, depression, headache,rash, weight gain, renal tubular acidosis, aplasticanaemia, ecchymosesLicensed use injection not licensed for use in childrenIndication and doseAcute hyperammonaemia due to urea cycledisorders (specialist use only). By continuous intravenous infusionNeonate initially 250 mg/kg over 90 minutes followedby 20 mg/kg/hour adjusted according toresponseChild 1 month–18 years initially 250 mg/kg over90 minutes followed by 20 mg/kg/hour adjustedaccording to responseMaintenance treatment of hyperammonaemiadue to urea cycle disorders (specialist use only). By mouthNeonate 75–150 mg/kg 3–4 times daily, with foodChild 1 month–18 years 75–150 mg/kg 3–4times daily, with food (max. 20 g daily)Administration Oral dose may be mixed with fruitdrinks, milk, or feedsSodium Phenylbutyrate (Non-proprietary) AInjection, sodium phenylbutyrate 200 mg/mL, 5-mLampNote Contains Na + 1.1 mmol /mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Administration for intravenous infusion, dilute to a concentrationof 20 mg/mL (max. 50 mg/mL) with Glucose 5% or 10%Ammonaps c (Swedish Orphan) ATablets, sodium phenylbutyrate 500 mg. ContainsNa + 2.7 mmol/tablet. Net price 250-tab pack =£493.00Granules, sodium phenylbutyrate 940 mg/g. ContainsNa + 5.4 mmol/g. Net price 266-g pack = £860.00Note Granules should be mixed with food before takingOther metabolic disordersOther metabolic disorders and the drugs used in theirmanagement include:Amino acid disorders: maple syrup urine disease (thiaminesection 9.6.2); tyrosinaemia type III, hawkinsinuria(Vitamin C, section 9.6.3); tyrosinaemia type I (nitisinone).Mitochondrial disorders: isolated carboxylase defects,defects of biotin metabolism (biotin, see below); mitochondrialmyopathies (ubidecarenone); congenital lacticacidosis (riboflavin and thiamine, section 9.6.2); respiratorychain defects (thiamine, section 9.6.2); pyruvatedehydrogenase defects (sodium dichloroacetate)Neimann-Pick type C disease: miglustat is availablefor the treatment of progressive neurological manifestationsof Neimann-Pick type C disease, a neurodegenerativedisorder characterised by impaired intracellularlipid trafficking.Homocystinuria and defects in cobalamin metabolism:betaine, pyridoxine (section 9.6.2), hydroxocobalamin(section 9.1.2)Tetrahydrofolate reductase deficiency: betaine, folicacid (section 9.1.2)The Scottish Medicines Consortium (p. 3) has advised(July 2010) that betaine anhydrous (Cystadane c ) isaccepted for restricted use within NHS Scotland forthe adjunctive treatment of homocystinuria involvingdeficiencies or defects in cystathionine beta-synthase,5,10-methylene-tetrahydrofolate reductase, or cobalamincofactor metabolism in patients who are notresponsive to pyridoxine treatment.BETAINECautions monitor plasma-methionine concentrationbefore and during treatment—interrupt treatment ifsymptoms of cerebral oedema occurPregnancy manufacturer advises avoid unless essential—limitedinformation availableBreast-feeding manufacturer advises caution—noinformation availableSide-effects less commonly gastro-intestinal disorders,anorexia, reversible cerebral oedema (see Cautions),agitation, depression, personality disorder,sleep disturbances, urinary incontinence, alopecia,and urticaria9 Nutrition and blood

496 9.8.1 Drugs used in metabolic disorders BNFC 2011–20129 Nutrition and bloodIndication and doseAdjunctive treatment of homocystinuria (specialistuse only). By mouthNeonate 50 mg/kg twice daily, dose and frequencyadjusted according to response; max.75 mg/kg twice dailyChild 1 month–10 years 50 mg/kg twice daily,dose and frequency adjusted according toresponse; max. 75 mg/kg twice dailyChild 10–18 years 3 g twice daily, adjustedaccording to response; max. 10 g twice dailyAdministration Powder should be mixed with water,juice, milk, formula, or food until completely dissolvedand taken immediately; measuring spoons are providedto measure 1 g, 150 mg, and 100 mg ofCystadane c powderBetaine (Non-proprietary) APowder (for oral solution), betaine anhydrous500 mg/mL when reconstituted.Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Tablets, betaine anhydrous 500 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Cystadane c (Orphan Europe) APowder, betaine (anhydrous), net price 180 g =£347.00BIOTIN(Vitamin H)Pregnancy no information availableBreast-feeding no information availableIndication and doseIsolated carboxylase defects. By mouth or by slow intravenous injectionNeonate 5 mg once daily, adjusted according toresponse; usual maintenance 10–50 mg daily,higher doses may be requiredChild 1 month–18 years 10 mg once daily,adjusted according to response; usual maintenance10–50 mg daily but up to 100 mg daily maybe requiredDefects of biotin metabolism. By mouth or by slow intravenous injectionNeonate 10 mg once daily adjusted according toresponse; usual maintenance 5–20 mg daily buthigher doses may be requiredChild 1 month–18 years 10 mg once dailyadjusted according to response; usual maintenance5–20 mg daily but higher doses may berequiredBiotin (Non-proprietary) ATablets, biotin 5 mg, 20-tab packInjection, biotin 5 mg/mLAvailable from ‘special order’ manufacturers or specialistimporting companies, see p. 809Administration For administration by mouth, tablets may becrushed and mixed with food or drinkMIGLUSTATCautions monitor cognitive and neurological function,growth, and platelet countHepatic impairment manufacturer advises caution—no information availableRenal impairment child 12–18 years, initially 200 mgtwice daily if estimated glomerular filtration rate 50–70 mL/minute/1.73 m 2 ; child 12–18 years, initially100 mg twice daily if estimated glomerular filtrationrate 30–50 mL/minute/1.73 m 2 ; avoid if estimatedglomerular filtration rate less than 30 mL/minute/1.73 m 2 ; child under 12 years—consult product literaturePregnancy manufacturer advises avoid (toxicity inanimal studies)—effective contraception must beused during treatment; also men should avoidfathering a child during and for 3 months after treatmentBreast-feeding manufacturer advises avoid—noinformation availableSide-effects diarrhoea, flatulence, abdominal pain,dyspepsia, constipation, nausea, vomiting, anorexia,weight changes; tremor, dizziness, headache, peripheralneuropathy, ataxia, hypoaesthesia, paraesthesia,insomnia, fatigue, asthenia; decreased libido; thrombocytopenia;muscle spasmIndication and doseNeimann-Pick type C disease (specialist supervisiononly). By mouthChild 4–12 yearsBody surface area less than 0.47 m 2 100 mgonce dailyBody surface area 0.47–0.73 m 2 100 mg twicedailyBody surface area 0.73–0.88 m 2 100 mg threetimes dailyBody surface area 0.88–1.25 m 2 200 mg twicedailyBody surface area greater than 1.25 m 2 200 mgthree times dailyChild 12–18 years 200 mg three times dailyZavesca c (Actelion) ACapsules, miglustat 100 mg, net price 84-cap pack =£3934.17 (hospital only)NITISINONE(NTBC)Cautions slit-lamp examination of eyes recommendedbefore treatment; monitor liver function regularly;monitor platelet and white blood cell count every 6monthsPregnancy manufacturer advises avoid unless potentialbenefit outweighs risk—toxicity in animal studiesBreast-feeding manufacturer advises avoid—adverseeffect in animal studiesSide-effects thrombocytopenia, leucopenia, granulocytopenia;conjunctivitis, photophobia, corneal opacity,keratitis, eye pain; less commonly leucocytosis,blepharitis, pruritus, exfoliative dermatitis, anderythematous rash

BNFC 2011–2012 9.8.2 Acute porphyrias 497Indication and doseHereditary tyrosinaemia type I (in combinationwith dietary restriction of tyrosine and phenylalanine). By mouthNeonate initially 500 micrograms/kg twice daily,adjusted according to response; max. 2 mg/kgdailyChild 1 month–18 years initially 500 micrograms/kgtwice daily, adjusted according toresponse; max. 2 mg/kg dailyAdministration capsules can be opened and the contentssuspended in a small amount of water or formuladiet and taken immediatelyOrfadin c (Swedish Orphan) ACapsules, nitisinone 2 mg, net price 60-cap pack =£564.00; 5 mg, 60-cap pack = £1127.00; 10 mg, 60-cappack = £2062.00SODIUM DICHLOROACETATEPregnancy no information availableBreast-feeding no information availableSide-effects polyneuropathy on prolonged use;abnormal oxalate metabolism; metabolic acidosisIndication and dosePyruvate dehydrogenase defects. By mouthNeonate initially 12.5 mg/kg 4 times daily,adjusted according to response; up to 200 mg/kgdaily may be requiredChild 1 month–18 years initially 12.5 mg/kg 4times daily, adjusted according to response; up to200 mg/kg daily may be requiredSodium dichloroacetate (Non-proprietary) APowder (for oral solution), sodium dichloroacetate50 mg/mL when reconstituted with waterAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809UBIDECARENONE(Ubiquinone, Co-enzyme Q10)Cautions may reduce insulin requirement in diabetesmellitus; interactions: Appendix 1 (ubidecarenone)Hepatic impairment reduce dose in moderate andsevere impairmentSide-effects nausea, diarrhoea, heartburn; rarelyheadache, irritability, agitation, dizzinessLicensed use not licensedIndication and doseMitochondrial disorders. By mouthNeonate initially 5 mg once or twice daily withfood, adjusted according to response, up to 200 mgdaily may be requiredChild 1 month–18 years initially 5 mg once ortwice daily with food, adjusted according toresponse, up to 300 mg daily may be requiredUbidecarenone (Non-proprietary) AOral solution, ubidecarenone 50 mg/10 mLTablets, ubidecarenone 10 mgCapsules, ubidecarenone 10 mg, 30 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 8099.8.2 Acute porphyriasThe acute porphyrias (acute intermittent porphyria,variegate porphyria, hereditary coproporphyria, and 5-aminolaevulinic acid dehydratase deficiency porphyria)are hereditary disorders of haem biosynthesis; they havea prevalence of about 1 in 10 000 of the population.Great care must be taken when prescribing for patientswith acute porphyria, since certain drugs can induceacute porphyric crises. Since acute porphyrias arehereditary, relatives of affected individuals should bescreened and advised about the potential danger ofcertain drugs. Acute attacks of porphyria are exceptionallyrare before puberty. When acute porphyria is suspectedin a child, support from an expert porphyriaservice should be sought.Treatment of serious or life-threatening conditionsshould not be withheld from patients with acute porphyria.When there is no safe alternative, treatmentshould be started and urinary porphobilinogen excretionshould be measured regularly; if it increases orsymptoms occur, the drug can be withdrawn and theacute attack treated. If an acute attack of porphyriaoccurs during pregnancy, contact an expert porphyriaservice for further advice.Haem arginate is administered by short intravenousinfusion as haem replacement in moderate, severe, orunremitting acute porphyria crises.Supplies of haem arginate may be obtained in an emergencyoutside office hours from the on-call pharmacistat:St Thomas’ HospitalLondonTel: (020) 7188 7188HAEM ARGINATE(Human hemin)Pregnancy manufacturer advises avoid unless essentialBreast-feeding manufacturer advises avoid unlessessential—no information availableSide-effects rarely hypersensitivity reactions andfever; pain and thrombophlebitis at injection siteIndication and doseAcute porphyrias (acute intermittent porphyria,porphyria variegata, hereditary coproporphyria). By intravenous infusionChild 1 month–18 years 3 mg/kg once daily(max. 250 mg daily) for 4 days; if response inadequate,repeat 4-day course with close biochemicalmonitoringNormosang c (Orphan Europe) TAConcentrate for intravenous infusion, haem arginate25 mg/mL, net price 10-mL amp = £434.25Administration administer over at least 30 minutes; diluterequisite dose in 100 mL Sodium Chloride 0.9% in glass bottle;administer within 1 hour after dilution; max. concentration2.5 mg/mL9 Nutrition and blood

498 9.8.2 Acute porphyrias BNFC 2011–2012Drugs unsafe for use in acuteporphyriasThe following list contains drugs on the UK market thathave been classified as ‘unsafe’ in porphyria becausethey have been shown to be porphyrinogenic in animalsor in vitro, or have been associated with acute attacks inpatients. Absence of a drug from the following lists doesnot necessarily imply that the drug is safe. For manydrugs no information about porphyria is available.An up-to-date list of drugs considered safe in acuteporphyrias is available at www.wmic.wales.nhs.uk/porphyria_info.php.Unsafe drug groups (check first)Further information may be obtained fromwww.porphyria-europe.org and also from:Welsh Medicines Information CentreUniversity Hospital of WalesCardiff, CF14 4XWTel: (029) 2074 2979/3877Note Quite modest changes in chemical structure can lead tochanges in porphyrinogenicity but where possible generalstatements have been made about groups of drugs; theseshould be checked first.Alkylating drugs 1AmfetaminesAnabolic steroidsAntidepressants 2Antihistamines 3Barbiturates 4 Calcium channel blockers 5Contraceptives, hormonal 6Ergot derivatives 7Gold saltsHormone replacement therapy 6Imidazole antifungals 8Non-nucleoside reverse transcriptaseinhibitors 1Progestogens 6Protease inhibitors 1Statins 9Sulfonamides 10 Sulfonylureas 11Taxanes 1TetracyclinesThiazolidinediones 1Triazole antifungals 8Unsafe drugs (check groups above first)9 Nutrition and bloodAceclofenacAlcoholAminophyllineAmiodaroneArtemether with lumefantrineBexaroteneBosentanBromocriptineBuspironeCabergolineCarbamazepineChloral hydrate 12ChloramphenicolChloroform 13ClindamycinCocaineColistimethate sodiumCycloserineDanazolDapsoneDexfenfluramineDiazepam 14DiclofenacDisopyramideDisulfiramErythromycinEtamsylateEthosuximideEtomidateFenfluramineFlupentixolFlutamideFosphenytoinGriseofulvinHalothaneHydralazineIndapamideIsometheptene mucateIsoniazidKetamineKetorolacLidocaine 15MebeverineMefenamic acid 16MeprobamateMethyldopaMetoclopramide 16MetolazoneMetronidazole 16MetyraponeMifepristoneMinoxidil 16MitotaneNalidixic acidNitrazepamNitrofurantoinOrphenadrineOxcarbazepineOxybutyninOxycodone 17Pentazocine 17PentoxifyllinePhenoxybenzaminePhenytoinPivmecillinamPorfimerPotassium canrenoate 18ProbenecidPyrazinamideRaloxifeneRifabutin 19Rifampicin 19RisperidoneSelegilineSpironolactoneSulfinpyrazoneTamoxifenTelithromycinTemoporfinTheophyllineTiagabineTinidazoleTopiramateToremifeneTrimethoprimValproate 14XipamideZidovudine 1Zuclopenthixol1. Contact Welsh Medicines Information Centre for further advice.2. Includes tricyclic (and related) antidepressants and MAOIs; fluoxetine, mianserin, and venlafaxine thought to be safe.3. Alimemazine, chlorphenamine, desloratadine, fexofenadine, ketotifen, loratadine, and promethazine thought to be safe.4. Includes primidone and thiopental.5. Amlodipine, felodipine, and nifedipine may be used with caution.6. Progestogens are more porphyrinogenic than oestrogens; oestrogens may be safe at least in replacement doses. Progestogensshould be avoided whenever possible by all young women susceptible to acute porphyria; however, when non-hormonalcontraception is inappropriate, progestogens may be used with extreme caution if the potential benefit outweighs risk. Therisk of an acute attack is greatest in young women who have had a previous attack. Long-acting progestogen preparationsshould never be used in those at risk of acute porphyria.7. Includes ergometrine (oxytocin probably safe) and pergolide.8. Applies to oral and intravenous use; topical antifungals are thought to be safe due to low systemic exposure.9. Rosuvastatin thought to be safe.10. Includes co-trimoxazole and sulfasalazine.11. Glipizide is thought to be safe.12. Although evidence of hazard is uncertain, manufacturer advises avoid.13. Small amounts in medicines probably safe.14. Status epilepticus has been treated successfully with intravenous diazepam.15. When used for local anaesthesia, articaine, bupivacaine, lidocaine, prilocaine, and tetracaine are thought to be safe.16. May be used with caution if safer alternative not available.17. Buprenorphine, codeine, diamorphine, dihydrocodeine, fentanyl, methadone, morphine, pethidine, and tramadol are thoughtto be safe.18. Evidence of hazard uncertain—contact Welsh Medicines Information Centre for further advice.19. Rifamycins have been used in a few patients without evidence of harm—use with caution if safer alternative not available.

BNFC 2011–2012 49910 Musculoskeletal and jointdiseases10.1 Drugs used in rheumatic diseases49910.1.1 Non-steroidal anti-inflammatorydrugs 49910.1.2 Corticosteroids 50610.1.2.1 Systemic corticosteroids 50610.1.2.2 Local corticosteroid injections 50610.1.3 Drugs that suppress the rheumaticdisease process 50710.1.4 Gout and cytotoxic-inducedhyperuricaemia 51110.1.5 Other drugs for rheumatic diseases51210.2 Drugs used in neuromusculardisorders 51210.2.1 Drugs that enhance neuromusculartransmission 51210.2.2 Skeletal muscle relaxants 51310.3 Drugs for the relief of soft-tissueinflammation and topicalpain relief 51610.3.1 Enzymes 51610.3.2 Rubefacients, topical NSAIDs,capsaicin, and poultices 516This chapter also includes advice on the drug managementof the following:dental and orofacial pain, p. 500extravasation, p. 516myasthenia gravis, p. 512soft-tissue and other musculoskeletal disorders,belowjuvenile idiopathic arthritis and other inflammatorydisorders, belowFor treatment of septic arthritis see Table 1, section5.1.10.1 Drugs used in rheumaticdiseases10.1.1 Non-steroidal anti-inflammatory drugs10.1.2 Corticosteroids10.1.3 Drugs that suppress the rheumaticdisease process10.1.4 Gout and cytotoxic-inducedhyperuricaemia10.1.5 Other drugs for rheumatic diseasesJuvenile idiopathic arthritis and otherinflammatory disordersRheumatic diseases require symptomatic treatment torelieve pain, swelling, and stiffness, together with treatmentto control and suppress disease activity. Treatmentof juvenile idiopathic arthritis may involve nonsteroidalanti-inflammatory drugs (NSAIDs) (section10.1.1), a disease modifying antirheumatic drug(DMARD) (section 10.1.3) such as methotrexate or acytokine modulator, and intra-articular, intravenous, ororal corticosteroids (section 10.1.2).Soft-tissue and musculoskeletaldisordersThe management of children with soft-tissue injuriesand strains, and musculoskeletal disorders, may includetemporary rest together with the local application ofheat or cold, local massage and physiotherapy. For painrelief, paracetamol (section 4.7.1) is often adequate andshould be used first. Alternatively, the lowest effectivedose of a NSAID (e.g. ibuprofen) can be used. If painrelief with either drug is inadequate, both paracetamol(in a full dose appropriate for the child) and a low doseof a NSAID may be required.10.1.1 Non-steroidal antiinflammatorydrugs10 Musculoskeletal and joint diseasesIn single doses non-steroidal anti-inflammatory drugs(NSAIDs) have analgesic activity comparable to that ofparacetamol (section 4.7.1), but paracetamol is preferred.In regular full dosage NSAIDs have both a lastinganalgesic and an anti-inflammatory effect whichmakes them particularly useful for the treatment ofcontinuous or regular pain associated with inflammation.

500 10.1.1 Non-steroidal anti-inflammatory drugs BNFC 2011–201210 Musculoskeletal and joint diseasesChoice Differences in anti-inflammatory activitybetween NSAIDs are small, but there is considerablevariation in individual response and tolerance to thesedrugs. A large proportion of children will respond to anyNSAID; of the others, those who do not respond to onemay well respond to another. Pain relief starts soon aftertaking the first dose and a full analgesic effect shouldnormally be obtained within a week, whereas an antiinflammatoryeffect may not be achieved (or may not beclinically assessable) for up to 3 weeks. However, injuvenile idiopathic arthritis NSAIDs may take 4–12weeks to be effective. If appropriate responses are notobtained within these times, another NSAID should betried. The availability of appropriate formulations needsto be considered when prescribing NSAIDs for children.NSAIDs reduce the production of prostaglandins byinhibiting the enzyme cyclo-oxygenase. They vary intheir selectivity for inhibiting different types of cyclooxygenase;selective inhibition of cyclo-oxygenase-2 isassociated with less gastro-intestinal intolerance. However,in children gastro-intestinal symptoms are rare inthose taking NSAIDs for short periods. The role ofselective inhibitors of cyclo-oxygenase-2 is undeterminedin children.Ibuprofen and naproxen are propionic acid derivativesused in children:Ibuprofen combines anti-inflammatory, analgesic, andantipyretic properties. It has fewer side-effects thanother NSAIDs but its anti-inflammatory properties areweaker.Naproxen combines good efficacy with a low incidenceof side-effects.Diclofenac, indometacin, mefenamic acid, andpiroxicam have properties similar to those of propionicacid derivatives:Diclofenac has actions and side-effects similar to thoseof naproxen.Indometacin has an action equal to or superior to thatof naproxen, but with a high incidence of side-effectsincluding headache, dizziness, and gastro-intestinal disturbances.It is rarely used in children and should bereserved for when other NSAIDs have been unsuccessful.Mefenamic acid has minor anti-inflammatory properties.It has occasionally been associated with diarrhoeaand haemolytic anaemia which require discontinuationof treatment.Piroxicam is as effective as naproxen and has a longduration of action which permits once-daily administration.However, it has more gastro-intestinal side-effectsthan most other NSAIDs, and is associated with morefrequent serious skin reactions (important: see CHMPadvice, p. 505).Meloxicam is a selective inhibitor of cyclo-oxygenase-2. Its use may be considered in adolescents intolerant toother NSAIDs.Ketorolac can be used for the short-term managementof postoperative pain (section 15.1.4.2).Etoricoxib, a selective inhibitor of cyclo-oxygenase-2, islicensed for the relief of pain in osteoarthritis, rheumatoidarthritis, ankylosing spondylitis, and acute gout inchildren aged 16 years and over.For the role of aspirin in children, see section 2.9.Dental and orofacial pain Most mild to moderatedental pain and inflammation is effectively relieved byibuprofen or diclofenac. In an appraisal of the relativesafety in adults of 7 non-selective NSAIDs, the CSMassessed ibuprofen to have the lowest risk of seriousgastro-intestinal side-effects (see below).For further information on the management of dentaland orofacial pain, see p. 199.Cautions and contra-indications NSAIDs should beused with caution in children with a history of hypersensitivityto any NSAID—which includes those inwhom attacks of asthma, angioedema, urticaria or rhinitishave been precipitated by any NSAID. NSAIDsshould also be used with caution in coagulation defects.Caution may also be required in children with allergicdisorders, and also in children with connective-tissuedisorders, see Side-effects below.In children with cardiac impairment, caution is requiredsince NSAIDs may impair renal function (see also Sideeffectsbelow). All NSAIDs are contra-indicated insevere heart failure. Non-selective NSAIDs should beused with caution in uncontrolled hypertension, heartfailure, ischaemic heart disease, peripheral arterial disease,cerebrovascular disease, and when used long termin children with risk factors for cardiovascular events.The selective inhibitor of cyclo-oxygenase-2, etoricoxib,is contra-indicated in ischaemic heart disease, cerebrovasculardisease, peripheral arterial disease, and mild tosevere heart failure. Etoricoxib should be used withcaution in children with a history of cardiac failure,left ventricular dysfunction, hypertension, in childrenwith oedema for any other reason, and in childrenwith risk factors for cardiovascular events.NSAIDs and cardiovascular eventsThe risk of cardiovascular events secondary toNSAID use is undetermined in children. In adults,all NSAID use can, to varying degrees, be associatedwith a small increased risk of thrombotic events (e.g.myocardial infarction and stroke) independent ofbaseline cardiovascular risk factors or duration ofNSAID use; however, the greatest risk may be inthose patients receiving high doses long term. Asmall increased thrombotic risk cannot be excludedin children.In adults, diclofenac (150 mg daily) and ibuprofen(2.4 g daily) are associated with an increased risk ofthrombotic events. The increased risk for diclofenacis similar to that of etoricoxib. Naproxen (in adults,1 g daily) is associated with a lower thrombotic risk,and lower doses of ibuprofen (in adults, 1.2 g daily orless) have not been associated with an increased riskof myocardial infarction.The lowest effective dose of NSAID should be prescribedfor the shortest period of time to controlsymptoms, and the need for long-term treatmentshould be reviewed periodically.NSAIDs are generally contra-indicated if there is activeor previous gastro-intestinal ulceration or bleeding;however, some children may require NSAIDs for effectiverelief of pain and stiffness. For advice on theprophylaxis and treatment of NSAID-associated gastro-intestinalulcers, see section 1.3.For interactions of NSAIDs, see Appendix 1 (NSAIDs).

BNFC 2011–2012 10.1.1 Non-steroidal anti-inflammatory drugs 501Hepatic impairment NSAIDs should be used withcaution in children with hepatic impairment; there is anincreased risk of gastro-intestinal bleeding and fluidretention. NSAIDs should be avoided in severe liverdisease; see also individual drugs.Renal impairment NSAIDs should be avoided ifpossible or used with caution in children with renalimpairment; the lowest effective dose should be usedfor the shortest possible duration, and renal functionshould be monitored. Sodium and water retention mayoccur and renal function may deteriorate, possibly leadingto renal failure; deterioration in renal function hasalso been reported after topical use; see also individualdrugs.Pregnancy Most manufacturers advise avoidingNSAIDs during pregnancy or avoiding them unless thepotential benefit outweighs risk. NSAIDs should beavoided during the third trimester because use is associatedwith a risk of closure of fetal ductus arteriosus inutero and possibly persistent pulmonary hypertensionof the newborn. In addition, the onset of labour may bedelayed and the duration may be increased.Breast-feeding NSAIDs should be used with cautionduring breast-feeding; see also individual drugs.Side-effects The side-effects of NSAIDs vary inseverity and frequency. Gastro-intestinal disturbancesincluding discomfort, nausea, diarrhoea, and occasionallybleeding and ulceration may occur (see also notesbelow and Cautions above).Gastro-intestinal side-effectsAll NSAIDs are associated with gastro-intestinaltoxicity. In adults, evidence on the relative safetyof NSAIDs indicates differences in the risks of seriousupper gastro-intestinal side-effects. Ibuprofenis associated with the lowest risk; piroxicam, indometacin,naproxen, and diclofenac are associatedwith intermediate risks (possibly higher in the caseof piroxicam, see also CHMP advice, p. 505). Selectiveinhibitors of cyclo-oxygenase-2 are associatedwith a lower risk of serious upper gastro-intestinalside-effects than non-selective NSAIDs.Children appear to tolerate NSAIDs better thanadults and gastro-intestinal side-effects are less common;use of gastro-protective drugs may not benecessary (see also section 1.3).Other side-effects include hypersensitivity reactions(particularly rashes, angioedema, and bronchospasm),headache, dizziness, nervousness, depression, drowsiness,insomnia, vertigo, hearing disturbances such astinnitus, photosensitivity, and haematuria. Blood disordershave also occurred. Fluid retention may occur(rarely precipitating congestive heart failure); bloodpressure may be raised.AsthmaAll NSAIDs have the potential to worsen asthma,either acutely or as a gradual worsening of symptoms;consider both prescribed NSAIDs and thosethat are purchased over the counter.Renal failure may be provoked by NSAIDs, especially inpatients with pre-existing renal impairment (important,see Renal impairment above). Rarely, papillary necrosisor interstitial fibrosis associated with NSAIDs can leadto renal failure. Hepatic damage, alveolitis, pulmonaryeosinophilia, pancreatitis, visual disturbances, Stevens-Johnson syndrome, and toxic epidermal necrolysis areother rare side-effects. Induction of or exacerbation ofcolitis or Crohn’s disease has been reported. Asepticmeningitis has been reported rarely with NSAIDs—children with connective tissue disorders such as systemiclupus erythematosus may be especially susceptible.Overdosage: see Emergency Treatment of Poisoning,p. 26.DICLOFENAC POTASSIUMCautions see notes above; avoid in acute porphyria(section 9.8.2)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment avoid in severe impairment; seealso notes abovePregnancy see notes aboveBreast-feeding amount in milk too small to beharmful; see also notes aboveSide-effects see notes aboveIndication and doseRheumatic disease, musculoskeletal disorders,postoperative pain. By mouthChild 14–18 years 75–100 mg daily in 2–3divided dosesDiclofenac Potassium (Non-proprietary) ATablets, diclofenac potassium 25 mg, net price 28-tabpack = 81p; 50 mg, 28-tab pack = £1.55. Label: 211Voltarol c Rapid (Novartis) ATablets, s/c, diclofenac potassium 25 mg (red), netprice 30-tab pack = £3.46; 50 mg (brown), 30-tab pack= £6.62. Label: 211. 12.5 mg tablets can be sold to the public for the treatment ofheadache, dental pain, period pain, rheumatic and muscularpain, backache and the symptoms of cold and flu (includingfever), in patients aged over 14 years subject to max. singledose of 25 mg, max. daily dose of 75 mg for max. 3 days, andmax. pack size of 18 12.5 mgDICLOFENAC SODIUMCautions see notes above; avoid in acute porphyria(section 9.8.2)Contra-indications see notes above; avoid injectionscontaining benzyl alcohol in neonates (see preparationsbelow)Intravenous use Additional contra-indications includeconcomitant NSAID or anticoagulant use (including lowdoseheparins), history of haemorrhagic diathesis, history ofconfirmed or suspected cerebrovascular bleeding, operationswith high risk of haemorrhage, history of asthma,moderate or severe renal impairment, hypovolaemia, dehydrationHepatic impairment see notes aboveRenal impairment avoid in severe impairment; seealso Intravenous Use and notes abovePregnancy see notes aboveBreast-feeding amount in milk too small to beharmful; see also notes above10 Musculoskeletal and joint diseases

502 10.1.1 Non-steroidal anti-inflammatory drugs BNFC 2011–201210 Musculoskeletal and joint diseasesSide-effects see notes above; suppositories maycause rectal irritation; injection site reactionsLicensed use not licensed for use in children under 1year; suppositories not licensed for use in childrenunder 6 years except for use in children over 1 yearfor juvenile idiopathic arthritis; solid dose formscontaining more than 25 mg not licensed for use inchildren; injection not licensed for use in childrenIndication and doseInflammation and mild to moderate pain. By mouth or by rectumChild 6 months–18 years 0.3–1 mg/kg (max.50 mg) 3 times dailyPostoperative pain. By rectumChild 6–18 years 0.5–1 mg/kg (max. 75 mg)twice daily for max. 4 days; total daily dose mayalternatively be given in 3 divided doses. By intravenous infusion or deep intramuscularinjection into gluteal muscleChild 2–18 years 0.3–1 mg/kg once or twicedaily for max. 2 days (max. 150 mg daily)Pain and inflammation in rheumatic diseaseincluding juvenile idiopathic arthritis. By mouthChild 6 months–18 years 1.5–2.5 mg/kg (max.75 mg) twice daily; total daily dose may alternativelybe given in 3 divided dosesAdministration for intravenous infusion, dilute 75 mgwith 100–500 mL Glucose 5% or Sodium Chloride0.9% (previously buffered with 0.5 mL SodiumBicarbonate 8.4% solution or with 1 mL SodiumBicarbonate 4.2% solution); give over 30–120 minutesDiclofenac Sodium (Non-proprietary) ATablets, both e/c, diclofenac sodium 25 mg, net price84-tab pack = £1.14; 50 mg, 84-tab pack = £1.31.Label: 5, 25Brands include Defenac c , Dicloflex c , Diclozip c , Fenactol c ,Flamrase cDispersible tablets, sugar-free, diclofenac sodium10 mgAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Suppositories, diclofenac sodium 100 mg, net price10 = £3.97Brands include Econac cVoltarol c (Novartis) ATablets, e/c, diclofenac sodium 25 mg (yellow), netprice 84-tab pack = £2.94; 50 mg (brown), 84-tab pack= £4.57. Label: 5, 25Dispersible tablets, sugar-free, pink, diclofenac,equivalent to diclofenac sodium 50 mg, net price 21-tab pack = £6.19. Label: 13, 21Injection, diclofenac sodium 25 mg/mL, net price 3-mL amp = 83pExcipients include benzyl alcohol (avoid in neonates, see Excipients,p. 2), propylene glycolSuppositories, diclofenac sodium 12.5 mg, net price10 = 58p; 25 mg, 10 = £1.03; 50 mg, 10 = £1.70;100 mg, 10 = £3.03Modified releaseDiclomax SR c (Galen) ACapsules, m/r, yellow, diclofenac sodium 75 mg, netprice 56-cap pack = £11.40. Label: 21, 25DosePain and inflammation. By mouthChild 12–18 years 1 capsule 1–2 times dailyDiclomax Retard c (Galen) ACapsules, m/r, diclofenac sodium 100 mg, net price28-cap pack = £8.20. Label: 21, 25DosePain and inflammation. By mouthChild 12–18 years 1 capsule once dailyMotifene c 75 mg (Daiichi Sankyo) ACapsules, e/c, m/r, diclofenac sodium 75 mg(enclosing e/c pellets containing diclofenac sodium25 mg and m/r pellets containing diclofenac sodium50 mg), net price 56-cap pack = £8.00. Label: 25Excipients include propylene glycol (see Excipients, p. 2)DosePain and inflammation. By mouthChild 12–18 years 1 capsule 1–2 times dailyVoltarol c 75 mg SR (Novartis) ATablets, m/r, pink, diclofenac sodium 75 mg, net price28-tab pack = £6.46; 56-tab pack = £12.92. Label: 21,25DosePain and inflammation. By mouthChild 12–18 years 1 tablet 1–2 times dailyNote Other brands of modified-release tablets containingdiclofenac sodium 75 mg include Defenac c SR, Dexomon c75 SR, Dicloflex c 75 SR, Fenactol c 75 mg SR, Flamatak c75 MR, Flamrase c SR, Flexotard c MR 75, Rheumatac cRetard 75, Rhumalgan c CR, Slofenac c SR, Volsaid cRetard 75Voltarol c Retard (Novartis) ATablets, m/r, red, diclofenac sodium 100 mg, netprice 28-tab pack = £9.47. Label: 21, 25DosePain and inflammation. By mouthChild 12–18 years 1 tablet once dailyNote Other brands of modified-release tablets containingdiclofenac sodium 100 mg include Defenac c Retard,Dexomon c Retard 100, Dicloflex c Retard, Fenactol cRetard 100 mg, Flamatak c 100 MR, Slofenac c SR,Volsaid c Retard 100ETORICOXIBCautions see notes above; also dehydration; monitorblood pressure before treatment, 2 weeks afterinitiation and periodically during treatmentContra-indications see notes above; inflammatorybowel disease; uncontrolled hypertension (persistentlyabove 140/90 mmHg)Hepatic impairment max. 60 mg daily in mildimpairment; max. 60 mg on alternate days or 30 mgonce daily in moderate impairment; see also notesabove

BNFC 2011–2012 10.1.1 Non-steroidal anti-inflammatory drugs 503Renal impairment avoid if estimated glomerular filtrationrate less than 30 mL/minute/1.73 m 2 ; see alsonotes abovePregnancy manufacturer advises avoid (teratogenic inanimal studies); see also notes aboveBreast-feeding manufacturer advises avoid—presentin milk in animal studies; see also notes aboveSide-effects see notes above; also palpitation, fatigue,influenza-like symptoms, ecchymosis; less commonlydry mouth, taste disturbance, mouth ulcer, appetiteand weight change, atrial fibrillation, transientischaemic attack, chest pain, flushing, cough, dyspnoea,epistaxis, anxiety, mental acuity impaired,paraesthesia, electrolyte disturbance, myalgia andarthralgia; very rarely confusion and hallucinationsIndication and doseOsteoarthritis. By mouthChild 16–18 years 30 mg once daily, increased ifnecessary to 60 mg once dailyRheumatoid arthritis and ankylosing spondylitis. By mouthChild 16–18 years 90 mg once dailyAcute gout. By mouthChild 16–18 years 120 mg once daily for max. 8daysArcoxia c (MSD) TATablets, f/c, etoricoxib 30 mg (blue-green), net price28-tab pack = £13.99; 60 mg (dark green), 28-tab pack= £20.11; 90 mg (white), 28-tab pack = £22.96; 120 mg(pale green), 7-tab pack = £6.03, 28-tab pack = £24.11IBUPROFENCautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment avoid in severe impairment; seealso notes abovePregnancy see notes aboveBreast-feeding amount too small to be harmful, butsome manufacturers advise avoid; see also notesaboveSide-effects see notes aboveLicensed use not licensed for use in children under 3months or body-weight under 5 kgIndication and doseMild to moderate pain, pain and inflammationof soft-tissue injuries, pyrexia with discomfort. By mouthChild 1–3 months 5 mg/kg 3–4 times dailyChild 3–6 months 50 mg 3 times daily; max.30 mg/kg daily in 3–4 divided dosesChild 6 months–1 year 50 mg 3–4 times daily;max. 30 mg/kg daily in 3–4 divided dosesChild 1–4 years 100 mg 3 times daily; max.30 mg/kg daily in 3–4 divided dosesChild 4–7 years 150 mg 3 times daily; max.30 mg/kg daily in 3–4 divided dosesChild 7–10 years 200 mg 3 times daily; max.30 mg/kg (max. 2.4 g) daily in 3–4 divided dosesChild 10–12 years 300 mg 3 times daily; max.30 mg/kg (max. 2.4 g) daily in 3–4 divided dosesChild 12–18 years initially 300–400 mg 3–4 timesdaily; increased if necessary to max. 600 mg 4times daily; maintenance dose of 200–400 mg 3times daily may be adequatePain and inflammation in rheumatic diseaseincluding juvenile idiopathic arthritis. By mouthChild 3 months–18 years 30–40 mg/kg (max.2.4 g) daily in 3–4 divided doses; in systemicjuvenile idiopathic arthritis up to 60 mg/kg (max.2.4 g) daily [unlicensed] in 4–6 divided dosesPost-immunisation pyrexia in infants (see alsop. 600). By mouthChild 2–3 months 50 mg as a single doserepeated once after 6 hours if necessaryClosure of patent ductus arteriosus in neonatessee section 2.141Ibuprofen (Non-proprietary) ATablets, coated, ibuprofen 200 mg, net price 84-tabpack = £1.62; 400 mg, 84-tab pack = £1.72; 600 mg,84-tab pack = £4.06. Label: 21Brands include Arthrofen c , Ebufac c , Rimafen cDental prescribing on NHS Ibuprofen Tablets may be prescribedOral suspension, ibuprofen 100 mg/5 mL, net price100 mL = £1.48, 150 mL = £2.71, 500 mL = £8.88.Label: 21Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionBrands include Calprofen c , Feverfen c , Nurofen c for Children,Orbifen c for ChildrenDental prescribing on NHS Ibuprofen Oral SuspensionSugar-free may be prescribed1. Can be sold to the public under certain circumstances; forexemptions see Medicines, Ethics and Practice, London,Pharmaceutical Press (always consult latest edition)Brufen c (Abbott) ATablets, f/c, ibuprofen 200 mg, net price 100-tab pack= £3.92; 400 mg, 100-tab pack = £8.16; 600 mg, 100-tab pack = £12.24. Label: 21Syrup, orange, ibuprofen 100 mg/5 mL, net price500 mL (orange-flavoured) = £8.88. Label: 21Granules, effervescent, ibuprofen 600 mg/sachet, netprice 20–sachet pack = £6.53. Label: 13, 21Contains sodium approx. 9 mmol/sachetModified releaseBrufen Retard c (Abbott) ATablets, m/r, ibuprofen 800 mg, net price 56-tab pack= £6.48. Label: 25, 27DosePain and inflammation. By mouthChild 12–18 years 2 tablets daily as a single dose,preferably in the early evening, increased in severe casesto 3 tablets daily in 2 divided doses10 Musculoskeletal and joint diseases

504 10.1.1 Non-steroidal anti-inflammatory drugs BNFC 2011–201210 Musculoskeletal and joint diseasesFenbid c (Goldshield) ASpansule c (= capsule m/r), maroon/pink, enclosingoff-white pellets, ibuprofen 300 mg, net price 120-cappack = £9.64. Label: 25DosePain and inflammation. By mouthChild 12–18 years initially 2 capsules twice daily,increased in severe cases to 3 capsules twice daily; then1–2 capsules twice dailyINDOMETACIN(Indomethacin)Cautions see notes above; also epilepsy, psychiatricdisturbances; during prolonged therapy ophthalmicand blood examinations particularly advisable; avoidrectal administration in proctitis and haemorrhoidsSkilled tasks Dizziness may affect performance of skilledtasks (e.g. driving)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment avoid in severe impairment; seealso notes abovePregnancy see notes aboveBreast-feeding amount probably too small to beharmful—manufacturer advises avoid; see also notesaboveSide-effects see notes above; rarely confusion, convulsions,psychiatric disturbances, syncope, blooddisorders (particularly thrombocytopenia), hyperglycaemia,peripheral neuropathy, and intestinalstrictures; suppositories may cause rectal irritationand occasional bleedingLicensed use not licensed for use in childrenIndication and doseRelief of pain and inflammation in rheumaticdiseases including juvenile idiopathic arthritis(but see p. 500). By mouthChild 1 month–18 years 0.5–1 mg/kg twicedaily; higher doses may be used under specialistsupervisionClosure of patent ductus arteriosus in prematurebabies section 2.14Indometacin (Non-proprietary) ACapsules, indometacin 25 mg, net price 28-cap pack= £2.33; 50 mg, 28-cap pack = £2.29. Label: 21,counselling, driving, see aboveBrands include Rimacid cSuppositories, indometacin 100 mg, net price 10 =£20.07. Counselling, driving, see aboveSuspension, indometacin 5 mg/mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Modified releaseIndometacin m/r preparations ACapsules, m/r, indometacin 75 mg. Label: 21, 25,counselling, driving, see aboveBrands include Indolar SR c , Pardelprin cMEFENAMIC ACIDCautions see notes above; epilepsy; acute porphyria(section 9.8.2)Contra-indications see notes above; inflammatorybowel diseaseHepatic impairment see notes aboveRenal impairment avoid in severe impairment; seealso notes abovePregnancy see notes aboveBreast-feeding amount too small to be harmful butmanufacturer advises avoid; see also notes aboveSide-effects see notes above; also diarrhoea or rashes(withdraw treatment), stomatitis; less commonlyparaesthesia and fatigue; rarely hypotension, palpitation,glucose intolerance, thrombocytopenia, haemolyticanaemia (positive Coombs’ test), and aplasticanaemiaIndication and doseAcute pain including dysmenorrhoea, menorrhagia. By mouthChild 12–18 years 500 mg 3 times dailyMefenamic Acid (Non-proprietary) ACapsules, mefenamic acid 250 mg, net price 100 =£2.83. Label: 21Tablets, mefenamic acid 500 mg, net price 28-tabpack = £2.20. Label: 21Suspension, mefenamic acid 50 mg/5 mL, net price125 mL = £79.98. Label: 21Excipients include ethanolPonstan c (Chemidex) ACapsules, blue/ivory, mefenamic acid 250 mg, netprice 100-cap pack = £8.17. Label: 21Forte tablets, yellow, mefenamic acid 500 mg, netprice 100-tab pack = £15.72. Label: 21MELOXICAMCautions see notes aboveContra-indications see notes aboveHepatic impairment see notes aboveRenal impairment avoid if estimated glomerular filtrationrate less than 25 mL/minute/1.73 m 2 ; see alsonotes abovePregnancy see notes aboveBreast-feeding present in milk in animal studies—manufacturer advises avoid; see also notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under16 yearsIndication and doseRelief of pain and inflammation in juvenileidiopathic arthritis and other musculoskeletaldisorders in children intolerant to other NSAIDs. By mouthChild 12–18 years and body-weight under50 kg 7.5 mg once dailyChild 12–18 years and body-weight over 50 kg15 mg once dailyAdministration Mobic c tablets may be dispersed inwater

BNFC 2011–2012 10.1.1 Non-steroidal anti-inflammatory drugs 505Meloxicam (Non-proprietary) ATablets, meloxicam 7.5 mg, net price 30-tab pack =£1.36; 15 mg, 30-tab pack = £1.62Mobic c (Boehringer Ingelheim) ATablets, yellow, scored, meloxicam 7.5 mg, net price30-tab pack = £9.30; 15 mg, 30-tab pack = £12.93.Label: 21NAPROXENCautions see notes above; interactions: Appendix 1(NSAIDs)Contra-indications see notes aboveHepatic impairment see notes aboveRenal impairment avoid if estimated glomerular filtrationrate less than 30 mL/minute/1.73 m 2 ; see alsonotes abovePregnancy see notes aboveBreast-feeding amount too small to be harmful butmanufacturer advises avoid; see also notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under 5years for juvenile idiopathic arthritis; not licensedfor use in children under 16 years for musculoskeletaldisorders or dysmenorrhoeaIndication and dosePain and inflammation in musculoskeletal disorders,dysmenorrhoea. By mouthChild 1 month–18 years 5 mg/kg twice daily(max. 1 g daily)Juvenile idiopathic arthritis. By mouthChild 2–18 years 5–7.5 mg/kg twice daily (max.1 g daily)1Naproxen (Non-proprietary) ATablets, naproxen 250 mg, net price 28-tab pack =£1.35; 500 mg, 28-tab pack = £1.72. Label: 21Brands include Arthroxen cTablets, e/c, naproxen 250 mg, net price 56-tab pack= £3.18; 375 mg, 56-tab pack = £26.82; 500 mg, 56-tabpack = £4.83. Label: 5, 25Suspension, naproxen 25 mg/mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 8091. Can be sold to the public for the treatment of primarydysmenorrhoea in women aged 15–50 years subject to max.single dose of 500 mg, max. daily dose of 750 mg for max. 3days, and a max. pack size of 9 250 mg tablets; forexemptions see Medicines, Ethics and Practice, London,Pharmaceutical Press (always consult latest edition)Naprosyn c (Roche) ATablets, yellow, scored, naproxen 250 mg, net price56-tab pack = £4.29; 500 mg, 56-tab pack = £8.56.Label: 21Tablets, e/c, (Naprosyn EC c ), naproxen 250 mg, netprice 56-tab pack = £4.29; 375 mg, 56-tab pack =£6.42; 500 mg, 56-tab pack = £8.56. Label: 5, 25Synflex c (Roche) ATablets, blue, naproxen sodium 275 mg, net price 60-tab pack = £7.10. Label: 21Note 275 mg naproxen sodium : 250 mg naproxenPIROXICAM UCautions see notes above and CHMP advice belowContra-indications inflammatory bowel disease; seealso notes aboveHepatic impairment see notes aboveRenal impairment see notes abovePregnancy see notes aboveBreast-feeding amount too small to be harmful; seealso notes aboveSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseRelief of pain and inflammation in juvenileidiopathic arthritis. By mouthChild 6–18 years and body-weight under 15 kg5 mg dailyChild 6–18 years and body-weight 16–25 kg10 mg dailyChild 6–18 years and body-weight 26–45 kg15 mg dailyChild 6–18 years and body-weight over 46 kg20 mg dailyCHMP advicePiroxicam (June 2007)The CHMP has recommended restrictions on the useof piroxicam because of the increased risk of gastrointestinalside effects and serious skin reactions. TheCHMP has advised that:. piroxicam should be initiated only by physicians experiencedin treating inflammatory or degenerative rheumaticdiseases. piroxicam should not be used as first-line treatment. in adults, use of piroxicam should be limited to the symptomaticrelief of osteoarthritis, rheumatoid arthritis, andankylosing spondylitis. piroxicam dose should not exceed 20 mg daily. piroxicam should no longer be used for the treatment ofacute painful and inflammatory conditions. treatment should be reviewed 2 weeks after initiatingpiroxicam, and periodically thereafter. concomitant administration of a gastro-protective agent(section 1.3) should be consideredNote Topical preparations containing piroxicam are notaffected by these restrictionsPiroxicam (Non-proprietary) AUCapsules, piroxicam 10 mg, net price 56-cap pack =£16.62; 20 mg, 28-cap pack = £22.45. Label: 21Dispersible tablets, piroxicam 10 mg, net price 56-tab pack = £9.96; 20 mg, 28-tab pack = £32.41.Label: 13, 21Brexidol c (Chiesi) AUTablets, yellow, scored, piroxicam (as betadex) 20 mg,net price 30-tab pack = £13.82. Label: 21Feldene c (Pfizer) AUCapsules, piroxicam 10 mg (red/blue), net price 30-cap pack = £3.86; 20 mg (white), 30-cap pack = £7.71.Label: 2110 Musculoskeletal and joint diseases

506 10.1.2 Corticosteroids BNFC 2011–201210 Musculoskeletal and joint diseasesTablets, (Feldene Melt c ), piroxicam 20 mg, net price30-tab pack = £10.53. Label: 10, patient informationleaflet, 21Excipients include aspartame equivalent to phenylalanine 140 micrograms/tablet(section 9.4.1)Note Tablets may be halved [unlicensed] to give 10-mg dose;tablet placed on tongue and allowed to dissolve or may beswallowed10.1.2 Corticosteroids10.1.2.1 Systemic corticosteroidsThe general actions, uses, and cautions of corticosteroidsare described in section 6.3. In children with rheumaticdiseases corticosteroids should be reserved forspecific indications (e.g. when other anti-inflammatorydrugs are unsuccessful) and should be used only underthe supervision of a specialist.Systemic corticosteroids may be considered for themanagement of juvenile idiopathic arthritis in systemicdisease or when several joints are affected. Systemiccorticosteroids may also be considered in severe, possiblylife-threatening conditions such as systemic lupuserythematosus, systemic vasculitis, juvenile dermatomyositis,Behçet’s disease, and polyarticular joint disease.In severe conditions, short courses (‘pulses’) of highdoseintravenous methylprednisolone or a pulsed oralcorticosteroid may be particularly effective for providingrapid relief, and has fewer long-term adverse effectsthan continuous treatment.Corticosteroid doses should be reduced with carebecause of the possibility of relapse if the reduction istoo rapid. If complete discontinuation of corticosteroidsis not possible, consideration should be given to alternate-day(or alternate high-dose, low-dose) administration;on days when no corticosteroid is given, or a lowerdose is given, an additional dose of a NSAID may behelpful. In some conditions, alternative treatment usingan antimalarial or concomitant use of an immunosuppressantdrug, such as azathioprine, methotrexate orcyclophosphamide may prove useful; in less severeconditions treatment with a NSAID alone may be adequate.Administration of corticosteroids may result in suppressionof growth and may affect the development ofpuberty. The risk of corticosteroid-induced osteoporosisshould be considered for those on long-term corticosteroidtreatment (section 6.6); corticosteroids may alsoincrease the risk of osteopenia in those unable to exercise.For the disadvantages of corticosteroid treatmentsee section 6.3.2.10.1.2.2 Local corticosteroid injectionsCorticosteroids are injected locally for an anti-inflammatoryeffect. In inflammatory conditions of the joints,including juvenile idiopathic arthritis, they are given byintra-articular injection as monotherapy, or as anadjunct to long-term therapy to reduce swelling anddeformity in one or a few joints. Aseptic precautions(e.g. a no-touch technique) are essential, as is a clinicianskilled in the technique; infected areas should beavoided and general anaesthesia, or local anaesthesia,or conscious sedation should be used. Occasionally anacute inflammatory reaction develops after an intraarticularor soft-tissue injection of a corticosteroid.This may be a reaction to the microcrystalline suspensionof the corticosteroid used, but must be distinguishedfrom sepsis introduced into the injection site.Triamcinolone hexacetonide [unlicensed] is preferredfor intra-articular injection because it is almost insolubleand has a long-acting (depot) effect. Triamcinoloneacetonide and methylprednisolone may also be consideredfor intra-articular injection into larger joints, whilsthydrocortisone acetate should be reserved for smallerjoints or for soft-tissue injections. Intra-articular corticosteroidinjections can cause flushing and, in adults, mayaffect the hyaline cartilage. Each joint should usually betreated no more than 3–4 times in one year.A smaller amount of corticosteroid may also be injecteddirectly into soft tissues for the relief of inflammation inconditions such as tennis or golfer’s elbow or compressionneuropathies, which occur rarely in children. Intendinitis, injections should be made into the tendonsheath and not directly into the tendon (due to theabsence of a true tendon sheath and a high risk ofrupture, the Achilles tendon should not be injected).Corticosteroid injections are also injected into soft tissuesfor the treatment of skin lesions (see section 13.4).LOCAL CORTICOSTEROIDINJECTIONSCautions see notes above and consult product literature;see also section 6.3.2Contra-indications see notes above and consult productliterature; avoid injections containing benzylalcohol in neonates (see preparation below)Side-effects see notes above and consult productliteratureLicensed use triamcinolone acetonide not licensedfor use in children under 6 yearsIndication and doseSee under preparationsHydrocortisone acetateHydrocortistab c (Sovereign) AInjection (aqueous suspension), hydrocortisoneacetate 25 mg/mL, net price 1-mL amp = £5.72Dose. By intra-articular injection(for details consult product literature)Child 1 month–12 years 5–30 mg according to size ofchild and jointChild 12–18 years 5–50 mg according to size of childand jointNote Where appropriate may be repeated at intervals of21 days; not more than 3 joints should be treated on anyone dayMethylprednisolone acetateDepo-Medrone c (Pharmacia) AInjection (aqueous suspension), methylprednisoloneacetate 40 mg/mL, net price 1-mL vial = £2.87; 2-mLvial = £5.15; 3-mL vial = £7.47Depo-Medrone c with Lidocaine (Pharmacia) AInjection (aqueous suspension), methylprednisoloneacetate 40 mg, lidocaine hydrochloride 10 mg/mL,net price 1-mL vial = £3.28; 2-mL vial = £5.88

BNFC 2011–2012 10.1.3 Drugs that suppress the rheumatic disease process 507Triamcinolone hexacetonideTriamcinolone hexacetonide (Non-proprietary) AInjection, various strengths available from ’specialorder’ manufacturers or specialist importing companies,see, p. 809Dose. By intra-articular injection(for details consult product literature)Child 1–18 years for larger joints 1 mg/kg (usual max.20 mg, but higher doses have been used); if appropriaterepeat treatment for relapseTriamcinolone acetonideAdcortyl c Intra-articular/Intradermal (Squibb) AInjection (aqueous suspension), triamcinoloneacetonide 10 mg/mL, net price 1-mL amp = 90p; 5-mL vial = £3.63Excipients include benzyl alcohol (avoid in neonates, see Excipients,p. 2)Dose. By intra-articular injection(for details consult product literature)Child 1–18 years for larger joints 2 mg/kg (max. 15 mg);for doses above 15 mg use Kenalog c Intra-articular/Intramuscular; if appropriate repeat treatment forrelapseKenalog c Intra-articular/Intramuscular (Squibb)AInjection (aqueous suspension), triamcinoloneacetonide 40 mg/mL, net price 1-mL vial = £1.49Dose. By intra-articular injection(for details consult product literature)Child 1–18 years for larger joints 2 mg/kg (usual max.40 mg, but higher doses have been used); if appropriaterepeat treatment for relapse10.1.3 Drugs that suppress therheumatic diseaseprocessCertain drugs, such as methotrexate, cytokine modulators,and sulfasalazine, are used to suppress the diseaseprocess in juvenile idiopathic arthritis (juvenile chronicarthritis); these drugs are known as disease-modifyingantirheumatic drugs (DMARDs). In children, diseasemodifyingantirheumatic drugs should be used underspecialist supervision.Some children with juvenile idiopathic arthritis do notrequire disease-modifying antirheumatic drugs. Methotrexateis effective in juvenile idiopathic arthritis; sulfasalazineis an alternative but should be avoided in systemic-onsetjuvenile idiopathic arthritis. Gold andpenicillamine are no longer used. For the role of cytokinemodulators in polyarticular juvenile idiopathicarthritis, see p. 509.Unlike NSAIDs, disease-modifying antirheumatic drugscan affect the progression of disease but they mayrequire 3–6 months of treatment for a full therapeuticresponse. Response to a disease-modifying antirheumaticdrug may allow the dose of the NSAID tobe reduced.Disease-modifying antirheumatic drugs can improvenot only the symptoms of inflammatory joint diseasebut also extra-articular manifestations such as vasculitis.They reduce the erythrocyte sedimentation rate and C-reactive protein.AntimalarialsThe antimalarial hydroxychloroquine is rarely used totreat juvenile idiopathic arthritis. Hydroxychloroquinecan also be useful for systemic or discoid lupus erythematosus,particularly involving the skin and joints, andin sarcoidosis.Retinopathy (see below) rarely occurs provided that therecommended doses are not exceeded.Mepacrine is used on rare occasions to treat discoidlupus erythematosus [unlicensed].Cautions Hydroxychloroquine should be used withcaution in neurological disorders (especially in thosewith a history of epilepsy), in severe gastro-intestinaldisorders, in G6PD deficiency (section 9.1.5), and inacute porphyria. Hydroxychloroquine may exacerbatepsoriasis and aggravate myasthenia gravis. Concurrentuse of hepatotoxic drugs should be avoided; otherinteractions: Appendix 1 (chloroquine and hydroxychloroquine).Pregnancy It is not necessary to withdraw an antimalarialdrug during pregnancy if the rheumatic diseaseis well controlled; however, the manufacturer ofhydroxychloroquine advises avoiding use.Breast-feeding Hydroxychloroquine is present inbreast milk leading to a risk of toxicity in infants—breast-feeding should be avoided when it is used totreat rheumatic disease.Screening for ocular toxicityHydroxychloroquine is rarely associated with oculartoxicity. The British Society for Paediatric and AdolescentRheumatology recommends that childrenshould have their vision tested before long-termtreatment with hydroxychloroquine and have anannual review of visual acuity. Children should bereferred to an ophthalmologist if there is visualimpairment, changes in visual acuity, or blurredvision. The Royal College of Ophthalmologists hasrecommended that a locally agreed protocolbetween the prescribing doctor and ophthalmologistbe established to monitor the vision of these children.ImportantTo avoid excessive dosage in obese children, thedose of hydroxychloroquine should be calculated onthe basis of ideal body-weight; ocular toxicity isunlikely with doses under 5–6.5 mg/kg or max.400 mg daily.Side-effects The side-effects of hydroxychloroquineinclude gastro-intestinal disturbances, headache, andskin reactions (rashes, pruritus); those occurring lessfrequently include ECG changes, convulsions, visualchanges, retinal damage (see above), keratopathy, oto-10 Musculoskeletal and joint diseases

508 10.1.3 Drugs that suppress the rheumatic disease process BNFC 2011–201210 Musculoskeletal and joint diseasestoxicity, hair depigmentation, hair loss, and discolorationof skin, nails, and mucous membranes. Side-effectsthat occur rarely include blood disorders (includingthrombocytopenia, agranulocytosis, and aplastic anaemia),mental changes (including emotional disturbancesand psychosis), myopathy (including cardiomyopathyand neuromyopathy), acute generalised exanthematouspustulosis, exfoliative dermatitis, Stevens-Johnsonsyndrome, photosensitivity, and hepatic damage; angioedemaand bronchospasm have also been reported.Important: very toxic in overdosage—immediateadvice from poisons centres essential (see also p. 29).HYDROXYCHLOROQUINE SULPHATECautions see notes aboveHepatic impairment use with caution in moderate tosevere impairmentRenal impairment manufacturer advises caution andmonitoring of plasma-hydroxychloroquine concentrationin severe impairmentPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseJuvenile idiopathic arthritis, systemic anddiscoid lupus erythematosus, dermatologicalconditions caused or aggravated by sunlight. By mouthChild 1 month–18 years based on ideal bodyweight,5–6.5 mg/kg (max. 400 mg) once dailyHydroxychloroquine (Non-proprietary) ATablets, hydroxychloroquine sulphate 200 mg, netprice 60-tab pack = £5.10. Label: 21, counselling,antacids (see below)Brands include Quinoric cCounselling Avoid antacids for at least 4 hours before orafter hydroxychloroquine to reduce possible interferencewith hydroxychloroquine absorptionPlaquenil c (Sanofi-Aventis) ATablets, f/c, hydroxychloroquine sulphate 200 mg,net price 60-tab pack = £5.25. Label: 21, counselling,antacids (see below)Counselling Avoid antacids for at least 4 hours before orafter hydroxychloroquine to reduce possible interferencewith hydroxychloroquine absorptionExtemporaneous formulations available seeExtemporaneous Preparations, p. 6Drugs affecting the immune responseMethotrexate, given as a once weekly dose, is thedisease-modifying antirheumatic drug of choice in thetreatment of juvenile idiopathic arthritis and also has arole in juvenile dermatomyositis, vasculitis, uveitis, systemiclupus erythematosus, localised scleroderma, andsarcoidosis; for these indications it is given by thesubcutaneous, oral, or rarely, the intramuscular route.Absorption from intramuscular or subcutaneous routesmay be more predictable than from the oral route; if theoral route is ineffective subcutaneous administration isgenerally preferred. Regular full blood counts (includingdifferential white cell count and platelet count), renaland liver function tests are required. Folic acid mayreduce mucosal or gastro-intestinal side-effects ofmethotrexate. The dosage regimen for folic acid hasnot been established—in children over 2 years a dose of5 mg weekly [unlicensed indication], may be given on adifferent day from the methotrexate.Azathioprine may be used in children for vasculitiswhich has failed to respond to other treatments, for themanagement of severe cases of systemic lupus erythematosusand other connective tissue disorders, in conjunctionwith corticosteroids for patients with severe orprogressive renal disease, and in cases of polymyositiswhich are resistant to corticosteroids. Azathioprine hasa corticosteroid-sparing effect in patients whosecorticosteroid requirements are excessive.Ciclosporin is rarely used in juvenile idiopathic arthritis,connective tissue diseases, vasculitis, and uveitis; it maybe considered if the condition has failed to respond toother treatments.AZATHIOPRINECautions section 8.2.1Contra-indications section 8.2.1Hepatic impairment section 8.2.1Renal impairment section 8.2.1Pregnancy section 8.2.1Breast-feeding section 8.2.1Side-effects section 8.2.1Indication and doseSystemic lupus erythematosus, vasculitis,auto-immune conditions usually when corticosteroidtherapy alone has proved inadequatesee also notes above. By mouthChild 1 month–18 years initially 1 mg/kg daily,adjusted according to response to max. 3 mg/kgdaily (consider withdrawal if no improvementwithin 3 months)Inflammatory bowel disease section 1.5.3Transplantation rejection section 8.2.1PreparationsSection 8.2.1METHOTREXATECautions section 8.1.3; see advice below (blood count,gastro-intestinal, liver, and pulmonary toxicity);extreme caution in blood disorders (avoid if severe);risk of accumulation in pleural effusion or ascites—drain before treatment; full blood count and liverfunction tests before starting treatment repeatedfortnightly for at least the first 4 weeks and at thisfrequency after any change in dose until therapystabilised, thereafter monthly; renal function testsbefore starting treatment and then regularly duringtreatment; children or their carers should report allsymptoms and signs suggestive of infection, especiallysore throat; treatment with folinic acid (as calciumfolinate, section 8.1) may be required in acutetoxicity; check immunity to varicella-zoster and considervaccination (section 14.4) before initiating therapy;acute porphyria (section 9.8.2); interactions: seebelow and Appendix 1 (methotrexate)Blood count Bone marrow suppression can occur abruptly;factors likely to increase toxicity include renal impairmentand concomitant use with another anti-folate drug. A clini-

BNFC 2011–2012 10.1.3 Drugs that suppress the rheumatic disease process 509cally significant drop in white cell count or platelet countcalls for immediate withdrawal of methotrexate and introductionof supportive therapyGastro-intestinal toxicity Withdraw treatment if stomatitisdevelops—may be first sign of gastro-intestinal toxicityLiver toxicity Persistent 2–fold rise in liver transaminasesmay necessitate dose reduction or rarely discontinuation;abrupt withdrawal should be avoided as this can lead todisease flarePulmonary toxicity Acute pulmonary toxicity is rare inchildren treated for juvenile idiopathic arthritis, but childrenand carers should seek medical attention if dyspnoea, coughor fever develops; discontinue if pneumonitis suspected.NSAIDs Children and carers should be advised to avoid selfmedicationwith over-the-counter ibuprofenContra-indications see Cautions above; also activeinfection and immunodeficiency syndromesHepatic impairment avoid—dose-related toxicity;see also Cautions aboveRenal impairment section 8.1.3Pregnancy section 8.1.3Breast-feeding section 8.1.3Side-effects section 8.1.3; chronic pulmonary fibrosis;blood dyscrasias (including fatalities); liver cirrhosisLicensed use Metoject c injection licensed for use inchildren over 3 years for polyarticular forms ofjuvenile idiopathic arthritis; other preparations notlicensed for use in children for non-malignantconditionsIndication and doseJuvenile idiopathic arthritis, juvenile dermatomyositis,vasculitis, uveitis, systemic lupuserythematosus, localised scleroderma, sarcoidosis. By mouth, subcutaneous injection, or intramuscularinjectionChild 1 month–18 years 10–15 mg/m 2 onceweekly initially, increased if necessary to max.25 mg/m 2 once weeklySafe PracticeNote that the above dose is a weekly dose. To avoiderror with low-dose methotrexate, it is recommendedthat:. the child or their carer is carefully advised of the dose andfrequency and the reason for taking methotrexate and anyother prescribed medicine (e.g. folic acid);. only one strength of methotrexate tablet (usually 2.5 mg) isprescribed and dispensed;. the prescription and the dispensing label clearly show thedose and frequency of methotrexate administration;. the child or their carer is warned to report immediately theonset of any feature of blood disorders (e.g. sore throat,bruising, and mouth ulcers), liver toxicity (e.g. nausea,vomiting, abdominal discomfort, and dark urine), and respiratoryeffects (e.g. shortness of breath).Severe Crohn’s disease section 1.5.3Malignant disease section 8.1.3Psoriasis section 13.5.3Methotrexate (Non-proprietary) ATablets, yellow, methotrexate 2.5 mg, net price 28-tabpack = £3.27. Counselling, dose, NSAIDsBrands include Maxtrex cTablets, yellow, methotrexate 10 mg, net price 100-tab pack = £56.49. Counselling, dose, NSAIDsSuspension, various strengths available from ‘special-order’manufacturers or specialist importingcompanies, see p. 809Parenteral preparationsSee also section 8.1.3Metoject c (Medac) AInjection, prefilled syringe, methotrexate (asdisodium salt) 50 mg/mL, net price 0.15 mL (7.5 mg)= £14.85, 0.2 mL (10 mg) = £15.29, 0.3 mL (15 mg) =£16.57, 0.4 mL (20 mg) = £17.84, 0.5 mL (25 mg) =£18.48, 0.6 mL (30 mg) = £18.95Cytokine modulatorsCytokine modulators should be used under specialistsupervision.Adalimumab, etanercept, and infliximab inhibit theactivity of tumour necrosis factor alpha (TNF-a). Adalimumaband etanercept can be used for the managementof active polyarticular juvenile idiopathic arthritis. Infliximabhas been used in refractory polyarticular juvenileidiopathic arthritis [unlicensed indication] when othertreatments, such as etanercept, have failed.NICE guidanceEtanercept for the treatment of juvenileidiopathic arthritis (March 2002)Etanercept is recommended in children aged 4–17years with active polyarticular-course juvenile idiopathicarthritis who have not responded adequatelyto methotrexate or who are intolerant of it. Etanerceptshould be used under specialist supervisionaccording to the guidelines of the British Societyfor Paediatric and Adolescent Rheumatology [previouslythe British Paediatric Rheumatology Group].Etanercept should be withdrawn if severe sideeffectsdevelop or if there is no response after 6months or if the initial response is not maintained. Adecision to continue therapy beyond 2 years shouldbe based on disease activity and clinical effectivenessin individual cases.Prescribers of etanercept should register consentingpatients with the Biologics Registry of the BritishSociety for Paediatric and Adolescent Rheumatology.Side-effects Adalimumab, etanercept, and infliximabhave been associated with infections, sometimes severe,including tuberculosis, septicaemia, and hepatitis Breactivation. Other side-effects include nausea, abdominalpain, worsening heart failure, hypersensitivityreactions, fever, headache, depression, antibody formation(including lupus erythematosus-like syndrome),pruritus, injection-site reactions, and blood disorders(including anaemia, leucopenia, thrombocytopenia,pancytopenia, aplastic anaemia).Abatacept prevents the full activation of T-lymphocytes;it can be used for the management of activepolyarticular juvenile idiopathic arthritis. Abatacept isnot recommended for use in combination with TNFinhibitors.10 Musculoskeletal and joint diseases

510 10.1.3 Drugs that suppress the rheumatic disease process BNFC 2011–201210 Musculoskeletal and joint diseasesABATACEPTCautions predisposition to infection (screen for latenttuberculosis and viral hepatitis); do not initiate untilactive infections are controlled; children should bebrought up to date with current immunisation schedule(section 14.1) before initiating therapy; progressivemultifocal leucoencephalopathy—discontinuetreatment if neurological symptoms present; interactions:Appendix 1 (abatacept)Contra-indications severe infection (see also Cautions)Pregnancy manufacturer advises avoid unless essential—effectivecontraception required during treatmentand for 14 weeks after last doseBreast-feeding present in milk in animal studies—manufacturer advises avoid breast-feeding duringtreatment and for 14 weeks after last doseSide-effects abdominal pain, diarrhoea, dyspepsia,nausea; flushing, hypertension; cough; dizziness, fatigue,headache; infection, rhinitis; rash; less commonlygastritis, stomatitis, tachycardia, bradycardia, palpitation,hypotension, dyspnoea, paraesthesia, weightgain, depression, anxiety, amenorrhoea, basal cellcarcinoma, thrombocytopenia, leucopenia, arthralgia,pain in extremities, conjunctivitis, visual disturbance,vertigo, bruising, alopecia, and dry skinIndication and doseModerate to severe active polyarticular juvenileidiopathic arthritis (in combination withmethotrexate) in children who have notresponded adequately to other disease-modifyingantirheumatic drugs (including at leastone tumour necrosis factor (TNF) inhibitor). By intravenous infusionChild 6–17 yearsBody-weight less than 75 kg 10 mg/kg, repeated2 weeks and 4 weeks after initial infusion, thenevery 4 weeksBody-weight 75–100 kg 750 mg, repeated 2weeks and 4 weeks after initial infusion, then every4 weeksBody-weight over 100 kg 1 g, repeated 2 weeksand 4 weeks after initial infusion, then every 4weeksNote Review treatment if no response within 6 monthsAdministration for intravenous infusion, reconstituteeach vial with 10 mL water for injections using thesilicone-free syringe provided; dilute requisite dose inSodium Chloride 0.9% to 100 mL (using the samesilicone-free syringe); give over 30 minutes through alow protein-binding filter (pore size 0.2–1.2 micron)Orencia c (Bristol-Myers Squibb) TAIntravenous infusion, powder for reconstitution,abatacept, net price 250-mg vial = £242.17Electrolytes Na +

BNFC 2011–2012 10.1.4 Gout and cytotoxic-induced hyperuricaemia 511hepatitis C infection; children should be brought up todate with current immunisation schedule (section14.1) before initiating therapy; heart failure (risk ofexacerbation); history or increased risk of demyelinatingdisorders; history or development of malignancy;monitor for skin cancer before and duringtreatment particularly in those at risk (including childrenwith psoriasis or a history of PUVA treatment);history of blood disorders; diabetes mellitus; interactions:Appendix 1 (etanercept)Tuberculosis Children should be evaluated for tuberculosisbefore treatment. Active tuberculosis should be treated withstandard treatment (section 5.1.9) for at least 2 monthsbefore starting etanercept. Children who have previouslyreceived adequate treatment for tuberculosis can start etanerceptbut should be monitored every 3 months for possiblerecurrence. In those without active tuberculosis but whowere previously not treated adequately, chemoprophylaxisshould ideally be completed before starting etanercept. Inchildren at high risk of tuberculosis who cannot be assessedby tuberculin skin test, chemoprophylaxis can be givenconcurrently with etanercept. Children and their carersshould be advised to seek medical attention if symptomssuggestive of tuberculosis (e.g. persistent cough, weight loss,and fever) developBlood disorders Children and their carers should be advisedto seek medical attention if symptoms suggestive of blooddisorders (such as fever, sore throat, bruising, or bleeding)developContra-indications active infection; avoid injectionscontaining benzyl alcohol in neonates (see preparationsbelow)Hepatic impairment use with caution in moderate tosevere alcoholic hepatitisPregnancy manufacturer advises avoid—no informationavailableBreast-feeding manufacturer advises avoid—presentin milk in animal studiesSide-effects see under Cytokine Modulators, p. 509;also less commonly interstitial lung disease, skincancer, uveitis, rash, new onset or worsening psoriasis;rarely demyelinating disorders, seizures,lymphoma, Stevens-Johnson syndrome, vasculitis;very rarely toxic epidermal necrolysis; also reportedappendicitis, gastritis, oesophagitis, inflammatorybowel disease, vomiting, diabetes mellitus, malignancy(including solid tumours and leukaemia),macrophage activation syndrome, and cutaneousulcerIndication and doseActive polyarticular juvenile idiopathic arthritisin children who have had an inadequateresponse to methotrexate or who cannot tolerateit. By subcutaneous injectionChild 4–17 years 400 micrograms/kg (max.25 mg) twice weekly, with an interval of 3–4 daysbetween dosesSevere plaque psoriasis section 13.5.3Enbrel c (Wyeth) TAInjection, powder for reconstitution, etanercept, netprice 25-mg vial (with solvent) = £89.38. Label: 10,alert card, counselling, tuberculosis and blood disordersPaediatric injection, powder for reconstitution, etanercept,net price 25-mg vial (with solvent) = £89.38.Label: 10, alert card, counselling, tuberculosis andblood disordersExcipients include benzyl alcohol (avoid in neonates, see Excipients,p. 2)Injection, etanercept, net price 25-mg prefilledsyringe = £89.38; 50-mg prefilled pen or prefilledsyringe = £178.75. Label: 10, alert card, counselling,tuberculosis and blood disordersSulfasalazineSulfasalazine has a beneficial effect in suppressing theinflammatory activity associated with some forms ofjuvenile idiopathic arthritis; it is generally not used insystemic-onset disease. Sulfasalazine may cause haematologicalabnormalities including leucopenia, neutropenia,and thrombocytopenia and close monitoring offull blood counts (including differential white cell countand platelet count) is necessary initially, and at monthlyintervals during the first 3 months (liver-function testsalso being performed at monthly intervals for the first 3months). Although the manufacturer recommends renalfunction tests, evidence of practical value is unsatisfactory.For use of sulfasalazine also see section 1.5.1,aminosalicylates.SULFASALAZINE(Sulphasalazine)Cautions see section 1.5.1 and notes aboveContra-indications see section 1.5.1Hepatic impairment section 1.5.1Renal impairment section 1.5.1Pregnancy section 1.5.1Breast-feeding section 1.5.1Side-effects see section 1.5.1 and notes aboveLicensed use not licensed for use in children forjuvenile idiopathic arthritisIndication and doseJuvenile idiopathic arthritis (see also notesabove). By mouthChild 2–18 years initially 5 mg/kg twice daily for1 week, then 10 mg/kg twice daily for 1 week, then20 mg/kg twice daily for 1 week, maintenancedose 20–25 mg/kg twice daily; Child 2–12 yearsmax. 2 g daily, Child 12–18 years max. 3 g dailyPreparationsSection 1.5.110.1.4 Gout and cytotoxicinducedhyperuricaemiaThis section is not included in BNF for Children. For therole of allopurinol and rasburicase in the prophylaxis ofhyperuricaemia associated with cancer chemotherapyand in enzyme disorders causing increased serum urate,see section 8.1. The management of gout in adolescentsrequires specialist supervision.10 Musculoskeletal and joint diseases

512 10.2 Drugs used in neuromuscular disorders BNFC 2011–201210 Musculoskeletal and joint diseases10.1.5 Other drugs for rheumaticdiseasesClassification not used in BNF for Children.10.2 Drugs used inneuromuscular disorders10.2.1 Drugs that enhance neuromusculartransmission10.2.2 Skeletal muscle relaxants10.2.1 Drugs that enhanceneuromusculartransmissionAnticholinesterases are used as first-line treatment inocular myasthenia gravis and as an adjunct to immunosuppressanttherapy for generalised myastheniagravis.Corticosteroids are used when anticholinesterases donot control symptoms completely. A second-line immunosuppressantsuch as azathioprine is frequently used toreduce the dose of corticosteroid.Plasmapheresis or infusion of intravenous immunoglobulin[unlicensed indication] may induce temporaryremission in severe relapses, particularly where bulbaror respiratory function is compromised or before thymectomy.AnticholinesterasesAnticholinesterase drugs enhance neuromuscular transmissionin voluntary and involuntary muscle in myastheniagravis. They prolong the action of acetylcholineby inhibiting the action of the enzyme acetylcholinesterase.Excessive dosage of these drugs can impairneuromuscular transmission and precipitate cholinergiccrises by causing a depolarising block. This may bedifficult to distinguish from a worsening myasthenicstate.Muscarinic side-effects of anticholinesterases includeincreased sweating, increased salivary and gastric secretions,increased gastro-intestinal and uterine motility,and bradycardia. These parasympathomimetic effectsare antagonised by atropine.Edrophonium has a very brief action and it is thereforeused mainly for the diagnosis of myasthenia gravis.However, such testing should be performed only bythose experienced in its use; other means of establishingthe diagnosis are available. A single test-dose usuallycauses substantial improvement in muscle power (lastingabout 5 minutes) in patients with the disease (ifrespiration already impaired, only in conjunction withsomeone skilled at intubation).Edrophonium can also be used to determine whether apatient with myasthenia is receiving inadequate orexcessive treatment with cholinergic drugs. If treatmentis excessive an injection of edrophonium will either haveno effect or will intensify symptoms (if respirationalready impaired, give only in conjunction with someoneskilled at intubation). Conversely, transientimprovement may be seen if the patient is being inadequatelytreated. The test is best performed just beforethe next dose of anticholinesterase.Neostigmine produces a therapeutic effect for up to 4hours. Its pronounced muscarinic action is a disadvantage,and simultaneous administration of an antimuscarinicdrug such as atropine or propanthelinemay be required to prevent colic, excessive salivation,or diarrhoea. In severe disease neostigmine can begiven every 2 hours. In infants, neostigmine by eithersubcutaneous or intramuscular injection is preferred forthe short-term management of myasthenia.Pyridostigmine is less powerful and slower in actionthan neostigmine but it has a longer duration of action.It is preferable to neostigmine because of its smootheraction and the need for less frequent dosage. It isparticularly preferred in patients whose muscles areweak on waking. It has a comparatively mild gastrointestinaleffect but an antimuscarinic drug may still berequired. It is inadvisable to use excessive dosesbecause acetylcholine receptor down regulation mayoccur. Immunosuppressant therapy may be consideredif high doses of pyridostigmine are needed. Neostigmineand pyridostigmine should be given to neonates 30minutes before feeds to improve suckling.Neostigmine and edrophonium are also used to reversethe actions of the non-depolarising neuromuscularblocking drugs (section 15.1.6).NEOSTIGMINECautions asthma (extreme caution), bradycardia,arrhythmias, recent myocardial infarction, epilepsy,hypotension, parkinsonism, vagotonia, peptic ulceration,hyperthyroidism; atropine or other antidote tomuscarinic effects may be necessary (particularlywhen neostigmine is given by injection), but not givenroutinely because it may mask signs of overdosage;interactions: Appendix 1 (parasympathomimetics)Contra-indications intestinal or urinary obstructionRenal impairment may need dose reductionPregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding amount probably too small to beharmfulSide-effects nausea, vomiting, increased salivation,diarrhoea, abdominal cramps (more marked withhigher doses); signs of overdosage include bronchoconstriction,increased bronchial secretions, lacrimation,excessive sweating, involuntary defaecation andmicturition, miosis, nystagmus, bradycardia, heartblock, arrhythmias, hypotension, agitation, excessivedreaming, and weakness eventually leading to fasciculationand paralysisIndication and doseTreatment of myasthenia gravis. By mouth (as neostigmine bromide)Neonate initially 1–2 mg, then 1–5 mg every 4hours, give 30 minutes before feeds

BNFC 2011–2012 10.2.2 Skeletal muscle relaxants 513Child up to 6 years initially 7.5 mg repeated atsuitable intervals throughout the day, total dailydose 15–90 mgChild 6–12 years initially 15 mg repeated at suitableintervals throughout the day, total daily dose15–90 mgChild 12–18 years initially 15–30 mg repeated atsuitable intervals throughout the day, total dailydose 75–300 mg (but max. most can tolerate is180 mg daily). By subcutaneous or intramuscular injection (asneostigmine metilsulfate)Neonate 150 micrograms/kg every 6–8 hours, 30minutes before feeds, increased to max. 300 micrograms/kgevery 4 hours, if necessary [unlicensed]Child 1 month–12 years 200–500 microgramsrepeated at suitable intervals throughout the dayChild 12–18 years 1–2.5 mg repeated at suitableintervals throughout the dayNeostigmine (Non-proprietary) ATablets, scored, neostigmine bromide 15 mg, netprice 140 = £56.10InjectionSection 15.1.6PYRIDOSTIGMINE BROMIDECautions see under Neostigmine; weaker muscarinicactionContra-indications see under NeostigmineRenal impairment reduce dose; excreted by kidneyPregnancy see under NeostigmineBreast-feeding see under NeostigmineSide-effects see under NeostigmineIndication and doseTreatment of myasthenia gravis. By mouthNeonate initially 1–1.5 mg/kg, increased graduallyto max. 10 mg, repeated throughout the day, give30–60 minutes before feedsChild 1 month–12 years initially 1–1.5 mg/kg/day, increased gradually to 7 mg/kg/day in 6divided doses; usual total daily dose 30–360 mgChild 12–18 years 30–120 mg, repeatedthroughout the day; usual total daily dose 300–600 mg (but consider immunosuppressant therapyif total daily dose exceeds 360 mg, down-regulationof acetylcholine receptors possible if totaldaily dose exceeds 450 mg; see notes above)Mestinon c (Meda) ATablets, scored, pyridostigmine bromide 60 mg, netprice 200 = £45.33Extemporaneous formulations available seeExtemporaneous Preparations, p. 6EDROPHONIUM CHLORIDECautions see under Neostigmine; have resuscitationfacilities; extreme caution in respiratory distress (seenotes above) and in asthmaNote Severe cholinergic reactions can be counteracted byinjection of atropine sulphate (which should always beavailable)Contra-indications see under NeostigminePregnancy see under NeostigmineBreast-feeding see under NeostigmineSide-effects see under NeostigmineIndication and doseDiagnostic test for myasthenia gravis. By intravenous injectionChild 1 month–12 years 20 micrograms/kg followedafter 30 seconds (if no adverse reaction hasoccurred) by 80 micrograms/kgChild 12–18 years 2 mg followed after 30 seconds(if no adverse reaction has occurred) by 8 mgDetection of overdosage or underdosage ofcholinergic drugs. By intravenous injectionChild 1 month–12 years 20 micrograms/kg(preferably just before next dose of anticholinesterase,see notes above)Child 12–18 years 2 mg (preferably just beforenext dose of anticholinesterase, see notes above)Edrophonium (Non-proprietary) AInjection, edrophonium chloride 10 mg/mL, net price1-mL amp = £19.50Immunosuppressant therapyA course of corticosteroids (section 6.3) is an establishedtreatment in severe cases of myasthenia gravisand may be particularly useful when antibodies to theacetylcholine receptor are present in high titre. Shortcourses of high-dose (’pulsed’) methylprednisolone followedby maintenance therapy with oral corticosteroidsmay also be useful.Corticosteroid treatment is usually initiated under specialistsupervision. For disadvantages of corticosteroidtreatment, see section 6.3.2. Transient but very seriousworsening of symptoms can occur in the first 2–3 weeks,especially if the corticosteroid is started at a high dose.Once remission has occurred (usually after 2–6 months),the dose of prednisolone should be reduced slowly tothe minimum effective dose.10.2.2 Skeletal muscle relaxantsThe drugs described below are used for the relief ofchronic muscle spasm or spasticity associated withneurological damage; they are not indicated for spasmassociated with minor injuries. They act principally onthe central nervous system with the exception of dantrolene,which has a peripheral site of action. They differin action from the muscle relaxants used in anaesthesia(section 15.1.5), which block transmission at the neuromuscularjunction.The underlying cause of spasticity should be treated andany aggravating factors (e.g. pressure sores, infection)10 Musculoskeletal and joint diseases

514 10.2.2 Skeletal muscle relaxants BNFC 2011–201210 Musculoskeletal and joint diseasesremedied. Skeletal muscle relaxants are effective inmost forms of spasticity except the rare alpha variety.The major disadvantage of treatment with these drugs isthat reduction in muscle tone can cause a loss ofsplinting action of the spastic leg and trunk musclesand sometimes lead to an increase in disability.Dantrolene acts directly on skeletal muscle and producesfewer central adverse effects. It is generally usedin resistant cases. The dose should be increased slowly.Baclofen inhibits transmission at spinal level and alsodepresses the central nervous system. The dose shouldbe increased slowly to avoid the major side-effects ofsedation and muscular hypotonia (other adverse eventsare uncommon).Diazepam has undoubted efficacy in some children.Sedation and occasionally extensor hypotonus aredisadvantages. Other benzodiazepines also havemuscle-relaxant properties.BACLOFENCautions psychiatric illness; respiratory impairment;epilepsy; history of peptic ulcer (avoid oral route inactive peptic ulceration); diabetes; hypertonic bladdersphincter; avoid abrupt withdrawal (risk of hyperactivestate, may exacerbate spasticity, and precipitateautonomic dysfunction including hyperthermia,psychiatric reactions and convulsions, see also underWithdrawal below); interactions: Appendix 1 (musclerelaxants)Withdrawal CSM has advised that serious side-effects canoccur on abrupt withdrawal; to minimise risk, discontinue bygradual dose reduction over at least 1–2 weeks (longer ifsymptoms occur)Skilled tasks Drowsiness may affect performance of skilledtasks (e.g. driving); effects of alcohol enhancedHepatic impairment manufacturer advises use bymouth with cautionRenal impairment risk of toxicity—use smaller oraldoses and if necessary increase dosage interval; ifestimated glomerular filtration rate less than 15 mL/minute/1.73m 2 use by mouth only if potential benefitoutweighs risk; excreted by kidneyPregnancy manufacturer advises use only if potentialbenefit outweighs risk (toxicity in animal studies)Breast-feeding present in milk—amount probably toosmall to be harmfulSide-effects gastro-intestinal disturbances, drymouth; hypotension, respiratory or cardiovasculardepression; sedation, drowsiness, confusion, dizziness,ataxia, hallucinations, nightmares, headache,euphoria, insomnia, depression, anxiety, agitation,tremor; seizure; urinary disturbances; myalgia; visualdisorders; rash, hyperhidrosis; rarely taste disturbances,abdominal pain, changes in hepatic function,paraesthesia, erectile dysfunction, dysarthria; veryrarely hypothermiaIndication and doseChronic severe spasticity of voluntary muscle. By mouthChild 1–2 years initially 300 micrograms/kg dailyin 4 divided doses, increased gradually to usualmaintenance dose of 0.75–2 mg/kg (max. 40 mg)daily in divided doses (or 10–20 mg daily in divideddoses); review treatment if no benefit within 6weeksChild 2–6 years initially 300 micrograms/kg dailyin 4 divided doses, increased gradually to usualmaintenance dose of 0.75–2 mg/kg (max. 40 mg)daily in divided doses (or 20–30 mg daily in divideddoses); review treatment if no benefit within 6weeksChild 6–8 years initially 300 micrograms/kg dailyin 4 divided doses, increased gradually to usualmaintenance dose of 0.75–2 mg/kg (max. 40 mg)daily in divided doses (or 30–40 mg daily in divideddoses); review treatment if no benefit within 6weeksChild 8–10 years initially 300 micrograms/kgdaily in 4 divided doses, increased gradually tousual maintenance dose of 0.75–2 mg/kg (max.60 mg) daily in divided doses; review treatment ifno benefit within 6 weeksChild 10–18 years initially 5 mg 3 times dailyincreased gradually; usual maintenance dose up to60 mg daily in divided doses (max. 100 mg daily);review treatment if no benefit within 6 weeksSevere chronic spasticity of cerebral originunresponsive to oral antispastic drugs (or oraltherapy not tolerated), as alternative to ablativeneurosurgical procedures—specialist useonly. By intrathecal injectionChild 4–18 years initial test dose 25 microgramsover at least 1 minute via catheter or lumbarpuncture, increased in 25-microgram steps (notmore often than every 24 hours) to max.100 micrograms to determine appropriate dosethen dose-titration phase, most often using infusionpump (implanted into chest wall or abdominalwall tissues) to establish maintenance dose (rangingfrom 24 micrograms to 1.2 mg daily in childrenunder 12 years or 1.4 mg daily for those over12 years) retaining some spasticity to avoid sensationof paralysisSafe PracticeConsult intrathecal injection product literature fordetails on dose testing and titration—important tomonitor patients closely in appropriately equippedand staffed environment during screening and immediatelyafter pump implantation. Resuscitation equipmentmust be available for immediate useBaclofen (Non-proprietary) ATablets, baclofen 10 mg, net price 84-tab pack =£1.58. Label: 2, 8, 21Oral solution, baclofen 5 mg/5 mL, net price 300 mL= £9.26. Label: 2, 8, 21Brands include Lyflex c (sugar-free)Lioresal c (Novartis) ATablets, scored, baclofen 10 mg, net price 84-tab pack= £8.67. Label: 2, 8, 21Excipients include glutenLiquid, sugar-free, raspberry–flavoured, baclofen5 mg/5 mL, net price 300 mL = £7.16. Label: 2, 8, 21By intrathecal injectionLioresal c (Novartis) AIntrathecal injection, baclofen, 50 micrograms/mL,net price 1-mL amp (for test dose) = £2.19;500 micrograms/mL, 20-mL amp (for use withimplantable pump) = £48.62; 2 mg/mL, 5-mL amp(for use with implantable pump) = £48.62

BNFC 2011–2012 10.2.2 Skeletal muscle relaxants 515DANTROLENE SODIUMCautions impaired cardiac and pulmonary function;therapeutic effect may take a few weeks to develop—discontinue if no response within 45 days; interactions:Appendix 1 (muscle relaxants)Hepatotoxicity Potentially life-threatening hepatotoxicityreported, usually if doses greater than 400 mg daily used, infemales, if history of liver disorders, or concomitant use ofhepatotoxic drugs; test liver function before and at intervalsduring therapy—discontinue if abnormal liver function testsor symptoms of liver disorder (counselling, see below); reintroduceonly if complete reversal of hepatotoxicityCounselling Children and their carers should be told how torecognise signs of liver disorder and advised to seek promptmedical attention if symptoms such as anorexia, nausea,vomiting, fatigue, abdominal pain, dark urine, or pruritusdevelopSkilled tasks Drowsiness may affect performance of skilledtasks (eg. driving); effects of alcohol enhancedContra-indications acute muscle spasm; avoid whenspasticity is useful, for example, locomotionHepatic impairment avoid—may cause severe liverdamage; injection may be used in an emergency formalignant hyperthermiaPregnancy avoid use in chronic spasticity—embryotoxicin animal studiesBreast-feeding present in milk—manufactureradvises avoid use in chronic spasticitySide-effects diarrhoea (withdraw if severe, discontinuetreatment if recurs on re-introduction), nausea,vomiting, anorexia, hepatotoxicity (see above),abdominal pain; pericarditis; pleural effusion, respiratorydepression; headache, drowsiness, dizziness,asthenia, fatigue, seizures, fever, chills; speech andvisual disturbances; rash; less commonly dysphagia,constipation, exacerbation of cardiac insufficiency,tachycardia, erratic blood pressure, dyspnoea,depression, confusion, nervousness, insomnia,increased urinary frequency, urinary incontinence orretention, haematuria, crystalluria, and increasedsweatingLicensed use not licensed for use in childrenIndication and doseChronic severe spasticity of voluntary muscle. By mouthChild 5–12 years initially 500 micrograms/kgonce daily; after 7 days increase to 500 micrograms/kg/dose3 times daily; every 7 daysincrease by further 500 micrograms/kg/dose untilsatisfactory response; max. 2 mg/kg 3–4 timesdaily (max. total daily dose 400 mg)Child 12–18 years initially 25 mg once daily;increase to 3 times daily after 7 days; every 7 daysincrease by further 500 micrograms/kg/dose untilsatisfactory response; max. 2 mg/kg 3–4 timesdaily (max. total daily dose 400 mg)Malignant hyperthermia section 15.1.8Dantrium c (SpePharm) ACapsules, orange/brown, dantrolene sodium 25 mg,net price 100 = £16.87; 100 mg, 100 = £43.07. Label: 2,counselling, driving, hepatotoxicityDIAZEPAMCautions section 4.8.2Contra-indications section 4.8.2Hepatic impairment section 4.8.2Renal impairment section 4.8.2Pregnancy section 4.8.2Breast-feeding section 4.8.2Side-effects section 4.8.2; also hypotoniaIndication and doseMuscle spasm in cerebral spasticity or inpostoperative skeletal muscle spasm. By mouthChild 1–12 months initially 250 microgram/kgtwice dailyChild 1–5 years initially 2.5 mg twice dailyChild 5–12 years initially 5 mg twice dailyChild 12–18 years initially 10 mg twice daily;max. total daily dose 40 mgTetanus. By intravenous injectionChild 1 month–18 years 100–300 micrograms/kg repeated every 1–4 hours. By intravenous infusion (or by nasoduodenaltube)Child 1 month–18 years 3–10 mg/kg over 24hours, adjusted according to responseStatus epilepticus section 4.8.2Febrile convulsions section 4.8.3Administration for continuous intravenous infusionof diazepam emulsion, dilute to a concentration ofmax. 400 micrograms/mL with Glucose 5% or 10%;max. 6 hours between addition and completion ofinfusion; diazepam adsorbed by plastics of infusionbags and giving setsFor continuous intravenous infusion of diazepamsolution, dilute to a concentration of max. 50 micrograms/mLwith Glucose 5% or Sodium Chloride0.9%; diazepam adsorbed by plastics of infusion bagsand giving setsDiazepam (Non-proprietary) KTablets, diazepam 2 mg, net price 28 = 89p; 5 mg, 28= 90p; 10 mg, 28 = 92p. Label: 2 or 19Brands include Rimapam c D, Tensium c DDental prescribing on NHS Diazepam Tablets may beprescribedOral solution, diazepam 2 mg/5 mL, net price 100 mL= £6.08. Label: 2 or 19Brands include Dialar c DDental prescribing on NHS Diazepam Oral Solution 2 mg/5 mL may be prescribedStrong oral solution, diazepam 5 mg/5 mL, net price100-mL pack = £6.38. Label: 2 or 19DBrands include Dialar c DParenteral preparationsSection 4.8.210 Musculoskeletal and joint diseases

516 10.3 Drugs for the relief of soft-tissue inflammation BNFC 2011–201210 Musculoskeletal and joint diseases10.3 Drugs for the relief ofsoft-tissue inflammationand topical pain relief10.3.1 Enzymes10.3.2 Rubefacients, topical NSAIDs,capsaicin, and poulticesExtravasationLocal guidelines for the management of extravasationshould be followed where they exist or specialistadvice sought.Extravasation injury follows leakage of drugs or intravenousfluids from the veins or inadvertent administrationinto the subcutaneous or subdermal tissue. It mustbe dealt with promptly to prevent tissue necrosis.Acidic or alkaline preparations and those with an osmolaritygreater than that of plasma can cause extravasationinjury; excipients including alcohol and polyethyleneglycol have also been implicated. Cytotoxic drugscommonly cause extravasation injury. Very young childrenare at increased risk. Those receiving anticoagulantsare more likely to lose blood into surroundingtissues if extravasation occurs, while those receivingsedatives or analgesics may not notice the early signsor symptoms of extravasation.Prevention of extravasation Precautions should betaken to avoid extravasation; ideally, drugs likely tocause extravasation injury should be given through acentral line and children receiving repeated doses ofhazardous drugs peripherally should have the cannularesited at regular intervals. Attention should be paid tothe manufacturers’ recommendations for administration.Placing a glyceryl trinitrate patch or using glyceryltrinitrate ointment distal to the cannula may improvethe patency of the vessel in children with small veins orin those whose veins are prone to collapse.Children or their carers should be asked to report anypain or burning at the site of injection immediately.The first method may be appropriate following extravasationof vesicant drugs and involves administrationof an antidote (if available) and the application of coldcompresses 3–4 times a day (consult specialist literaturefor details of specific antidotes). Spreading and dilutingthe offending substance involves infiltrating the areawith physiological saline, applying warm compresses,elevating the affected limb, and administering hyaluronidase(section 10.3.1). A saline flush-out technique(involving flushing the subcutaneous tissue with physiologicalsaline) may be effective but requires specialistadvice. Hyaluronidase should not be administered followingextravasation of vesicant drugs (unless it is eitherspecifically indicated or used in the saline flush-outtechnique).10.3.1 EnzymesHyaluronidase is used for the management of extravasationFor preparations, see BNF section 10.3.1.10.3.2 Rubefacients, topicalNSAIDs, capsaicin, andpoulticesClassification not used in BNF for Children.Management of extravasation If extravasation issuspected the infusion should be stopped immediatelybut the cannula should not be removed until after anattempt has been made to aspirate the area (through thecannula) in order to remove as much of the drug aspossible. Aspiration is sometimes possible if the extravasationpresents with a raised bleb or blister at theinjection site and is surrounded by hardened tissue, butit is often unsuccessful if the tissue is soft or soggy.Corticosteroids are usually given to treat inflammation,although there is little evidence to support their use inextravasation. Hydrocortisone or dexamethasone (section6.3.2) can be given either locally by subcutaneousinjection or intravenously at a site distant from theinjury. Antihistamines (section 3.4.1) and analgesics(section 4.7) may be required for symptom relief.The management of extravasation beyond these measuresis not well standardised and calls for specialistadvice. Treatment depends on the nature of the offendingsubstance; one approach is to localise and neutralisethe substance whereas another is to spread and dilute it.

BNFC 2011–2012 51711 Eye11.1 Administration of drugs to theeye 51711.2 Control of microbial contamination51811.3 Anti-infective eye preparations 51811.3.1 Antibacterials 51811.3.2 Antifungals 52011.3.3 Antivirals 52111.4 Corticosteroids and other antiinflammatorypreparations 52111.4.1 Corticosteroids 52111.4.2 Other anti-inflammatory preparations52211.5 Mydriatics and cycloplegics 52411.6 Treatment of glaucoma 52511.7 Local anaesthetics 52911.8 Miscellaneous ophthalmicpreparations 52911.8.1 Tear deficiency, ocular lubricants,and astringents 52911.8.2 Ocular diagnostic and perioperativepreparations 53211.9 Contact lenses 53311.1 Administration of drugsto the eyeDrugs are most commonly administered to the eye bytopical application as eye drops or eye ointments. Whena higher drug concentration is required within the eye, alocal injection may be necessary.Eye-drop dispenser devices are available to aid theinstillation of eye drops from plastic bottles; they areparticularly useful for children in whom normal applicationis difficult, for the visually impaired, or otherwisephysically limited patients.Eye drops and eye ointments Eye drops are generallyinstilled into the pocket formed by gently pullingdown the lower eyelid and keeping the eye closed for aslong as possible after application; in neonates andinfants it may be more appropriate to administer thedrop in the inner angle of the open eye. One drop is allthat is needed; instillation of more than one drop at atime should be discouraged because it may increasesystemic side-effects. A small amount of eye ointment isapplied similarly; the ointment melts rapidly and blinkinghelps to spread it.When two different eye-drop preparations are used atthe same time of day, dilution and overflow may occurwhen one immediately follows the other. The carer orchild should therefore leave an interval of at least 5minutes between the two. Eye ointment should beapplied after drops. Both drops and ointment maycause transient blurred vision; children should bewarned, where appropriate, not to perform skilledtasks (e.g. cycling or driving) until vision is clear.Systemic effects may arise from absorption of drugs intothe general circulation from conjunctival vessels or fromthe nasal mucosa after the excess preparation hasdrained down through the tear ducts. The extent ofsystemic absorption following ocular administration ishighly variable; nasal drainage of drugs is associatedwith eye drops much more often than with eye ointments.Pressure on the lacrimal punctum for at least aminute after applying eye drops reduces nasolacrimaldrainage and therefore decreases systemic absorptionfrom the nasal mucosa.For warnings relating to eye drops and contact lenses,see section 11.9.11 EyeEye lotions These are solutions for the irrigation of theconjunctival sac. They act mechanically to flush outirritants or foreign bodies as a first-aid treatment. Sterilesodium chloride 0.9% solution (section 11.8.1) is usuallyused. Clean water will suffice in an emergency.Other preparations Subconjunctival injection may beused to administer anti-infective drugs, mydriatics, or

518 11.2 Control of microbial contamination BNFC 2011–201211 Eyecorticosteroids for conditions not responding to topicaltherapy. The drug diffuses through the cornea and sclerato the anterior and posterior chambers and vitreoushumour. However, because the dose-volume is limited,this route is suitable only for drugs which are readilysoluble.Drugs such as antimicrobials and corticosteroids maybe administered systemically to treat an eye condition.Preservatives and sensitisers Information on preservativesand on substances identified as skin sensitisers(section 13.1.3) is provided under preparationentries.11.2 Control of microbialcontaminationPreparations for the eye should be sterile when issued.Eye drops in multiple-application containers include apreservative but care should nevertheless be taken toavoid contamination of the contents during use.Eye drops in multiple-application containers for homeuse should not be used for more than 4 weeks after firstopening (unless otherwise stated).Eye drops for use in hospital wards are normally discarded1 week after first opening (24 hours if preservative-free).Individual containers should be provided foreach child, and for each eye if there are special concernsabout contamination. Containers used before an operationshould be discarded at the time of the operation andfresh containers supplied. A fresh supply should also beprovided upon discharge from hospital; in specialistophthalmology units it may be acceptable to issueeye-drop bottles that have been dispensed to the patienton the day of discharge.In out-patient departments single-application packsshould preferably be used; if multiple-applicationpacks are used, they should be discarded at the end ofeach day. In clinics for eye diseases and in accident andemergency departments, where the dangers of infectionare high, single-application packs should be used; if amultiple-application pack is used, it should be discardedafter single use.Diagnostic dyes (section 11.8.2) should be used onlyfrom single-application packs.In eye surgery single-application containers should beused if possible; if a multiple-application pack is used, itshould be discarded after single use. Preparations usedduring intra-ocular procedures and others that maypenetrate into the anterior chamber must be isotonicand without preservatives and buffered if necessary to aneutral pH. Specially formulated fluids should be usedfor intra-ocular surgery; large volume intravenous infusionpreparations are not suitable for this purpose. Forall surgical procedures, a previously unopened containeris used for each patient.11.3 Anti-infective eyepreparations11.3.1 Antibacterials11.3.2 Antifungals11.3.3 AntiviralsEye infections Most acute superficial eye infectionscan be treated topically. Blepharitis and conjunctivitisare often caused by staphylococci; keratitis andendophthalmitis may be bacterial, viral, or fungal.Bacterial blepharitis is treated by lid hygiene and applicationof antibacterial eye drops to the conjunctival sacor to the lid margins. Systemic treatment may berequired and may be necessary for 3 months or longer.Most cases of acute bacterial conjunctivitis are selflimiting;where treatment is appropriate, antibacterialeye drops or an eye ointment are used. A poor responsemight indicate viral or allergic conjunctivitis or antibioticresistance.Corneal ulcer and keratitis require specialist treatment,usually under inpatient care, and may call for intensivetopical, subconjunctival, or systemic administration ofantimicrobials.Endophthalmitis is a medical emergency which alsocalls for specialist management and often requires parenteral,subconjunctival, or intra-ocular administrationof antimicrobials.For reference to the treatment of crab lice of the eyelashes,see section 13.10.411.3.1 AntibacterialsBacterial eye infections are generally treated topicallywith eye drops and eye ointments; systemic treatment issometimes appropriate in blepharitis.Chloramphenicol has a broad spectrum of activity andis the drug of choice for superficial eye infections.Chloramphenicol eye drops are well tolerated and therecommendation that chloramphenicol eye dropsshould be avoided because of an increased risk ofaplastic anaemia is not well founded.Other antibacterials with a broad spectrum of activityinclude the quinolones, ciprofloxacin, levofloxacin,moxifloxacin, and ofloxacin; the aminoglycosides,gentamicin, neomycin, and tobramycin are also activeagainst a wide variety of bacteria. Gentamicin, tobramycin,quinolones (except moxifloxacin), and polymyxinB are effective for infections caused by Pseudomonasaeruginosa.Ciprofloxacin eye drops are licensed for corneal ulcers;intensive application (especially in the first 2 days) isrequired throughout the day and night.Trachoma, which results from chronic infection withChlamydia trachomatis, can be treated with azithromycinby mouth [unlicensed indication].Fusidic acid is useful for staphylococcal infections.Propamidine isetionate is of little value in bacterialinfections but is used by specialists to treat the rare butpotentially sight-threatening condition of acanthamoebakeratitis (see also section 11.9).

BNFC 2011–2012 11.3.1 Antibacterials 519Other antibacterial eye drops may be prepared asepticallyin a specialist manufacturing unit from materialsupplied for injection, see section 11.8.Neonates Antibacterial eye drops are used to treatacute bacterial conjunctivitis in neonates (ophthalmianeonatorum); where possible the causative microorganismshould be identified. Chloramphenicol orneomycin eye drops are used to treat mild conjunctivitis;more serious infections also require a systemicantibacterial. Failure to respond to initial treatmentrequires further investigation; chlamydial infection isone of the most frequent causes of neonatal conjunctivitisand should be considered.Gonococcal eye infections are treated with a single-doseof parenteral cefotaxime or ceftriaxone. Chlamydialeye infections should be managed with oral erythromycin.Gentamicin eye drops together with appropriatesystemic antibacterials are used in the treatment ofpseudomonal eye infections; high-strength gentamicineye drops (1.5%) [unlicensed] are available for severeinfections.With corticosteroids Many antibacterial preparationsalso incorporate a corticosteroid but such mixturesshould not be used unless a patient is under closespecialist supervision. In particular they should not beprescribed for undiagnosed ‘red eye’ which is sometimescaused by the herpes simplex virus and may bedifficult to diagnose (section 11.4).Administration Frequency of application depends onthe severity of the infection and the potential for irreversibleocular damage; antibacterial eye preparationsare usually administered as follows.Eye drops. Apply 1 drop at least every 2 hours in severeinfection then reduce frequency as infection is controlledand continue for 48 hours after healing. Forless severe infection 3–4 times daily is generally sufficient.Eye ointment. Apply either at night (if eye drops usedduring the day) or 3–4 times daily (if eye ointment usedalone).CHLORAMPHENICOLSide-effects transient stinging; see also notes aboveIndication and doseSee notes aboveSingle useMinims c Chloramphenicol (Bausch & Lomb) AEye drops, chloramphenicol 0.5%. Net price 20 0.5 mL = £9.17CIPROFLOXACINCautions not recommended for children under 1 yearPregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding manufacturer advises cautionSide-effects local burning and itching; lid margincrusting; hyperaemia; taste disturbances; cornealstaining, keratitis, lid oedema, lacrimation, photophobia,corneal infiltrates; nausea and visual disturbancesreportedLicensed use eye ointment not licensed for use inchildren under 1 yearIndication and doseSuperficial bacterial infectionsSee notes aboveCorneal ulcerApply eye drops throughout day and night, day 1apply every 15 minutes for 6 hours then every 30minutes, day 2 apply every hour, days 3–14 applyevery 4 hours (max. duration of treatment 21 days)Apply eye ointment throughout day and night;apply 1.25 cm ointment every 1–2 hours for 2 daysthen every 4 hours for next 12 daysCiloxan c (Alcon) AOphthalmic solution (= eye drops), ciprofloxacin (ashydrochloride) 0.3%. Net price 5 mL = £4.70Excipients include benzalkonium chlorideEye ointment, ciprofloxacin (as hydrochloride) 0.3%.Net price 3.5 g = £5.22FUSIDIC ACIDIndication and doseSee notes above and under preparation belowFucithalmic c (LEO) AEye drops, m/r, fusidic acid 1% in gel basis (liquifieson contact with eye). Net price 5 g = £1.96Excipients include benzalkonium chloride, disodium edetateDoseApply twice daily11 EyeChloramphenicol (Non-proprietary) AEye drops, chloramphenicol 0.5%. Net price 10 mL =£2.05Eye ointment, chloramphenicol 1%. Net price 4 g =£2.04Note Chloramphenicol 0.5% eye drops (max. pack size 10 mL)and 1% eye ointment (max. pack size 4 g) can be sold to thepublic for treatment of acute bacterial conjunctivitis in childrenover 2 years; max. duration of treatment 5 daysChloromycetin c (Goldshield) ARedidrops (= eye drops), chloramphenicol 0.5%. Netprice 5 mL = £1.65; 10 mL = 90pExcipients include phenylmercuric acetateOphthalmic ointment (= eye ointment), chloramphenicol1%. Net price 4 g = £1.08GENTAMICINIndication and doseSee notes aboveGenticin c (Amdipharm) ADrops (for ear or eye), gentamicin 0.3% (as sulphate).Net price 10 mL = £2.13Excipients include benzalkonium chlorideGentamicin (Non-proprietary) AEye drops, gentamicin 1.5%, 10 mL, available as amanufactured special from Moorfields Eye Hospital,see also ‘special-order’ manufacturers or specialistimporting companies, p. 809

520 11.3.2 Antifungals BNFC 2011–201211 EyeLEVOFLOXACINPregnancy manufacturer advises avoid—systemicquinolones have caused arthropathy in animal studiesBreast-feeding manufacturer advises avoidSide-effects transient ocular irritation, visual disturbances,lid margin crusting, lid or conjunctivaloedema, hyperaemia, conjunctival follicles, photophobia,headache, rhinitisLicensed use not licensed for use in children under 1yearIndication and doseSee notes aboveOftaquix c (Kestrel Ophthalmics) TAEye drops, levofloxacin 0.5%, net price 5 mL = £6.95MOXIFLOXACINCautions not recommended for neonatesSide-effects taste disturbances, ocular discomfort(including pain, irritation and dryness), hyperaemia;less commonly vomiting, headache, paraesthesia,corneal disorders (including keratitis, erosion, andstaining), conjunctival haemorrhage, eyelid erythema,visual disturbances, nasal discomfort, pharyngolaryngealpain; also reported nausea, palpitation, dyspnoea,dizziness, raised intra-ocular pressure, photophobia,rash, pruritusIndication and doseLocal treatment of infections (see also notesabove)Child 1 month–18 years apply 3 times daily(continue treatment for 2–3 days after infectionimproves; review if no improvement within 5 days)Moxivig c (Alcon) TAEye drops, moxifloxacin (as hydrochloride) 0.5%. Netprice 5 mL = £9.80NEOMYCIN SULPHATEIndication and doseSee notes aboveNeomycin (Non-proprietary) AEye drops, neomycin sulphate 0.5% (3500 units/mL).Net price 10 mL = £3.11Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Eye ointment, neomycin sulphate 0.5% (3500 units/g). Net price 3 g = £2.44Available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809OFLOXACINCautions not to be used for more than 10 daysPregnancy manufacturer advises use only if benefitoutweighs risk; systemic quinolones have causedarthropathy in animal studiesBreast-feeding manufacturer advises avoidSide-effects local irritation including photophobia;dizziness, numbness, nausea and headache reportedLicensed use not licensed for use in neonatesIndication and doseLocal treatment of infections (see also notesabove)Apply every two to four hours for the first two daysthen reduce frequency to four times daily (max. 10days treatment)Exocin c (Allergan) AOphthalmic solution (= eye drops), ofloxacin 0.3%.Net price 5 mL = £2.17Excipients include benzalkonium chloridePOLYMYXIN B SULPHATEIndication and doseSee notes aboveWith other antibacterialsPolyfax c (TEVA UK) AEye ointment, polymyxin B sulphate 10 000 units,bacitracin zinc 500 units/g. Net price 4 g = £3.26PROPAMIDINE ISETIONATEIndication and doseSee under preparations belowBrolene c (Sanofi-Aventis)Eye drops, propamidine isetionate 0.1%. Net price10 mL = £2.80Excipients include benzalkonium chlorideDoseLocal treatment of infections (but see notes above)Apply 4 times dailyNote Eye drops containing propamidine isetionate 0.1% alsoavailable from Typharm (Golden Eye Drops)Eye ointment, dibrompropamidine isetionate 0.15%.Net price 5 g = £2.92DoseLocal treatment of infections (but see notes above)Apply 1–2 times dailyNote Eye ointment containing dibrompropamidine isetionate0.15% also available from Typharm (Golden Eye Ointment)TOBRAMYCINIndication and doseLocal treatment of infections (see also notesabove)Child 1–18 years apply twice daily for 6–8 days;in severe infection, apply 4 times daily on the firstday, then twice daily for 5–7 daysTobravisc c (Alcon) AEye drops, tobramycin 0.3%, net price 5 mL = £4.74Excipients include benzododecinium bromide11.3.2 AntifungalsFungal infections of the cornea are rare. Orbital mycosisis rarer, and when it occurs it is usually because of directspread of infection from the paranasal sinuses. Debilityor immunosuppression can encourage fungal proliferation.The spread of infection through blood occasionallyproduces metastatic endophthalmitis.

BNFC 2011–2012 11.3.3 Antivirals 521Many different fungi are capable of producing ocularinfection; they can be identified by appropriate laboratoryprocedures.Antifungal preparations for the eye are not generallyavailable. Treatment is normally carried out at specialistcentres, but requests for information about supplies ofpreparations not available commercially should beaddressed to the Strategic Health Authority (or equivalentin Scotland or Northern Ireland), or to the nearesthospital ophthalmology unit, or to Moorfields Eye Hospital,162 City Road, London EC1V 2PD (tel. (020) 72533411) or www.moorfields.nhs.uk11.3.3 AntiviralsHerpes simplex infections producing, for example,dendritic corneal ulcers can be treated with aciclovir.Aciclovir eye ointment is used in combination withsystemic treatment for ophthalmic zoster (section5.3.2.1).For systemic treatment of CMV retinitis, see section5.3.2.2.Topical corticosteroids should normally only be usedunder expert supervision; three main dangers are associatedwith their use:. a ‘red eye’, when the diagnosis is unconfirmed, maybe due to herpes simplex virus, and a corticosteroidmay aggravate the condition, leading to cornealulceration, with possible damage to vision andeven loss of the eye. Bacterial, fungal, and amoebicinfections pose a similar hazard;. ‘steroid glaucoma’ may follow the use of corticosteroideye preparations in susceptible individuals;. a ‘steroid cataract’ may follow prolonged use.Other side-effects of ocular corticosteroids include thinningof the cornea and sclera. Prolonged use in neonatesand infants can cause adrenal suppression.Products combining a corticosteroid with an antimicrobialare used after ocular surgery to reduce inflammationand prevent infection: use of combination productsis otherwise rarely justified.Systemic corticosteroids (section 6.3.2) may be usefulfor ocular conditions. The risk of producing a ‘steroidcataract’ increases with the dose and duration ofcorticosteroid use.ACICLOVIR(Acyclovir)Side-effects local irritation and inflammation, superficialpunctate keratopathy; rarely blepharitis; veryrarely hypersensitivity reactions including angioedemaIndication and doseLocal treatment of herpes simplex infectionsApply 5 times daily (continue for at least 3 daysafter complete healing)Herpes simplex skin infections section 13.10.3Herpes simplex and varicella–zoster infectionssection 5.3.2.1Zovirax c (GSK) AEye ointment, aciclovir 3%. Net price 4.5 g = £9.3411.4 Corticosteroids and otheranti-inflammatorypreparations11.4.1 Corticosteroids11.4.2 Other anti-inflammatory preparations11.4.1 CorticosteroidsCorticosteroids administered locally to the eye or givenby mouth are effective for treating anterior segmentinflammation in uveitis (section 11.5) and followingsurgery.BETAMETHASONECautions see notes aboveSide-effects see notes aboveIndication and doseLocal treatment of inflammation (short-term)Apply eye drops every 1–2 hours until controlledthen reduce frequency; eye ointment 2–4 timesdaily or at night when used with eye dropsBetnesol c (UCB Pharma) ADrops (for ear, eye, or nose), betamethasone sodiumphosphate 0.1%. Net price 10 mL = £2.23Excipients include benzalkonium chloride, disodium edetateEye ointment, betamethasone sodium phosphate0.1%. Net price 3 g = £1.36Vistamethasone c (Martindale) ADrops (for ear, eye, or nose), betamethasone sodiumphosphate 0.1%. Net price 5 mL = £1.02; 10 mL =£1.16Excipients include benzalkonium chlorideWith neomycinBetnesol-N c (UCB Pharma) AUDrops (for ear, eye, or nose), see section 12.1.1DEXAMETHASONECautions see notes aboveSide-effects see notes aboveIndication and doseLocal treatment of inflammation (short-term)Apply eye drops 4–6 times daily; severe conditionsevery 30–60 minutes until controlled then reducefrequencyMaxidex c (Alcon) AEye drops, dexamethasone 0.1%, hypromellose 0.5%.Net price 5 mL = £1.42; 10 mL = £2.80Excipients include benzalkonium chloride, disodium edetate, polysorbate8011 Eye

522 11.4.2 Other anti-inflammatory preparations BNFC 2011–201211 EyeSingle useMinims c Dexamethasone (Bausch & Lomb) AEye drops, dexamethasone sodium phosphate 0.1%.Net price 20 0.5 mL = £9.38Excipients include disodium edetateWith antibacterialsMaxitrol c (Alcon) AUEye drops, dexamethasone 0.1%, hypromellose 0.5%,neomycin 0.35% (as sulphate), polymyxin B sulphate6000 units/mL. Net price 5 mL = £1.68Excipients include benzalkonium chloride, polysorbate 20Eye ointment, dexamethasone 0.1%, neomycin0.35% (as sulphate), polymyxin B sulphate6000 units/g. Net price 3.5 g = £1.44Excipients include hydroxybenzoates (parabens), wool fatSofradex c (Sanofi-Aventis) AUDrops (for ear or eye), see section 12.1.1FLUOROMETHOLONECautions see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under 2yearsIndication and doseLocal treatment of inflammation (short-term)Apply 2–4 times daily (initially every hour for 24–48 hours then reduce frequency)FML c (Allergan) AOphthalmic suspension (= eye drops), fluorometholone0.1%, polyvinyl alcohol (Liquifilm c ) 1.4%.Net price 5 mL = £1.71; 10 mL = £2.95Excipients include benzalkonium chloride, disodium edetate, polysorbate80HYDROCORTISONE ACETATECautions see notes aboveSide-effects see notes aboveIndication and doseLocal treatment of inflammation (short-term)Apply eye drops 4 times daily; apply eye ointmenttwice daily or at nightHydrocortisone (Non-proprietary) AEye drops, hydrocortisone acetate 1%. Net price10 mL = £3.21Eye ointment, hydrocortisone acetate 0.5%, net price3 g = £2.88; 1%, 3 g = £6.71PREDNISOLONECautions see notes aboveSide-effects see notes aboveIndication and doseLocal treatment of inflammation (short-term)Apply every 1–2 hours until controlled then reducefrequencyPred Forte c (Allergan) AEye drops, prednisolone acetate 1%. Net price 5 mL =£1.52; 10 mL = £3.05Excipients include benzalkonium chloride, disodium edetate, polysorbate80Predsol c (UCB Pharma) ADrops (for ear or eye), prednisolone sodium phosphate0.5%. Net price 10 mL = £1.92Excipients include benzalkonium chloride, disodium edetateSingle useMinims c Prednisolone Sodium Phosphate (Bausch& Lomb) AEye drops, prednisolone sodium phosphate 0.5%. Netprice 20 0.5 mL = £10.08Excipients include disodium edetateWith neomycinPredsol-N c (UCB Pharma) AUDrops (for ear or eye), see section 12.1.111.4.2 Other anti-inflammatorypreparationsEye drops containing antihistamines, such as antazoline(with xylometazoline as Otrivine-Antistin c ),azelastine, epinastine, ketotifen, and olopatadine,can be used for allergic conjunctivitis.Sodium cromoglicate and nedocromil sodium eyedrops may be useful for vernal keratoconjunctivitisand other allergic forms of conjunctivitis.Lodoxamide eye drops are used for allergic conjunctivalconditions including seasonal allergic conjunctivitis.Emedastine eye drops are licensed for seasonal allergicconjunctivitis.ANTAZOLINE SULPHATEIndication and doseAllergic conjunctivitisSee preparation belowOtrivine-Antistin c (Novartis Consumer Health)Eye drops, antazoline sulphate 0.5%, xylometazolinehydrochloride 0.05%. Net price 10 mL = £2.35Excipients include benzalkonium chloride, disodium edetateDoseChild 12–18 years apply 2–3 times daily (max. duration7 days)Note Xylometazoline is a sympathomimetic; it should beused with caution in patients susceptible to angle-closureglaucoma; absorption of antazoline and xylometazoline mayresult in systemic side-effects and the possibility of interactionwith other drugs, see Appendix 1 (antihistamines andsympathomimetics)AZELASTINE HYDROCHLORIDESide-effects mild transient irritation; bitter tastereportedIndication and doseAllergic conjunctivitis, seasonal allergic conjunctivitisChild 4–18 years apply twice daily, increased ifnecessary to 4 times dailyPerennial conjunctivitisChild 12–18 years apply twice daily, increased ifnecessary to 4 times daily; max. duration oftreatment 6 weeks

BNFC 2011–2012 11.4.2 Other anti-inflammatory preparations 523Optilast c (Meda) AEye drops, azelastine hydrochloride 0.05%. Net price8 mL = £6.40Excipients include benzalkonium chloride, disodium edetateEMEDASTINESide-effects transient burning or stinging; blurredvision, local oedema, keratitis, irritation, dry eye,lacrimation, corneal infiltrates (discontinue) andstaining; photophobia; headache, and rhinitis occasionallyreportedIndication and doseSeasonal allergic conjunctivitisChild 3–18 years apply twice dailyEmadine c (Alcon) AEye drops, emedastine 0.05% (as difumarate), netprice 5 mL = £7.31Excipients include benzalkonium chlorideAlomide c (Alcon) AOphthalmic solution (= eye drops), lodoxamide 0.1%(as trometamol). Net price 10 mL = £5.21Excipients include benzalkonium chloride, disodium edetateNote Lodoxamide 0.1% eye drops can be sold to the publicfor treatment of allergic conjunctivitis in children over 4yearsNEDOCROMIL SODIUMSide-effects transient burning and stinging; distinctivetaste reportedIndication and doseSeasonal and perennial allergic conjunctivitisChild 6–18 years apply twice daily increased ifnecessary to 4 times daily; max. 12 weeks treatmentfor seasonal allergic conjunctivitisVernal keratoconjunctivitisChild 6–18 years apply 4 times dailyEPINASTINE HYDROCHLORIDESide-effects burning; less commonly dry mouth, tastedisturbance; nasal irritation, rhinitis; headache, blepharoptosis,conjunctival oedema and hyperaemia,dry eye, local irritation, photophobia, visual disturbance;pruritusIndication and doseSeasonal allergic conjunctivitisChild 12–18 years apply twice daily; max. durationof treatment 8 weeksRelestat c (Allergan) AEye drops, epinastine hydrochloride 500 micrograms/mL,net price 5 mL = £9.90Excipients include benzalkonium chloride, disodium edetateKETOTIFENSide-effects transient burning or stinging, punctatecorneal epithelial erosion; less commonly dry eye,subconjunctival haemmorhage, photophobia; headache,drowsiness, skin reactions, and dry mouth alsoreportedIndication and doseSeasonal allergic conjunctivitisChild 3–18 years apply twice dailyZaditen c (Novartis) AEye drops, ketotifen (as fumarate) 250 micrograms/mL, net price 5 mL = £7.80Excipients include benzalkonium chlorideLODOXAMIDESide-effects burning, stinging, itching, blurred vision,tear production disturbance, and ocular discomfort;less commonly, flushing, nasal dryness, dizziness,drowsiness, headache, blepharitis, and keratitisIndication and doseAllergic conjunctivitisChild 4–18 years apply 4 times dailyNote Improvement of symptoms may sometimes requiretreatment for up to 4 weeksRapitil c (Sanofi-Aventis) AEye drops, nedocromil sodium 2%. Net price 5 mL =£4.92Excipients include benzalkonium chloride, disodium edetateOLOPATADINESide-effects local irritation; less commonly keratitis,dry eye, local oedema, photophobia; headache, asthenia,dizziness; dry nose also reportedIndication and doseSeasonal allergic conjunctivitisChild 3–18 years apply twice daily; max. durationof treatment 4 monthsOpatanol c (Alcon) AEye drops, olopatadine (as hydrochloride) 1 mg/mL,net price 5 mL = £3.91Excipients include benzalkonium chlorideSODIUM CROMOGLICATE(Sodium cromoglycate)Side-effects transient burning and stingingIndication and doseAllergic conjunctivitis, vernal keratoconjunctivitisApply eye drops 4 times dailySodium Cromoglicate (Non-proprietary) AEye drops, sodium cromoglicate 2%. Net price13.5 mL = £1.79Brands include Hay-Crom c Aqueous, Opticrom c Aqueous,Vividrin cNote Sodium cromoglicate 2% eye drops can be sold to thepublic (in max. pack size of 10 mL) for treatment of acuteseasonal and perennial allergic conjunctivitisSingle useCatacrom c (Moorfields)Eye drops, sodium cromoglicate 2%, net price 30 x0.3 mL = £8.9911 Eye

524 11.5 Mydriatics and cycloplegics BNFC 2011–201211 Eye11.5 Mydriatics andcycloplegicsAntimuscarinics dilate the pupil and paralyse the ciliarymuscle; they vary in potency and duration of action.Short-acting, relatively weak mydriatics, such as tropicamide0.5% (action lasts for 4–6 hours), facilitate theexamination of the fundus of the eye. Cyclopentolate1% (action up to 24 hours) or atropine (action up to 7days) are preferable for producing cycloplegia forrefraction in young children; tropicamide may be preferredin neonates. Phenylephrine 2.5% is used formydriasis in diagnostic or therapeutic procedures;mydriasis occurs within 60–90 minutes and lasts up to5–7 hours. Phenylephrine 10% drops are contra-indicatedin children owing to the risk of systemic effects.Mydriatics and cycloplegics are used in the treatment ofanterior uveitis, usually as an adjunct to corticosteriods(section 11.4.1). Atropine is used in anterior uveitismainly to prevent posterior synechiae and to relieveciliary spasm; cyclopentolate or homatropine (actionup to 3 days) can also be used and may be preferredbecause they have a shorter duration of action.Cautions and contra-indications Darkly pigmentedirides are more resistant to pupillary dilatation andcaution should be exercised to avoid overdosage.Mydriasis can precipitate acute angle-closure glaucomain the very few children who are predisposed to thecondition because of a shallow anterior chamber. Atropine,cyclopentolate, and homatropine should be usedwith caution in children under 3 months owing to thepossible association between cycloplegia and the developmentof amblyopia; also, neonates are at increasedrisk of systemic toxicity.Skilled tasks Children may not be able to undertake skilledtasks until vision clears after mydriasis.Side-effects Ocular side-effects of mydriatics andcycloplegics include transient stinging and raisedintra-ocular pressure; on prolonged administration,local irritation, hyperaemia, oedema, and conjunctivitiscan occur. Contact dermatitis can occur with the antimuscarinicmydriatic drugs, especially atropine.Toxic systemic reactions to atropine and cyclopentolatecan occur in neonates and children; see section 1.2 forsystemic side-effects of antimuscarinic drugs.AntimuscarinicsATROPINE SULPHATECautions risk of systemic effects with eye drops ininfants under 3 months, see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children foruveitisIndication and doseCycloplegiaChild 3 months–18 years apply drops or ointmenttwice daily for 3 days before procedureAnterior uveitisChild 2–18 years 1 drop up to 4 times dailyAtropine (Non-proprietary) AEye drops, atropine sulphate 0.5%, net price 10 mL =£2.78; 1%, 10 mL = £9.50Single useMinims c Atropine Sulphate (Bausch & Lomb) AEye drops, atropine sulphate 1%. Net price 20 0.5 mL = £12.71CYCLOPENTOLATE HYDROCHLORIDECautions see notes aboveSide-effects see notes aboveIndication and doseSee notes aboveCycloplegiaChild 3 months–12 years 1 drop of 1% eye drops30–60 minutes before examinationChild 12–18 years 1 drop of 0.5% eye drops 30–60 minutes before examinationUveitisChild 3 months–18 years 1 drop of 0.5% eyedrops (1% for deeply pigmented eyes) 2–4 timesdailyMydrilate c (Intrapharm) AEye drops, cyclopentolate hydrochloride 0.5%, netprice 5 mL = £6.73; 1%, 5 mL = £6.73Excipients include benzalkonium chlorideSingle useMinims c Cyclopentolate Hydrochloride (Bausch &Lomb) AEye drops, cyclopentolate hydrochloride 0.5% and1%. Net price 20 0.5 mL (both) = £9.64HOMATROPINE HYDROBROMIDECautions see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under 3monthsIndication and doseSee notes aboveChild 3 months–2 years (0.5% only) 1 drop dailyor on alternate days adjusted according toresponseChild 2–18 years 1 drop twice daily adjustedaccording to responseHomatropine (Non-proprietary) AEye drops, homatropine hydrobromide 1%, net price10 mL = £2.57; 2%, 10 mL = £2.71Available without preservatives as manufacturedspecials from Moorfields Eye HospitalEye drops, homatropine 0.125% and 0.5%, 10 mL,available as a manufactured special from MoorfieldsEye Hospital, see also ‘special-order’ manufacturersor specialist importing companies, p. 809Excipients include chlorhexidineTROPICAMIDECautions see notes aboveSide-effects see notes above

BNFC 2011–2012 11.6 Treatment of glaucoma 525Indication and doseSee notes aboveFunduscopyNeonate and child apply 0.5% eye drops 20minutes before examinationMydriacyl c (Alcon) AEye drops, tropicamide 0.5%, net price 5 mL = £1.29;1%, 5 mL = £1.60Excipients include benzalkonium chloride, disodium edetateSingle useMinims c Tropicamide (Bausch & Lomb) AEye drops, tropicamide 0.5% and 1%. Net price 20 0.5 mL (both) = £9.01SympathomimeticsPHENYLEPHRINE HYDROCHLORIDECautions cardiovascular disease (avoid or use 2.5%strength only); tachycardia; hyperthyroidism; diabetes;susceptibility to angle-closure glaucoma; seealso notes aboveContra-indications 10% drops in neonates and childrenSide-effects eye pain and stinging; blurred vision,photophobia; systemic effects include palpitations,arrhythmias, hypertension, coronary artery spasm;very rarely angle-closure glaucomaIndication and doseMydriasisSee notes aboveSingle useMinims c Phenylephrine Hydrochloride (Bausch &Lomb)Eye drops, phenylephrine hydrochloride 2.5%, netprice 20 0.5 mL = £9.53Excipients include disodium edetate, sodium metabisulphite11.6 Treatment of glaucomaGlaucoma describes a group of disorders characterisedby a loss of visual field associated with cupping of theoptic disc and optic nerve damage and is generallyassociated with raised intra-ocular pressure.Glaucoma is rare in children and should always bemanaged by a specialist. Primary congenital glaucomais the most common form of glaucoma in children,followed by secondary glaucomas, such as followinghereditary anterior segment malformations; juvenileopen-angle glaucoma is less common and usuallyoccurs in older children. Primary angle closure glaucoma(acute closed-angle glaucoma, narrow angle glaucoma)is very rare in children; it results from blockage ofaqueous humour flow into the anterior chamber and is amedical emergency that requires urgent reduction ofintra-ocular pressure, see below.Treatment of glaucoma is determined by the pathophysiologyand usually involves controlling raised intraocularpressure with surgery and drug therapy. Drugsthat reduce intra-ocular pressure by different mechanismsare available for managing glaucoma. A topicalbeta-blocker or a prostaglandin analogue can be used. Itmay be necessary to combine these drugs or add others,such as miotics, sympathomimetics, or carbonicanhydrase inhibitors, to control intra-ocular pressure.For urgent reduction of intra-ocular pressure and beforesurgery, mannitol 20% (up to 500 mL) is given by slowintravenous infusion until the intra-ocular pressure hasbeen satisfactorily reduced (see section 2.2.5). Acetazolamideby intravenous injection can also be used forthe emergency management of raised intra-ocular pressure.Standard antiglaucoma therapy is used if supplementarytreatment is required after iridotomy, iridectomy, or adrainage operation in either primary open-angle oracute closed-angle glaucoma.Beta-blockersTopical application of a beta-blocker to the eye reducesintra-ocular pressure effectively in primary open-angleglaucoma, probably by reducing the rate of productionof aqueous humour. Administration by mouth alsoreduces intra-ocular pressure but this route is not usedsince side-effects may be troublesome.Cautions, contra-indications, and side-effectsSystemic absorption can follow topical application tothe eye; therefore, eye drops containing a beta-blockerare contra-indicated in bradycardia, heart block, oruncontrolled heart failure. Important: for a warning toavoid in asthma, see below. Consider also other cautions,contra-indications, and side-effects of beta-blockers(p. 87). Local side-effects of eye drops include ocularstinging, burning, pain, itching, erythema, dry eyes andallergic reactions including anaphylaxis and blepharoconjunctivitis;occasionally corneal disorders have beenreported.Important Beta-blockers, even those with apparent cardioselectivity,should not be used in patients with asthma or ahistory of bronchospasm, unless no alternative treatment isavailable. In such cases the risk of inducing bronchospasmshould be appreciated and appropriate precautions taken.Interactions Since systemic absorption may followtopical application the possibility of interactions, inparticular with drugs such as verapamil, should beborne in mind. See also Appendix 1 (beta-blockers).BETAXOLOLCautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseSee notes aboveApply twice dailyBetaxolol (Non-proprietary) AEye drops, solution, betaxolol (as hydrochloride)0.5%, net price 5 mL = £1.90Excipients may include benzalkonium chloride, disodium edetate11 Eye

526 11.6 Treatment of glaucoma BNFC 2011–201211 EyeBetoptic c (Alcon) AOphthalmic solution (= eye drops), betaxolol (ashydrochloride) 0.5%, net price 5 mL = £1.90Excipients include benzalkonium chloride, disodium edetateOphthalmic suspension (= eye drops), betaxolol (ashydrochloride) 0.25%, net price 5 mL = £2.66Excipients include benzalkonium chloride, disodium edetateUnit dose eye drop suspension, betaxolol (ashydrochloride) 0.25%, net price 50 0.25 mL =£13.77CARTEOLOL HYDROCHLORIDECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseSee notes aboveApply twice dailyTeoptic c (Spectrum Thea) AEye drops, carteolol hydrochloride 1%, net price 5 mL= £7.60; 2%, 5 mL = £8.40Excipients include benzalkonium chlorideLEVOBUNOLOL HYDROCHLORIDECautions see notes aboveContra-indications see notes aboveSide-effects see notes above; anterior uveitis occasionallyreportedLicensed use not licensed for use in childrenIndication and doseSee notes aboveApply once or twice dailyLevobunolol (Non-proprietary) AEye drops, levobunolol hydrochloride 0.5%. Net price5 mL = £3.05Excipients may include benzalkonium chloride, disodium edetate, sodiummetabisulphiteBetagan c (Allergan) AEye drops, levobunolol hydrochloride 0.5%, polyvinylalcohol (Liquifilm c ) 1.4%. Net price 5-mL = £1.85Excipients include benzalkonium chloride, disodium edetate, sodiummetabisulphiteUnit dose eye drops, levobunolol hydrochloride0.5%, polyvinyl alcohol (Liquifilm c ) 1.4%. Net price30 0.4 mL = £9.98Excipients include disodium edetateTIMOLOL MALEATECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseSee notes aboveApply twice daily; long-acting preparations, seeunder preparations belowTimolol (Non-proprietary) AEye drops, timolol (as maleate) 0.25%, net price 5 mL= £1.56; 0.5%, 5 mL = £1.56Timoptol c (MSD) AEye drops, in Ocumeter c metered-dose unit, timolol(as maleate) 0.25%, net price 5 mL = £3.12; 0.5%,5 mL = £3.12Excipients include benzalkonium chlorideUnit dose eye drops, timolol (as maleate) 0.25%, netprice 30 0.2 mL = £8.45; 0.5%, 30 0.2 mL = £9.65Once-daily preparationsNyogel c (Novartis) AEye gel (= eye drops), timolol (as maleate) 0.1%, netprice 5 g = £2.85Excipients include benzalkonium chlorideDoseChild 12–18 years apply once daily in the morningTimoptol c -LA (MSD) AOphthalmic gel-forming solution (= eye drops),timolol (as maleate) 0.25%, net price 2.5 mL = £3.12;0.5%, 2.5 mL = £3.12Excipients include benzododecinium bromideDoseApply eye drops once dailyWith dorzolamideSee under DorzolamideProstaglandin analoguesThe prostaglandin analogues latanoprost, and travoprost,and the synthetic prostamide, bimatoprost,increase uveoscleral outflow and subsequently reduceintra-ocular pressure. They are used to reduce intraocularpressure. Only latanoprost is licensed for use inchildren; for prescribing information, see BNF section11.6. Children receiving prostaglandin analogues shouldbe managed by a specialist and monitored for anychanges to eye coloration since an increase in thebrown pigment in the iris can occur; particular care isrequired in those with mixed coloured irides and thosereceiving treatment to one eye only.SympathomimeticsApraclonidine (section 11.8.2) is an alpha 2 -adrenoceptoragonist. Eye drops containing apraclonidine0.5% are used for a short period to delay laser treatmentor surgery for glaucoma in patients not adequatelycontrolled by another drug; eye drops containing 1%are used for control of intra-ocular pressure after anteriorsegment laser surgery.Brimonidine is an alpha 2 -adrenoceptor agonist thatreduces intra-ocular pressure; it is contra-indicated inneonates and children under 2 years (risk of severesystemic side-effects), and should be used with cautionin children 2–12 years (increased risk of drowsiness).Carbonic anhydrase inhibitors andsystemic drugsThe carbonic anhydrase inhibitors, acetazolamide,brinzolamide, and dorzolamide, reduce intra-ocularpressure by reducing aqueous humour production. Systemicuse of acetazolamide also produces weak diuresis.

BNFC 2011–2012 11.6 Treatment of glaucoma 527Acetazolamide is given by mouth or, rarely in children,by intravenous injection (intramuscular injections arepainful because of the alkaline pH of the solution). It isused as an adjunct to other treatment for reducing intraocularpressure. Acetazolamide is a sulfonamide derivative;blood disorders, rashes, and other sulfonamiderelatedside-effects occur occasionally; children andtheir carers should be told to report any unusual skinrash. It is not generally recommended for long-term use;electrolyte disturbances and metabolic acidosis thatoccur can be corrected by administering potassiumbicarbonate (as effervescent potassium tablets, section9.2.1.3).Dorzolamide and brinzolamide are topical carbonicanhydrase inhibitors. They are unlicensed in childrenbut are used in those resistant to beta-blockers or thosein whom beta-blockers are contra-indicated. They areused alone or as an adjunct to a topical beta-blocker.Systemic absorption can rarely cause sulfonamide-likeside-effects and may require discontinuation if severe.The osmotic diuretics, intravenous hypertonic mannitol(section 2.2.5) or glycerol by mouth, are usefulshort-term ocular hypotensive drugs.ACETAZOLAMIDECautions not generally recommended for prolongeduse but if given monitor blood count and plasmaelectrolyte concentration; pulmonary obstruction andimpaired alveolar ventilation (risk of acidosis); diabetesmellitus; renal calculi; avoid extravasation atinjection site (risk of necrosis); interactions: Appendix1 (diuretics)Contra-indications hypokalaemia, hyponatraemia,hyperchloraemic acidosis; adrenocortical insufficiency;long-term administration in chronic angleclosureglaucoma; sulfonamide hypersensitivityHepatic impairment manufacturer advises avoidRenal impairment avoid; metabolic acidosisPregnancy manufacturer advises avoid, especially infirst trimester (toxicity in animal studies)Breast-feeding amount too small to be harmfulSide-effects see notes above; also nausea, vomiting,diarrhoea, taste disturbance, loss of appetite, paraesthesia,flushing, headache, dizziness, fatigue, irritability,excitement, ataxia, depression, thirst, polyuria; lesscommonly melaena, drowsiness, confusion, hearingdisturbances, fever, glycosuria, metabolic acidosis andelectrolyte disturbances on long-term therapy, haematuria,crystalluria, renal and ureteral colic, renallesions or calculi, renal failure, blood disorders, bonemarrow suppression, rash (including Stevens-Johnsonsyndrome and toxic epidermal necrosis); rarely fulminanthepatic necrosis, hepatitis, cholestatic jaundice,flaccid paralysis, convulsions, photosensitivity;also reported transient myopiaLicensed use not licensed for use in children fortreatment of glaucomaIndication and doseReduction of intra-ocular pressure in openangleglaucoma, secondary glaucoma, perioperativelyin angle-closure glaucoma. By mouth or by intravenous injectionChild 1 month–12 years 5 mg/kg 2–4 times daily,adjusted according to response, max. 750 mg dailyChild 12–18 years 250 mg 2–4 times dailyEpilepsy. By mouth or slow intravenous injectionNeonate initially 2.5 mg/kg 2–3 times daily, followedby 5–7 mg/kg 2–3 times daily (maintenancedose)Child 1 month–12 years initially 2.5 mg/kg 2–3times daily, followed by 5–7 mg/kg 2–3 times daily,max. 750 mg daily (maintenance dose)Child 12–18 years 250 mg 2–4 times dailyRaised intracranial pressure. By mouth or slow intravenous injectionChild 1 month–12 years initially 8 mg/kg 3 timesdaily, increased as necessary to max. 100 mg/kgdailyDiamox c (Goldshield) ATablets, acetazolamide 250 mg. Net price 112-tabpack = £12.68. Label: 3Sodium Parenteral (= injection), powder for reconstitution,acetazolamide (as sodium salt). Net price500-mg vial = £14.76Modified releaseDiamox c SR (Goldshield) ACapsules, m/r, orange, enclosing orange f/c pellets,acetazolamide 250 mg. Net price 30-cap pack =£13.88. Label: 3, 25DoseChild 12–18 years glaucoma, 1–2 capsules dailyExtemporaneous formulations available seeExtemporaneous Preparations, p. 6BRINZOLAMIDECautions systemic absorption follows topical application;neonates and infants with immature renaltubules—risk of metabolic acidosis; interactions:Appendix 1 (brinzolamide)Contra-indications hyperchloraemic acidosisHepatic impairment manufacturer advises avoidRenal impairment see Cautions above; also avoid ifestimated glomerular filtration rate less than 30 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid unless essential—toxicityin animal studiesBreast-feeding manufacturer advises avoidSide-effects local irritation, taste disturbance; lesscommonly nausea, dyspepsia, dry mouth, chest pain,epistaxis, haemoptysis, dyspnoea, rhinitis, pharyngitis,bronchitis, paraesthesia, depression, dizziness,headache, dermatitis, alopecia, corneal erosionLicensed use not licensed for use in childrenIndication and doseAdjunct to beta-blockers or used alone in raisedintra-ocular pressure in ocular hypertensionand in open-angle glaucoma if beta-blockeralone inadequate or inappropriateApply twice daily increased to 3 times daily ifnecessaryAzopt c (Alcon) AEye drops, brinzolamide 10 mg/mL, net price 5 mL =£6.56Excipients include benzalkonium chloride, disodium edetate11 Eye

528 11.6 Treatment of glaucoma BNFC 2011–201211 EyeDORZOLAMIDECautions systemic absorption follows topical application;history of renal calculi; neonates and infants withimmature renal tubules—risk of metabolic acidosis;chronic corneal defects, history of intra-ocular surgery;interactions: Appendix 1 (dorzolamide)Contra-indications hyperchloraemic acidosisHepatic impairment manufacturer advises caution—no information availableRenal impairment see Cautions above; also avoid ifestimated glomerular filtration rate less than 30 mL/minute/1.73 m 2Pregnancy manufacturer advises avoid—toxicity inanimal studiesBreast-feeding manufacturer advises avoid—noinformation availableSide-effects nausea, bitter taste; headache, asthenia;ocular irritation, blurred vision, lacrimation, conjunctivitis,superficial punctuate keratitis, eyelidinflammation; less commonly iridocyclitis; rarelyhypersensitivity reactions (including urticaria, angioedema,bronchospasm), dizziness, paraesthesia, urolithiasis,eyelid crusting, transient myopia, cornealoedema, epistaxis, dry mouth, throat irritation; alsoreported metabolic acidosisLicensed use not licensed for use in childrenIndication and doseRaised intra-ocular pressure in ocular hypertension,open-angle glaucoma, pseudo-exfoliativeglaucoma either as adjunct to betablockeror used alone in patients unresponsiveto beta-blockers or if beta-blockers contraindicatedUsed alone, apply 3 times daily; with topical betablocker,apply twice dailyDorzolamide (Non-proprietary) AEye drops, dorzolamide (as hydrochloride) 2%, netprice 5 mL = £5.61Excipients may include benzalkonium chlorideBrands include Dorzant cTrusopt c (MSD) AOphthalmic solution (= eye drops), in Ocumeter cPlus metered-dose unit, dorzolamide (as hydrochloride)2%, net price 5 mL = £6.33Excipients include benzalkonium chlorideUnit dose eye drops, dorzolamide (as hydrochloride)2%, net price 60 0.2 mL = £24.18With timololFor prescribing information on timolol, see section11.6, Beta-blockersDorzolamide with Timolol (Non-proprietary) AEye drops, dorzolamide (as hydrochloride) 2%,timolol (as maleate) 0.5%, net price 5 mL = £10.05Excipients may include benzalkonium chlorideCosopt c (MSD) AOphthalmic solution (= eye drops), in Ocumeter cPlus metered-dose unit, dorzolamide (as hydrochloride)2%, timolol (as maleate) 0.5%, net price5 mL = £10.05Excipients include benzalkonium chlorideUnit dose eye drops, dorzolamide (as hydrochloride)2%, timolol (as maleate) 0.5%, net price 60 0.2 mL =£28.59DoseRaised intra-ocular pressure in open-angle glaucoma,or pseudoexfoliative glaucoma when beta-blockersalone not adequateApply twice dailyMioticsPilocarpine is a miotic used in the management ofraised intra-ocular pressure. The small pupil is anunwanted effect of these drugs (except when pilocarpineis used temporarily before an operation forangle-closure glaucoma). Miotics act by opening upthe inefficient drainage channels in the trabecular meshwork.Cautions A darkly pigmented iris may require a higherconcentration of the miotic or more frequent administrationand care should be taken to avoid overdosage.Retinal detachment has occurred in susceptible individualsand those with retinal disease; therefore fundusexamination is advised before starting treatment with amiotic. Care is also required in conjunctival or cornealdamage. Intra-ocular pressure and visual fields shouldbe monitored in those with chronic simple glaucomaand those receiving long-term treatment with a miotic.Miotics should be used with caution in patients withpeptic ulceration, gastro-intestinal spasm, cardiac disease,hypertension, hypotension, asthma, epilepsy,hyperthyroidism, and urinary-tract obstruction.Counselling Blurred vision may affect performance of skilledtasks (e.g. driving) particularly at night or in reduced lightingContra-indications Miotics are contra-indicated inconditions where pupillary constriction is undesirablesuch as acute iritis, anterior uveitis and some forms ofsecondary glaucoma. They should be avoided in acuteinflammatory disease of the anterior segment.Pregnancy Miotics should be avoided unless thepotential benefit outweighs the risk—limited informationavailable.Breast-feeding Miotics should be avoided unless thepotential benefit outweighs the risk—no informationavailable.Side-effects Ciliary spasm leads to headache andbrowache which may be more severe in the initial 2–4weeks of treatment. Ocular side-effects include burning,itching, smarting, blurred vision, conjunctival vascularcongestion, myopia, lens changes with chronic use,vitreous haemorrhage, and pupillary block. Systemicside-effects are rare following application to the eye.PILOCARPINECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children

BNFC 2011–2012 11.7 Local anaesthetics 529Indication and doseSee also notes aboveRaised intra-ocular pressure in ocular hypertensionand open-angle glaucomaChild 1 month–2 years 1 drop of 0.5% or 1%solution 3 times dailyChild 2–18 years 1 drop 4 times dailyPre-operatively in goniotomy and trabeculotomyChild 1 month–18 years apply 1% or 2% solutiononce dailyPilocarpine Hydrochloride (Non-proprietary) AEye drops, pilocarpine hydrochloride 1%, 10 mL =£3.00; 2%, 10 mL = £2.87; 4%, 10 mL = £3.83Excipients may include benzalkonium chlorideSingle useMinims c Pilocarpine Nitrate (Bausch & Lomb) AEye drops, pilocarpine nitrate 2%, net price 20 0.5 mL = £10.0411.7 Local anaestheticsOxybuprocaine and tetracaine are widely used topicallocal anaesthetics. Proxymetacaine causes less initialstinging and is particularly useful for children. Oxybuprocaineor a combined preparation of lidocaineand fluorescein is used for tonometry. Tetracaine producesmore profound anaesthesia and is suitable for usebefore minor surgical procedures, such as the removalof corneal sutures. It has a temporary disruptive effecton the corneal epithelium. Lidocaine, with or withoutadrenaline (epinephrine), is injected into the eyelids forminor surgery, while retrobulbar or peribulbar injectionsare used for surgery of the globe itself, see section 15.2,p. 649. Local anaesthetics should never be used for themanagement of ocular symptoms.Caution Local anaesthetic eye drops should beavoided in preterm neonates because of the immaturityof the metabolising enzyme system.LIDOCAINE HYDROCHLORIDE(Lignocaine hydrochloride)Contra-indications avoid in preterm neonatesIndication and doseLocal anaestheticUse as requiredMinims c Lidocaine and Fluorescein (Bausch & Lomb)AEye drops, lidocaine hydrochloride 4%, fluoresceinsodium 0.25%. Net price 20 0.5 mL = £10.61OXYBUPROCAINE HYDROCHLORIDE(Benoxinate hydrochloride)Contra-indications avoid in preterm neonatesIndication and doseLocal anaestheticUse as requiredMinims c Oxybuprocaine Hydrochloride (Bausch &Lomb) AEye drops, oxybuprocaine hydrochloride 0.4%. Netprice 20 0.5 mL = £8.92PROXYMETACAINEHYDROCHLORIDEContra-indications avoid in preterm neonatesIndication and doseLocal anaestheticUse as requiredMinims c Proxymetacaine (Bausch & Lomb) AEye drops, proxymetacaine hydrochloride 0.5%. Netprice 20 0.5 mL = £9.51With fluoresceinMinims c Proxymetacaine and Fluorescein (Bausch& Lomb) AEye drops, proxymetacaine hydrochloride 0.5%,fluorescein sodium 0.25%. Net price 20 0.5 mL =£10.59TETRACAINE HYDROCHLORIDE(Amethocaine hydrochloride)Contra-indications avoid in preterm neonatesIndication and doseLocal anaestheticUse as requiredMinims c Tetracaine Hydrochloride (Bausch & Lomb)AEye drops, tetracaine hydrochloride 0.5% and 1%.Net price 20 0.5 mL (both) = £8.9311.8 Miscellaneousophthalmic preparationsCertain eye drops, e.g. amphotericin, ceftazidime, cefuroxime,colistimethate sodium, desferrioxamine, dexamethasone,gentamicin, and vancomycin, can be preparedaseptically in a specialist manufacturing unit frommaterial supplied for injection.Preparations may also be available from Moorfields EyeHospital as manufactured specials, see also ‘specialorder’manufacturers or specialist importing companies,p. 809.11.8.1 Tear deficiency, ocularlubricants, andastringentsChronic soreness of the eyes associated with reduced orabnormal tear secretion often responds to tear replacementtherapy. The severity of the condition and thechild’s preference will often guide the choice of preparation.Hypromellose is the traditional choice of treatment fortear deficiency. It may need to be instilled frequently11 Eye

530 11.8.1 Tear deficiency, ocular lubricants, and astringents BNFC 2011–201211 Eye(e.g. hourly) for adequate relief. Ocular surface mucin isoften abnormal in tear deficiency and the combinationof hypromellose with a mucolytic such as acetylcysteinecan be helpful.The ability of carbomers to cling to the eye surface mayhelp reduce frequency of application to 4 times daily.Polyvinyl alcohol increases the persistence of the tearfilm and is useful when the ocular surface mucin isreduced.Sodium hyaluronate eye drops are also used in themanagement of tear deficiency.Sodium chloride 0.9% drops are sometimes useful intear deficiency, and can be used as ‘comfort drops’ bycontact lens wearers, and to facilitate lens removal.Special presentations of sodium chloride 0.9% andother irrigation solutions are used routinely for intraocularsurgery and in first-aid for removal of harmfulsubstances.Eye ointments containing a paraffin can be used tolubricate the eye surface, especially in cases of recurrentcorneal epithelial erosion. They may cause temporaryvisual disturbance and are best suited for applicationbefore sleep. Ointments should not be used duringcontact lens wear.ACETYLCYSTEINEIndication and doseTear deficiency, impaired or abnormal mucusproductionApply 3–4 times dailyIlube c (Moorfields) AEye drops, acetylcysteine 5%, hypromellose 0.35%.Net price 10 mL = £10.09Excipients include benzalkonium chloride, disodium edetateCARBOMERS(Polyacrylic acid)Synthetic high molecular weight polymers of acrylic acid crosslinkedwith either allyl ethers of sucrose or allyl ethers ofpentaerithritylLicensed use some preparations not licensed for usein childrenIndication and doseDry eyes including keratoconjunctivitis sicca,unstable tear filmApply 3–4 times daily or as requiredGelTears c (Bausch & Lomb)Gel (= eye drops), carbomer 980 (polyacrylic acid)0.2%, net price 10 g = £2.80Excipients include benzalkonium chlorideLiposic c (Bausch & Lomb)Gel (= eye drops), carbomer 980 (polyacrylic acid)0.2%, net price 10 g = £2.96Excipients include cetrimideLumecare c Long Lasting Tear Gel (Medicom)Gel (= eye drops), carbomer 980 (polyacrylic acid)0.2%, net price 10 g = £2.10Excipients include cetrimideViscotears c (Novartis)Liquid gel (= eye drops), carbomer 980 (polyacrylicacid) 0.2%, net price 10 g = £2.94Excipients include cetrimideLiquid gel (= eye drops), carbomer 980 (polyacrylicacid) 0.2%, net price 30 0.6-mL single-dose units =£5.42CARMELLOSE SODIUMIndication and doseDry eye conditionsApply as requiredOptive c (Allergan)Eye drops, carmellose sodium 0.5%, glycerol, netprice 10 mL = £7.49Single useCarmellose (Non-proprietary)Eye drops, carmellose sodium 0.5%, net price 30 0.4 mL = £5.75Note Each unit is resealable for up to 12 hoursCarmize c (Aspire)Eye drops, carmellose sodium 0.5%, net price 30 0.4 mL = £5.75, 90 0.4 mL = £15.53; 1%, 30 0.4 mL = £3.00, 60 0.4 mL = £6.00Celluvisc c (Allergan)Eye drops, carmellose sodium 0.5%, net price 30 0.4 mL = £5.75, 90 0.4 mL = £15.53; 1%, 30 0.4 mL = £3.00, 60 0.4 mL = £10.99HYDROXYETHYLCELLULOSEIndication and doseTear deficiencyApply as requiredMinims c Artificial Tears (Bausch & Lomb)Eye drops, hydroxyethylcellulose 0.44%, sodiumchloride 0.35%. Net price 20 0.5 mL = £8.21HYDROXYPROPYL GUARIndication and doseDry eye conditionsApply as requiredSystane c (Alcon)Eye drops, hydroxypropyl guar, net price 10 mL =£4.66Single useSystane c (Alcon)Eye drops, hydroxypropyl guar, net price 28 0.8 mL= £4.66HYPROMELLOSEIndication and doseTear deficiencyApply as requiredNote The Royal Pharmaceutical Society has stated thatwhere it is not possible to ascertain the strength ofhypromellose prescribed, the prescriber should be contactedto clarify the strength intended.Hypromellose (Non-proprietary)Eye drops, hypromellose 0.3%, net price 10 mL =£1.61Excipients may include benzalkonium chlorideBrands include Lumecare c Hypromellose

BNFC 2011–2012 11.8.1 Tear deficiency, ocular lubricants, and astringents 531Artelac c (Pharma-Global)Eye drops, hypromellose 0.32%, net price 10 mL =£4.99Excipients include cetrimide, disodium edetateIsopto Alkaline c (Alcon)Eye drops, hypromellose 1%, net price 10 mL = 94pExcipients include benzalkonium chlorideIsopto Plain c (Alcon)Eye drops, hypromellose 0.5%, net price 10 mL = 81pExcipients include benzalkonium chlorideTears Naturale c (Alcon)Eye drops, hypromellose 0.3%, dextran ‘70’ 0.1%, netprice 15 mL = £1.60Excipients include benzalkonium chloride, disodium edetateSingle useArtelac c SDU (Pharma-Global)Eye drops, hypromellose 0.32%, net price 30 0.5 mL = £16.95Hydromoor c (Moorfields)Eye drops, hypromellose 0.3%, net price 30 0.4 mL= £5.75Lumecare c Preservative Free Tear Drops (Medicom)Eye drops, hypromellose 0.3%, net price 30 0.5 mL= £5.72Tears Naturale c Single Dose (Alcon)Eye drops, hypromellose 0.3%, dextran ‘70’ 0.1%, netprice 28 0.4 mL = £13.26LIQUID PARAFFINIndication and doseDry eye conditionsApply as requiredLacri-Lube c (Allergan)Eye ointment, white soft paraffin 57.3%, liquid paraffin42.5%, wool alcohols 0.2%. Net price 3.5 g =£2.51, 5 g = £3.32PARAFFIN, YELLOW, SOFTIndication and doseSee notes aboveApply 2 hourly as requiredSimple Eye OintmentOintment, liquid paraffin 10%, wool fat 10%, in yellowsoft paraffin. Net price 4 g = £3.06POLYVINYL ALCOHOLIndication and doseTear deficiencyApply as requiredLiquifilm Tears c (Allergan)Ophthalmic solution (= eye drops), polyvinyl alcohol1.4%. Net price 15 mL = £1.93Excipients include benzalkonium chloride, disodium edetateOphthalmic solution (= eye drops), polyvinyl alcohol1.4%, povidone 0.6%. Net price 30 0.4 mL = £5.35Sno Tears c (Bausch & Lomb)Eye drops, polyvinyl alcohol 1.4%. Net price 10 mL =£1.06Excipients include benzalkonium chloride, disodium edetateSODIUM CHLORIDEIndication and doseIrrigation, including first-aid removal of harmfulsubstancesUse as requiredSodium Chloride 0.9% SolutionsSee section 13.11.1Balanced Salt SolutionSolution (sterile), sodium chloride 0.64%, sodiumacetate 0.39%, sodium citrate 0.17%, calcium chloride0.048%, magnesium chloride 0.03%, potassiumchloride 0.075%For intra-ocular or topical irrigation during surgical proceduresBrands include Iocare cSingle useMinims c Saline (Bausch & Lomb)Eye drops, sodium chloride 0.9%. Net price 20 0.5 mL = £6.59SODIUM HYALURONATEIndication and doseDry eye conditionsApply as requiredHyabak c (Spectrum Thea)Eye drops, sodium hyaluronate 0.15%, net price10 mL = £7.99Hylo-Care c (Scope Ophthalmics)Eye drops, sodium hyaluronate 0.1%, dexpanthenol2%, net price 10 mL = £10.30Hylo-Forte c (Scope Opthalmics)Eye drops, sodium hyaluronate 0.2%, net price 10 mL= £10.80Hylo-Tear c (Scope Opthalmics)Eye drops, sodium hyaluronate 0.1%, net price 10 mL= £9.80Lumecare c Sodium Hyaluronate (Medicom)Eye drops, sodium hyaluronate 0.15%, net price10 mL = £3.97Oxyal c (Kestrel Ophthalmics)Eye drops, sodium hyaluronate 0.15%, net price10 ml = £4.15Vismed c Multi (TRB Chemedica)Eye drops, sodium hyaluronate 0.18%, net price10 mL = £6.81Single useClinitas c (Altacor)Eye drops, sodium hyaluronate 0.4%, net price 30 0.5 mL = £5.70Note Each unit is resealable for up to 12 hoursOcusan c (Agepha)Eye drops, sodium hyaluronate 0.2%, net price 20 0.5 mL = £5.25Vismed c (TRB Chemedica)Eye drops, sodium hyaluronate 0.18%, net price 20 0.3 mL = £5.10Vismed c Gel (TRB Chemedica)Eye drops, sodium hyaluronate 0.3%, net price 20 0.45 mL = £5.9811 Eye

532 11.8.2 Ocular diagnostic and peri-operative preparations BNFC 2011–201211 Eye11.8.2 Ocular diagnostic andperi-operativepreparationsOcular diagnostic preparationsFluorescein sodium is used in diagnostic proceduresand for locating damaged areas of the cornea due toinjury or disease.FLUORESCEIN SODIUMIndication and doseDetection of lesions and foreign bodiesSufficient to stain damaged areasMinims c Fluorescein Sodium (Bausch & Lomb)Eye drops, fluorescein sodium 1% or 2%. Net price 20 0.5 mL (both) = £7.53With local anaestheticSection 11.7Ocular peri-operative drugsDrugs used to prepare the eye for surgery and drugs thatare injected into the anterior chamber at the time ofsurgery are included here.Sodium hyaluronate is used during surgical procedureson the eye.Apraclonidine, an alpha 2 -adrenoceptor agonist,reduces intra-ocular pressure possibly by reducing theproduction of aqueous humour. It is used for short-termtreatment only.Balanced Salt Solution is used routinely in intra-ocularsurgery (section 11.8.1).ACETYLCHOLINE CHLORIDECautions gastro-intestinal spasm, peptic ulcer; heartfailure; asthma; hyperthyroidism; urinary-tractobstructionPregnancy avoid unless potential benefit outweighsrisk—no information availableBreast-feeding avoid unless potential benefit outweighsrisk—no information availableLicensed use not licensed for use in childrenIndication and doseCataract surgery, penetrating keratoplasty, iridectomy,other anterior segment surgeryrequiring rapid complete miosisConsult product literatureMiochol-E c (Novartis) AIntra-ocular irrigation, powder for reconstitution,acetylcholine chloride 10 mg/mL (1%) when reconstituted,net price 20-mg vial (with solvent) = £7.28Miphtel c (SD Healthcare) AIntra-ocular irrigation, powder for reconstitution,acetylcholine chloride 10 mg/mL (1%) when reconstituted,net price 20-mg vial (with solvent) = £7.28APRACLONIDINENote Apraclonidine is a derivative of clonidineCautions history of angina, severe coronary insufficiency,recent myocardial infarction, heart failure,cerebrovascular disease, vasovagal attack, chronicrenal failure; depression; pregnancy and breast-feeding;monitor intra-ocular pressure and visual fields;loss of effect may occur over time; suspend treatmentif reduction in vision occurs in end-stage glaucoma;monitor for excessive reduction in intra-ocular pressurefollowing peri-operative use; interactions:Appendix 1 (alpha 2 -adrenoceptor stimulants)Skilled tasks Drowsiness may affect performance of skilledtasks (e.g. driving)Contra-indications history of severe or unstable anduncontrolled cardiovascular diseaseSide-effects dry mouth, taste disturbance; hyperaemia,ocular pruritus, discomfort and lacrimation(withdraw if ocular intolerance including oedema oflids and conjunctiva); headache, asthenia, dry nose;lid retraction, conjunctival blanching and mydriasisreported after peri-operative use; since absorptionmay follow topical application systemic effects (seeClonidine, section 2.5.2) may occurLicensed use 0.5% drops not licensed for use inchildren under 12 years; 1% drops not licensed foruse in childrenIndication and doseSee preparations belowIopidine c (Alcon) AOphthalmic solution (= eye drops), apraclonidine 1%(as hydrochloride). Net price 12 2 single use 0.25-mL units = £77.81DoseControl or prevention of postoperative elevation ofintra-ocular pressure after anterior segment lasersurgeryApply 1 drop 1 hour before laser procedure then 1 dropimmediately after completion of procedureOphthalmic solution (= eye drops), apraclonidine0.5% (as hydrochloride). Net price 5 mL = £10.88Excipients include benzalkonium chlorideDoseShort-term adjunctive treatment of chronic glaucomain patients not adequately controlled by another drug(see note below)Child 12–18 years apply 1 drop 3 times daily usually formax. 1 monthNote May not provide additional benefit if patient alreadyusing two drugs that suppress the production of aqueoushumourDICLOFENAC SODIUMLicensed use not licensed for use in childrenIndication and doseInhibition of intra-operative miosis during cataractsurgery (but does not possess intrinsicmydriatic properties), postoperative inflammationin cataract surgery, strabismus surgery,argon laser trabeculoplastyconsult product literature

BNFC 2011–2012 11.9 Contact lenses 533Voltarol c Ophtha Multidose (Novartis) AEye drops, diclofenac sodium 0.1%, net price 5 mL =£6.68Excipients include benzalkonium chloride, disodium edetate, propyleneglycolSingle useVoltarol c Ophtha (Novartis) AEye drops, diclofenac sodium 0.1%. Net price pack of5 single-dose units = £4.00, 40 single-dose units =£32.00FLURBIPROFEN SODIUMLicensed use not licensed for use in childrenIndication and doseInhibition of intra-operative miosis (but doesnot possess intrinsic mydriatic properties),control of postoperative and post-laser trabeculoplastyinflammation (if corticosteroidscontra-indicated)consult product literatureOcufen c (Allergan) AOphthalmic solution (= eye drops), flurbiprofensodium 0.03%, polyvinyl alcohol (Liquifilm c ) 1.4%.Net price 40 0.4 mL = £37.15KETOROLAC TROMETAMOLLicensed use not licensed for use in childrenIndication and doseProphylaxis and reduction of inflammation andassociated symptoms following ocular surgeryconsult product literaturetap water coming into contact with the lenses. Thecondition is especially associated with the use of softlenses (including frequently replaced lenses) and shouldbe treated by specialists.Contact lenses and drug treatment Special care isrequired in prescribing eye preparations for contact lensusers. Some drugs and preservatives in eye preparationscan accumulate in hydrogel lenses and can causeadverse reactions. Therefore, unless medically indicated,the lenses should be removed before instillationof the eye preparation, and not worn during the periodof treatment. Alternatively, unpreserved drops can beused. Eye drops may, however, be instilled whilepatients are wearing rigid corneal contact lenses. Ointmentpreparations should never be used in conjunctionwith contact lens wear; oily eye drops should also beavoided.Many drugs given systemically can also have adverseeffects on contact lens wear. These include oral contraceptives(particularly those with a higher oestrogencontent), drugs which reduce blink rate (e.g. anxiolytics,hypnotics, antihistamines, and muscle relaxants), drugswhich reduce lacrimation (e.g. antihistamines, antimuscarinics,phenothiazines and related drugs, somebeta-blockers, diuretics, and tricyclic antidepressants),and drugs which increase lacrimation (including ephedrineand hydralazine). Other drugs that can affectcontact lens wear are isotretinoin (can cause conjunctivalinflammation), aspirin (salicylic acid appears in tearsand can be absorbed by contact lenses—leading toirritation), and rifampicin and sulfasalazine (can discolourlenses).Acular c (Allergan) AEye drops, ketorolac trometamol 0.5%. Net price5 mL = £3.00Excipients include benzalkonium chloride, disodium edetate11.9 Contact lensesSome children and adolescents prefer to wear contactlenses rather than spectacles for both cosmetic andmedical reasons. Visual defects are corrected by eitherrigid (‘hard’ or gas permeable) lenses or soft (hydrogel)lenses; soft lenses are the most popular type, becausethey are initially the most comfortable, but they may notgive the best vision. Lenses should usually be worn for aspecified number of hours each day and removed forsleeping. The risk of infectious and non-infectious keratitisis increased with extended continuous contact lenswear in children, and it is not recommended exceptwhere medically indicated.Contact lenses require meticulous care. Poor compliancewith directions for use, and with daily cleaning anddisinfection, can result in complications including ulcerativekeratitis or conjunctivitis. One-day disposablelenses, which are worn only once and therefore requireno disinfection or cleaning, are becoming increasinglypopular.Acanthamoeba keratitis, a painful and sight-threateningcondition, is associated with ineffective lens cleaningand disinfection, the use of contaminated lens cases, or11 Eye

534 BNFC 2011–201212 Ear, nose, and oropharynx12 Ear, nose, and oropharynx12.1 Drugs acting on the ear 53412.1.1 Otitis externa 53412.1.2 Otitis media 53712.1.3 Removal of ear wax 53712.2 Drugs acting on the nose 53812.2.1 Drugs used in nasal allergy 53812.2.2 Topical nasal decongestants 54112.2.3 Nasal preparations for infection 54212.3 Drugs acting on the oropharynx54312.3.1 Drugs for oral ulceration andinflammation 54312.3.2 Oropharyngeal anti-infectivedrugs 54512.3.3 Lozenges and sprays 54612.3.4 Mouthwashes and gargles 54612.3.5 Treatment of dry mouth 548This chapter also includes advice on the drug managementof the following:allergic rhinitis, p. 538nasal polyps, p. 538oropharyngeal infections, p. 545periodontitis, p. 54312.1 Drugs acting on the ear12.1.1 Otitis externa12.1.2 Otitis media12.1.3 Removal of ear wax12.1.1 Otitis externaOtitis externa is an inflammatory reaction of the liningof the ear canal usually associated with an underlyingseborrhoeic dermatitis or eczema; it is important toexclude an underlying chronic otitis media before treatmentis commenced. Many cases recover after thoroughcleansing of the external ear canal by suction or drymopping.A frequent problem in resistant cases is the difficulty inapplying lotions and ointments satisfactorily to therelatively inaccessible affected skin. The most effectivemethod is to introduce a ribbon gauze dressing orsponge wick soaked with corticosteroid ear drops orwith an astringent such as aluminium acetate solution.When this is not practical, the ear should be gentlycleansed with a probe covered in cotton wool and thepatient encouraged to lie with the affected ear uppermostfor ten minutes after the canal has been filled witha liberal quantity of the appropriate solution.Secondary infection in otitis externa may be of bacterial,fungal, or viral origin. If infection is present, a topicalanti-infective which is not used systemically (such asneomycin or clioquinol) may be used, but for onlyabout a week because excessive use may result in fungalinfections that are difficult to treat. Sensitivity to theanti-infective or solvent may occur and resistance toantibacterials is a possibility with prolonged use. Aluminiumacetate ear drops are also effective againstbacterial infection and inflammation of the ear. Chloramphenicolmay be used, but the ear drops containpropylene glycol and cause hypersensitivity reactions inabout 10% of patients. Solutions containing an antiinfectiveand a corticosteroid (such as Locorten-Vioform c ) are used for treating children when infectionis present with inflammation and eczema. Clotrimazole1% solution is used topically to treat fungal infection inotitis externa.In view of reports of ototoxicity in patients with aperforated tympanic membrane (eardrum), manufacturerscontra-indicate treatment with a topical aminoglycosideantibiotic in those with a tympanic perforation.However, many specialists do use these dropscautiously in the presence of a perforation in childrenwith otitis media (section 12.1.2) and when other measureshave failed for otitis externa.A solution of acetic acid 2% acts as an antifungal andantibacterial in the external ear canal and may be usedto treat mild otitis externa. More severe cases requiretreatment with an anti-inflammatory preparation with

BNFC 2011–2012 12.1.1 Otitis externa 535or without an anti-infective drug. A proprietary preparationcontaining acetic acid 2% (EarCalm c spray) is onsale to the public for children over 12 years.For severe pain associated with otitis externa, a simpleanalgesic, such as paracetamol (section 4.7.1) or ibuprofen(section 10.1.1), can be used. A systemic antibacterial(Table 1, section 5.1) can be used if there isspreading cellulitis or if the child is systemically unwell.When a resistant staphylococcal infection (a boil) ispresent in the external auditory canal, oral flucloxacillin(section 5.1.1.2) is the drug of choice; oral ciprofloxacin(section 5.1.12) or a systemic aminoglycosidemay be needed for pseudomonal infections, particularlyin children with diabetes or compromised immunity.The skin of the pinna adjacent to the ear canal is oftenaffected by eczema. A topical corticosteroid (section13.4) cream or ointment is then required, but prolongeduse should be avoided.Administration To administer ear drops, lay the childdown with the head turned to one side; for an infant pullthe earlobe back and down, for an older child pull theearlobe back and up.BETAMETHASONE SODIUMPHOSPHATECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use licensed for use in children (age rangenot specified by manufacturers)Indication and doseEczematous inflammation in otitis externa (seenotes above); for dose, see under preparationsEye section 11.4.1Nose section 12.2.1 and section 12.2.3Betnesol c (UCB Pharma) ADrops (for ear, eye, or nose), betamethasone sodiumphosphate 0.1%. Net price 10 mL = £2.23Excipients include benzalkonium chloride, disodium edetateDoseear, instil 2–3 drops every 2–3 hours; reduce frequencywhen relief obtainedAstringent preparationsALUMINIUM ACETATELicensed use not licensedIndication and doseInflammation in otitis externa (see notes above)Insert into meatus or apply on a ribbon gauzedressing or sponge wick which should be keptsaturated with the ear dropsAluminium Acetate (Non-proprietary)Ear drops 13%, aluminium sulphate 2.25 g, calciumcarbonate 1 g, tartaric acid 450 mg, acetic acid (33%)2.5 mL, purified water 7.5 mLAvailable as manufactured specialEar drops 8%, dilute 8 parts aluminium acetate eardrops (13%) with 5 parts purified water. Must befreshly preparedAnti-inflammatory preparationsCorticosteroidsTopical corticosteroids are used to treat inflammationand eczema in otitis externa.Cautions Prolonged use of topical corticosteroid earpreparations should be avoided.Contra-indications Corticosteroid ear preparationsshould be avoided in the presence of an untreated earinfection. If infection is present, the corticosteroidshould be used in combination with a suitable antiinfective(see notes above).Side-effects Local sensitivity reactions may occur.Vistamethasone c (Martindale) ADrops (for ear, eye, or nose), betamethasone sodiumphosphate 0.1%. Net price 5 mL = £1.02; 10 mL =£1.16Excipients include benzalkonium chloride, disodium edetateDoseear, instil 2–3 drops every 3–4 hours; reduce frequencywhen relief obtainedWith antibacterialBetnesol-N c (UCB Pharma) ADrops (for ear, eye, or nose), betamethasone sodiumphosphate 0.1%, neomycin sulphate 0.5%. Net price10 mL = £2.30Excipients include benzalkonium chloride, disodium edetateDoseear, instil 2–3 drops 3–4 times dailyDEXAMETHASONECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use Sofradex c licensed for use in children(age range not specified by manufacturers)Indication and doseEczematous inflammation in otitis externa (seenotes above); for dose, see under preparationsWith antibacterialOtomize c (GSK Consumer Healthcare) AEar spray, dexamethasone 0.1%, neomycin sulphate3250 units/mL, glacial acetic acid 2%. Net price 5-mLpump-action aerosol unit = £3.71Excipients include hydroxybenzoates (parabens)DoseChild 2–18 years ear, apply 1 metered spray 3 timesdaily12 Ear, nose, and oropharynx

536 12.1.1 Otitis externa BNFC 2011–201212 Ear, nose, and oropharynxSofradex c (Sanofi-Aventis) AUDrops (for ear or eye), dexamethasone (as sodiummetasulphobenzoate) 0.05%, framycetin sulphate0.5%, gramicidin 0.005%. Net price 10 mL = £6.25Excipients include polysorbate 80Doseear, instil 2–3 drops 3–4 times daily; eye, section 11.4.1FLUMETASONE PIVALATE(Flumethasone Pivalate)Cautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveIndication and doseEczematous inflammation in otitis externa (seenotes above); for dose, see under preparationWith antibacterialLocorten-Vioform c (Amdipharm) AEar drops, flumetasone pivalate 0.02%, clioquinol 1%.Net price 7.5 mL = £1.76Contra-indications iodine sensitivityDoseChild 2–18 years instil 2–3 drops into the ear twice dailyfor 7–10 daysNote Clioquinol stains skin and clothingHYDROCORTISONECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use Otosporin c not licensed for use inchildren under 3 years; other preparations licensedfor use in children (age range not specified bymanufacturers)Indication and doseEczematous inflammation in otitis externa (seenotes above); for dose, see under preparationsWith antibacterialGentisone c HC (Amdipharm) AEar drops, hydrocortisone acetate 1%, gentamicin0.3% (as sulphate). Net price 10 mL = £3.92Excipients include benzalkonium chloride, disodium edetateDoseear, instil 2–4 drops 3–4 times daily and at nightOtosporin c (GSK) AUEar drops, hydrocortisone 1%, neomycin sulphate3400 units, polymyxin B sulphate 10 000 units/mL.Net price 5 mL = £2.00; 10 mL = £4.00Excipients include cetostearyl alcohol, hydroxybenzoates (parabens),polysorbate 20DoseChild 3–18 years instil 3 drops into the ear 3–4 timesdailyLicensed use licensed for use in children (age rangenot specified by manufacturers)Indication and doseEczematous inflammation in otitis externa (seenotes above); for dose, see under preparationsEye section 11.4.1Predsol c (UCB Pharma) ADrops (for ear or eye), prednisolone sodium phosphate0.5%. Net price 10 mL = £1.92Excipients include benzalkonium chloride, disodium edetateDoseear, instil 2–3 drops every 2–3 hours; reduce frequencywhen relief obtainedWith antibacterialPredsol-N c (UCB Pharma) ADrops (for ear or eye), prednisolone sodium phosphate0.5%, neomycin sulphate 0.5%. Net price 10 mL= £2.27Excipients include benzalkonium chloride, disodium edetateDoseear, instil 2–3 drops 3–4 times dailyAnti-infective preparationsCHLORAMPHENICOL UCautions avoid prolonged use (see notes above)Side-effects high incidence of sensitivity reactions tovehicleLicensed use licensed for use in children (age rangenot specified by manufacturers)Indication and doseBacterial infection in otitis externa (but see notesabove); for dose, see under preparationChloramphenicol (Non-proprietary) AUEar drops, chloramphenicol in propylene glycol, netprice 5%, 10 mL = £6.22; 10%, 10 mL = £5.62Excipients include propylene glycolDoseear, instil 2–3 drops 2–3 times dailyCLOTRIMAZOLESide-effects occasional local irritation or sensitivityLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseFungal infection in otitis externa (see notesabove); for dose, see under preparationPREDNISOLONE SODIUMPHOSPHATECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveCanesten c (Bayer Consumer Care)Solution, clotrimazole 1% in polyethylene glycol 400(macrogol 400). Net price 20 mL = £2.43Doseear, apply 2–3 times daily continuing for at least 14 daysafter disappearance of infection

BNFC 2011–2012 12.1.2 Otitis media 537FRAMYCETIN SULPHATECautions avoid prolonged use (see notes above)Contra-indications perforated tympanic membrane(see p. 534)Side-effects local sensitivityIndication and doseBacterial infection in otitis externa (see notesabove)Eye section 11.3.1With corticosteroidSofradex c see Dexamethasone, p. 536GENTAMICINCautions avoid prolonged use (see notes above)Contra-indications perforated tympanic membrane(but see p. 534 and section 12.1.2)Side-effects local sensitivityLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseBacterial infection in otitis externa (see notesabove); for dose, see under preparationsGenticin c (Amdipharm) ADrops (for ear or eye), gentamicin 0.3% (as sulphate).Net price 10 mL = £2.13Excipients include benzalkonium chlorideDoseear, instil 2–3 drops 3–4 times daily and at night; eye,section 11.3.1With corticosteroidGentisone c HC see Hydrocortisone, p. 536NEOMYCIN SULPHATECautions avoid prolonged use (see notes above)Contra-indications perforated tympanic membrane(see p. 534)Side-effects local sensitivityIndication and doseBacterial infection in otitis externa (see notesabove)With corticosteroidBetnesol-N c A see Betamethasone, p. 535Otomize c see Dexamethasone, p. 535Otosporin c see Hydrocortisone, p. 536Predsol-N c see Prednisolone, p. 53612.1.2 Otitis mediaAcute otitis media Acute otitis media is the commonestcause of severe aural pain in young children andmay occur with even minor upper respiratory tractinfections. Children diagnosed with acute otitis mediashould not be prescribed antibacterials routinely asmany infections, especially those accompanying coryza,are caused by viruses. Most uncomplicated casesresolve without antibacterial treatment and a simpleanalgesic, such as paracetamol, may be sufficient. Inchildren without systemic features, a systemic antibacterial(Table 1, section 5.1) may be started after72 hours if there is no improvement, or earlier if there isdeterioration, if the child is systemically unwell, if thechild is at high risk of serious complications (e.g. inimmunosuppression, cystic fibrosis), if mastoiditis ispresent, or in children under 2 years of age with bilateralotitis media. Perforation of the tympanic membrane inchildren with acute otitis media usually heals spontaneouslywithout treatment; if there is no improvement,e.g. pain or discharge persists, a systemic antibacterial(Table 1, section 5.1) can be given. Topical antibacterialtreatment of acute otitis media is ineffective and there isno place for ear drops containing a local anaesthetic.Otitis media with effusion Otitis media with effusion(‘glue ear’) occurs in about 10% of children and in90% of children with cleft palates. Antimicrobials, corticosteroids,decongestants, and antihistamines have littleplace in the routine management of otitis media witheffusion. If ‘glue ear’ persists for more than a month ortwo, the child should be referred for assessment andfollow up because of the risk of long-term hearingimpairment which can delay language development.Untreated or resistant glue ear may be responsible forsome types of chronic otitis media.Chronic otitis media Opportunistic organisms areoften present in the debris, keratin, and necrotic bone ofthe middle ear and mastoid in children with chronicotitis media. The mainstay of treatment is thoroughcleansing with aural microsuction, which may completelyresolve long-standing infection. Cleansing may befollowed by topical treatment as for otitis externa (section12.1.1); this is particularly beneficial for dischargingears or infections of the mastoid cavity. Acute exacerbationsof chronic infection may require treatment withan oral antibacterial (Table 1, section 5.1); a swab shouldbe taken to identify infecting organisms and antibacterialsensitivity. Parenteral antibacterial treatmentis required if Pseudomonas aeruginosa or Proteus spp.are present.Manufacturers contra-indicate topical treatment withototoxic antibacterials in the presence of a perforation(section 12.1.1). However, many specialists use eardrops containing aminoglycosides (e.g. neomycin) orpolymyxins if the otitis media has failed to settle withsystemic antibacterials; it is considered that the pus inthe middle ear associated with otitis media carries ahigher risk of ototoxicity than the drops themselves.Ciprofloxacin or ofloxacin ear drops [both unlicensed;available from ‘special-order’ manufacturers or specialistimporting companies, see p. 809] or eye drops usedin the ear [unlicensed indication] are an effective alternativeto aminoglycoside ear drops for chronic otitismedia in patients with perforation of the tympanicmembrane.12.1.3 Removal of ear waxEar wax (cerumen) is a normal bodily secretion whichprovides a protective film on the meatal skin and needonly be removed if it causes hearing loss or interfereswith a proper view of the ear drum.12 Ear, nose, and oropharynx

538 12.2 Drugs acting on the nose BNFC 2011–201212 Ear, nose, and oropharynxEar wax causing discomfort or impaired hearing may besoftened with simple remedies such as olive oil eardrops or almond oil ear drops; sodium bicarbonateear drops are also effective, but may cause dryness ofthe ear canal. If the wax is hard and impacted, the dropscan be used twice daily for several days and this mayreduce the need for mechanical removal of the wax. Thechild should lie with the affected ear uppermost for 5 to10 minutes after a generous amount of the softeningremedy has been introduced into the ear. Proprietarypreparations containing organic solvents can irritate themeatal skin, and in most cases the simple remediesindicated above are just as effective and less likely tocause irritation. Docusate sodium or urea hydrogenperoxide are ingredients in a number of proprietarypreparations for softening ear wax.If necessary, wax may be removed by irrigation withwater (warmed to body temperature). Ear irrigation isgenerally best avoided in young children, in childrenunable to co-operate with the procedure, in childrenwho have had otitis media in the last 6 weeks, in otitisexterna, in children with cleft palate, a history of eardrum perforation, or previous ear surgery. A child whohas hearing in one ear only should not have that earirrigated because even a very slight risk of damage isunacceptable in this situation.For administration of ear drops, see p. 535.Almond Oil (Non-proprietary)Ear drops, almond oil in a suitable containerAllow to warm to room temperature before useOlive Oil (Non-proprietary)Ear drops, olive oil in a suitable containerAllow to warm to room temperature before useSodium Bicarbonate (Non-proprietary)Ear drops, sodium bicarbonate 5%, net price 10 mL =£1.25Cerumol c (Thornton & Ross) UEar drops, chlorobutanol 5%, arachis (peanut) oil57.3%. Net price 11 mL = £1.76Exterol c (Dermal) UEar drops, urea–hydrogen peroxide complex 5% inglycerol. Net price 8 mL = £1.75Molcer c (Wallace Mfg) UEar drops, docusate sodium 5%. Net price 15 mL =£5.60Excipients include propylene glycolOtex c (DDD) UEar drops, urea–hydrogen peroxide 5%. Net price8 mL = £2.64Waxsol c (Norgine) UEar drops, docusate sodium 0.5%. Net price 10 mL =£1.2112.2 Drugs acting on the nose12.2.1 Drugs used in nasal allergy12.2.2 Topical nasal decongestants12.2.3 Nasal preparations for infectionRhinitis is often self-limiting but bacterial sinusitis mayrequire treatment with antibacterials (Table 1, section5.1). Many nasal preparations contain sympathomimeticdrugs (section 12.2.2) which can give rise torebound congestion (rhinitis medicamentosa) and maydamage the nasal cilia. Sodium chloride 0.9% solutionmay be used as a douche or ‘sniff’ following endonasalsurgery.Administration To administer nasal drops, lay thechild face-upward with the neck extended, instil thedrops, then sit the child up and tilt the head forward.Nasal polyps Short-term use of corticosteroid nasaldrops helps to shrink nasal polyps; to be effective, thedrops must be administered with the child in the ‘headdown’ position. A short course of a systemic corticosteroid(section 6.3.2) may be required initially to shrinklarge polyps. A corticosteroid nasal spray can be used tomaintain the reduction in swelling and also for the initialtreatment of small polyps.12.2.1 Drugs used in nasalallergyMild allergic rhinitis is controlled by antihistamines(see also section 3.4.1) or topical nasal corticosteroids;systemic nasal decongestants (section 3.10) are notrecommended for use in children. Topical nasaldecongestants can be used for a short period to relievecongestion and allow penetration of a topical nasalcorticosteroid.More persistent symptoms can be relieved by topicalnasal corticosteroids; cromoglycate is an alternative,but may be less effective. The topical antihistamine,azelastine, is useful for controlling breakthrough symptomsin allergic rhinitis. Azelastine is less effective thannasal corticosteroids, but probably more effective thansodium cromoglicate. In seasonal allergic rhinitis (e.g.hay fever), treatment should begin 2 to 3 weeks beforethe season commences and may have to be continuedfor several months; continuous long-term treatmentmay be required in perennial rhinitis.Montelukast (section 3.3.2) is less effective than topicalnasal corticosteroids; montelukast can be used in childrenwith seasonal allergic rhinitis (unresponsive toother treatments) and concomitant asthma.Children with disabling symptoms of seasonal rhinitis(e.g. students taking important examinations), may betreated with oral corticosteroids (section 6.3.2) forshort periods. Oral corticosteroids may also be used atthe beginning of a course of treatment with a corticosteroidspray to relieve severe mucosal oedema andallow the spray to penetrate the nasal mucosa.Sometimes allergic rhinitis is accompanied by vasomotorrhinitis. In this situation, the addition of topicalnasal ipratropium bromide (section 12.2.2) can reducewatery rhinorrhoea.Pregnancy If a pregnant woman cannot tolerate thesymptoms of allergic rhinitis, treatment with nasalbeclometasone, budesonide, fluticasone propionate, orsodium cromoglicate may be considered.

BNFC 2011–2012 12.2.1 Drugs used in nasal allergy 539AntihistaminesAZELASTINE HYDROCHLORIDESide-effects irritation of nasal mucosa; bitter taste (ifapplied incorrectly)Indication and doseTreatment of allergic rhinitis for dose, see underpreparationRhinolast c (Meda) ANasal spray, azelastine hydrochloride 140 micrograms(0.14 mL)/metered spray. Net price 22 mL(157-spray unit with metered pump) = £10.45Excipients include sodium edetateDoseChild 5–18 years apply 140 micrograms (1 spray) intoeach nostril twice dailyNote Preparations of azelastine hydrochloride can be sold tothe public for nasal administration in aqueous form (otherthan by aerosol) for the treatment of seasonal allergic rhinitisor perennial allergic rhinitis in children over 5 years, subjectto max. single dose of 140 micrograms per nostril, max. dailydose of 280 micrograms per nostril, and a pack size limit of36 dosesCorticosteroidsNasal preparations containing corticosteroids have auseful role in the prophylaxis and treatment of allergicrhinitis (see notes above). They are also used for thesymptomatic treatment of adenoidal hypertrophy.Cautions Corticosteroid nasal preparations should beavoided in the presence of untreated nasal infections,and also after nasal surgery (until healing has occurred);they should also be avoided in pulmonary tuberculosis.Systemic absorption may follow nasal administrationparticularly if high doses are used or if treatment isprolonged; for cautions and side-effects of systemiccorticosteroids, see section 6.3.2. The risk of systemiceffects may be greater with nasal drops than with nasalsprays; drops are administered incorrectly more oftenthan sprays. The height of children receiving prolongedtreatment with nasal corticosteroids should be monitored;if growth is slowed, referral to a paediatricianshould be considered.Side-effects Local side-effects include dryness, irritationof nose and throat, and epistaxis. Nasal ulcerationhas been reported, and occurs commonly with nasalpreparations containing fluticasone furoate or mometasonefuroate. Nasal septal perforation (usually followingnasal surgery) occurs very rarely. Raised intra-ocularpressure or glaucoma may occur rarely. Headache,smell and taste disturbances may also occur. Hyperactivity,sleep disturbances, anxiety, depression, andaggression have been reported. Hypersensitivity reactions,including bronchospasm, have also been reported.BECLOMETASONE DIPROPIONATE(Beclomethasone Dipropionate)Cautions see notes aboveSide-effects see notes aboveIndication and doseProphylaxis and treatment of allergic andvasomotor rhinitisChild 6–18 years apply 100 micrograms (2sprays) into each nostril twice daily; max. total400 micrograms (8 sprays) daily; when symptomscontrolled, dose reduced to 50 micrograms (1spray) into each nostril twice dailyBeclometasone (Non-proprietary) ANasal spray, beclometasone dipropionate 50 micrograms/meteredspray. Net price 200-spray unit =£2.52Brands include Nasobec Aqueous cBeconase c (A&H) ANasal spray (aqueous suspension), beclometasonedipropionate 50 micrograms/metered spray. Net price200-spray unit with applicator = £2.19Excipients include benzalkonium chloride, polysorbate 80BETAMETHASONE SODIUMPHOSPHATECautions see notes aboveSide-effects see notes aboveLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseNon-infected inflammatory conditions of nosefor dose, see under preparationsEye section 11.4.1Ear section 12.1.1Betnesol c (UCB Pharma) ADrops (for ear, eye, or nose), betamethasone sodiumphosphate 0.1%, net price 10 mL = £2.23Excipients include benzalkonium chloride, disodium edetateDosenose, instil 2–3 drops into each nostril 2–3 times dailyVistamethasone c (Martindale) ADrops (for ear, eye, or nose), betamethasone sodiumphosphate 0.1%. Net price 5 mL = £1.02, 10 mL =£1.16Excipients include benzalkonium chloride, disodium edetateDosenose, instil 2–3 drops into each nostril twice dailyBUDESONIDECautions see notes above; interactions: Appendix 1(corticosteroids)Side-effects see notes aboveIndication and doseSee under preparations12 Ear, nose, and oropharynx

540 12.2.1 Drugs used in nasal allergy BNFC 2011–201212 Ear, nose, and oropharynxBudesonide (Non-proprietary) ANasal spray, budesonide 100 micrograms/meteredspray, net price 100-spray unit = £5.90DoseProphylaxis and treatment of allergic and vasomotorrhinitisChild 12–18 years apply 200 micrograms (2 sprays) intoeach nostril once daily in the morning or 100 micrograms(1 spray) into each nostril twice daily; when controlachieved reduce to 100 micrograms (1 spray) into eachnostril once dailyNasal polypsChild 12–18 years apply 100 micrograms (1 spray) intoeach nostril twice daily for up to 3 monthsRhinocort Aqua c (AstraZeneca) ANasal spray, budesonide 64 micrograms/meteredspray. Net price 120-spray unit = £2.49Excipients include disodium edetate, polysorbate 80, potassium sorbateDoseRhinitisChild 12–18 years 128 micrograms (2 sprays) into eachnostril once daily in the morning or 64 micrograms (1spray) into each nostril twice daily; when controlachieved reduce to 64 micrograms (1 spray) into eachnostril once daily; max. duration of treatment 3 monthsNasal polypsChild 12–18 years 64 micrograms (1 spray) into eachnostril twice daily for up to 3 monthsFLUNISOLIDECautions see notes aboveSide-effects see notes aboveIndication and doseProphylaxis and treatment of allergic rhinitisChild 5–14 years initially 25 micrograms (1 spray)into each nostril up to 3 times daily then reducedfor maintenanceChild 14–18 years 50 micrograms (2 sprays) intoeach nostril twice daily, increased if necessary tomax. 3 times daily then reduced for maintenanceSyntaris c (IVAX) AAqueous nasal spray, flunisolide 25 micrograms/metered spray. Net price 240-spray unit with pumpand applicator = £5.05Excipients include benzalkonium chloride, butylated hydroxytoluene,disodium edetate, polysorbate 20, propylene glycolFLUTICASONE PROPIONATECautions see notes above; interactions: Appendix 1(corticosteroids)Side-effects see notes aboveIndication and doseProphylaxis and treatment of allergic rhinitisChild 4–12 years 50 micrograms (1 spray) intoeach nostril once daily, preferably in the morning,increased to max. twice daily if requiredChild 12–18 years 100 micrograms (2 sprays)into each nostril once daily, preferably in themorning, increased to max. twice daily if required;when control achieved reduce to 50 micrograms (1spray) into each nostril once dailyNasal polyps see Flixonase Nasule c belowFlixonase c (A&H) AAqueous nasal spray, fluticasone propionate50 micrograms/metered spray. Net price 150-sprayunit with applicator = £11.01Excipients include benzalkonium chloride, polysorbate 80Flixonase Nasule c (A&H) ANasal drops, fluticasone propionate 400 micrograms/unitdose, net price 28 0.4-mL units =£12.99Excipients include polysorbate 20DoseNasal polypsChild 16–18 years instil 200 micrograms (approx. 6drops) into each nostril once or twice daily; consideralternative treatment if no improvement after 4–6 weeksNasofan c (IVAX) AAqueous nasal spray, fluticasone propionate50 micrograms/metered spray. Net price 150–sprayunit = £8.41Excipients include benzalkonium chloride, polysorbate 80Fluticasone furoateAvamys c (GSK) TANasal spray, fluticasone furoate 27.5 micrograms/metered spray, net price 120-spray unit = £6.44Excipients include benzalkonium chloride, disodium edetate, polysorbate80DoseProphylaxis and treatment of allergic rhinitisChild 6–12 years 27.5 micrograms (1 spray) into eachnostril once daily, increased if necessary to 55 micrograms(2 sprays) into each nostril once daily; whencontrol achieved reduce to 27.5 micrograms (1 spray)into each nostril once dailyChild 12–18 years 55 micrograms (2 sprays) into eachnostril once daily; when control achieved reduce tominimum effective dose, 27.5 micrograms (1 spray) intoeach nostril once daily may be sufficientMOMETASONE FUROATECautions see notes aboveSide-effects see notes aboveIndication and doseSee under preparationNasonex c (Schering-Plough) ANasal spray, mometasone furoate 50 micrograms/metered spray. Net price 140-spray unit = £7.68Excipients include benzalkonium chloride, polysorbate 80DoseProphylaxis and treatment of allergic rhinitisChild 6–12 years 50 micrograms (1 spray) into eachnostril once dailyChild 12–18 years 100 micrograms (2 sprays) into eachnostril once daily, increased if necessary to max.200 micrograms (4 sprays) into each nostril once daily;when control achieved reduce to 50 micrograms (1 spray)into each nostril once dailyTRIAMCINOLONE ACETONIDECautions see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under 6years

BNFC 2011–2012 12.2.2 Topical nasal decongestants 541Indication and doseTreatment of allergic rhinitisChild 2–6 years 55 micrograms (1 spray) intoeach nostril once daily; max. duration of treatment3 monthsChild 6–12 years 55 micrograms (1 spray) intoeach nostril once daily, increased if necessary to110 micrograms (2 sprays) into each nostril oncedaily; when control achieved, reduce to 55 micrograms(1 spray) into each nostril once daily; max.duration of treatment 3 monthsChild 12–18 years 110 micrograms (2 sprays)into each nostril once daily; when controlachieved, reduce to 55 micrograms (1 spray) intoeach nostril once dailyNasacort c (Sanofi-Aventis) AAqueous nasal spray, triamcinolone acetonide55 micrograms/metered spray. Net price 120-sprayunit = £7.39Excipients include benzalkonium chloride, disodium edetate, polysorbate80CromoglicateSODIUM CROMOGLICATE(Sodium Cromoglycate)Side-effects local irritation; rarely transient bronchospasmLicensed use licensed for use in children (age rangenot specified by manufacturers)Indication and doseProphylaxis of allergic rhinitis for dose, see underpreparationsRynacrom c (Sanofi-Aventis)4% aqueous nasal spray, sodium cromoglicate 4%(5.2 mg/spray). Net price 22 mL (150-spray unit withpump) = £17.07Excipients include benzalkonium chloride, disodium edetateDosenose, 1 spray into each nostril 2–4 times dailyVividrin c (Pharma-Global)Nasal spray, sodium cromoglicate 2%. Net price15 mL (approx. 110-spray unit) = £11.60Excipients include benzalkonium chloride, edetic acid, polysorbate 80DoseNose, 1 spray into each nostril 4–6 times daily12.2.2 Topical nasaldecongestantsSodium chloride 0.9% given as nasal drops or spraymay relieve nasal congestion by helping to liquefymucous secretions in children with rhinitis. In infants,1–2 drops of sodium chloride 0.9% solution in eachnostril before feeds will help relieve congestion andallow more effective suckling.Inhalation of warm moist air is useful in the treatmentof symptoms of acute nasal congestion in infants andchildren, but the use of boiling water for steam inhalationis dangerous for children and should not be recommended.Volatile substances (section 3.8) such asmenthol and eucalyptus may encourage inhalation ofwarm moist air.Topical nasal decongestants containing sympathomimeticscan cause rebound congestion (rhinitismedicamentosa) following prolonged use (more than 7days), and are therefore of limited value in the treatmentof nasal congestion.Ephedrine nasal drops is the least likely of the sympathomimeticnasal decongestants to cause reboundcongestion and can provide relief for several hours.The more potent sympathomimetic drugs oxymetazolineand xylometazoline are more likely to causea rebound effect.The CHM/MHRA has stated that non-prescriptioncough and cold medicines containing ephedrine, oxymetazoline,or xylometazoline can be considered for upto 5 days’ treatment in children aged 6–12 years afterbasic principles of best care have been tried; thesemedicines should not be used in children under 6years of age (section 3.9.1).Non-allergic watery rhinorrhoea often responds well totreatment with the antimuscarinic ipratropiumbromide.Recurrent, persistent bleeding may respond to the useof a sympathomimetic nasal spray; if infection is present,chlorhexidine and neomycin (Naseptin c ) cream(section 12.2.3) may be effective.Systemic nasal decongestants—see section 3.10.Sinusitis and oral pain Sinusitis affecting the maxillaryantrum can cause pain in the upper jaw. Wherethis is associated with blockage of the opening from thesinus into the nasal cavity, it may be helpful to relievethe congestion with inhalation of warm moist air (section3.8) or with ephedrine nasal drops (see above).For antibacterial treatment of sinusitis, see Table 1,section 5.1.SympathomimeticsEPHEDRINE HYDROCHLORIDECautions see notes above; also avoid excessive orprolonged use; hyperthyroidism; diabetes mellitus;cardiovascular disease (including hypertension);interactions: Appendix 1 (sympathomimetics)Pregnancy avoidBreast-feeding avoidSide-effects local irritation, nausea, headache; afterexcessive use tolerance with diminished effect,rebound congestion; cardiovascular effects alsoreportedLicensed use not licensed for use in children under12 yearsIndication and doseNasal congestion (see notes above)Child 12–18 years instil 1–2 drops (0.5%strength) into each nostril up to 3 or 4 times dailywhen required; max. duration 7 days12 Ear, nose, and oropharynx

542 12.2.3 Nasal preparations for infection BNFC 2011–201212 Ear, nose, and oropharynx1Ephedrine (Non-proprietary)Nasal drops, ephedrine hydrochloride 0.5%, net price10 mL = £1.39; 1%, 10 mL = £1.63Note The BP directs that if no strength is specified 0.5%drops should be suppliedDental prescribing on NHS Ephedrine nasal drops may beprescribed1. Can be sold to the public provided no more than 180 mg ofephedrine base (or salts) are supplied at one time, andpseudoephedrine salts are not supplied at the same time; forconditions that apply to supplies made at the request of apatient, see Medicines, Ethics and Practice, London,Pharmaceutical Press (always consult latest edition)XYLOMETAZOLINE HYDROCHLORIDECautions see under Ephedrine Hydrochloride andnotes above; also avoid excessive or prolonged usePregnancy avoidSide-effects see under Ephedrine Hydrochloride andnotes above; in small children, also restlessness, sleepdisturbances, and hallucinations (discontinue treatment)Indication and doseNasal congestion for dose, see under preparationsXylometazoline (Non-proprietary)Nasal drops, xylometazoline hydrochloride 0.1%, netprice 10 mL = £1.91DoseChild 12–18 years instil 2–3 drops into each nostril 2–3times daily when required; max. duration 7 daysBrands include Otradrops c , Otrivine c DPaediatric nasal drops, xylometazoline hydrochloride0.05%, net price 10 mL = £1.59DoseChild 6–12 years instil 1–2 drops into each nostril 1–2times daily when required; max. duration 5 daysBrands include Otradrops c , Otrivine c DNasal spray, xylometazoline hydrochloride 0.1%, netprice 10 mL = £1.91DoseChild 12–18 years apply 1 spray into each nostril 1–3times daily when required; max. duration 7 daysBrands include Otrivine c DAntimuscarinicIPRATROPIUM BROMIDECautions see section 3.1.2; avoid spraying near eyesSide-effects epistaxis, nasal dryness, and irritation;less frequently nausea, headache, and pharyngitis;very rarely antimuscarinic effects such as gastrointestinalmotility disturbances, palpitations, andurinary retentionIndication and doseRhinorrhoea associated with allergic and nonallergicrhinitisChild 12–18 years apply 42 micrograms (2sprays) into each nostril 2–3 times dailyAsthma and reversible airways obstructionsection 3.1.2Rinatec c (Boehringer Ingelheim) ANasal spray 0.03%, ipratropium bromide 21 micrograms/meteredspray. Net price 180-dose unit =£3.99Excipients include benzalkonium chloride, disodium edetate12.2.3 Nasal preparations forinfectionThere is no evidence that topical anti-infective nasalpreparations have any therapeutic value in rhinitis orsinusitis; for elimination of nasal staphylococci, seebelow. Acute complications such as periorbital cellulitisrequire hospital treatment. For systemic treatment ofsinusitis, see Table 1, section 5.1.Betnesol-N c (UCB Pharma) AUDrops (for ear, eye, or nose), betamethasone sodiumphosphate 0.1%, neomycin sulphate 0.5%. Net price10 mL = £2.30Excipients include benzalkonium chloride, disodium edetateDosenose, instil 2–3 drops into each nostril 2–3 times dailyNote Betnesol-N c licensed for use in children (age range notspecified by manufacturer)Nasal staphylococciElimination of organisms such as staphylococci from thenasal vestibule can be achieved by the use of a creamcontaining chlorhexidine and neomycin (Naseptin c ),but re-colonisation frequently occurs. Coagulase-positivestaphylococci are present in the noses of 40% of thepopulation. A nasal ointment containing mupirocin isalso available; it should probably be held in reserve forresistant infections. In hospitals or in care establishments,mupirocin nasal ointment should be reserved forthe eradication (in both patients and staff) of nasalcarriage of meticillin-resistant Staphylococcus aureus(MRSA). The ointment should be applied 3 times dailyfor 5 days and a sample taken 2 days after treatment toconfirm eradication. The course may be repeated if thesample is positive (and the throat is not colonised). Toavoid the development of resistance, the treatmentcourse should not exceed 7 days and the course shouldnot be repeated on more than one occasion. If theMRSA strain is mupirocin-resistant or does not respondafter 2 courses, consider alternative products such aschlorhexidine and neomycin cream. For eradication ofMRSA also consult local infection control policy. Seesection 13.10.1 for treatment of MRSA-infected openwounds. See section 5.1.1.2 for treatment of childrenwith MRSA-positive throat swabs or systemic MRSAinfection.Bactroban Nasal c (GSK) ANasal ointment, mupirocin 2% (as calcium salt) inwhite soft paraffin basis. Net price 3 g = £5.80DoseFor eradication of nasal carriage of staphylococci,including meticillin-resistant Staphylococcus aureus(MRSA)Apply 2–3 times daily to the inner surface of each nostril(see notes above)

BNFC 2011–2012 12.3 Drugs acting on the oropharynx 543Naseptin c (Alliance) ACream, chlorhexidine hydrochloride 0.1%, neomycinsulphate 0.5%, net price 15 g = £1.90Excipients include arachis (peanut) oil, cetostearyl alcoholDoseFor eradication of nasal carriage of staphylococciApply to nostrils 4 times daily for 10 daysFor preventing nasal carriage of staphylococciApply to nostrils twice daily12.3 Drugs acting on theoropharynx12.3.1 Drugs for oral ulceration andinflammation12.3.2 Oropharyngeal anti-infective drugs12.3.3 Lozenges and sprays12.3.4 Mouthwashes and gargles12.3.5 Treatment of dry mouth12.3.1 Drugs for oral ulcerationand inflammationUlceration of the oral mucosa may be caused by trauma(physical or chemical), recurrent aphthous ulcers, infections,carcinoma, dermatological disorders, nutritionaldeficiencies, gastro-intestinal disease, haematopoieticdisorders, and drug therapy. It is important to establishthe diagnosis in each case as the majority of theselesions require specific management in addition tolocal treatment. Local treatment aims to protect theulcerated area, to relieve pain, to reduce inflammation,or to control secondary infection. Children with anunexplained mouth ulcer of more than 3 weeks’ durationrequire urgent referral to hospital to exclude secondarycauses such as leukaemia.Simple mouthwashes A saline mouthwash (section12.3.4) may relieve the pain of traumatic ulceration. Themouthwash is made up with warm water and used atfrequent intervals until the discomfort and swellingsubsides.Antiseptic mouthwashes Secondary bacterial infectionmay be a feature of any mucosal ulceration; it canincrease discomfort and delay healing. Use of chlorhexidinemouthwash (section 12.3.4) is often beneficialand may accelerate healing of recurrent aphthousulcers.Corticosteroids Topical corticosteroid therapy maybe used for some forms of oral ulceration; for aphthousulcers it is most effective if applied in the ‘prodromal’phase. Thrush or other types of candidiasis are recognisedcomplications of corticosteroid treatment.Hydrocortisone oromucosal tablets are useful inrecurrent aphthous ulcers and erosive lichenoid lesions.Beclometasone dipropionate inhaler (p. 147) 50–100 micrograms sprayed twice daily on the oral mucosais used to manage oral ulceration [unlicensed indication].Alternatively, betamethasone soluble tablets dissolvedin water, can be used as a mouthwash to treatoral ulceration.Systemic corticosteroid therapy (section 6.3.2) isreserved for severe conditions such as pemphigus vulgaris.Local analgesics Local analgesics have a limited rolein the management of oral ulceration. When appliedtopically their action is of a relatively short duration andanalgesia cannot be maintained continuously throughoutthe day. When local anaesthetics are used in themouth, care must be taken not to produce anaesthesiaof the pharynx before meals as this might lead tochoking.Benzydamine mouthwash or spray may be useful inreducing the discomfort associated with a variety ofulcerative conditions. It has also been found to beeffective in reducing the discomfort of tonsillectomyand post-irradiation mucositis. Some children find thefull-strength mouthwash causes some stinging and, forthem, it should be diluted with an equal volume of water.Flurbiprofen lozenges are licensed for the relief of sorethroat in adolescents.Choline salicylate dental gel has some analgesic actionand may provide relief for recurrent aphthous ulcers inchildren over 16 years of age.Periodontitis Low-dose doxycycline (Periostat c ) islicensed as an adjunct to scaling and root planing for thetreatment of periodontitis in children over 12 years; alow dose of doxycycline reduces collagenase activitywithout inhibiting bacteria associated with periodontitis.For anti-infectives used in the treatment of destructive(refractory) forms of periodontal disease, see section12.3.2 and Table 1, section 5.1. For mouthwashes usedfor oral hygiene and plaque inhibition, see section12.3.4.BENZYDAMINE HYDROCHLORIDESide-effects occasional numbness or stinging; rarelyhypersensitivity reactionsLicensed use Difflam c Spray licensed for use inchildren (age range not specified by manufacturer)Indication and dosePainful inflammatory conditions of oropharynxfor dose, see under preparationsDifflam c (3M)Oral rinse, green, benzydamine hydrochloride 0.15%,net price 200 mL (Difflam c Sore Throat Rinse) =£2.50; 300 mL = £4.01DoseChild 12–18 years rinse or gargle, using 15 mL (dilutewith an equal volume of water if stinging occurs) every1½–3 hours as required, usually for not more than 7 daysDental prescribing on NHS May be prescribed as BenzydamineMouthwash 0.15%12 Ear, nose, and oropharynx

544 12.3.1 Drugs for oral ulceration and inflammation BNFC 2011–201212 Ear, nose, and oropharynxSpray, benzydamine hydrochloride 0.15%. Net price30-mL unit = £3.17DoseChild under 6 years 1 puff per 4 kg body-weight to max.4 puffs onto affected area every 1½–3 hoursChild 6–12 years 4 puffs onto affected area every 1½–3hoursChild 12–18 years 4–8 puffs onto affected area every1½–3 hoursDental prescribing on NHS May be prescribed as BenzydamineOromucosal Spray 0.15%CORTICOSTEROIDSContra-indications untreated oral infectionSide-effects occasional exacerbation of local infection;thrush or other candidal infectionsLicensed use Hydrocortisone mucoadhesive buccaltablets licensed for use in children (under 12years—on medical advice only)Indication and doseOral and perioral lesions for dose, see underpreparationsHydrocortisone (Non-proprietary)Mucoadhesive buccal tablets (= oromucosaltablets), hydrocortisone 2.5 mg (as sodium succinate).Net price 20 = £2.03Dose1 lozenge 4 times daily, allowed to dissolve slowly in themouth in contact with the ulcerDental prescribing on NHS May be prescribed as HydrocortisoneOromucosal TabletsBetnesol c (UCB Pharma) ASoluble tablets, pink, scored, betamethasone500 micrograms (as sodium phosphate), net price 100-tab pack = £4.97. Label: 10, steroid card, 13, 21DoseOral ulcerationChild 12–18 years 500 micrograms dissolved in 20 mLwater and rinsed around the mouth 4 times daily; not tobe swallowedDental prescribing on NHS May be prescribed as BetamethasoneSoluble Tablets 500 microgramsDOXYCYCLINECautions section 5.1.3; monitor for superficial fungalinfection, particularly if predisposition to oral candidiasisContra-indications section 5.1.3Hepatic impairment section 5.1.3Renal impairment section 5.1.3Pregnancy section 5.1.3Breast-feeding section 5.1.3Side-effects section 5.1.3; fungal superinfectionIndication and doseSee under preparationsOral herpes section 12.3.2Other indications section 5.1.3Periostat c (Alliance) ATablets, f/c, doxycycline (as hyclate) 20 mg, net price56-tab pack = £16.50. Label: 6, 11, 27, counselling,postureDosePeriodontitis (as an adjunct to gingival scaling androot planing)Child 12–18 years 20 mg twice daily for 3 monthsCounselling Tablets should be swallowed whole with plentyof fluid, while sitting or standingDental prescribing on NHS May be prescribed as DoxycyclineTablets 20 mgLocal applicationFor severe recurrent aphthous ulceration, a 100 mgdoxycycline dispersible tablet can be stirred into asmall amount of water then rinsed around the mouthfor 2–3 minutes 4 times daily usually for 3 days; itshould preferably not be swallowed [unlicensed indication].Note Doxycycline stains teeth; avoid in children under 12 yearsof ageFLURBIPROFENCautions section 10.1.1Contra-indications section 10.1.1Hepatic impairment section 10.1.1Renal impairment section 10.1.1Pregnancy section 10.1.1Breast-feeding section 10.1.1Side-effects taste disturbance, mouth ulcers (movelozenge around mouth); see also section 10.1.1Indication and doseRelief of sore throat for dose, see under preparationStrefen c (Reckitt Benckiser)Lozenges, flurbiprofen 8.75 mg, net price 16 = £2.24DoseChild 12–18 years allow 1 lozenge to dissolve slowly inthe mouth every 3–6 hours, max. 5 lozenges in 24 hours,for max. 3 daysSALICYLATESCautions frequent application, especially in children,may give rise to salicylate poisoningContra-indications children under 16 yearsReye’s syndrome The CHM has advised that topical oralpain relief products containing salicylate salts should not beused in children under 16 years, as a cautionary measure dueto the theoretical risk of Reye’s syndromeIndication and doseMild oral and perioral lesions for dose, see underpreparationsCholine salicylateCholine Salicylate Dental Gel, BPOral gel, choline salicylate 8.7% in a flavoured gelbasis, net price 15 g = £1.89Brands include Bonjela c (sugar-free)DoseChild 16–18 years apply ½-inch of gel with gentlemassage not more often than every 3 hoursDental prescribing on NHS Choline Salicylate Dental Gelmay be prescribed

BNFC 2011–2012 12.3.2 Oropharyngeal anti-infective drugs 545Salicylic acidPyralvex c (Norgine)Oral paint, brown, rhubarb extract (anthraquinoneglycosides 0.5%), salicylic acid 1%. Net price 10 mLwith brush = £3.25DoseChild 16–18 years apply 3–4 times daily; max duration7 days12.3.2 Oropharyngeal antiinfectivedrugsSore throat is usually a self-limiting condition oftencaused by viral infection which does not benefit fromanti-infective treatment. Adequate analgesia may be allthat is required. Systemic antibacterials (Table 1, section5.1) should only be used in severe cases wherethere is concern for the child’s overall clinical condition.Acute ulcerative gingivitis (Vincent’s infection) requirestreatment with oral metronidazole (section 5.1.11).Benzydamine (section 12.3.1) may be beneficial inrelieving pain and dysphagia in children, especiallyafter tonsillectomy or the use of a nasogastric tube.Oropharyngeal viral infectionsChildren with varicella–zoster infection often developpainful lesions in the mouth and throat. Benzydamine(section 12.3.1) may be used to provide local analgesia.Chlorhexidine mouthwash or gel (section 12.3.4) willcontrol plaque accumulation if toothbrushing is painfuland will also help to control secondary infection ingeneral.In severe herpetic stomatitis systemic aciclovir orvalaciclovir (section 5.3.2.1) may be used for orallesions associated with herpes zoster. Aciclovir andvalaciclovir are also used to prevent frequently recurringherpes simplex lesions of the mouth particularlywhen associated with the initiation of erythema multiforme.For the treatment of labial herpes simplex infections,see section 13.10.3.Herpes infections of the mouth in children aged over 12years may also respond to rinsing the mouth withdoxycycline (section 12.3.1).Oropharyngeal fungal infectionsFungal infections of the mouth are usually caused byCandida spp. (candidiasis or candidosis). Differenttypes of oropharyngeal candidiasis are managed asfollows:Thrush Acute pseudomembranous candidiasis(thrush), is usually an acute infection but it may persistfor months in patients receiving inhaled corticosteroids,cytotoxics, or broad-spectrum antibacterials. Thrushalso occurs in patients with serious systemic diseaseassociated with reduced immunity such as leukaemia,other malignancies, and HIV infection. Any predisposingcondition should be managed appropriately. Whenthrush is associated with corticosteroid inhalers, rinsingthe mouth with water (or cleaning a child’s teeth)immediately after using the inhaler may avoid theproblem. Treatment with nystatin or miconazolemay be needed. Fluconazole (section 5.2.1) is effectivefor unresponsive infections or if a topical antifungaldrug cannot be used. Topical therapy may not beadequate in immunocompromised children and anoral triazole antifungal is preferred (section 5.2.1).Acute erythematous candidiasis Acute erythematous(atrophic) candidiasis is a relatively uncommoncondition associated with corticosteroid and broadspectrumantibacterial use and with HIV disease. It isusually treated with fluconazole (section 5.2.1).Angular cheilitis Angular cheilitis (angular stomatitis)is characterised by soreness, erythema and fissuring atthe angles of the mouth. It may represent a nutritionaldeficiency or it may be related to orofacial granulomatosisor HIV infection. Both yeasts (Candida spp.) andbacteria (Staphylococcus aureus and beta-haemolyticstreptococci) are commonly involved as interacting,infective factors. While the underlying cause is beingidentified and treated, it is often helpful to apply miconazolecream (p. 588) or sodium fusidate ointment(p. 587); if the angular cheilitis is unresponsive to treatment,miconazole and hydrocortisone cream or ointment(p. 559) can be used.Immunocompromised patients For advice on preventionof fungal infections in immunocompromisedchildren see p. 301.For the role of antiseptic mouthwashes in the preventionof oral candidiasis in immunocompromised children,see section 12.3.4.Drugs used in oropharyngeal candidiasis Nystatinis not absorbed from the gastro-intestinal tract andis applied locally (as a suspension) to the mouth fortreating local fungal infections. Miconazole is used bylocal application (as an oral gel) in the mouth but it isalso absorbed to the extent that potential interactionsneed to be considered. Miconazole also has someactivity against Gram-positive bacteria including streptococciand staphylococci. In neonates, nystatin oralsuspension or miconazole oral gel is used for the treatmentof oropharyngeal candidiasis; to prevent re-infectionit is important to ensure that the mother’s breastnipples and the teats of feeding bottles are cleanedadequately.Fluconazole (section 5.2.1) given by mouth is reliablyabsorbed; it is used for infections that do not respond totopical therapy or when topical therapy cannot be used.Itraconazole (section 5.2.1) can be used for fluconazole-resistantinfections.If candidal infection fails to respond after 1 to 2 weeks oftreatment with antifungal drugs the child should be sentfor investigation to eliminate the possibility of underlyingdisease. Persistent infection may also be caused byre-infection from the genito-urinary or gastro-intestinaltract.MICONAZOLECautions avoid in acute porphyria (section 9.8.2);interactions: Appendix 1 (antifungals, imidazole)Contra-indications impaired swallowing reflexHepatic impairment avoidPregnancy manufacturer advises avoid if possible—toxicity at high doses in animal studies12 Ear, nose, and oropharynx

546 12.3.3 Lozenges and sprays BNFC 2011–201212 Ear, nose, and oropharynxBreast-feeding manufacturer advises caution—noinformation availableSide-effects nausea and vomiting, very rarely diarrhoea(usually on long-term treatment), hepatitis, rash,toxic epidermal necrolysis, and Stevens-JohnsonsyndromeLicensed use not licensed for use in children under 4months of age or during first 5–6 months of life of aninfant born pre-termIndication and dosePrevention and treatment of oral and intestinalfungal infections. By mouthNeonate (oral fungal infections only) 1 mL 2–4times daily smeared around the mouth after feedsChild 1 month–2 years 2.5 mL twice dailysmeared around the mouth after foodChild 2–6 years 5 mL twice daily after food; retainnear lesions before swallowingChild 6–12 years 5 mL 4 times daily after food;retain near lesions before swallowingChild 12–18 years 5–10 mL 4 times daily afterfood; retain near lesions before swallowingNote Treatment should be continued for 48 hours afterlesions have healedLocalised lesionsChild 2–18 years smear small amount on affectedarea with clean finger 4 times daily for 5–7 days(orthodontic appliances should be removed atnight and brushed with gel); continue treatment for48 hours after lesions have healed1Daktarin c (Janssen) AOral gel, sugar-free, orange-flavoured, miconazole24 mg/mL (20 mg/g). Net price 15-g tube = £2.85, 80-g tube = £4.38. Label: 9, counselling, hold in mouth,after foodDental prescribing on NHS May be prescribed as MiconazoleOromucosal Gel1. 15-g tube can be sold to the publicNYSTATINSide-effects oral irritation and sensitisation, nauseareportedLicensed use suspension not licensed for use inneonates for the treatment of candidiasisIndication and doseOral and perioral fungal infectionsNeonate 100 000 units 4 times daily after feedsChild 1 month–18 years 100 000 units 4 timesdaily after foodNote Treatment is usually given for 7 days, and continued for48 hours after lesions have healed.Skin infections section 13.10.2Nystan c (Squibb) AOral suspension, yellow, nystatin 100 000 units/mL.Net price 30 mL with pipette = £1.91. Label: 9, counselling,use of pipette, hold in mouth, after foodDental prescribing on NHS May be prescribed as NystatinOral Suspension12.3.3 Lozenges and spraysThere is no convincing evidence that antisepticlozenges and sprays have a beneficial action and theysometimes irritate and cause sore tongue and sore lips.Some preparations also contain local anaestheticswhich relieve pain but may cause sensitisation.12.3.4 Mouthwashes andgarglesSuperficial infections of the mouth are often helped bywarm mouthwashes which have a mechanical cleansingeffect and cause some local hyperaemia. However, to beeffective, they must be used frequently and vigorously.Mouthwashes may not be suitable for children under 7years (risk of the solution being swallowed); themouthwash or dental gel may be applied using a cottonbud.A warm saline mouthwash is ideal for its cleansing effectand can be prepared either by dissolving half a teaspoonfulof salt in a glassful of warm water or by dilutingcompound sodium chloride mouthwash with an equalvolume of warm water. Mouthwash solution-tabletscontaining thymol are used to remove unpleasant tastes.Mouthwashes containing an oxidising agent, such ashydrogen peroxide, may be useful in the treatment ofacute ulcerative gingivitis (Vincent’s infection).Hydrogen peroxide solution has also a mechanicalcleansing effect arising from frothing when in contactwith oral debris, but in concentrations greater than 1.5%may cause ulceration and tissue damage.Chlorhexidine is an effective antiseptic which has theadvantage of inhibiting plaque formation on the teeth. Itdoes not, however, completely control plaque depositionand is not a substitute for effective toothbrushing.Moreover, chlorhexidine preparations do not penetratesignificantly into stagnation areas and are therefore oflittle value in the control of dental caries or of periodontaldisease once pocketing has developed. Chlorhexidinepreparations are of little value in the control ofacute necrotising ulcerative gingivitis. With prolongeduse, chlorhexidine causes reversible brown staining ofteeth and tongue. Chlorhexidine may be incompatiblewith some ingredients in toothpaste, causing an unpleasanttaste in the mouth; allow at least 30 minutesbetween using the mouthwash and toothpaste.Chlorhexidine can be used as a mouthwash, spray or gelfor secondary infection in mucosal ulceration and forcontrolling gingivitis, as an adjunct to other oral hygienemeasures. These preparations may also be used insteadof toothbrushing where there is a painful periodontalcondition (e.g. primary herpetic stomatitis) or if the childhas a haemorrhagic disorder, or is disabled. Chlorhexidinemouthwash is used in the prevention of oral candidiasisin immunocompromised patients. Chlorhexidinemouthwash reduces the incidence of alveolar osteitisfollowing tooth extraction. Chlorhexidine mouthwashshould not be used for the prevention of endocarditisin children undergoing dental procedures.

BNFC 2011–2012 12.3.4 Mouthwashes and gargles 547CHLORHEXIDINE GLUCONATESide-effects mucosal irritation (if desquamationoccurs, discontinue treatment or dilute mouthwashwith an equal volume of water); taste disturbance;reversible brown staining of teeth, and of silicate orcomposite restorations; tongue discoloration; parotidgland swelling reportedNote Chlorhexidine gluconate may be incompatible withsome ingredients in toothpaste; leave an interval of at least30 minutes between using mouthwash and toothpasteLicensed use licensed for use in children (age rangenot specified by manufacturer); Corsodyl c notlicensed for use in children under 12 years (unlesson the advice of a healthcare professional)Indication and doseSee under preparations belowChlorhexidine (Non-proprietary)Mouthwash, chlorhexidine gluconate 0.2%, net price300 mL = £2.51DoseOral hygiene and plaque inhibition, oral candidiasis,gingivitis, and management of aphthous ulcersRinse mouth with 10 mL for about 1 minute twice dailyDental prescribing on NHS Chlorhexidine Mouthwash maybe prescribedCorsodyl c (GSK Consumer Healthcare)Dental gel, chlorhexidine gluconate 1%. Net price50 g = £1.21DoseOral hygiene and plaque inhibition and gingivitisBrush on the teeth once or twice dailyWith chlorobutanolEludril c (Fabre)Mouthwash or gargle, chlorhexidine gluconate 0.1%,chlorobutanol 0.5% (mint-flavoured), net price 90 mL= £1.36, 250 mL = £2.83, 500 mL = £5.06DoseOral hygiene and plaque inhibitionUse 10–15 mL (diluted with warm water in measuringcup provided) 2–3 times dailyHEXETIDINESide-effects local irritation; very rarely taste disturbanceand transient anaesthesiaIndication and doseOral hygiene for dose, see preparation belowOraldene c (McNeil)Mouthwash or gargle, red or blue-green (mint-flavoured),hexetidine 0.1%. Net price 100 mL = £1.31;200 mL = £2.02DoseChild 6–18 years use 15 mL (undiluted) 2–3 times dailyOral candidiasis and management of aphthous ulcersApply to affected areas once or twice dailyDental prescribing on NHS May be prescribed as ChlorhexidineGluconate GelMouthwash, chlorhexidine gluconate 0.2%. Net price300 mL (original or mint) = £2.18, 600 mL (mint) =£3.85DoseOral hygiene and plaque inhibition, oral candidiasis,gingivitis, and management of aphthous ulcersRinse mouth with 10 mL for about 1 minute twice dailyOral spray, chlorhexidine gluconate 0.2% (mint-flavoured).Net price 60 mL = £4.10DoseOral hygiene and plaque inhibition, oral candidiasis,gingivitis, and management of aphthous ulcersApply as required to tooth, gingival, or ulcer surfacesusing up to 12 actuations (approx. 0.14 mL/actuation)twice dailyDental prescribing on NHS May be prescribed as ChlorhexidineOral SprayPeriogard c (Colgate-Palmolive)Oromucosal solution, alcohol-free, chlorhexidinegluconate 0.2%, net price 300 mL = £1.96DoseShort-term treatment of inflammation of gingival andoral mucosaChild 6–18 years rinse mouth with 10 mL for about 1minute twice dailyDental prescribing on NHS May be prescribed as ChlorhexidineOromucosal Solution, Alcohol-free, 0.2%HYDROGEN PEROXIDESide-effects hypertrophy of papillae of tongue onprolonged useIndication and doseOral hygiene (see notes above); for dose, see underpreparationsHydrogen Peroxide Mouthwash, BPMouthwash, consists of Hydrogen Peroxide Solution6% (= approx. 20 volume) BPDoseRinse the mouth for 2–3 minutes with 15 mL diluted inhalf a tumblerful of warm water 2–3 times daily (see notesabove)Dental prescribing on NHS Hydrogen Peroxide Mouthwashmay be prescribedPeroxyl c (Colgate-Palmolive)Mouthwash, hydrogen peroxide 1.5%, net price300 mL = £2.54DoseChild 6–18 years, rinse the mouth with 10 mL for about1 minute 3 times daily (after meals and at bedtime) formax. 7 days12 Ear, nose, and oropharynx

548 12.3.5 Treatment of dry mouth BNFC 2011–201212 Ear, nose, and oropharynxSODIUM CHLORIDEIndication and doseOral hygiene (see notes above); for dose, see underpreparationSodium Chloride Mouthwash, Compound, BPMouthwash, sodium bicarbonate 1%, sodium chloride1.5% in a suitable vehicle with a peppermintflavourDoseExtemporaneous preparations should be preparedaccording to the following formula: sodium chloride 1.5 g,sodium bicarbonate 1 g, concentrated peppermint emulsion2.5 mL, double-strength chloroform water 50 mL,water to 100 mLTo be diluted with an equal volume of warm waterDental prescribing on NHS Compound Sodium ChlorideMouthwash may be prescribedTHYMOLIndication and doseOral hygiene (see notes above); for dose, see underpreparationMouthwash Solution-tabletsConsist of tablets which may contain antimicrobial,colouring, and flavouring agents in a suitable solubleeffervescent basis to make a mouthwash suitable fordental purposes. Net price 100-tab pack = £15.09DoseDissolve 1 tablet in a tumblerful of warm waterNote Mouthwash Solution-tablets may contain ingredientssuch as thymolDental prescribing on NHS Mouthwash Solution-tabletsmay be prescribed12.3.5 Treatment of dry mouthDry mouth (xerostomia) may be caused by drugs withantimuscarinic (anticholinergic) side-effects (e.g. antispasmodicsand sedating antihistamines), by irradiationof the head and neck region or by damage to or diseaseof the salivary glands. Children with a persistently drymouth may develop a burning or scalded sensation andhave poor oral hygiene; they may develop dental caries,periodontal disease, and oral infections (particularlycandidiasis). Dry mouth may be relieved in manypatients by simple measures such as frequent sips ofcool drinks or sucking pieces of ice or sugar-free fruitpastilles. Sugar-free chewing gum stimulates salivationin patients with residual salivary function.Artificial saliva can provide useful relief of dry mouth.A properly balanced artificial saliva should be of aneutral pH and contain electrolytes (including fluoride)to correspond approximately to the composition ofsaliva. The acidic pH of some artificial saliva productsmay be inappropriate.Local treatmentArtificial saliva products with ACBS approval may beprescribed for children with dry mouth as a result ofhaving (or having undergone) radiotherapy, or siccasyndrome. SST tablets may also be prescribed on theNHS.AS Saliva Orthana c (AS Pharma)Oral spray, gastric mucin (porcine) 3.5%, xylitol 2%,sodium fluoride 4.2 mg/litre, with preservatives andflavouring agents, pH neutral, net price 50-mL bottle= £4.92; 500-mL refill = £34.27Dose(ACBS) spray 2–3 times onto oral and pharyngealmucosa, when requiredDental prescribing on NHS AS Saliva Orthana c Oral Spraymay be prescribedLozenges, mucin 65 mg, xylitol 59 mg, in a sorbitolbasis, pH neutral, net price 30-lozenge pack = £3.50Note AS Saliva Orthana c lozenges do not contain fluorideDental prescribing on NHS AS Saliva Orthana c Lozengesmay be prescribedBiotène Oralbalance c (GSK)Saliva replacement gel, lactoperoxidase, lactoferrin,lysozyme, glucose oxidase, xylitol in a gel basis, netprice 50-g tube = £4.10; 24 12.4 mL tube = £30.40(for hospital use)DoseSymptomatic treatment of dry mouthApply to gums and tongue as requiredNote Avoid use with toothpastes containing detergents(including foaming agents)Dental prescribing on NHS Biotène Oralbalance c SalivaReplacement Gel may be prescribedBioXtra c (RIS Products)Gel, lactoperoxidase, lactoferrin, lysozyme, wheycolostrum, xylitol and other ingredients, net price 40-mL tube = £3.94, 50-mL spray = £3.94Dose(ACBS) apply to oral mucosa as requiredDental prescribing on NHS BioXtra c Gel may beprescribedGlandosane c (Fresenius Kabi)Aerosol spray, carmellose sodium 500 mg, sorbitol1.5 g, potassium chloride 60 mg, sodium chloride42.2 mg, magnesium chloride 2.6 mg, calcium chloride7.3 mg, and dipotassium hydrogen phosphate17.1 mg/50 g, pH 5.75, net price 50-mL unit (neutral,lemon or peppermint flavoured) = £4.82Dose(ACBS) spray onto oral and pharyngeal mucosa asrequiredDental prescribing on NHS Glandosane c Aerosol Spraymay be prescribedSaliveze c (Wyvern)Oral spray, carmellose sodium (sodium carboxymethylcellulose),calcium chloride, magnesiumchloride, potassium chloride, sodium chloride, anddibasic sodium phosphate, pH neutral, net price 50-mL bottle (mint-flavoured) = £3.50Dose(ACBS) 1 spray onto oral mucosa as requiredDental prescribing on NHS Saliveze c Oral Spray may beprescribed

BNFC 2011–2012 12.3.5 Treatment of dry mouth 549Salivix c (Galen)Pastilles, sugar-free, reddish-amber, acacia, malicacid and other ingredients. Net price 50-pastille pack= £3.50Dose(ACBS) suck 1 pastille when requiredDental prescribing on NHS Salivix c Pastilles may beprescribedSST (Medac)Tablets, sugar-free, citric acid, malic acid and otheringredients in a sorbitol base, net price 100-tab pack =£4.86DoseSymptomatic treatment of dry mouth in patients withimpaired salivary gland function and patent salivaryductsAllow 1 tablet to dissolve slowly in the mouth whenrequiredDental prescribing on NHS May be prescribed as SalivaStimulating TabletsXerotin c (SpePharm)Oral spray, sugar-free, water, sorbitol, carmellose(carboxymethylcellulose), potassium chloride, sodiumchloride, potassium phosphate, magnesium chloride,calcium chloride and other ingredients, pH neutral.Net price 100-mL unit = £6.86DoseSymptomatic treatment of dry mouthSpray as requiredDental prescribing on NHS Xerotin c Oral Spray may beprescribed as Artificial Saliva Oral Spray12 Ear, nose, and oropharynx

550 BNFC 2011–201213 Skin13 Skin13.1 Management of skin conditions55013.1.1 Vehicles 55113.1.2 Suitable quantities for prescribing55113.1.3 Excipients and sensitisation 55113.2 Emollient and barrier preparations55213.2.1 Emollients 55213.2.1.1 Emollient bath additives andshower preparations 55413.2.2 Barrier preparations 55613.3 Topical antipruritics 55713.4 Topical corticosteroids 55813.5 Preparations for eczema andpsoriasis 56513.5.1 Preparations for eczema 56513.5.2 Preparations for psoriasis 56613.5.3 Drugs affecting the immuneresponse 57213.6 Acne and rosacea 57413.6.1 Topical preparations for acne 57413.6.2 Oral preparations for acne 57813.7 Preparations for warts andcalluses 58013.8 Sunscreens and camouflagers 58213.8.1 Sunscreen preparations 58213.8.2 Camouflagers 58313.9 Shampoos and other preparationsfor scalp conditions 58313.10 Anti-infective skin preparations58513.10.1 Antibacterial preparations 58513.10.1.1 Antibacterial preparations onlyused topically 58613.10.1.2 Antibacterial preparations alsoused systemically 58713.10.2 Antifungal preparations 58813.10.3 Antiviral preparations 59113.10.4 Parasiticidal preparations 59113.10.5 Preparations for minor cuts andabrasions 59313.11 Skin cleansers, antiseptics,and preparations for promotionof wound healing 59413.11.1 Alcohols and saline 59413.11.2 Chlorhexidine salts 59513.11.3 Cationic surfactants and soaps 59513.11.4 Iodine 59613.11.5 Phenolics 59613.11.6 Oxidisers and dyes 59613.11.7 Preparations for promotion ofwound healing 59613.12 Antiperspirants 59713.13 Topical circulatory preparations597This chapter also includes advice on the managementof the following:candidiasis, p. 588dermatophytoses, p. 588head lice, p. 592nappy rash, p. 556pityriasis versicolor, p. 588scabies, p. 592For information on wound management products andelasticated garments, see the relevant BNF appendix.The British Association of Dermatologists’ list of preferredunlicensed dermatological preparations (specials)is available at www.bad.org.uk/site/495/default.aspx.13.1 Management of skinconditionsWhen prescribing topical preparations for the treatmentof skin conditions in children, the site of application, thecondition being treated, and the child’s (and carer’s)preference for a particular vehicle all need to be takeninto consideration.Neonates Caution is required when prescribing topicalpreparations for neonates—their large body surfacearea in relation to body mass increases susceptibilityto toxicity from systemic absorption of substancesapplied to the skin. Topical preparations containingpotentially sensitising substances such as corticosteroids,aminoglycosides, iodine, and parasiticidal drugsshould be avoided. Preparations containing alcoholshould be avoided because they can dehydrate theskin, cause pain if applied to raw areas, and the alcoholcan cause necrosis.In preterm neonates, the skin is more fragile and offers apoor barrier, especially in the first fortnight after birth.Preterm infants, especially if below 32 weeks post-

BNFC 2011–2012 13.1.1 Vehicles 551menstrual age, may also require special measures tomaintain skin hydration.13.1.1 VehiclesThe vehicle in topical preparations for the skin affectsthe degree of hydration, has a mild anti-inflammatoryeffect, and aids the penetration of the active drug.Therefore, the vehicle, as well as the active drug, shouldbe chosen on the basis of their suitability for the child’sskin condition.Applications are usually viscous solutions, emulsions,or suspensions for application to the skin (including thescalp) or nails.Collodions are painted on the skin and allowed to dry toleave a flexible film over the site of application.Creams are emulsions of oil and water and are generallywell absorbed into the skin. They may contain an antimicrobialpreservative unless the active ingredient orbasis is intrinsically bactericidal and fungicidal. Generally,creams are cosmetically more acceptable thanointments because they are less greasy and easier toapply.Gels consist of active ingredients in suitable hydrophilicor hydrophobic bases; they generally have a high watercontent. Gels are particularly suitable for application tothe face and scalp.Lotions have a cooling effect and may be preferred toointments or creams for application over a hairy area.Lotions in alcoholic basis can sting if used on brokenskin. Shake lotions (such as calamine lotion) containinsoluble powders which leave a deposit on the skinsurface.Ointments are greasy preparations which are normallyanhydrous and insoluble in water, and are more occlusivethan creams. They are particularly suitable forchronic, dry lesions. The most commonly used ointmentbases consist of soft paraffin or a combination of soft,liquid and hard paraffin. Some ointment bases have bothhydrophilic and lipophilic properties; they may haveocclusive properties on the skin surface, encouragehydration, and also be miscible with water; they oftenhave a mild anti-inflammatory effect. Water-solubleointments contain macrogols which are freely solublein water and are therefore readily washed off; they havea limited but useful role where ready removal is desirable.Pastes are stiff preparations containing a high proportionof finely powdered solids such as zinc oxide andstarch suspended in an ointment. They are used forcircumscribed lesions such as those which occur inlichen simplex, chronic eczema, or psoriasis. They areless occlusive than ointments and can be used to protectinflamed, lichenified, or excoriated skin.Dusting powders are used only rarely. They reducefriction between opposing skin surfaces. Dusting powdersshould not be applied to moist areas because theycan cake and abrade the skin. Talc is a lubricant but itdoes not absorb moisture; it can cause respiratoryirritation. Starch is less lubricant but absorbs water.Dilution The BP directs that creams and ointmentsshould not normally be diluted but that should dilutionbe necessary care should be taken, in particular, toprevent microbial contamination. The appropriate diluentshould be used and heating should be avoidedduring mixing; excessive dilution may affect the stabilityof some creams. Diluted creams should normally beused within 2 weeks of their preparation.13.1.2 Suitable quantities forprescribingSuitable quantities of dermatological preparationsto be prescribed for specific areasof the bodyArea of the bodyCreams andOintments LotionsFace 15–30 g 100 mLBoth hands 25–50 g 200 mLScalp 50–100 g 200 mLBoth arms or both legs 100–200 g 200 mLTrunk 400 g 500 mLGroins and genitalia 15–25 g 100 mLThe amounts shown above are usually suitable forchildren 12–18 years for twice daily application for 1week; smaller quantities will be required for childrenunder 12 years. These recommendations do not applyto corticosteroid preparations.13.1.3 Excipients andsensitisationExcipients in topical products rarely cause problems. If apatch test indicates allergy to an excipient, then productscontaining the substance should be avoided (seealso Anaphylaxis, p. 159). The following excipients intopical preparations may rarely be associated withsensitisation; the presence of these excipients is indicatedin the entries for topical products. See also Excipients,under General Guidance, p. 2.BeeswaxImidureaBenzyl alcoholIsopropyl palmitateButylated hydroxyanisole N-(3-Chloroallyl)hexaminiumchloride (quater-Butylated hydroxytolueneCetostearyl alcohol (includingcetyl and stearyl Polysorbatesnium 15)alcohol)Propylene glycolChlorocresolSodium metabisulphiteEdetic acid (EDTA)Sorbic acidEthylenediamineWool fat and related substancesincludingFragrancesHydroxybenzoates (parabens)lanolin 11. Purified versions of wool fat have reduced the problem13 Skin

552 13.2 Emollient and barrier preparations BNFC 2011–201213 Skin13.2 Emollient and barrierpreparations13.2.1 Emollients13.2.2 Barrier preparationsBorderline substances The preparations marked‘ACBS’ are regarded as drugs when prescribed in accordancewith the advice of the Advisory Committee onBorderline Substances for the clinical conditions listed.Prescriptions issued in accordance with this advice andendorsed ‘ACBS’ will normally not be investigated. SeeAppendix 2 for listing by clinical condition.13.2.1 EmollientsEmollients hydrate the skin, soften the skin, act asbarrier to water and external irritants, and are indicatedfor all dry or scaling disorders. Their effects are shortlivedand they should be applied frequently even afterimprovement occurs. They are useful in dry and eczematousdisorders, and to a lesser extent in psoriasis(section 13.5.2); they should be applied in the directionof hair growth immediately after washing or bathing tomaximise the effect of skin hydration. The choice of anappropriate emollient will depend on the severity of thecondition, the child’s (or carer’s) preference, and the siteof application. Ointments may exacerbate acne andfolliculitis. Some ingredients rarely cause sensitisation(section 13.1.3) and this should be suspected if aneczematous reaction occurs. The use of aqueouscream as a leave-on emollient may increase the risk ofskin reactions, particularly in eczema.Fire hazard with paraffin-based emollientsEmulsifying ointment or 50% Liquid Paraffin and50% White Soft Paraffin Ointment in contact withdressings and clothing is easily ignited by a nakedflame. The risk is greater when these preparationsare applied to large areas of the body, and clothing ordressings become soaked with the ointment. Childrenand their carers should be told to keep awayfrom fire or flames and not to smoke when usingthese preparations. The risk of fire should be consideredwhen using large quantities of any paraffinbasedemollient.Preparations such as aqueous cream and emulsifyingointment can be used as soap substitutes; the preparationis rubbed on the skin before rinsing off completely.The addition of a bath oil (section 13.2.1.1) may also behelpful.In the neonate, a preservative-free paraffin-based emollienthydrates the skin without affecting the normal skinflora; substances such as olive oil are also used. Thedevelopment of blisters (epidermolysis bullosa) orichthyosis may be alleviated by applying liquid andwhite soft paraffin ointment while awaiting dermatologicalinvestigation.Preparations containing an antibacterial (section13.10.1) should be avoided unless infection is presentor is a frequent complication of the dry skin condition.Urea is a keratin softener and hydrating agent used inthe treatment of dry, scaling conditions (includingichthyosis). It is occasionally used with other topicalagents such as corticosteroids to enhance penetration ofthe skin.Non-proprietary emollient preparationsAqueous Cream, BPCream, emulsifying ointment 30%, 1 phenoxyethanol1% in freshly boiled and cooled purified water, netprice 100 g = £1.51, 500 g = £1.86Excipients include cetostearyl alcohol1. The BP permits use of alternative antimicrobials providedtheir identity and concentration are stated on the labelEmulsifying Ointment, BPOintment, emulsifying wax 30%, white soft paraffin50%, liquid paraffin 20%, net price 500 g = £2.22Excipients include cetostearyl alcoholHydrous Ointment, BPOintment, (oily cream), dried magnesium sulphate0.5%, phenoxyethanol 1%, wool alcohols ointment50%, in freshly boiled and cooled purified water, netprice 500 g = £2.92Liquid and White Soft Paraffin Ointment, NPFOintment, liquid paraffin 50%, white soft paraffin50%, net price 500 g = £6.09Paraffin, White Soft, BPWhite petroleum jelly, net price 100 g = 51pParaffin, Yellow Soft, BPYellow petroleum jelly, net price 100 g = 49pProprietary emollient preparationsAquamol c (Thornton & Ross)Cream, containing liquid paraffin, white soft paraffin,net price 50 g = £1.22, 500-g pump pack = £6.40Excipients include cetostearyl alcohol, chlorocresolAveeno c (J&J)Cream, colloidal oatmeal in emollient basis, net price100 mL = £3.78, 300-mL pump pack = £6.80Excipients include benzyl alcohol, cetyl alcohol, isopropyl palmitateACBS: For endogenous and exogenous eczema, xeroderma, andichthyosisLotion, colloidal oatmeal in emollient basis, net price400 mL = £6.42Excipients include benzyl alcohol, cetyl alcohol, isopropyl palmitateACBS: as for Aveeno c CreamCetraben c (Genus)Emollient cream, white soft paraffin 13.2%, light liquidparaffin 10.5%, net price 50-g pump pack = £1.40,150-g pump pack = £3.98, 500-g pump pack = £5.99,1.05-kg pump pack = £11.62Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)Dermamist c (Alliance)Spray application, white soft paraffin 10% in a basiscontaining liquid paraffin, fractionated coconut oil,net price 250-mL pressurised aerosol unit = £5.97Excipients none as listed in section 13.1.3Note FlammableDiprobase c (Schering-Plough)Cream, cetomacrogol 2.25%, cetostearyl alcohol7.2%, liquid paraffin 6%, white soft paraffin 15%,water-miscible basis used for Diprosone c cream, netprice 50 g = £1.28; 500-g pump pack= £6.32Excipients include cetostearyl alcohol, chlorocresolOintment, liquid paraffin 5%, white soft paraffin 95%,basis used for Diprosone c ointment, net price 50 g =£1.28, 500 g = £5.99Excipients none as listed in section 13.1.3

BNFC 2011–2012 13.2.1 Emollients 553Doublebase c (Dermal)Gel, isopropyl myristate 15%, liquid paraffin 15%, netprice 100 g = £2.65, 500 g = £5.82Excipients none as listed in section 13.1.3E45 c (Reckitt Benckiser)Cream, light liquid paraffin 12.6%, white soft paraffin14.5%, hypoallergenic anhydrous wool fat (hypoallergeniclanolin) 1% in self-emulsifying monostearin,net price 50 g = £1.40, 125 g = £2.55, 350 g = £4.46,500-g pump pack = £4.89Excipients include cetyl alcohol, hydroxybenzoates (parabens)Lotion, light liquid paraffin 4%, cetomacrogol, whitesoft paraffin 10%, hypoallergenic anhydrous wool fat(hypoallergenic lanolin) 1% in glyceryl monostearate,net price 200 mL = £2.40, 500-mL pump pack = £4.50Excipients include isopropyl palmitate, hydroxybenzoates (parabens),benzyl alcoholACBS: for symptomatic relief of dry skin conditions, such as thoseassociated with atopic eczema and contact dermatitisEmollin c (C D Medical)Spray, liquid paraffin 50%, white soft paraffin 50% inaerosol basis, net price 150 mL = £3.74, 240 mL =£5.98Excipients none as listed in section 13.1.3Epaderm c (Mölnlycke)Cream, yellow soft paraffin 15%, liquid paraffin 10%,emulsifying wax 5%, net price 50-g pump pack =£1.60, 500-g pump pack = £6.55Excipients include cetostearyl alcohol, chlorocresolOintment, emulsifying wax 30%, yellow soft paraffin30%, liquid paraffin 40%, net price 125 g = £3.72,500 g = £6.30, 1 kg = £11.61Excipients include cetostearyl alcoholHydromol c (Alliance)Cream, sodium pidolate 2.5%, liquid paraffin 13.8%,net price 50 g = £2.04, 100 g = £3.80, 500 g = £11.09Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)Ointment, yellow soft paraffin 30%, emulsifying wax30%, liquid paraffin 40%, net price 125 g = £2.79,500 g = £4.74, 1 kg = £8.81Excipients include cetostearyl alcoholLipobase c (Astellas)Cream, fatty cream basis used for LocoidLipocream c , net price 50 g = £1.46Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)For dry skin conditions, also for use during treatment with topicalcorticosteroid and as diluent for Locoid Lipocream cOilatum c (Stiefel)Cream, light liquid paraffin 6%, white soft paraffin15%, net price 40 g = £1.30, 150 g = £2.46, 500-mLpump pack = £4.99, 1.05-litre pump pack = £9.98Excipients include benzyl alcohol, cetostearyl alcoholOilatum c Junior Cream, light liquid paraffin 6%,white soft paraffin 15%, 150 g = £3.38, 350-mL pumppack = £4.65, 500-mL pump pack = £4.99, 1.05-litrepump pack = £9.98Excipients include benzyl alcohol, cetostearyl alcoholQV c (Crawford)Cream, glycerol 10%, light liquid paraffin 10%, whitesoft paraffin 5%, net price 100 g = £1.95, 500 g = £5.60Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)Lotion, white soft paraffin 5%, net price 250 mL =£3.00Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)Ultrabase c (Bayer Schering)Cream, water-miscible, containing liquid paraffin andwhite soft paraffin, net price 50 g = £1.58, 500-g pumppack = £16.23Excipients include fragrance, hydroxybenzoates (parabens), disodiumedetate, stearyl alcoholUnguentum M c (Almirall)Cream, containing saturated neutral oil, liquid paraffin,white soft paraffin, net price 50 g = £1.41, 100 g= £2.78, 200-mL pump pack = £5.50, 500 g = £8.48Excipients include cetostearyl alcohol, polysorbate 40, propylene glycol,sorbic acidZerobase c (Thornton & Ross)Cream, liquid paraffin 11%, net price 50 g = £1.04,500-g pump pack = £5.26Excipients include cetostearyl alcohol, chlorocresolZerocream c (Thornton & Ross)Cream, liquid paraffin 12.6%, white soft paraffin14.5%, net price 50 g = £1.17, 500-g pump pack =£4.08Excipients include cetyl alcohol, hydroxybenzoates (parabens), lanolinanhydrousZeroguent c (Thornton & Ross)Cream, light liquid paraffin 8%, white soft paraffin 4%,refined soya bean oil 5%, net price 100 g = £2.33,500 g = £7.07Excipients include cetostearyl alcohol, polysorbate 40, propylene glycol,sorbic acidPreparations containing ureaAquadrate c (Alliance)Cream, urea 10%, net price 100 g = £4.37Excipients none as listed in section 13.1.3DoseApply thinly twice dailyBalneum c (Almirall)Cream, urea 5%, ceramide 0.1%, net price 50-g pumppack = £2.80, 500-g pump pack = £9.80Excipients include cetostearyl alcohol, polysorbates, propylene glycolDoseApply twice dailyBalneum c Plus Cream, urea 5%, lauromacrogols 3%,net price 100 g = £3.29, 500-g pump pack = £16.42Excipients include benzyl alcohol, polysorbatesDoseApply twice dailyCalmurid c (Galderma)Cream, urea 10%, lactic acid 5%, net price 100 g =£5.70, 500-g pump pack = £27.42Excipients none as listed in section 13.1.3DoseApply a thick layer for 3–5 minutes, massage into area,and remove excess, usually twice daily. Use half-strengthcream for 1 week if stinging occursNote Can be diluted with aqueous cream (life of dilutedcream 14 days)Dermatonics Heel Balm c (Dermatonics)Cream, urea 25 %, net price 75 mL = £4.00, 200 mL =£9.50Excipients include beeswax, lanolinDoseChild 12–18 years apply once daily to dry skin on solesof feet13 Skin

554 13.2.1 Emollients BNFC 2011–201213 SkinE45 c Itch Relief Cream (Reckitt Benckiser)Cream, urea 5%, macrogol lauryl ether 3%, net price50 g = £2.55, 100 g = £3.47, 500-g pump pack = £14.99Excipients include benzyl alcohol, polysorbatesDoseApply twice dailyEucerin c Intensive (Beiersdorf)Cream, urea 10%, net price 100 mL = £7.59Excipients include benzyl alcohol, isopropyl palmitate, wool fatDoseApply thinly and rub into area twice dailyLotion, urea 10%, net price 250 mL = £7.93Excipients include benzyl alcohol, isopropyl palmitateDoseApply sparingly and rub into area twice dailyHydromol c Intensive (Alliance)Cream, urea 10%, net price 30 g = £1.64, 100 g = £4.37Excipients none as listed in section 13.1.3DoseApply thinly twice dailyNutraplus c (Galderma)Cream, urea 10%, net price 100 g = £4.37Excipients include hydroxybenzoates (parabens), propylene glycolDoseApply 2–3 times dailyWith antimicrobialsDermol c (Dermal)Cream, benzalkonium chloride 0.1%, chlorhexidinehydrochloride 0.1%, isopropyl myristate 10%, liquidparaffin 10%, net price 100-g tube = £2.86, 500-gpump pack = £6.63Excipients include cetostearyl alcoholDoseApply to skin or use as soap substituteDermol c 500 Lotion, benzalkonium chloride 0.1%,chlorhexidine hydrochloride 0.1%, liquid paraffin2.5%, isopropyl myristate 2.5%, net price 500-mLpump pack = £6.03Excipients include cetostearyl alcoholDoseApply to skin or use as soap substituteEczmol c (Genus)Cream, chlorhexidine gluconate 1% in emollientbasis, net price 250 mL = £3.70Excipients include cetostearyl alcoholDoseApply to skin or use as soap substitute13.2.1.1 Emollient bath additives andshower preparationsEmollient bath additives should be added to bath water;some can be applied to wet skin undiluted and rinsedoff. Hydration can be improved by soaking in the bathfor 10–20 minutes. In dry skin conditions soap should beavoided (see section 13.2.1 for soap substitutes).The quantities of bath additives recommended for olderchildren are suitable for an adult-size bath. Proportionatelyless should be used for a child-size bath or awashbasin; recommended bath additive quantities foryounger children reflect this.These preparations make skin and surfaces slippery—particularcare is needed when bathing achild.Aveeno c (J&J)Bath oil, colloidal oatmeal, white oat fraction inemollient basis, net price 250 mL = £4.28Excipients include beeswax, fragranceACBS: for endogenous and exogenous eczema, xeroderma, andichthyosisDoseChild 2–18 years add 20–30 mL to bath water or applyto wet skin and rinseColloidal c bath additive, oatmeal, white oat fractionin emollient basis, net price 10 50-g sachets = £7.33;Baby Bath Additive c , 10 15-g sachets = £4.39Excipients none as listed in section 13.1.3ACBS: as for Aveeno c Bath oilDoseChild 1 month–12 years add 15 g to bath waterChild 12–18 years add 50 g to bath waterBalneum c (Almirall)Balneum c bath oil, soya oil 84.75%, net price200 mL = £2.48, 500 mL = £5.38, 1 litre = £10.39Excipients include butylated hydroxytoluene, propylene glycol, fragranceDoseNeonate add 5–15 mL to bath water; do not use undilutedChild 1 month–2 years add 5–15 mL to bath water; donot use undilutedChild 2–18 years add 20–60 mL to bath water; do notuse undilutedBalneum Plus c bath oil, soya oil 82.95%, mixedlauromacrogols 15%, net price 500 mL = £6.66Excipients include butylated hydroxytoluene, propylene glycol, fragranceDoseNeonate add 5 mL to bath water or apply to wet skin andrinseChild 1 month–2 years add 5 mL to bath water or applyto wet skin and rinseChild 2–18 years add 10–20 mL to bath water or applyto wet skin and rinseCetraben c (Genus)Emollient bath additive, light liquid paraffin 82.8%,net price 500 mL = £5.75Excipients none as listed in section 13.1.3DoseNeonate add ½ capful to bath water or apply to wet skinand rinseChild 1 month–12 years add ½–1 capful to bath wateror apply to wet skin and rinseChild 12–18 years add 1–2 capfuls to bath water orapply to wet skin and rinseDermalo c (Dermal)Bath emollient, acetylated wool alcohols 5%, liquidparaffin 65%, net price 500 mL = £3.44Excipients none as listed in section 13.1.3DoseNeonate add 5 mL to bath water or apply to wet skin andrinse

BNFC 2011–2012 13.2.1 Emollients 555Child 1 month–12 years add 5–10 mL to bath water orapply to wet skin and rinseChild 12–18 years add 15–20 mL to bath water or applyto wet skin and rinseDiprobath c (Schering-Plough)Bath additive, isopropyl myristate 39%, light liquidparaffin 46%, net price 500 mL = £6.71Excipients none as listed in section 13.1.3DoseNeonate add 5 mL to bath water; do not use undilutedChild 1 month–12 years add 10 mL to bath water; donot use undilutedChild 12–18 years add 25–50 mL to bath water; do notuse undilutedDoublebase c (Dermal)Emollient bath additive, liquid paraffin 65%, netprice 500 mL = £5.45Excipients include cetostearyl alcoholDoseNeonate add 5–10 mL to bath waterChild 1 month–12 years add 5–10 mL to bath waterChild 12–18 years add 15–20 mL to bath waterEmollient shower gel, isopropyl myristate 15%, liquidparaffin 15%, net price 200 g = £5.21Excipients none as listed in section 13.1.3Note Also available as Doublebase c Emollient Wash GelDoseApply to wet or dry skin and rinse, or apply to dry skinafter showeringE45 c (Reckitt Benckiser)Emollient bath oil, cetyl dimeticone 5%, liquid paraffin91%, net price 250 mL = £3.19, 500 mL = £5.11Excipients none as listed in section 13.1.3ACBS: for endogenous and exogenous eczema, xeroderma, andichthyosisDoseNeonate add 5 mL to bath water or apply to wet skin andrinseChild 1 month–12 years add 5–10 mL to bath water orapply to wet skin and rinseChild 12–18 years add 15 mL to bath water or apply towet skin and rinseEmollient wash cream, zinc oxide 5% in an emollientbasis, net price 250-mL pump pack = £3.19Excipients none as listed in section 13.1.3ACBS: for endogenous and exogenous eczema, xeroderma, andichthyosisDoseUse as a soap substituteHydromol c (Alliance)Bath and Shower Emollient, isopropyl myristate13%, light liquid paraffin 37.8%, net price 350 mL =£3.61, 500 mL = £4.11, 1 litre = £8.19Excipients none as listed in section 13.1.3DoseNeonate add ½ capful to bath water or apply to wet skinand rinseChild 1 month–12 years add ½–2 capfuls to bath wateror apply to wet skin and rinseChild 12–18 years add 1–3 capfuls to bath water orapply to wet skin and rinseOilatum c (Stiefel)Emollient bath additive (emulsion), light liquid paraffin63.4%, net price 250 mL = £2.75, 500 mL = £4.57Excipients include acetylated lanolin alcohols, isopropyl palmitate, fragranceDoseNeonate add ½ capful to bath water or apply to wet skinand rinseChild 1 month–12 years add ½–2 capfuls to bath wateror apply to wet skin and rinseChild 12–18 years add 1–3 capfuls to bath water orapply to wet skin and rinseJunior bath additive, light liquid paraffin 63.4%, netprice 150 mL = £2.82, 250 mL = £3.25, 300 mL =£5.10, 600 mL = £5.89Excipients include acetylated lanolin alcohols, isopropyl palmitateDoseNeonate add ½ capful to bath water or apply to wet skinand rinseChild 1 month–12 years add ½–2 capfuls to bath wateror apply to wet skin and rinseChild 12–18 years add 1–3 capfuls to bath water orapply to wet skin and rinseShower emollient (gel), light liquid paraffin 70%, netprice (with fragrance or fragrance-free) 150 g = £5.15DoseApply to wet skin and rinseQV c (Crawford)Bath oil, light liquid paraffin 85.09%, net price 200 mL= £2.20, 500 mL = £4.50Excipients include hydroxybenzoates (parabens)DoseChild 1 month–1 year add 4 mL to bath water or applyto wet skin and rinseChild 1–12 years add 7 mL to bath water or apply to wetskin and rinseChild 12–18 years add 10 mL to bath water or apply towet skin and rinseWash, glycerol 10%, net price 200 mL = £2.50Excipients include hydroxybenzoates (parabens)DoseUse as a soap substituteZerolatum c (Thornton & Ross)Emollient medicinal bath oil, liquid paraffin 65%, netprice 500 mL = £4.79Excipients include acetylated wool alcoholsDoseChild 1 month–12 years add 5–10 mL to bath waterChild 12–18 years add 15–20 mL to bath waterZeroneum c (Thornton & Ross)Bath oil, refined soya bean oil 83.35%, net price500 mL = £4.48Excipients include butylated hydroxytoluene, fragrance, propylene glycolDoseChild 1 month–12 years add 5 mL to bath waterChild 12–18 years add 20 mL to bath water13 Skin

556 13.2.2 Barrier preparations BNFC 2011–201213 SkinZerozole c (Thornton & Ross)Bath oil, refined soya bean oil 83.45%, macrogol 4-lauryl ether 15%, net price 500 mL = £5.55Excipients include butylated hydroxytoluene, fragrance, propylene glycolDoseNeonate add 5–15 mL to bath waterChild 1 month–12 years add 5–15 mL to bath water, orapply to wet skin and rinseChild 12–18 years add 20–60 mL to bath water, or applyto wet skin and rinseWith antimicrobialsDermol c (Dermal)Dermol c 600 bath emollient, benzalkonium chloride0.5%, liquid paraffin 25%, isopropyl myristate 25%,net price 600 mL = £7.55Excipients include polysorbate 60DoseChild 1 month–2 years add 5–15 mL to bath water; donot use undilutedChild 2–18 years add 15–30 mL to bath water; do notuse undilutedDermol c 200 Shower Emollient, benzalkoniumchloride 0.1%, chlorhexidine hydrochloride 0.1%,liquid paraffin 2.5%, isopropyl myristate 2.5%, netprice 200 mL = £3.55Excipients include cetostearyl alcoholDoseApply to skin or use as soap substituteEmulsiderm c (Dermal)Liquid emulsion, benzalkonium chloride 0.5%, liquidparaffin 25%, isopropyl myristate 25%, net price300 mL (with 15-mL measure) = £3.85, 1 litre (with 30-mL measure) = £12.00Excipients include polysorbate 60DoseChild 1 month–2 years add 5–10 mL to bath water orrub into dry skin until absorbedChild 2–18 years add 10–30 mL to bath water or rubinto dry skin until absorbedOilatum c Plus (Stiefel)Bath additive, benzalkonium chloride 6%, triclosan2%, light liquid paraffin 52.5%, net price 500 mL =£6.98Excipients include acetylated lanolin alcohols, isopropyl palmitateDoseChild 6 months–1 year add 1 mL to bath water; do notuse undilutedChild 1–18 years add 1–2 capfuls to bath water; do notuse undilutedZerolatum c Plus (Thornton & Ross)Bath additive, benzalkonium chloride 6%, triclosan2%, light liquid paraffin 51.66%, net price 500 mL =£5.81Excipients include acetylated lanolin alcohols, isopropyl palmitate,polysorbate 80DoseChild 6 months–1 year add 1 mL to bath water; do notuse undilutedChild 1–18 years add 1–2 capfuls to bath water; do notuse undilutedWith tarSection 13.5.213.2.2 Barrier preparationsBarrier preparations often contain water-repellent substancessuch as dimeticone, natural oils, and paraffins,to help protect the skin from abrasion and irritation;they are used to protect intact skin around stomas andpressure sores, and as a barrier against nappy rash. Inneonates, barrier preparations which do not containpotentially sensitising excipients (section 13.1.3) arepreferred. Where the skin has broken down, barrierpreparations have a limited role in protecting adjacentskin. Zinc ointments or barrier creams with zinc oxideor titanium salts, are used to aid healing of uninfected,excoriated skin.Nappy rash (Dermatitis) The first line of treatment isto ensure that nappies are changed frequently and thattightly fitting water-proof pants are avoided. The rashmay clear when left exposed to the air and a barrierpreparation, applied with each nappy change, can behelpful. A mild corticosteroid such as hydrocortisone0.5% or 1% (section 13.4) can be used if inflammation iscausing discomfort, but it should be avoided in neonates.The barrier preparation should be applied afterthe corticosteroid preparation to prevent furtherdamage. Preparations containing hydrocortisone shouldbe applied for no more than a week; the hydrocortisoneshould be discontinued as soon as the inflammationsubsides. The occlusive effect of nappies and waterproofpants may increase absorption of corticosteroids(for cautions, see section 13.4). If the rash is associatedwith candidal infection, a topical antifungal such asclotrimazole cream (section 13.10.2) can be used. Topicalantibacterial preparations (section 13.10.1) can beused if bacterial infection is present; treatment with anoral antibacterial may occasionally be required in severeor recurrent infection. Hydrocortisone may be used incombination with antimicrobial preparations if there isconsiderable inflammation, erosion, and infection.Non-proprietary barrier preparationsZinc Cream, BPCream, zinc oxide 32%, arachis (peanut) oil 32%,calcium hydroxide 0.045%, oleic acid 0.5%, wool fat8%, in freshly boiled and cooled purified water, netprice 50 g = 75pZinc Ointment, BPOintment, zinc oxide 15%, in Simple Ointment BP1988 (which contains wool fat 5%, hard paraffin 5%,cetostearyl alcohol 5%, white soft paraffin 85%), netprice 25 g = 30pZinc and Castor Oil Ointment, BPOintment, zinc oxide 7.5%, castor oil 50%, arachis(peanut) oil 30.5%, white beeswax 10%, cetostearylalcohol 2%, net price 500 g = £2.93Proprietary barrier preparationsConotrane c (Astellas)Cream, benzalkonium chloride 0.1%, dimeticone 22%,net price 100 g = 88p, 500 g = £3.51Excipients include cetostearyl alcohol, fragrance

BNFC 2011–2012 13.3 Topical antipruritics 557Drapolene c (Chefaro UK)Cream, benzalkonium chloride 0.01%, cetrimide 0.2%in a basis containing white soft paraffin, cetyl alcoholand wool fat, net price 100 g = £1.54, 200 g = £2.50,350 g = £3.75Excipients include cetyl alcohol, chlorocresol, wool fatMedicaid c (LPC)Cream, cetrimide 0.5% in a basis containing lightliquid paraffin, white soft paraffin, cetostearyl alcohol,glyceryl monostearate, net price 50 g = £1.69Excipients include cetostearyl alcohol, fragrance, hydroxybenzoates(parabens), wool fatMetanium c (Thornton & Ross)Ointment, titanium dioxide 20%, titanium peroxide5%, titanium salicylate 3% in a basis containingdimeticone, light liquid paraffin, white soft paraffin,and benzoin tincture, net price 30 g = £2.01Excipients none as listed in section 13.1.3Morhulin c (Actavis)Ointment, cod-liver oil 11.4%, zinc oxide 38%, in abasis containing liquid paraffin and yellow soft paraffin,net price 50 g = £1.91Excipients include wool fat derivativeSiopel c (Derma UK)Barrier cream, dimeticone ‘1000’ 10%, cetrimide0.3%, arachis (peanut) oil, net price 50 g = £2.15Excipients include butylated hydroxytoluene, cetostearyl alcohol,hydroxybenzoates (parabens)Sprilon c (Ayrton Saunders)Spray application, dimeticone 1.04%, zinc oxide12.5%, in a basis containing wool alcohols, cetostearylalcohol, dextran, white soft paraffin, liquid paraffin,propellants, net price 115-g pressurised aerosol unit =£3.54Excipients include cetostearyl alcohol, hydroxybenzoates (parabens),wool fatNote FlammableSudocrem c (Forest)Cream, benzyl alcohol 0.39%, benzyl benzoate 1.01%,benzyl cinnamate 0.15%, hydrous wool fat (hypoallergeniclanolin) 4%, zinc oxide 15.25%, net price 60 g= £1.25, 125 g = £1.84, 250 g = £3.09, 400 g = £4.34Excipients include beeswax (synthetic), propylene glycol, butylatedhydroxyanisole, fragranceVasogen c (Forest)Barrier cream, dimeticone 20%, calamine 1.5%, zincoxide 7.5%, net price 100 g = £2.72Excipients include hydroxybenzoates (parabens), wool fat13.3 Topical antipruriticsPruritus may be caused by systemic disease (such asobstructive jaundice, endocrine disease, chronic renaldisease, iron deficiency, and certain malignant diseases),skin disease (such as eczema, psoriasis, urticaria, andscabies), drug hypersensitivity, or as a side-effect ofopioid analgesics. Where possible, the underlyingcause should be treated. For the treatment of pruritusin palliative care, see Prescribing in Palliative Care,p. 19. Pruritus caused by cholestasis generally requiresa bile acid sequestrant (section 1.9.2).An emollient (section 13.2.1) may be of value where thepruritus is associated with dry skin. Preparations containingcalamine or crotamiton are sometimes usedbut are of uncertain value.A topical preparation containing doxepin 5% is licensedfor the relief of pruritus in eczema in children over 12years; it can cause drowsiness and there may be a risk ofsensitisation.Topical antihistamines and local anaesthetics (section15.2) are only marginally effective and occasionallycause sensitisation. For insect stings and insect bites, ashort course of a topical corticosteroid is appropriate.Short-term treatment with a sedating antihistamine(section 3.4.1) may help in insect stings and in intractablepruritus where sedation is desirable. Calaminepreparations are of little value for the treatment of insectstings or bites.In pruritus ani, the underlying cause such as faecalsoiling, eczema, psoriasis, or helminth infection shouldbe treated; for preparations used to relieve pruritus ani,see section 1.7.CALAMINE UIndication and dosePruritus but see notes aboveCalamine (Non-proprietary) UAqueous cream, calamine 4%, zinc oxide 3%, liquidparaffin 20%, self-emulsifying glyceryl monostearate5%, cetomacrogol emulsifying wax 5%, phenoxyethanol0.5%, freshly boiled and cooled purifiedwater 62.5%, net price 100 mL = 84pLotion (= cutaneous suspension), calamine 15%, zincoxide 5%, glycerol 5%, bentonite 3%, sodium citrate0.5%, liquefied phenol 0.5%, in freshly boiled andcooled purified water, net price 200 mL = 63pOily lotion (BP 1980), calamine 5%, arachis (peanut)oil 50%, oleic acid 0.5%, wool fat 1%, in calciumhydroxide solution, net price 200 mL = £1.57CROTAMITONCautions avoid use near eyes and broken skin; use ondoctor’s advice for children under 3 yearsContra-indications acute exudative dermatosesIndication and dosePruritus (including pruritus after scabies—section13.10.4) see notes aboveApply 2–3 times daily (for pruritus after scabies inchildren under 3 years apply once daily only)Eurax c (Novartis Consumer Health)Cream, crotamiton 10%, net price 30 g = £2.38, 100 g= £4.15Excipients include beeswax, fragrance, hydroxybenzoates (parabens),stearyl alcoholLotion, crotamiton 10%, net price 100 mL = £3.14Excipients include cetyl alcohol, fragrance, propylene glycol, sorbicacid, stearyl alcoholDOXEPIN HYDROCHLORIDECautions susceptibility to angle-closure glaucoma;urinary retention; mania; cardiac arrhythmias; severeheart disease; avoid application to large areas; interactions:Appendix 1 (antidepressants, tricyclic)Skilled tasks Drowsiness may affect performance of skilledtasks (e.g. driving); effects of alcohol enhancedHepatic impairment manufacturer advises caution insevere liver disease13 Skin

558 13.4 Topical corticosteroids BNFC 2011–201213 SkinPregnancy manufacturer advises use only if potentialbenefit outweighs riskBreast-feeding manufacturer advises use only ifpotential benefit outweighs riskSide-effects drowsiness; local burning, stinging, irritation,tingling and rash; systemic side-effects such asantimuscarinic affects, headache, fever, dizziness,gastro-intestinal disturbances also reportedIndication and dosePruritus in eczemaChild 12–18 years apply thinly 3–4 times daily;usual max. 3 g per application; usual total max.12 g daily; coverage should be less than 10% ofbody surface areaDepressive illness section 4.3.1Xepin c (CHS) ACream, doxepin hydrochloride 5%, net price 30 g =£11.70. Label: 2, 10, patient information leafletExcipients include benzyl alcohol13.4 Topical corticosteroidsTopical corticosteroids are used for the treatment ofinflammatory conditions of the skin (other than thosearising from an infection), particularly eczema (section13.5.1), contact dermatitis, insect stings (p. 34), andeczema of scabies (section 13.10.4). Corticosteroidssuppress the inflammatory reaction during use; theyare not curative and on discontinuation a reboundexacerbation of the condition may occur. They aregenerally used to relieve symptoms and suppresssigns of the disorder when other measures such asemollients are ineffective.Children, especially infants, are particularly susceptibleto side-effects. However, concern about the safety oftopical corticosteroids in children should not result inthe child being undertreated. The aim is to control thecondition as well as possible; inadequate treatment willperpetuate the condition. Carers of young childrenshould be advised that treatment should not necessarilybe reserved to ‘treat only the worst areas’ and they mayneed to be advised that patient information leaflets maycontain inappropriate advice for the child’s condition.In an acute flare-up of atopic eczema, it may be appropriateto use more potent formulations of topical corticosteroidsfor a short period to regain control of thecondition. Continuous daily application of a mildcorticosteroid such as hydrocortisone 1% is equivalentto a potent corticosteroid such as betamethasone 0.1%applied intermittently.Topical corticosteroids are of no value in the treatmentof urticaria. They may worsen ulcerated or secondarilyinfected lesions. They should not be used indiscriminatelyin pruritus (where they will only benefit if inflammationis causing the itch) and are not recommendedfor acne vulgaris.Systemic or potent topical corticosteroids should beavoided or given only under specialist supervision inpsoriasis because, although they may suppress the psoriasisin the short term, relapse or vigorous reboundoccurs on withdrawal (sometimes precipitating severepustular psoriasis). Topical use of potent corticosteroidson widespread psoriasis can lead to systemic as well asto local side-effects. It is reasonable, however, to prescribea mild to moderate topical corticosteroid for ashort period (2–4 weeks) for flexural and facial psoriasis,and to use a more potent corticosteroid such asbetamethasone or fluocinonide for psoriasis of thescalp, palms, or soles (see below for cautions in psoriasis).In general, the most potent topical corticosteroidsshould be reserved for recalcitrant dermatoses such aschronic discoid lupus erythematosus, lichen simplexchronicus, hypertrophic lichen planus, and palmoplantarpustulosis. Potent corticosteroids should generallybe avoided on the face and skin flexures, but specialistsoccasionally prescribe them for use on these areas incertain circumstances.When topical treatment has failed, intralesional corticosteroidinjections (section 10.1.2.2) may be used. Theseare more effective than the very potent topical corticosteroidpreparations and should be reserved for severecases where there are localised lesions such as keloidscars, hypertrophic lichen planus, or localised alopeciaareata.Choice Water-miscible corticosteroid creams are suitablefor moist or weeping lesions whereas ointmentsare generally chosen for dry, lichenified or scaly lesionsor where a more occlusive effect is required. Lotionsmay be useful when minimal application to a large orhair-bearing area is required or for the treatment ofexudative lesions. Occlusive polythene or hydrocolloiddressings increase absorption, but also increase the riskof side-effects; they are therefore used only under supervisionon a short-term basis for areas of very thick skin(such as the palms and soles). Disposable nappies andtight fitting pants also increase the risk of side-effects byincreasing absorption of the corticosteroid. The inclusionof urea or salicylic acid also increases the penetrationof the corticosteroid.‘Wet-wrap bandaging’ (section 13.5.1) increases absorptioninto the skin, but should be initiated only by adermatologist and application supervised by a healthcareprofessional trained in the technique.In the BNF for Children, topical corticosteroids for theskin are categorised as ‘mild’, ‘moderately potent’,‘potent’ or ‘very potent’ (see p. 559); the least potentpreparation which is effective should be chosen butdilution should be avoided whenever possible.Topical hydrocortisone is usually used in children under1 year of age. Moderately potent and potent topicalcorticosteroids should be used with great care in childrenand for short periods (1–2 weeks) only. A verypotent corticosteroid should be initiated under thesupervision of a specialist.Appropriate topical corticosteroids for specific conditionsare:. insect bites and stings—mild corticosteroid such ashydrocortisone 1% cream;. inflamed nappy rash causing discomfort in infantover 1 month (section 13.2.2)—mild corticosteroidsuch as hydrocortisone 0.5 or 1% for up to 7 days(combined with antimicrobial if infected);. mild to moderate eczema, flexural and facial eczemaor psoriasis—mild corticosteroid such ashydrocortisone 1%;

BNFC 2011–2012 13.4 Topical corticosteroids 559. severe eczema of the face and neck—moderatelypotent corticosteroid for 3–5 days only, if not controlledby a mild corticosteroid;. severe eczema on the trunk and limbs—moderatelypotent or potent corticosteroid for 1–2 weeks only,switching to a less potent preparation as the conditionimproves;. eczema affecting area with thickened skin (e.g.soles of feet)—potent topical corticosteroid in combinationwith urea or salicylic acid (to increasepenetration of corticosteroid).Perioral lesions Hydrocortisone cream 1% can beused for up to 7 days to treat uninfected inflammatorylesions on the lips. Hydrocortisone and miconazolecream or ointment is useful where infection by susceptibleorganisms and inflammation co-exist, particularlyfor initial treatment (up to 7 days) e.g. in angular cheilitis(see also p. 545). Organisms susceptible to miconazoleinclude Candida spp. and many Gram-positive bacteriaincluding streptococci and staphylococci.Cautions Avoid prolonged use of a topical corticosteroidparticularly on the face (and keep away fromeyes). Use potent or very potent corticosteroids underspecialist supervision; extreme caution is required indermatoses of infancy including nappy rash—treatmentshould be limited to 5–7 days.Psoriasis The use of potent or very potent corticosteroids inpsoriasis can result in rebound relapse, development of generalisedpustular psoriasis, and local and systemic toxicity, seenotes above.Contra-indications Topical corticosteroids are contra-indicatedin untreated bacterial, fungal, or viral skinlesions, in acne, and in perioral dermatitis; potent corticosteroidsare contra-indicated in widespread plaquepsoriasis (see notes above).Side-effects Mild and moderately potent topicalcorticosteroids are associated with few side-effects butparticular care is required when treating neonates andinfants, and in the use of potent and very potent corticosteroids.Absorption through the skin can rarely causeadrenal suppression and even Cushing’s syndrome (section6.3.2), depending on the area of the body beingtreated and the duration of treatment. Absorption ofcorticosteroid is greatest from severely inflamed skin,thin skin (especially on the face or genital area), fromflexural sites (e.g. axillae, groin), and in infants whereskin surface area is higher in relation to body-weight;absorption is increased by occlusion. Local side-effectsinclude:. spread and worsening of untreated infection;. thinning of the skin which may be restored over aperiod after stopping treatment but the originalstructure may never return;. irreversible striae atrophicae and telangiectasia;. contact dermatitis;. perioral dermatitis;. acne, or worsening of acne or rosacea;. mild depigmentation which may be reversible;. hypertrichosis also reported.Children and their carers should be reassured that sideeffects such as skin thinning and systemic effects rarelyoccur when topical corticosteroids are used appropriately.Safe PracticeIn order to minimise the side-effects of a topicalcorticosteroid, it is important to apply it thinly toaffected areas only, no more frequently than twicedaily, and to use the least potent formulation whichis fully effective.Application Topical corticosteroid preparationsshould be applied no more frequently than twice daily;once daily is often sufficient.Topical corticosteroids should be spread thinly on theskin but in sufficient quantity to cover the affected areas.The length of cream or ointment expelled from a tubemay be used to specify the quantity to be applied to agiven area of skin. This length can be measured in termsof a fingertip unit (the distance from the tip of the adultindex finger to the first crease). One fingertip unit(approximately 500 mg) is sufficient to cover an areathat is twice that of the flat adult palm.If a child is using topical corticosteroids of differentpotencies, the child and their carers should be told whento use each corticosteroid. The potency of each topicalcorticosteroid (see Topical Corticosteroid PreparationPotencies, below) should be included on the label withthe directions for use. The label should be attached tothe container (for example, the tube) rather than theouter packaging.Mixing topical preparations on the skin should beavoided where possible; several minutes should elapsebetween application of different preparations.Compound preparations The advantages of includingother substances (such as antibacterials or antifungals)with corticosteroids in topical preparationsare uncertain, but such combinations may have aplace where inflammatory skin conditions are associatedwith bacterial or fungal infection, such as infectedeczema. In these cases the antimicrobial drug should bechosen according to the sensitivity of the infectingorganism and used regularly for a short period (typicallytwice daily for 1 week). Longer use increases the likelihoodof resistance and of sensitisation.The keratolytic effect of salicylic acid facilitates theabsorption of topical corticosteroids; however, excessiveand prolonged use of topical preparations containingsalicylic acid may cause salicylism.Topical corticosteroid potenciesPotency of a topical corticosteroid preparation dependsupon the formulation as well as the corticosteroid.Therefore, proprietary names are shown below.MildHydrocortisone 0.1–2.5%, Dioderm, Mildison,Synalar 1 in 10 DilutionMild with antimicrobials Canesten HC,Daktacort, Econacort, Fucidin H, Nystaform-HC, TimodineMild with crotamiton Eurax-Hydrocortisone13 Skin

560 13.4 Topical corticosteroids BNFC 2011–201213 SkinModeratePotentBetnovate-RD, Eumovate, Haelan, Modrasone,Synalar 1 in 4 Dilution, Ultralanum PlainModerate with antimicrobials TrimovateModerate with urea Alphaderm, CalmuridHC, Hydromol HC IntensiveBeclometasone dipropionate 0.025%, Betamethasonevalerate 0.1%, Betacap, Bettamousse,Betnovate, Cutivate, Diprosone,Elocon, Hydrocortisone butyrate, Locoid,Locoid Crelo, Metosyn, Nerisone, SynalarPotent with antimicrobials Aureocort,Betnovate-C, Betnovate-N, Fucibet, Lotriderm,Synalar C, Synalar NPotent with salicylic acid DiprosalicVery potentDermovate, Nerisone ForteVery potent with antimicrobials Dermovate-NNHYDROCORTISONECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveIndication and doseMild inflammatory skin disorders such aseczemas (but for over-the-counter preparations,see below); nappy rash (see also section13.2.2)Apply thinly 1–2 times dailyOver-the-counter hydrocortisone preparationsSkin creams and ointments containing hydrocortisone(alone or with other ingredients) can be sold to thepublic for the treatment of allergic contact dermatitis,irritant dermatitis, insect bite reactions and mild tomoderate eczema in children over 10 years, to beapplied sparingly over the affected area 1–2 timesdaily for max. 1 week. Over-the-counter hydrocortisonepreparations should not be sold without medicaladvice for children under 10 years or for pregnantwomen; they should not be sold for application to theface, anogenital region, broken or infected skin(including cold sores, acne, and athlete’s foot); overthe-counterhydrocortisone preparations containingclotrimazole or miconazole nitrate can be sold tothe public for treatment of athlete’s foot and candidalintertrigoHydrocortisone (Non-proprietary) ACream, hydrocortisone 0.5%, net price, 15 g = £1.92,30 g = £5.19; 1%, 15 g = £1.64, 30 g = £1.99, 50 g =£4.06; 2.5%, 15 g = £19.70. Label: 28, counselling,application, see p. 559. Potency: mildDental prescribing on NHS Hydrocortisone Cream 1% 15 gmay be prescribedOintment, hydrocortisone 0.5%, net price 15 g =£3.05, 30 g = £5.23; 1%, 15 g = £3.34, 30 g = £2.70,50 g = £6.87; 2.5%, 15 g = £23.78. Label: 28, counselling,application, see p. 559. Potency: mildWhen hydrocortisone cream or ointment is prescribed and nostrength is stated, the 1% strength should be suppliedProprietary hydrocortisone preparationsDioderm c (Dermal) ACream, hydrocortisone 0.1%, net price 30 g = £2.39.Label: 28, counselling, application, see p. 559.Potency: mildExcipients include cetostearyl alcohol, propylene glycolNote Although this contains only 0.1% hydrocortisone, theformulation is designed to provide a clinical activity comparableto that of Hydrocortisone Cream 1% BPMildison c (Astellas) ALipocream, hydrocortisone 1%, net price 30 g = £1.71.Label: 28, counselling, application, see p. 559.Potency: mildExcipients include cetostearyl alcohol, hydroxybenzoates (parabens)Compound preparationsCompound preparations with coal tar see section13.5.2Alphaderm c (Alliance) ACream, hydrocortisone 1%, urea 10%, net price 30 g =£2.38; 100 g = £7.03. Label: 28, counselling, application,see p. 559. Potency: moderateExcipients none as listed in section 13.1.3Calmurid HC c (Galderma) ACream, hydrocortisone 1%, urea 10%, lactic acid 5%,net price 30 g = £2.80, 50 g = £4.67. Label: 28, counselling,application, see p. 559. Potency: moderateExcipients none as listed in section 13.1.3Note If stinging occurs, manufacturer advises dilute to halfstrengthwith aqueous cream for 1 week then transfer toundiluted preparation (but see section 13.1.1 for advice toavoid dilution where possible)1Eurax-Hydrocortisone c (Novartis Consumer Health)ACream, hydrocortisone 0.25%, crotamiton 10%, netprice 30 g = 87p. Label: 28, counselling, application,see p. 559. Potency: mildExcipients include fragrance, hydroxybenzoates (parabens), propyleneglycol, stearyl alcohol1. A 15-g tube is on sale to the public for treatment of contactdermatitis and insect bites in children 10–18 years.Hydromol HC Intensive c (Alliance) ACream, hydrocortisone 1%, urea 10%, net price 30 g =£2.38, 100 g = £7.03. Label: 28, counselling, application,see p. 559. Potency: moderateExcipients none as listed in section 13.1.3With antimicrobialsSee notes above for comment on compound preparations1Canesten HC c (Bayer Consumer Care) ACream, hydrocortisone 1%, clotrimazole 1%, net price30 g = £2.42. Label: 28, counselling, application, seep. 559. Potency: mildExcipients include benzyl alcohol, cetostearyl alcohol1. A 15-g tube is on sale to the public for the treatment ofathlete’s foot and fungal infection of skin folds withassociated inflammation in children 10–18 years.Daktacort c (Janssen) ACream, hydrocortisone 1%, miconazole nitrate 2%,net price 30 g = £2.28. Label: 28, counselling, application,see p. 559. Potency: mildExcipients include butylated hydroxyanisole, disodium edetateDental prescribing on NHS May be prescribed as Miconazoleand Hydrocortisone Cream for max. 7 daysNote A 15-g tube is on sale to the public for the treatment ofathlete’s foot and candidal intertrigo in children 10–18 years

BNFC 2011–2012 13.4 Topical corticosteroids 561Ointment, hydrocortisone 1%, miconazole nitrate 2%,net price 30 g = £2.28. Label: 28, counselling, application,see p. 559. Potency: mildExcipients none as listed in section 13.1.3Dental prescribing on NHS May be prescribed as Miconazoleand Hydrocortisone Ointment for max. 7 daysFucidin H c (LEO) ACream, hydrocortisone acetate 1%, fusidic acid 2%,net price 30 g = £4.99, 60 g = £9.98. Label: 28, counselling,application, see p. 559. Potency: mildExcipients include butylated hydroxyanisole, cetyl alcohol, polysorbate60, potassium sorbateNystaform-HC c (Typharm) ACream, hydrocortisone 0.5%, nystatin 100 000 units/g, chlorhexidine hydrochloride 1%, net price 30 g =£2.66. Label: 28, counselling, application, see p. 559.Potency: mildExcipients include benzyl alcohol, cetostearyl alcohol, polysorbate ‘60’Ointment, hydrocortisone 1%, nystatin 100 000 units/g, chlorhexidine acetate 1%, net price 30 g = £2.66.Label: 28, counselling, application, see p. 559.Potency: mildExcipients none as listed in section 13.1.3Timodine c (Alliance) ACream, hydrocortisone 0.5%, nystatin 100 000 units/g, benzalkonium chloride solution 0.2%, dimeticone‘350’ 10%, net price 30 g = £2.03. Label: 28, counselling,application, see p. 559. Potency: mildExcipients include butylated hydroxyanisole, cetostearyl alcohol,hydroxybenzoates (parabens), sodium metabisulphite, sorbic acidHYDROCORTISONE BUTYRATECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveIndication and doseSevere inflammatory skin disorders such aseczemas unresponsive to less potent corticosteroids,psoriasis see notes aboveChild 1–18 years apply thinly 1–2 times dailyLocoid c (Astellas) ACream, hydrocortisone butyrate 0.1%, net price 30 g =£1.60, 100 g = £4.93. Label: 28, counselling, application,see p. 559. Potency: potentExcipients include cetostearyl alcohol, hydroxybenzoates (parabens)Lipocream, hydrocortisone butyrate 0.1%, net price30 g = £1.69, 100 g = £5.17. Label: 28, counselling,application, see p. 559. Potency: potentExcipients include benzyl alcohol, cetostearyl alcohol, hydroxybenzoates(parabens)Note For bland cream basis see Lipobase c , section 13.2.1Ointment, hydrocortisone butyrate 0.1%, net price30 g = £1.60, 100 g = £4.93. Label: 28, counselling,application, see p. 559. Potency: potentExcipients none as listed in section 13.1.3Scalp lotion, hydrocortisone butyrate 0.1%, in anaqueous isopropyl alcohol basis, net price 100 mL =£6.83. Label: 15, 28, counselling, application, seep. 559. Potency: potentExcipients none as listed in section 13.1.3Locoid Crelo c (Astellas) ALotion (topical emulsion), hydrocortisone butyrate0.1% in a water-miscible basis, net price 100 g (withapplicator nozzle) = £5.91. Label: 28, counselling,application, see p. 559. Potency: potentExcipients include butylated hydroxytoluene, cetostearyl alcohol,hydroxybenzoates (parabens), propylene glycolALCLOMETASONE DIPROPIONATECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseInflammatory skin disorders such as eczemasApply thinly 1–2 times dailyModrasone c (TEVA UK) ACream, alclometasone dipropionate 0.05%, net price50 g = £2.68. Label: 28, counselling, application, seep. 559. Potency: moderateExcipients include cetostearyl alcohol, chlorocresol, propylene glycolOintment, alclometasone dipropionate 0.05%, netprice 50 g = £2.68. Label: 28, counselling, application,see p. 559. Potency: moderateExcipients include beeswax, propylene glycolBECLOMETASONE DIPROPIONATE(Beclometasone dipropionate)Cautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under 1yearIndication and doseSevere inflammatory skin disorders such aseczemas unresponsive to less potent corticosteroids,psoriasis see notes aboveApply thinly 1–2 times dailyBeclometasone (Non-proprietary) ACream, beclometasone dipropionate 0.025%, netprice 30 g = £68.00. Label: 28, counselling, application,see p. 559. Potency: potentOintment, beclometasone dipropionate 0.025%, netprice 30 g = £68.00. Label: 28, counselling, application,see p. 559. Potency: potentBETAMETHASONE ESTERSCautions see notes above; use of more than 100 g perweek of 0.1% preparation likely to cause adrenalsuppressionContra-indications see notes aboveSide-effects see notes aboveLicensed use Betacap c , Betnovate c , Betnovate-C c , and Betnovate-RD c not licensed for use inchildren under 1 year; Bettamousse c and Fucibet cLipid Cream not licensed for use in children under 6years; Betnovate-N c not licensed for use in childrenunder 2 years; Lotriderm c not licensed for use inchildren under 12 years; all other preparationslicensed for use in children (age range not specifiedby manufacturer)Indication and doseSevere inflammatory skin disorders such aseczemas unresponsive to less potent corticosteroids,psoriasis see notes aboveApply thinly 1–2 times daily13 Skin

562 13.4 Topical corticosteroids BNFC 2011–201213 SkinBetamethasone Valerate (Non-proprietary) ACream, betamethasone (as valerate) 0.1%, net price30 g = £2.36, 100 g = £4.93. Label: 28, counselling,application, see p. 559. Potency: potentOintment, betamethasone (as valerate) 0.1%, netprice 30 g = £2.27, 100 g = £4.67. Label: 28, counselling,application, see p. 559. Potency: potentBetacap c (Dermal) AScalp application, betamethasone (as valerate) 0.1%in a water-miscible basis containing coconut oil derivative,net price 100 mL = £3.75. Label: 15, 28,counselling, application, see p. 559. Potency: potentExcipients none as listed in section 13.1.3Betnovate c (GSK) ACream, betamethasone (as valerate) 0.1% in a watermisciblebasis, net price 30 g = £1.43, 100 g = £4.05.Label: 28, counselling, application, see p. 559.Potency: potentExcipients include cetostearyl alcohol, chlorocresolOintment, betamethasone (as valerate) 0.1% in ananhydrous paraffin basis, net price 30 g = £1.43, 100 g= £4.05. Label: 28, counselling, application, see p. 559.Potency: potentExcipients none as listed in section 13.1.3Lotion, betamethasone (as valerate) 0.1%, net price100 mL = £4.58. Label: 28, counselling, application,see p. 559. Potency: potentExcipients include cetostearyl alcohol, hydroxybenzoates (parabens)Scalp application, betamethasone (as valerate) 0.1%in a water-miscible basis, net price 100 mL = £4.99.Label: 15, 28, counselling, application, see p. 559.Potency: potentExcipients none as listed in section 13.1.3Betnovate-RD c (GSK) ACream, betamethasone (as valerate) 0.025% in awater-miscible basis (1 in 4 dilution of Betnovate ccream), net price 100 g = £3.15. Label: 28, counselling,application, see p. 559. Potency: moderateExcipients include cetostearyl alcohol, chlorocresolOintment, betamethasone (as valerate) 0.025% in ananhydrous paraffin basis (1 in 4 dilution of Betnovate cointment), net price 100 g = £3.15. Label: 28,counselling, application, see p. 559. Potency: moderateExcipients none as listed in section 13.1.3Bettamousse c (UCB Pharma) AFoam (= scalp application), betamethasone valerate0.12% (: betamethasone 0.1%), net price 100 g =£9.37. Label: 28, counselling, application, see p. 559.Potency: potentExcipients include cetyl alcohol, polysorbate 60, propylene glycol,stearyl alcoholNote FlammableDiprosone c (Schering-Plough) ACream, betamethasone (as dipropionate) 0.05%, netprice 30 g = £2.16, 100 g = £6.12. Label: 28, counselling,application, see p. 559. Potency: potentExcipients include cetostearyl alcohol, chlorocresolOintment, betamethasone (as dipropionate) 0.05%,net price 30 g = £2.16, 100 g = £6.12. Label: 28,counselling, application, see p. 559. Potency: potentExcipients none as listed in section 13.1.3Lotion, betamethasone (as dipropionate) 0.05%, netprice 30 mL = £2.73, 100 mL = £7.80. Label: 28,counselling, application, see p. 559. Potency: potentExcipients none as listed in section 13.1.3With salicylic acidSee notes above for comment on compound preparationsFor prescribing information on salicylic acid, see p. 571Diprosalic c (Schering-Plough) AOintment, betamethasone (as dipropionate) 0.05%,salicylic acid 3%, net price 30 g = £3.18, 100 g = £9.14.Label: 28, counselling, application, see p. 559.Potency: potentExcipients none as listed in section 13.1.3DoseApply thinly 1–2 times dailyScalp application, betamethasone (as dipropionate)0.05%, salicylic acid 2%, in an alcoholic basis, netprice 100 mL = £10.10. Label: 28, counselling, application,see p. 559. Potency: potentExcipients include disodium edetateDoseApply a few drops 1–2 times dailyWith antimicrobialsSee notes above for comment on compound preparationsBetnovate-C c (Chemidex) ACream, betamethasone (as valerate) 0.1%, clioquinol3%, net price 30 g = £1.76. Label: 28, counselling,application, see p. 559. Potency: potentExcipients include cetostearyl alcohol, chlorocresolNote Stains clothingOintment, betamethasone (as valerate) 0.1%, clioquinol3%, net price 30 g = £1.76. Label: 28, counselling,application, see p. 559. Potency: potentExcipients none as listed in section 13.1.3Note Stains clothingBetnovate-N c (Chemidex) ACream, betamethasone (as valerate) 0.1%, neomycinsulphate 0.5%, net price 30 g = £1.76, 100 g = £4.88.Label: 28, counselling, application, see p. 559.Potency: potentExcipients include cetostearyl alcohol, chlorocresolOintment, betamethasone (as valerate) 0.1%, neomycinsulphate 0.5%, net price 30 g = £1.76, 100 g =£4.88. Label: 28, counselling, application, see p. 559.Potency: potentExcipients none as listed in section 13.1.3Fucibet c (LEO) ACream, betamethasone (as valerate) 0.1%, fusidic acid2%, net price 30 g = £5.29, 60 g = £10.58. Label: 28,counselling, application, see p. 559. Potency: potentExcipients include cetostearyl alcohol, chlorocresolLipid cream, betamethasone (as valerate) 0.1%, fusidicacid 2%, net price 30 g = £5.62. Label: 28, counselling,application, see p. 559. Potency: potentExcipients include cetostearyl alcohol, hydroxybenzoates (parabens)Lotriderm c (TEVA UK) ACream, betamethasone dipropionate 0.064% (:betamethasone 0.05%), clotrimazole 1%, net price30 g = £6.34. Label: 28, counselling, application, seep. 559. Potency: potentExcipients include benzyl alcohol, cetostearyl alcohol, propylene glycolCLOBETASOL PROPIONATECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use Dermovate c not licensed for use inchildren under 1 year; Dermovate-NN c notlicensed for use in children under 2 years

BNFC 2011–2012 13.4 Topical corticosteroids 563Indication and doseShort-term treatment only of severe resistantinflammatory skin disorders such as recalcitranteczemas unresponsive to less potentcorticosteroids, psoriasis see notes aboveApply thinly 1–2 times daily for up to 4 weeksDermovate c (GSK) ACream, clobetasol propionate 0.05%, net price 30 g =£2.69, 100 g = £7.90. Label: 28, counselling, application,see p. 559. Potency: very potentExcipients include beeswax (or beeswax substitute), cetostearylalcohol, chlorocresol, propylene glycolOintment, clobetasol propionate 0.05%, net price 30 g= £2.69, 100 g = £7.90. Label: 28, counselling, application,see p. 559. Potency: very potentExcipients include propylene glycolScalp application, clobetasol propionate 0.05%, in athickened alcoholic basis, net price 30 mL = £3.07,100 mL = £10.42. Label: 15, 28, counselling, application,see p. 559. Potency: very potentExcipients none as listed in section 13.1.3With antimicrobialsSee notes above for comment on compound preparationsDermovate-NN c (Chemidex) ACream, clobetasol propionate 0.05%, neomycin sulphate0.5%, nystatin 100 000 units/g, net price 30 g =£3.91. Label: 28, counselling, application, see p. 559.Potency: very potentExcipients include arachis (peanut) oil, beeswax or beeswax substituteOintment, clobetasol propionate 0.05%, neomycinsulphate 0.5%, nystatin 100 000 units/g, in a paraffinbasis, net price 30 g = £3.91. Label: 28, counselling,application, see p. 559. Potency: very potentExcipients none as listed in section 13.1.3CLOBETASONE BUTYRATECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseEczemas and dermatitis of all types; maintenancebetween courses of more potent corticosteroidsApply thinly 1–2 times daily1Eumovate c (GSK) ACream, clobetasone butyrate 0.05%, net price 30 g =£1.86, 100 g = £5.44. Label: 28, counselling, application,see p. 559. Potency: moderateExcipients include beeswax substitute, cetostearyl alcohol, chlorocresolOintment, clobetasone butyrate 0.05%, net price 30 g= £1.86, 100 g = £5.44. Label: 28, counselling, application,see p. 559. Potency: moderateExcipients none as listed in section 13.1.31. Cream can be sold to the public for short-term symptomatictreatment and control of patches of eczema and dermatitis(but not seborrhoeic dermatitis) in children over 12 yearsprovided pack does not contain more than 15 gWith antimicrobialsSee notes above for comment on compound preparationsTrimovate c (GSK) ACream, clobetasone butyrate 0.05%, oxytetracycline3% (as calcium salt), nystatin 100 000 units/g, netprice 30 g = £3.29. Label: 28, counselling, application,see p. 559. Potency: moderateExcipients include cetostearyl alcohol, chlorocresol, sodium metabisulphiteNote Stains clothingDIFLUCORTOLONE VALERATECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use Nerisone c licensed for use in children(age range not specified by manufacturer); NerisoneForte c not licensed for use in children under 4 yearsIndication and doseSevere inflammatory skin disorders such aseczemas unresponsive to less potent corticosteroids;high strength (0.3%), short-termtreatment of severe exacerbations, psoriasissee notes aboveApply thinly 1–2 times daily for up to 4 weeks(0.1% preparations) or 2 weeks (0.3% preparations),reducing strength as condition respondsNerisone c (Meadow) ACream, diflucortolone valerate 0.1%, net price 30 g =£1.59. Label: 28, counselling, application, see p. 559.Potency: potentExcipients include disodium edetate, hydroxybenzoates (parabens),stearyl alcoholOily cream, diflucortolone valerate 0.1%, net price30 g = £2.56. Label: 28, counselling, application, seep. 559. Potency: potentExcipients include beeswaxOintment, diflucortolone valerate 0.1%, net price 30 g= £1.59. Label: 28, counselling, application, see p. 559.Potency: potentExcipients none as listed in section 13.1.3Nerisone Forte c (Meadow) AOily cream, diflucortolone valerate 0.3%, net price15 g = £2.09. Label: 28, counselling, application, seep. 559. Potency: very potentExcipients include beeswaxOintment, diflucortolone valerate 0.3%, net price 15 g= £2.09. Label: 28, counselling, application, see p. 559.Potency: very potentExcipients none as listed in section 13.1.3FLUDROXYCORTIDE(Flurandrenolone)Cautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseInflammatory skin disorders such as eczemasApply thinly 1–2 times dailyHaelan c (Typharm) ACream, fludroxycortide 0.0125%, net price 60 g =£3.26. Label: 28, counselling, application, see p. 559.Potency: moderateExcipients include cetyl alcohol, propylene glycolOintment, fludroxycortide 0.0125%, net price 60 g =£3.26. Label: 28, counselling, application, see p. 559.Potency: moderateExcipients include beeswax, cetyl alcohol, polysorbate13 Skin

564 13.4 Topical corticosteroids BNFC 2011–201213 SkinTape, polythene adhesive film impregnated with fludroxycortide4 micrograms /cm 2 , net price 7.5 cm 50 cm = £9.27, 7.5 cm 200 cm = £24.95DoseChronic localised recalcitrant dermatoses (but notacute or weeping)Cut tape to fit lesion, apply to clean, dry skin shorn ofhair, usually for 12 hours dailyFLUOCINOLONE ACETONIDECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under 1yearIndication and doseSevere inflammatory skin disorders such aseczemas, psoriasis see notes aboveApply thinly 1–2 times daily, reducing strength ascondition respondsSynalar c (GP Pharma) ACream, fluocinolone acetonide 0.025%, net price 30 g= £3.76, 100 g = £10.68. Label: 28, counselling,application, see p. 559. Potency: potentExcipients include benzyl alcohol, cetostearyl alcohol, polysorbates,propylene glycolGel, fluocinolone acetonide 0.025%, net price 30 g =£5.56. For use on scalp and other hairy areas.Label: 28, counselling, application, see p. 559.Potency: potentExcipients include hydroxybenzoates (parabens), propylene glycolOintment, fluocinolone acetonide 0.025%, net price30 g = £3.76, 100 g = £10.68. Label: 28, counselling,application, see p. 559. Potency: potentExcipients include propylene glycol, wool fatSynalar 1 in 4 Dilution c (GP Pharma) ACream, fluocinolone acetonide 0.00625%, net price50 g = £4.40. Label: 28, counselling, application, seep. 559. Potency: moderateExcipients include benzyl alcohol, cetostearyl alcohol, polysorbates,propylene glycolOintment, fluocinolone acetonide 0.00625%, netprice 50 g = £4.40. Label: 28, counselling, application,see p. 559. Potency: moderateExcipients include propylene glycol, wool fatSynalar 1 in 10 Dilution c (GP Pharma) ACream, fluocinolone acetonide 0.0025%, net price50 g = £4.16. Label: 28, counselling, application, seep. 559. Potency: mildExcipients include benzyl alcohol, cetostearyl alcohol, polysorbates,propylene glycolWith antibacterialsSee notes above for comment on compound preparationsSynalar C c (GP Pharma) ACream, fluocinolone acetonide 0.025%, clioquinol3%, net price 15 g = £2.42. Label: 28, counselling,application, see p. 559. Potency: potentExcipients include cetostearyl alcohol, disodium edetate, hydroxybenzoates(parabens), polysorbates, propylene glycolOintment, fluocinolone acetonide 0.025%, clioquinol3%, net price 15 g = £2.42. Label: 28, counselling,application, see p. 559. Potency: potent.Note stains clothingExcipients include propylene glycol, wool fatSynalar N c (GP Pharma) ACream, fluocinolone acetonide 0.025%, neomycinsulphate 0.5%, net price 30 g = £3.96. Label: 28,counselling, application, see p. 559. Potency: potentExcipients include cetostearyl alcohol, hydroxybenzoates (parabens),polysorbates, propylene glycolOintment, fluocinolone acetonide 0.025%, neomycinsulphate 0.5%, in a greasy basis, net price 30 g =£3.96. Label: 28, counselling, application, see p. 559.Potency: potentExcipients include propylene glycol, wool fatFLUOCINONIDECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under 1yearIndication and doseSevere inflammatory skin disorders such aseczemas unresponsive to less potent corticosteroids,psoriasis see notes aboveApply thinly 1–2 times dailyMetosyn c (GP Pharma) AFAPG cream, fluocinonide 0.05%, net price 25 g =£3.30, 100 g = £11.12. Label: 28, counselling, application,see p. 559. Potency: potentExcipients include propylene glycolOintment, fluocinonide 0.05%, net price 25 g = £2.92,100 g = £10.96. Label: 28, counselling, application, seep. 559. Potency: potentExcipients include propylene glycol, wool fatFLUOCORTOLONECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseSevere inflammatory skin disorders such aseczemas unresponsive to less potent corticosteroids,psoriasis see notes aboveApply thinly 1–2 times dailyUltralanum Plain c (Meadow) ACream, fluocortolone caproate 0.25%, fluocortolonepivalate 0.25%, net price 50 g = £2.95. Label: 28,counselling, application, see p. 559. Potency: moderateExcipients include disodium edetate, fragrance, hydroxybenzoates(parabens), stearyl alcoholOintment, fluocortolone 0.25%, fluocortolone caproate0.25%, net price 50 g = £2.95. Label: 28, counselling,application, see p. 559. Potency: moderateExcipients include wool fat, fragranceFLUTICASONE PROPIONATECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use not licensed for use in children under 3months

BNFC 2011–2012 13.5 Preparations for eczema and psoriasis 565Indication and doseInflammatory skin disorders such as dermatitisand eczemas unresponsive to less potent corticosteroids,psoriasis see notes aboveApply thinly 1–2 times dailyCutivate c (GSK) ACream, fluticasone propionate 0.05%, net price 15 g =£2.27, 30 g = £4.24. Label: 28, counselling, application,see p. 559. Potency: potentExcipients include cetostearyl alcohol, imidurea, propylene glycolOintment, fluticasone propionate 0.005%, net price15 g = £2.27, 30 g = £4.24. Label: 28, counselling,application, see p. 559. Potency: potentExcipients include propylene glycolMOMETASONE FUROATECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseSevere inflammatory skin disorders such aseczemas unresponsive to less potent corticosteroids,psoriasis see notes aboveApply thinly once daily (to scalp in case of lotion)Elocon c (Schering-Plough) ACream, mometasone furoate 0.1%, net price 30 g =£4.36, 100 g = £12.58. Label: 28, counselling, application,see p. 559. Potency: potentExcipients include propylene glycol, stearyl alcoholOintment, mometasone furoate 0.1%, net price 30 g =£4.32, 100 g = £12.44. Label: 28, counselling, application,see p. 559. Potency: potentExcipients include propylene glycolScalp lotion, mometasone furoate 0.1% in anaqueous isopropyl alcohol basis, net price 30 mL =£4.36. Label: 28, counselling, application, see p. 559.Potency: potentExcipients include propylene glycolTRIAMCINOLONE ACETONIDECautions see notes aboveContra-indications see notes aboveSide-effects see notes aboveLicensed use Aureocort c not licensed for use inchildren under 8 yearsIndication and doseSevere inflammatory skin disorders such aseczemas unresponsive to less potent corticosteroids,psoriasis see notes aboveApply thinly 1–2 times dailyWith antimicrobialsSee notes above for comment on compound preparationsAureocort c (Goldshield) AOintment, triamcinolone acetonide 0.1%, chlortetracyclinehydrochloride 3%, in an anhydrous greasybasis containing wool fat and white soft paraffin, netprice 15 g = £2.70. Label: 28, counselling, application,see p. 559. Potency: potentExcipients include wool fatNote Stains clothing13.5 Preparations for eczemaand psoriasis13.5.1 Preparations for eczema13.5.2 Preparations for psoriasis13.5.3 Drugs affecting the immune response13.5.1 Preparations for eczemaThe main types of eczema (dermatitis) in children areatopic, irritant and allergic contact; different types mayco-exist. Atopic eczema is the most common type and itusually involves dry skin as well as infection and lichenificationcaused by scratching and rubbing. Seborrhoeicdermatitis (see below) is also common in infants.Management of eczema involves the removal or treatmentof contributory factors; known or suspected irritantsand contact allergens should be avoided. Rarely,ingredients in topical medicinal products may sensitisethe skin (section 13.1.3); BNF for Children lists activeingredients together with excipients that have beenassociated with skin sensitisation.Skin dryness and the consequent irritant eczemarequires emollients (section 13.2.1) applied regularlyand liberally to the affected area; this can be supplementedwith bath or shower emollients. The use ofemollients should continue even if the eczema improvesor if other treatment is being used.Topical corticosteroids (section 13.4) are also requiredin the management of eczema; the potency of thecorticosteroid should be appropriate to the severityand site of the condition, and the age of the child.Mild corticosteroids are generally used on the faceand on flexures; the more potent corticosteroids aregenerally required for use on lichenified areas of eczemaor for severe eczema on the scalp, limbs, and trunk.Treatment should be reviewed regularly, especially if apotent corticosteroid is required. In children with frequentflares (2–3 per month), a topical corticosteroidcan be applied on 2 consecutive days each week toprevent further flares.Bandages (including those containing zinc and ichthammol)are sometimes applied over topical corticosteroidsor emollients to treat eczema of the limbs. Wetelasticated viscose stockinette is used for ‘wet-wrap’bandaging over topical corticosteroids or emollients tocool the skin and relieve itching, but there is anincreased risk of infection and excessive absorption ofthe corticosteroid; ‘wet-wrap’ bandaging should be usedunder specialist supervision.For details of elasticated viscose stockinette tubularbandages and garments, and silk clothing, see BNFsection A8.8.3For the role of topical pimecrolimus and tacrolimus inatopic eczema, see section 13.5.3.Infection Bacterial infection (commonly with Staphylococcusaureus and occasionally with Streptococcuspyogenes) can exacerbate eczema. A topical antibacterialsuch as fusidic acid (section 13.10.1) may beused for small areas of mild infection; treatment shouldbe limited to a short course (typically 1 week) to reducethe risk of drug resistance or skin sensitisation. Associatedeczema is treated simultaneously with a moder-13 Skin

566 13.5.2 Preparations for psoriasis BNFC 2011–201213 Skinately potent or potent topical corticosteroid which canbe combined with an antimicrobial such as clioquinol.Eczema involving moderate to severe, widespread, orrecurrent infection requires the use of a systemic antibacterial(section 5.1, table 1) that is active against theinfecting organism. Preparations that combine an antisepticwith an emollient application (section 13.2.1) andwith a bath emollient (section 13.2.1.1) can also be used;antiseptic shampoos (section 13.9) can be used on thescalp.Intertriginous eczema commonly involves candida andbacteria; it is best treated with a mild or moderatelypotent topical corticosteroid combined with a suitableantimicrobial drug. For the treatment of nappy rash, seesection 13.2.2.Widespread herpes simplex infection may complicateatopic eczema (eczema herpeticum) and treatmentunder specialist supervision with a systemic antiviraldrug (section 5.3.2.1) is indicated. Secondary bacterialinfection often exacerbates eczema herpeticum.The management of seborrhoeic dermatitis is describedbelow.Management of other features of eczema Lichenification,which results from repeated scratching, istreated initially with a potent corticosteroid. Bandagescontaining ichthammol (to reduce pruritus) and othersubstances such as zinc oxide can be applied over thecorticosteroid or emollient. Coal tar (section 13.5.2) andichthammol can be useful in some cases of chroniceczema. Discoid eczema, with thickened plaques inchronic atopic eczema, is usually treated with a topicalantiseptic preparation, a potent topical corticosteroid,and paste bandages containing zinc oxide and ichthammol.A non-sedating antihistamine (section 3.4.1) may be ofsome value in relieving severe itching or urticaria associatedwith eczema. A sedating antihistamine (section3.4.1) can be used at night if itching causes sleepdisturbance, but a large dose may be needed anddrowsiness may persist on the following day.Exudative (‘weeping’) eczema requires a potent corticosteroidinitially; infection may also be present andrequire specific treatment (see above). Potassium permanganatesolution (1 in 10 000) can be used as a soakin exudating eczema for its antiseptic and astringenteffects; treatment should be stopped when exudationstops.Severe refractory eczema is best managed under specialistsupervision; it may require phototherapy or drugsthat act on the immune system (section 13.5.3).Seborrhoeic dermatitis Seborrhoeic dermatitis(seborrhoeic eczema) is associated with species of theyeast Malassezia. Infantile seborrhoeic dermatitisaffects particularly the body folds, nappy area andscalp; it is treated with emollients and mild topicalcorticosteroids with suitable antimicrobials. Infantileseborrhoeic dermatitis affecting the scalp (cradle cap)is treated by hydrating the scalp using natural oils andthe use of mild shampoo (section 13.9).In older children, seborrhoeic dermatitis affects thescalp, paranasal areas, and eyebrows. Shampoos activeagainst the yeast (including those containing ketoconazoleand coal tar, section 13.9) and combinations ofmild topical corticosteroids with suitable antimicrobials(section 13.4) are used to treat older children.ICHTHAMMOLSide-effects skin irritationLicensed use no information availableIndication and doseChronic lichenified eczemaChild 1–18 years apply 1–3 times dailyIchthammol Ointment, BP 1980Ointment, ichthammol 10%, yellow soft paraffin 45%,wool fat 45%Zinc and Ichthammol Cream, BPCream, ichthammol 5%, cetostearyl alcohol 3%, woolfat 10%, in zinc creamMedicated bandagesZinc paste bandages are used with coal tar or ichthammolin chronic lichenified skin conditions such aschronic eczema (ichthammol often being preferredsince its action is considered to be milder). They arealso used with calamine in milder eczematous skinconditions.For information on available medicated bandages andstockings, see the BNF appendix on wound managementproducts and elasticated garments.13.5.2 Preparations for psoriasisPsoriasis is characterised by epidermal thickening andscaling. It commonly affects extensor surfaces and thescalp. For mild psoriasis, reassurance and treatmentwith an emollient may be all that is necessary. Guttatepsoriasis is a distinctive form of psoriasis that characteristicallyoccurs in children and young adults, oftenfollowing a streptococcal throat infection or tonsillitis.Occasionally psoriasis is provoked or exacerbated bydrugs such as lithium, chloroquine and hydroxychloroquine,beta-blockers, non-steroidal anti-inflammatorydrugs, and ACE inhibitors. Psoriasis may not occuruntil the drug has been taken for weeks or months.Emollients (section 13.2.1), in addition to their effectson dryness, scaling and cracking, may have an antiproliferativeeffect in psoriasis. They are particularlyuseful in inflammatory psoriasis and in chronic stableplaque psoriasis.For chronic stable plaque psoriasis on extensor surfacesof trunk and limbs preparations containing coal tar aremoderately effective, but the smell is unacceptable tosome children. Vitamin D and its analogues are effectiveand cosmetically acceptable alternatives to preparationscontaining coal tar or dithranol. Dithranol isthe most effective topical antipsoriatic agent but itirritates and stains the skin and it should be used onlyunder specialist supervision. Adverse effects of dithranolare minimised by using a ‘short-contact technique’(see below) and by starting with low concentrationpreparations. Tazarotene, a topical retinoid for thetreatment of mild to moderate plaque psoriasis, is notrecommended for use in children under 18 years. Thesemedications can irritate the skin particularly in theflexures and they are not suitable for the more inflammatoryforms of psoriasis; their use should be suspendedduring an inflammatory phase of psoriasis. The efficacyand the irritancy of each substance varies betweenpatients. If a substance irritates significantly, it should

BNFC 2011–2012 13.5.2 Preparations for psoriasis 567be stopped or the concentration reduced; if it is tolerated,its effects should be assessed after 4 to 6 weeksand treatment continued if it is effective.Widespread unstable psoriasis of erythrodermic or generalisedpustular type requires urgent specialist assessment.Initial topical treatment should be limited to usingemollients frequently and generously. More localisedacute or subacute inflammatory psoriasis with hot,spreading or itchy lesions, should be treated topicallywith emollients or with a corticosteroid of moderatepotency.Scalp psoriasis is usually scaly, and the scale may bethick and adherent. This requires softening with anemollient ointment, cream, or oil and usually combinedwith salicylic acid as a keratolytic.Some preparations for psoriasis affecting the scalpcombine salicylic acid with coal tar or sulphur. Thepreparation should be applied generously and left on forat least an hour, often more conveniently overnight,before washing it off. If a corticosteroid lotion or gel isrequired (e.g. for itch), it can be used in the morning.Calcipotriol and tacalcitol are analogues of vitamin Dthat affect cell division and differentiation. Calcitriol isan active form of vitamin D. Vitamin D and its analoguesare used as first-line treatment for plaque psoriasis; theydo not smell or stain and they may be more acceptablethan tar or dithranol products. Of the vitamin D analogues,tacalcitol and calcitriol are less likely to irritate.Coal tar has anti-inflammatory properties that are usefulin chronic plaque psoriasis; it also has antiscalingproperties. Contact of coal tar products with normalskin is not normally harmful and preparations containingcoal tar can be used for widespread small lesions;however, irritation, contact allergy, and sterile folliculitiscan occur. Leave-on preparations that remain in contactwith the skin, such as creams or ointments, containingup to 6% coal tar may be used on children 1 month to 2years; leave-on preparations containing coal tar 10%may be used on children over 2 years with more severepsoriasis. Tar baths and tar shampoos (see section 13.9)may also be helpful.Dithranol is effective for chronic plaque psoriasis. Itsmajor disadvantages are irritation (for which individualsusceptibility varies) and staining of skin and of clothing.It should be applied to chronic extensor plaques only,carefully avoiding normal skin. Dithranol is not generallysuitable for widespread small lesions nor should itbe used in the flexures or on the face. Treatment shouldbe started with a low concentration such as dithranol0.1%, and the strength increased gradually every fewdays up to 3%, according to tolerance. Proprietarypreparations are more suitable for home use; they areusually washed off after 20–30 minutes (‘short contact’technique). Specialist nurses may apply intensive treatmentwith dithranol paste which is covered bystockinette dressings and usually retained overnight.Dithranol should be discontinued if even a low concentrationcauses acute inflammation; continued use canresult in the psoriasis becoming unstable. When applyingdithranol, hands should be protected by gloves orthey should be washed thoroughly afterwards.A topical corticosteroid (section 13.4) is not generallysuitable as the sole treatment of extensive chronicplaque psoriasis; any early improvement is not usuallymaintained and there is a risk of the condition deterioratingor of precipitating an unstable form of psoriasis(e.g. erythrodermic psoriasis or generalised pustularpsoriasis). However, it may be appropriate to treat psoriasisin specific sites such as the face and flexuresusually with a mild corticosteroid, and psoriasis of thescalp, palms and soles with a potent corticosteroid.Combining the use of a corticosteroid with anotherspecific topical treatment may be beneficial in chronicplaque psoriasis; the drugs may be used separately atdifferent times of the day or used together in a singleformulation. Eczema co-existing with psoriasis may betreated with a corticosteroid, or coal tar, or both. Systemicor potent topical corticosteroids should beavoided or used only under specialist supervision;although corticosteroids may suppress psoriasis in theshort term, relapse or vigorous rebound occurs onwithdrawal.Phototherapy Phototherapy is available in specialistcentres under the supervision of a dermatologist. Narrowband ultraviolet B (UVB) radiation is usually effectivefor chronic stable psoriasis and for guttate psoriasis.It can be considered for children with moderately severepsoriasis in whom topical treatment has failed, but itmay irritate inflammatory psoriasis. The use of phototherapyand photochemotherapy in children is limitedby concerns over carcinogenicity and premature ageing.Photochemotherapy combining long-wave ultravioletA radiation with a psoralen (PUVA) is available inspecialist centres under the supervision of a dermatologist.The psoralen, which enhances the effect of irradiation,is administered either by mouth or topically.PUVA is effective in most forms of psoriasis, includingthe localised palmoplantar pustular psoriasis. Earlyadverse effects include phototoxicity and pruritus. Highercumulative doses exaggerate skin ageing, increasethe risk of dysplastic and neoplastic skin lesions especiallysquamous cancer, and pose a theoretical risk ofcataracts.Phototherapy combined with coal tar, dithranol, topicalvitamin D or vitamin D analogues, or oral acitretin,allows reduction of the cumulative dose of phototherapyrequired to treat psoriasis.Systemic treatment Systemic treatment is requiredfor severe, resistant, unstable or complicated forms ofpsoriasis, and it should be initiated only under specialistsupervision. Systemic drugs for psoriasis include acitretinand drugs that affect the immune response (section13.5.3).Acitretin, a metabolite of etretinate, is a retinoid (vitaminA derivative); it is prescribed by specialists. Themain indication of acitretin is severe psoriasis resistantto other forms of therapy. It is also used in disorders ofkeratinisation such as severe Darier’s disease (keratosisfollicularis), and some forms of ichthyosis. Although aminority of cases of psoriasis respond well to acitretinalone, it is only moderately effective in many cases;adverse effects are a limiting factor. A therapeutic effectoccurs after 2 to 4 weeks and the maximum benefit after4 to 6 weeks or longer. Continuous treatment for longerthan 6 months is not usually necessary in psoriasis.However, some patients, particularly those with severeichthyosis, may benefit from longer treatment, providedthat the lowest effective dose is used, patients aremonitored carefully for adverse effects, and the needfor treatment is reviewed regularly. Topical preparationscontaining keratolytics should normally be stoppedbefore administration of acitretin. Liberal use of emol-13 Skin

568 13.5.2 Preparations for psoriasis BNFC 2011–201213 Skinlients should be encouraged and topical corticosteroidscan be continued if necessary.Acitretin is teratogenic; in females of child-bearing age,the possibility of pregnancy must be excluded beforetreatment and effective contraception must be usedduring treatment and for at least 3 years afterwards(oral progestogen-only contraceptives not consideredeffective). Common side-effects derive from its widespreadbut reversible effects on epithelia, such as dryand cracking lips, dry skin and mucosal surfaces, hairthinning, paronychia, and soft and sticky palms andsoles.Topical preparations for psoriasisVitamin D and analoguesCalcipotriol, calcitriol, and tacalcitol are used for themanagement of plaque psoriasis. They should beavoided by those with calcium metabolism disorders,and used with caution in generalised pustular or erythrodermicexfoliative psoriasis (enhanced risk of hypercalcaemia).Local skin reactions (itching, erythema,burning, paraesthesia, dermatitis) are common. Handsshould be washed thoroughly after application to avoidinadvertent transfer to other body areas. Aggravation ofpsoriasis has also been reported.CALCIPOTRIOLCautions see notes above; avoid use on face; avoidexcessive exposure to sunlight and sunlampsContra-indications see notes abovePregnancy manufacturer advises avoid unless essentialBreast-feeding no information availableSide-effects see notes above; also photosensitivity,dry skin; rarely facial or perioral dermatitisLicensed use Calcipotriol ointment and scalp solution,Dovobet c , and Xamiol c not licensed for use inchildrenIndication and dosePlaque psoriasisChild 6–18 years apply cream or ointment twicedaily; 6–12 years max. 50 g weekly, over 12 yearsmax. 75 g weekly (less with scalp solution, seebelow)Note Patient information leaflets for Dovonex c creamand ointment advise liberal application (but note max.recommended weekly dose, above)Scalp psoriasis (specialist use only)Child 6–12 years apply scalp solution twice daily;max. 30 mL weekly (less when used with cream orointment, see below)Child 12–18 years apply scalp solution twicedaily; max. 45 mL weekly (less when used withcream or ointment, see below)Note When preparations used together max. total calcipotriol2.5 mg in any one week for child 6–12 years (e.g. scalpsolution 20 mL with cream or ointment 30 g); max. 3.75 mg inany one week for child 12–18 years (e.g. scalp solution 30 mLwith cream or ointment 45 g)Calcipotriol (Non-proprietary) AOintment, calcipotriol 50 micrograms/g, net price120 g = £24.04Scalp solution, calcipotriol 50 micrograms/mL, netprice 60 mL = £12.53, 120 mL = £26.07Dovonex c (LEO) ACream, calcipotriol (as hydrate) 50 micrograms/g, netprice 120 g = £22.66Excipients include cetostearyl alcohol, disodium edetateOintment, calcipotriol 50 micrograms/g, net price120 g = £23.10Excipients include disodium edetate, propylene glycolWith betamethasoneFor prescribing information, and for comment on the limitedrole of corticosteroids in psoriasis, see section 13.4.Dovobet c (LEO) AOintment, betamethasone (as dipropionate) 0.05%,calcipotriol (as monohydrate) 50 micrograms/g, netprice 60 g = £32.99, 120 g = £61.27. Label: 28Excipients none as listed in section 13.1.3DoseStable plaque psoriasis (specialist use only)Child 12–18 years apply once daily to max. 30% ofbody surface for up to 4 weeks; max. 75 g weekly; ifnecessary, subsequent courses repeated on the advice ofa specialistNote When different preparations containing calcipotriolused together, max. total calcipotriol 3.75 mg in any oneweek for child 12–18 yearsGel, betamethasone (as dipropionate) 0.05%, calcipotriol(as monohydrate) 50 micrograms/g, netprice 60 g = £36.50, 2 60 g = £67.79. Label: 28Excipients include butylated hydroxytolueneDoseScalp psoriasis (specialist use only)Child 12–18 years apply 1–4 g to scalp once daily,shampoo off after leaving on scalp overnight or duringthe day; usual duration of therapy 4 weeks; if necessary,subsequent courses repeated on the advice of a specialistMild to moderate plaque psoriasis (specialist useonly)Child 12–18 years apply once daily to max. 30% ofbody surface for up to 4 weeks; max. 75 g weekly; ifnecessary, subsequent courses repeated on the advice ofa specialistNote When different preparations containing calcipotriolused together, max. total calcipotriol 3.75 mg in any oneweek for child 12–18 yearsXamiol c (LEO) AScalp gel, betamethasone (as dipropionate) 0.05%,calcipotriol (as monohydrate) 50 micrograms/g, netprice 60 g = £36.50. Label: 28Excipients include butylated hydroxytolueneDoseScalp psoriasis (specialist use only)Child 12–18 years apply 1–4 g to scalp once daily,shampoo off after leaving on scalp overnight or duringthe day; usual duration of therapy 4 weeks; if necessary,subsequent courses repeated on the advice of a specialistNote When different preparations containing calcipotriolused together, max. total calcipotriol 3.75 mg in any oneweek for child 12–18 yearsCALCITRIOL(1,25-Dihydroxycholecalciferol)Cautions see notes aboveContra-indications see notes above; do not applyunder occlusionHepatic impairment manufacturer advises avoid—noinformation availableRenal impairment manufacturer advises avoid—noinformation available

BNFC 2011–2012 13.5.2 Preparations for psoriasis 569Pregnancy manufacturer advises use in restrictedamounts only if clearly necessary and to monitorurine- and serum-calcium concentrationBreast-feeding manufacturer advises avoidSide-effects see notes aboveIndication and doseMild to moderate plaque psoriasisChild 12–18 years apply twice daily; not morethan 35% of body surface to be treated daily, max.30 g dailySilkis c (Galderma) AOintment, calcitriol 3 micrograms/g, net price 100 g= £13.87Excipients none as listed in section 13.1.3TACALCITOLCautions see notes above; avoid eyes; monitor serumcalciumconcentration if risk of hypercalcaemia; ifused in conjunction with UV treatment, UV radiationshould be given in the morning and tacalcitol appliedat bedtimeContra-indications see notes aboveRenal impairment monitor serum-calcium concentrationPregnancy manufacturer advises avoid unless no saferalternative—no information availableBreast-feeding manufacturer advises avoid applicationto breast area; no information available on presencein milkSide-effects see notes aboveIndication and dosePlaque psoriasisChild 12–18 years apply once daily preferably atbedtime; max. 10 g ointment or 10 mL lotion dailyNote When lotion and ointment used together, max. totaltacalcitol 280 micrograms in any one week (e.g. lotion30 mL with ointment 40 g)Curatoderm c (Almirall) ALotion, tacalcitol (as monohydrate) 4 micrograms/g,net price 30 mL = £12.73Excipients include disodium edetate, propylene glycolOintment, tacalcitol (as monohydrate) 4 micrograms/g, net price 30 g = £13.40, 60 g = £23.14, 100 g =£30.86Excipients none as listed in section 13.1.3TarsTARSCautions application to face and skin flexures; usesuitable chemical protection gloves for extemporaneouspreparationContra-indications not for use in sore, acute, orpustular psoriasis or in presence of infection; avoideyes, mucosa, genital or rectal areas; broken orinflamed skinSide-effects skin irritation and acne-like eruptions,photosensitivity; stains skin, hair, and fabricIndication and dosePsoriasis and occasionally chronic atopic eczemaApply 1–3 times daily starting with low-strengthpreparations; proprietary preparations, see individualentries belowNote For shampoo preparations see section 13.9Non-proprietary preparationsMay be difficult to obtain. Patients may find newer proprietarypreparations more acceptableCoal Tar Paste, BPPaste, strong coal tar solution 7.5%, in compoundzinc pasteZinc and Coal Tar Paste, BPPaste, zinc oxide 6%, coal tar 6%, emulsifying wax5%, starch 38%, yellow soft paraffin 45%Excipients include cetostearyl alcoholProprietary preparationsCarbo-Dome c (Sandoz)Cream, coal tar solution 10%, in a water-misciblebasis, net price 30 g = £4.77, 100 g = £16.38Excipients include beeswax, hydroxybenzoates (parabens)DosePsoriasisApply to skin 2–3 times dailyCocois c (UCB Pharma)Scalp ointment, coal tar solution 12%, salicylic acid2%, precipitated sulphur 4%, in a coconut oil emollientbasis, net price 40 g (with applicator nozzle) =£5.98, 100 g = £11.23Excipients include cetostearyl alcoholDoseScaly scalp disorders including psoriasis, eczema,seborrhoeic dermatitis and dandruffChild 6–12 years medical supervision requiredChild 12–18 years apply to scalp once weekly asnecessary (if severe use daily for first 3–7 days), shampoooff after 1 hourExorex c (Forest)Lotion, coal tar solution 5% in an emollient basis, netprice 100 mL = £8.11, 250 mL = £16.24Excipients include hydroxybenzoates (parabens)DosePsoriasisApply to skin or scalp 2–3 times daily; product can bediluted with a few drops of water before applyingPsoriderm c (Dermal)Cream, coal tar 6%, lecithin 0.4%, net price 225 mL =£9.42Excipients include isopropyl palmitate, propylene glycolDosePsoriasisApply to skin or scalp 1–2 times dailyScalp lotion—section 13.9Sebco c (Derma UK)Scalp ointment, coal tar solution 12%, salicylic acid2%, precipitated sulphur 4%, in a coconut oil emollientbasis, net price 40 g = £4.54, 100 g = £8.52Excipients include cetostearyl alcoholDoseScaly scalp disorders including psoriasis, eczema,seborrhoeic dermatitis and dandruffChild 6–12 years medical supervision requiredChild 12–18 years apply to scalp as necessary (if severeuse daily for first 3–7 days), shampoo off after 1 hour13 Skin

570 13.5.2 Preparations for psoriasis BNFC 2011–201213 SkinBath preparationsCoal Tar Solution, BPSolution, coal tar 20%, polysorbate ‘80’ 5%, in alcohol(96%), net price 500 mL = £8.16. Label: 15Excipients include polysorbatesDoseUse 100 mL in an adult-size bath, and proportionally lessfor a child’s bathNote Strong Coal Tar Solution BP contains coal tar 40%Pinetarsol c (Crawford)Bath oil, tar 2.3% in a light liquid paraffin basis, netprice 200 mL = £4.75, 500 mL = £7.95Excipients include fragranceDoseEczema and psoriasisUse 15–30 mL in adult-size bath or apply directly to wetskin and rinse after a few minutes; can be used as a soapsubstituteGel, tar 1.6%, net price 100 g = £4.95DoseEczema and psoriasisApply directly to wet skin and rinse after a few minutes;can be used as a soap substituteSolution, tar 2.3%, net price 200 mL = £4.45, 500 mL= £7.45DoseEczema and psoriasisUse 15–30 mL in adult-size bath or dilute 15 mL with 3litres of water and apply to affected areas or applysolution directly to wet skin and rinse after a few minutes;can be used as a soap substitutePolytar Emollient c (Stiefel)Bath additive, coal tar solution 2.5%, arachis (peanut)oil extract of coal tar 7.5%, tar 7.5%, cade oil 7.5%,liquid paraffin 35%, net price 500 mL = £5.78Excipients include isopropyl palmitateDosePsoriasis, eczema, atopic and pruritic dermatosesUse 2–4 capfuls (15–30 mL) in adult-size bath and proportionallyless for a child’s bath; soak for 20 minutesPsoriderm c (Dermal)Bath emulsion, coal tar 40%, net price 200 mL =£2.74Excipients include polysorbate 20DosePsoriasisUse 30 mL in adult-size bath, and proportionally less for achild’s bath; soak for 5 minutesWith corticosteroidsAlphosyl HC c (GSK Consumer Healthcare) ACream, coal tar extract 5%, hydrocortisone 0.5%,allantoin 2%, net price 100 g = £3.10. Label: 28.Potency: mildExcipients include beeswax, cetyl alcohol, hydroxybenzoates (parabens),isopropyl palmitateDosePsoriasisChild 5–18 years apply thinly twice dailyDithranolDITHRANOL(Anthralin)Cautions avoid use near eyes and sensitive areas ofskin; see also notes aboveContra-indications hypersensitivity; acute and pustularpsoriasisPregnancy no adverse effects reportedBreast-feeding no adverse effects reportedSide-effects local burning sensation and irritation;stains skin, hair, and fabricsLicensed use Dithrocream c and Psorin c licensedfor use in children (age range not specified bymanufacturer); Micanol c licensed for use inchildren, but not recommended for infants or youngchildren (age range not specified by manufacturer)Indication and doseSubacute and chronic psoriasisSee notes above and under preparationsNote Some of these dithranol preparations also containcoal tar or salicylic acid—for prescribing information seeunder Tars or under Salicylic AcidNon-proprietary preparations1Dithranol Ointment, BP AOintment, dithranol, in yellow soft paraffin; usualstrengths 0.1–2%. Part of basis may be replaced byhard paraffin if a stiffer preparation is required.Label: 281. A if dithranol content more than 1%, otherwise may besold to the publicDithranol Paste, BPPaste, dithranol in zinc and salicylic acid (Lassar’s)paste. Usual strengths 0.1–1% of dithranol. Label: 28Proprietary preparationsDithrocream c (Dermal)Cream, dithranol 0.1%, net price 50 g = £3.77; 0.25%,50 g = £4.04; 0.5%, 50 g = £4.66; 1%, 50 g = £5.42; A2%, 50 g = £6.79. Label: 28Excipients include cetostearyl alcohol, chlorocresolDoseFor application to skin or scalp; 0.1–0.5% cream suitablefor overnight treatment, 1–2% cream for max. 1 hourMicanol c (GP Pharma)Cream, dithranol 1% in a lipid-stabilised basis, netprice 50 g = £13.48; A 3%, 50 g = £16.79. Label: 28Excipients none as listed in section 13.1.3DoseFor application to skin or scalp, apply 1% cream for up to30 minutes once daily, if necessary 3% cream can be usedunder medical supervisionNote At the end of contact time, use plenty of lukewarm (nothot) water to rinse off cream; soap may be used after thecream has been rinsed off; use shampoo before applyingcream to scalp and if necessary after cream has been rinsedoffPsorin c (LPC)Ointment, dithranol 0.11%, coal tar 1%, salicylic acid1.6%, net price 50 g = £9.22, 100 g = £18.44. Label: 28Excipients include beeswax, wool fatDoseFor application to skin up to twice daily

BNFC 2011–2012 13.5.2 Preparations for psoriasis 571Scalp gel, dithranol 0.25%, salicylic acid 1.6% in gelbasis containing methyl salicylate, net price 50 g =£7.03. Label: 28Excipients none as listed in section 13.1.3DoseFor application to scalp, initially apply on alternate daysfor 10–20 minutes; may be increased to daily applicationfor max. 1 hour and then wash offSalicylic acidSALICYLIC ACIDFor coal tar preparations containing salicylic acid, see underTars p. 569; for dithranol preparations containing salicylic acidsee under Dithranol, aboveCautions see notes above; avoid broken or inflamedskinSalicylate toxicity Salicylate toxicity may occur particularlyif applied on large areas of skin or on neonatal skinSide-effects sensitivity, excessive drying, irritation,systemic effects after widespread use (see underCautions)Indication and doseHyperkeratotic skin disorders see under preparationAcne section 13.6.1Warts and calluses section 13.7Scalp conditions section 13.9Fungal nail infections section 13.10.2Zinc and Salicylic Acid Paste, BPPaste, (Lassar’s Paste), zinc oxide 24%, salicylic acid2%, starch 24%, white soft paraffin 50%, net price 25 g= 17pDoseChild 1 month–18 years apply twice dailyOral retinoids for psoriasisACITRETINNote Acitretin is a metabolite of etretinateCautions in children use only in exceptional circumstances(premature epiphyseal closure reported); infemales of childbearing age exclude pregnancy beforestarting (test for pregnancy within 2 weeks beforetreatment and monthly thereafter; start treatment onday 2 or 3 of menstrual cycle)—females of childbearingage (including those with history of infertility)should avoid pregnancy and use effective contraceptionfor at least 1 month before, during, and for atleast 3 years after treatment (oral progestogen-onlycontraceptives not considered effective); patientsshould avoid concomitant tetracycline or methotrexate,high doses of vitamin A (more than 4000–5000 units daily), and use of keratolytics, and shouldnot donate blood during or for at least 1 year afterstopping therapy (teratogenic risk); check liver functionat start, at least every 4 weeks for first 2 monthsand then every 3 months; monitor serum-triglycerideand serum-cholesterol concentrations at least every 4weeks for first 2 months, then every 3 months; diabetes(can alter glucose tolerance—initial frequentblood glucose checks); radiographic assessment onlong-term treatment; investigate atypical musculoskeletalsymptoms; avoid excessive exposure to sunlightand unsupervised use of sunlamps; interactions:Appendix 1 (retinoids)Contra-indications hyperlipidaemiaHepatic impairment avoid—risk of further impairmentRenal impairment avoid; increased risk of toxicityPregnancy avoid—teratogenic; effective contraceptionmust be used—see Cautions aboveBreast-feeding avoidSide-effects dryness of mucous membranes (sometimeserosion), of skin (sometimes scaling, thinning,erythema especially of face, and pruritus), and ofconjunctiva (sometimes conjunctivitis and decreasedtolerance of contact lenses); sticky skin, dermatitis;other side-effects reported include palmoplantarexfoliation, epistaxis, epidermal and nail fragility,peripheral oedema, vulvovaginal candidiasis, paronychia,granulomatous lesions, bullous eruptions,reversible hair thinning and alopecia, myalgia andarthralgia, occasional nausea, headache, malaise,drowsiness, rhinitis, sweating, taste disturbance,stomatitis, cheilitis, and gingivitis; benign intracranialhypertension (discontinue if severe headache, vomiting,diarrhoea, abdominal pain, and visual disturbanceoccur; avoid concomitant tetracyclines);photosensitivity, corneal ulceration, rarely jaundiceand hepatitis (avoid concomitant methotrexate);raised serum-triglyceride or serum-cholesterol concentration;decreased night vision reported; skeletalhyperostosis and extraosseous calcification reportedfollowing long-term administration of etretinate (andpremature epiphyseal closure in children, see Cautionsabove)Indication and doseHarlequin ichthyosis (under expert supervisiononly). By mouthNeonate 500 micrograms/kg once daily with foodor milk (occasionally up to 1 mg/kg daily) withcareful monitoring of musculoskeletal developmentSevere extensive psoriasis resistant to otherforms of therapy, palmoplantar pustular psoriasis,severe congenital ichthyosis, severeDarier’s disease (keratosis follicularis) (all underexpert supervision only). By mouthChild 1 month–12 years 500 micrograms/kgonce daily with food or milk (occasionally up to1 mg/kg daily) to max. 35 mg daily with carefulmonitoring of musculoskeletal development (seealso p. 567)Child 12–18 years initially 25–30 mg daily(Darier’s disease 10 mg daily) for 2–4 weeks, thenadjusted according to response, usual range 25–50 mg daily; up to 75 mg daily for short periods inpsoriasis and ichthyosis (see also p. 567)13 Skin

572 13.5.3 Drugs affecting the immune response BNFC 2011–201213 SkinNeotigason c (Actavis) ACapsules, acitretin 10 mg (brown/white), net price60-cap pack = £23.80; 25 mg (brown/yellow), 60-cappack = £55.24. Label: 10, patient information leaflet,11, 21Extemporaneous formulations available seeExtemporaneous Preparations, p. 613.5.3 Drugs affecting theimmune responseDrugs affecting the immune response are used for eczemaor psoriasis.Pimecrolimus by topical application is licensed for mildto moderate atopic eczema. Tacrolimus is licensed fortopical use in moderate to severe atopic eczema. Bothare drugs whose long-term safety is still being evaluatedand they should not usually be considered first-linetreatment unless there is a specific reason to avoid orreduce the use of topical corticosteroids. Treatmentwith topical pimecrolimus or topical tacrolimus shouldbe initiated only by prescribers experienced in treatingatopic eczema.NICE guidanceTacrolimus and pimecrolimus for atopiceczema (August 2004)Topical pimecrolimus and tacrolimus are options foratopic eczema not controlled by maximal topicalcorticosteroid treatment or if there is a risk ofimportant corticosteroid side-effects (particularlyskin atrophy).Topical pimecrolimus is recommended for moderateatopic eczema on the face and neck of children aged2–16 years and topical tacrolimus is recommendedfor moderate to severe atopic eczema in childrenover 2 years. Pimecrolimus and tacrolimus should beused within their licensed indications.The Scottish Medicines Consortium (p. 3) has advised(March 2010) that tacrolimus ointment (Protopic c ) isaccepted for restricted use within NHS Scotland for theprevention of flares in children aged over 2 years withmoderate to severe atopic eczema in accordance withthe licensed indication; it’s use is restricted to initiationby doctors (including general practioners) with aspecialist interest and experience in treating atopiceczema with immunomodulatory therapy.For the role of topical corticosteroids in eczema, seesection 13.5.1, and for comment on their limited role inpsoriasis, see section 13.4. A systemic corticosteroid(section 6.3.2) such as prednisolone may be used insevere refractory eczema.Systemic drugs acting on the immune system are generallyused by specialists in a hospital setting.Ciclosporin by mouth can be used for severe psoriasisand for severe eczema. Azathioprine (section 8.2.1) ormycophenolate mofetil (section 8.2.1) are also used forsevere refractory eczema in children.Methotrexate can be used for severe resistant psoriasis;the dose is given once weekly and adjusted accordingto severity of the condition and haematological andbiochemical measurements. Folic acid (section 9.1.2)should be given to reduce the possibility of methotrexatetoxicity. Folic acid can be given at a dose of5 mg once weekly [unlicensed indication]; alternativeregimens may be used in some settings.Etanercept (a cytokine modulator) is licensed in childrenover 8 years of age for the treatment of severeplaque psoriasis that is inadequately controlled by othersystemic treatments and photochemotherapy, or whenthese other treatments cannot be used because of intoleranceor contra-indications.CICLOSPORIN(Cyclosporin)Cautions section 8.2.2Additional cautions in atopic dermatitis and psoriasisContra-indicated in abnormal renal function, uncontrolledhypertension (see also below), infections not under control,and malignancy (see also below). Dermatological and physicalexamination, including blood pressure and renal functionmeasurements required at least twice before starting.During treatment, monitor serum creatinine every 2 weeksfor first 3 months then every month; reduce dose by 25–50%if serum creatinine increases more than 30% above baseline(even if within normal range) and discontinue if reductionnot successful within one month. Discontinue if hypertensiondevelops that cannot be controlled by dose reduction orantihypertensive therapy. Avoid excessive exposure to sunlightand avoid use of UVB or PUVA. In atopic dermatitis,also allow herpes simplex infections to clear before starting(if they occur during treatment withdraw if severe); Staphylococcusaureus skin infections not absolute contra-indicationproviding controlled (but avoid erythromycin unless noother alternative—see also interactions: Appendix 1(ciclosporin)); investigate lymphadenopathy that persistsdespite improvement in atopic dermatitis. In psoriasis, alsoexclude malignancies (including those of skin and cervix)before starting (biopsy any lesions not typical of psoriasis)and treat patients with malignant or pre-malignant conditionsof skin only after appropriate treatment (and if no otheroption); discontinue if lymphoproliferative disorder developsHepatic impairment section 8.2.2Renal impairment see Cautions abovePregnancy section 8.2.2Breast-feeding section 8.2.2Side-effects section 8.2.2Licensed use not licensed for use in children under16 years for atopic eczema (dermatitis) or psoriasisIndication and doseShort-term treatment (usually max. 8 weeksbut may be used for longer under specialistsupervision) of severe atopic dermatitis whereconventional therapy ineffective or inappropriate. By mouth, administered in accordance withexpert adviceChild 1 month–18 years initially 1.25 mg/kgtwice daily, if good initial response not achievedwithin 2 weeks, increase rapidly to max. 2.5 mg/kgtwice daily; initial dose of 2.5 mg/kg twice daily ifvery severeImportant For preparations and counselling and foradvice on conversion between the preparations, seesection 8.2.2Severe psoriasis where conventional therapyineffective or inappropriate. By mouth, administered in accordance withexpert adviceChild 1 month–18 years initially 1.25 mg/kgtwice daily, increased gradually to max.2.5 mg/kg twice daily if no improvement within 1

BNFC 2011–2012 13.5.3 Drugs affecting the immune response 573month (discontinue if response still insufficientafter 6 weeks); initial dose of 2.5 mg/kg twice dailyjustified if condition requires rapid improvementImportant For preparations and counselling and foradvice on conversion between the preparations, seesection 8.2.2Refractory ulcerative colitis section 1.5.3Transplantation and graft-versus-host diseasesection 8.2.2PreparationsSection 8.2.2METHOTREXATECautions see section 8.1.3, also photosensitivity—psoriasis lesions aggravated by UV radiation (skinulceration reported)Contra-indications section 8.1.3Hepatic impairment avoid—dose-related toxicityRenal impairment section 8.1.3Pregnancy section 8.1.3Breast-feeding section 8.1.3Side-effects section 8.1.3Licensed use not licensed for use in children withpsoriasisIndication and doseSevere uncontrolled psoriasis unresponsive toconventional therapy (specialist use only). By mouthChild 2–18 years initially 200 micrograms/kg(max. 10 mg) once weekly increased according toresponse to 400 micrograms/kg (max. 25 mg)once weeklySafe PracticeNote that the above dose is a weekly dose. To avoiderror with low-dose methotrexate, it is recommendedthat:. the child or their carer is carefully advised of the dose andfrequency and the reason for taking methotrexate and anyother prescribed medicine (e.g. folic acid);. only one strength of methotrexate tablet (usually 2.5 mg) isprescribed and dispensed;. the prescription and the dispensing label clearly show thedose and frequency of methotrexate administration;. the child or their carer is warned to report immediately theonset of any feature of blood disorders (e.g. sore throat,bruising, and mouth ulcers), liver toxicity (e.g. nausea,vomiting, abdominal discomfort, and dark urine), and respiratoryeffects (e.g. shortness of breath).Malignant disease section 8.1.3Rheumatoid arthritis section 10.1.3Severe Crohn’s disease section 1.5.3PreparationsSection 10.1.3PIMECROLIMUSCautions UV light (avoid excessive exposure to sunlightand sunlamps), avoid other topical treatmentsexcept emollients at treatment site; alcohol consumption(risk of facial flushing and skin irritation)Contra-indications contact with eyes and mucousmembranes, application under occlusion, infection attreatment site; congenital epidermal barrier defects;generalised erythroderma; immunodeficiency; concomitantuse with drugs that cause immunosuppression(may be prescribed in exceptional circumstancesby specialists); application to malignant or potentiallymalignant skin lesionsSide-effects burning sensation, pruritus, erythema,skin infections (including folliculitis and less commonlyimpetigo, herpes simplex and zoster, molluscumcontagiosum); rarely papilloma, skin discoloration,local reactions including pain, paraesthesia,peeling, dryness, oedema, and worsening of eczema;skin malignancy reportedIndication and doseShort-term treatment of mild to moderate atopiceczema (including flares) when topical corticosteroidscannot be used; see also notesaboveChild 2–18 years apply twice daily until symptomsresolve (stop treatment if eczema worsens orno response after 6 weeks)Elidel c (Novartis) ACream, pimecrolimus 1%, net price 30 g = £19.69,60 g = £37.41, 100 g = £59.07. Label: 4, 28Excipients include benzyl alcohol, cetyl alcohol, propylene glycol,stearyl alcoholTACROLIMUSCautions infection at treatment site, UV light (avoidexcessive exposure to sunlight and sunlamps); alcoholconsumption (risk of facial flushing and skin irritation)Contra-indications hypersensitivity to macrolides;congenital epidermal barrier defects; generalisederythroderma; immunodeficiency; concomitant usewith drugs that cause immunosuppression (may beprescribed in exceptional circumstances by specialists);application to malignant or potentially malignantskin lesions; application under occlusion; avoidcontact with eyes and mucous membranesPregnancy manufacturer advises avoid unless essential;toxicity in animal studies following systemicadministrationBreast-feeding manufacturer advises avoid—presentin milk following systemic administrationSide-effects application-site reactions including rash,irritation, pain, and paraesthesia; herpes simplexinfection, Kaposi’s varicelliform eruption; applicationsiteinfections; less commonly acne; rosacea, and skinmalignancy also reportedIndication and doseShort-term treatment of moderate to severeatopic eczema (including flares) either unresponsiveto, or in children intolerant of conventionaltherapy; see also notes aboveChild 2–16 years initially apply 0.03% ointmentthinly twice daily for up to 3 weeks (consider othertreatment if eczema worsens or if no improvementafter 2 weeks) then reduce to once daily untillesion clearsChild 16–18 years initially apply 0.1% ointmentthinly twice daily until lesion clears (consider other13 Skin

574 13.6 Acne and rosacea BNFC 2011–201213 Skintreatment if eczema worsens or if no improvementafter 2 weeks); reduce to once daily or switch to0.03% ointment if clinical condition allowsPrevention of flares in children with moderateto severe atopic eczema and 4 or more flares ayear, who have responded to initial treatmentwith topical tacrolimusChild 2–16 years apply 0.03% ointment thinlytwice weekly (with an interval of 2–3 days betweenapplications); use short-term treatment regimenduring an acute flare; interrupt preventative therapyafter 1 year to reassess conditionChild 16–18 years apply 0.1% ointment thinlytwice weekly (with an interval of 2–3 days betweenapplications); use short-term treatment regimenduring an acute flare; review need for preventativetherapy after 1 yearOther indications section 8.2.2Protopic c (Astellas) AOintment, tacrolimus (as monohydrate) 0.03%, netprice 30 g = £19.44, 60 g = £35.46; 0.1%, 30 g =£21.60, 60 g = £39.40. Label: 4, 11, 28Excipients include beeswaxCytokine modulatorsETANERCEPTCautions section 10.1.3Contra-indications section 10.1.3Hepatic impairment section 10.1.3Pregnancy section 10.1.3Breast-feeding section 10.1.3Side-effects section 10.1.3Indication and doseSevere plaque psoriasis. By subcutaneous injectionChild 8–18 years 800 micrograms/kg (max.50 mg) once weekly; max. treatment duration 24weeks; discontinue if no response after 12 weeksPolyarticular-course juvenile idiopathic arthritissection 10.1.3whether the acne is predominantly inflammatory orcomedonal.Mild to moderate acne is generally treated with topicalpreparations, such as benzoyl peroxide, azelaic acid, andretinoids, (section 13.6.1).For moderate to severe inflammatory acne or wheretopical preparations are not tolerated or are ineffectiveor where application to the site is difficult, systemictreatment (section 13.6.2) with oral antibacterials maybe effective. Co-cyprindiol (cyproterone acetate withethinylestradiol) has anti-androgenic properties andmay be useful in young women with acne refractoryto other treatments.Severe acne, acne unresponsive to prolonged courses oforal antibacterials, acne with scarring, or acne associatedwith psychological problems calls for early referralto a consultant dermatologist who may prescribeoral isotretinoin (section 13.6.2).Neonatal and infantile acne Inflammatory papules,pustules, and occasionally comedones may develop atbirth or within the first month; most neonates with acnedo not require treatment. Acne developing at 3–6months of age may be more severe and persistent;lesions are usually confined to the face. Topical preparationscontaining benzoyl peroxide (at the loweststrength possible to avoid irritation), adapalene, ortretinoin may be used if treatment for infantile acne isnecessary. In infants with inflammatory acne, oralerythromycin (section 5.1.5) is used because topicalpreparations for acne are not well tolerated. In cases oferythromycin-resistant acne, oral isotretinoin (section13.6.2) can be given on the advice of a consultantdermatologist.Rosacea The adult form of rosacea rarely occurs inchildren. Persistent or repeated use of potent topicalcorticosteroids may cause periorificial rosacea (steroidacne). The pustules and papules of rosacea may betreated for at least 6 weeks with a topical metronidazolepreparation (section 13.10.1.2), or a systemicantibacterial such as erythromycin (section 5.1.5), orfor a child over 12 years, oxytetracycline (section5.1.3). Tetracyclines are contra-indicated in childrenunder 12 years of age.PreparationsSection 10.1.313.6.1 Topical preparations foracne13.6 Acne and rosacea13.6.1 Topical preparations for acne13.6.2 Oral preparations for acneAcne vulgaris Acne vulgaris commonly affects childrenaround puberty and occasionally affects infants.Treatment of acne should be commenced early toprevent scarring; lesions may worsen before improving.The choice of treatment depends on age, severity, andIn mild to moderate acne, comedones and inflamedlesions respond well to benzoyl peroxide (see below)or topical retinoids (see p. 576). Alternatively, topicalapplication of an antibacterial such as erythromycin orclindamycin may be effective for inflammatory acne.However, topical antibacterials are probably no moreeffective than benzoyl peroxide and may promote theemergence of resistant organisms. If topical preparationsprove inadequate oral preparations may be needed(section 13.6.2). The choice of product and formulation(gel, solution, lotion, or cream) is largely determined byskin type, patient preference, and previous usage ofacne products.

BNFC 2011–2012 13.6.1 Topical preparations for acne 575Benzoyl peroxide and azelaic acidBenzoyl peroxide is effective in mild to moderate acne.Both comedones and inflamed lesions respond well tobenzoyl peroxide. The lower concentrations seem to beas effective as higher concentrations in reducing inflammation.It is usual to start with a lower strength and toincrease the concentration of benzoyl peroxide gradually.Adverse effects include local skin irritation, particularlywhen therapy is initiated, but the scaling andredness often subside with a reduction in benzoyl peroxideconcentration, frequency, and area of application.If the acne does not respond after 2 months then use of atopical antibacterial should be considered.Azelaic acid has antimicrobial and anticomedonalproperties. It may be used as an alternative to benzoylperoxide or to a topical retinoid for treating mild tomoderate comedonal acne, particularly of the face;azelaic acid is less likely to cause local irritation thanbenzoyl peroxide.BENZOYL PEROXIDECautions avoid contact with eyes, mouth, and mucousmembranes; may bleach fabrics and hair; avoidexcessive exposure to sunlightSide-effects skin irritation (reduce frequency or suspenduse until irritation subsides and re-introduce atreduced frequency)Licensed use Quinoderm c is licensed for use inchildren; all other preparations, not licensed for usein treatment of infantile acneIndication and doseAcne vulgarisChild 12–18 years apply 1–2 times daily preferablyafter washing with soap and water, starttreatment with lower-strength preparationsNote May bleach clothingInfantile acneChild 1 month–2 years apply 1–2 times daily;start treatment with lower-strength preparationsAcnecide c (Galderma)Gel, benzoyl peroxide 5% in an aqueous gel basis, netprice 60 g = £10.88Excipients include propylene glycolWith antimicrobialsDuac c Once Daily (GSK) AGel, benzoyl peroxide 5%, clindamycin 1% (as phosphate)in an aqueous basis, net price 25 g = £9.95, 50 g= £19.90Excipients include disodium edetateDoseAcne vulgarisChild 12–18 years apply once daily in the eveningQuinoderm c (Ferndale)Cream, benzoyl peroxide 5%, potassium hydroxyquinolinesulphate 0.5%, in an astringent vanishingcreambasis, net price 50 g = £2.21Excipients include cetostearyl alcohol, edetic acid (EDTA)Cream, benzoyl peroxide 10%, potassium hydroxyquinolinesulphate 0.5%, in an astringent vanishingcreambasis, net price 25 g = £1.30, 50 g = £2.49Excipients include cetostearyl alcohol, edetic acid (EDTA)DoseAcne vulgaris, acneform eruptions, folliculitisApply 2–3 times dailyAZELAIC ACIDCautions avoid contact with eyes, mouth, and mucousmembranesSide-effects local irritation (reduce frequency or discontinuetemporarily); less commonly skin discoloration;very rarely photosensitisationIndication and doseSee under preparationsFinacea c (Meda) AGel, azelaic acid 15%, net price 30 g = £7.48Excipients include disodium edetate, polysorbate 80, propylene glycolDoseFacial acne vulgarisChild 12–18 years apply twice daily; discontinue if noimprovement after 1 monthSkinoren c (Bayer Schering) ACream, azelaic acid 20%, net price 30 g = £3.74Excipients include propylene glycolDoseAcne vulgarisApply twice daily (sensitive skin, once daily for firstweek). Extended treatment may be required but manufactureradvises period of treatment should not exceed 6months13 SkinBrevoxyl c (GSK)Cream, benzoyl peroxide 4% in an aqueous basis, netprice 40 g = £3.30Excipients include cetyl alcohol, fragrance, stearyl alcoholPanOxyl c (Stiefel)Aquagel (= aqueous gel), benzoyl peroxide 2.5%, netprice 40 g = £1.76; 5%, 40 g = £1.92; 10%, 40 g = £2.13Excipients include propylene glycolCream, benzoyl peroxide 5% in a non-greasy basis,net price 40 g = £1.89Excipients include isopropyl palmitate, propylene glycolGel, benzoyl peroxide 5% in an aqueous alcoholicbasis, net price 40 g = £1.51; 10%, 40 g = £1.69Excipients include fragranceWash, benzoyl peroxide 10% in a detergent basis, netprice 150 mL = £4.00Excipients include imidureaTopical antibacterials for acneIn the treatment of mild to moderate inflammatoryacne, topical antibacterials may be no more effectivethan topical benzoyl peroxide or tretinoin. Topical antibacterialsare probably best reserved for children whowish to avoid oral antibacterials or who cannot toleratethem.Topical preparations of erythromycin and clindamycinmay be used to treat inflamed lesions in mildto moderate acne when topical benzoyl peroxide ortretinoin is ineffective or poorly tolerated. Topical benzoylperoxide, azelaic acid, or retinoids used in combinationwith an antibacterial (topical or systemic) may bemore effective than an antibacterial used alone. Topicalantibacterials can produce mild irritation of the skin,and on rare occasions cause sensitisation.

576 13.6.1 Topical preparations for acne BNFC 2011–201213 SkinAntibacterial resistance of Propionibacterium acnes isincreasing; there is cross-resistance between erythromycinand clindamycin. To avoid development of resistance:. when possible use non-antibiotic antimicrobials(such as benzoyl peroxide or azelaic acid);. avoid concomitant treatment with different oral andtopical antibacterials;. if a particular antibacterial is effective, use it forrepeat courses if needed (short intervening coursesof benzoyl peroxide or azelaic acid may eliminateany resistant propionibacteria);. do not continue treatment for longer than necessary(but treatment with a topical preparation should becontinued for at least 6 months).ANTIBACTERIALSCautions some manufacturers advise preparationscontaining alcohol are not suitable for use withbenzoyl peroxideIndication and doseAcne vulgaris for dose, see under preparationsDalacin T c (Pharmacia) ATopical solution, clindamycin 1% (as phosphate), inan aqueous alcoholic basis, net price (both withapplicator) 30 mL = £4.34, 50 mL = £7.23Excipients include propylene glycolDoseApply twice dailyLotion, clindamycin 1% (as phosphate) in an aqueousbasis, net price 30 mL = £5.08, 50 mL = £8.47Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)DoseApply twice dailyStiemycin c (Stiefel) ASolution, erythromycin 2% in an alcoholic basis, netprice 50 mL = £7.69Excipients include propylene glycolDoseApply twice dailyZindaclin c (Crawford) AGel, clindamycin 1% (as phosphate), net price 30 g =£8.66Excipients include propylene glycolDoseChild 12–18 years apply once dailyZineryt c (Astellas) ATopical solution, powder for reconstitution, erythromycin40 mg, zinc acetate 12 mg/mL when reconstitutedwith solvent containing ethanol, net price perpack of powder and solvent to provide 30 mL = £7.71,90 mL = £16.68Excipients none as listed in section 13.1.3DoseApply twice dailyTopical retinoids and relatedpreparations for acneTopical tretinoin, its isomer isotretinoin, and adapalene(a retinoid-like drug), are useful for treating comedonesand inflammatory lesions in mild to moderateacne. Patients should be warned that some redness andskin peeling can occur initially but settles with time.Several months of treatment may be needed to achievean optimal response and the treatment should be continueduntil no new lesions develop.Tretinoin can be used under specialist supervision totreat infantile acne; adapalene can also be used. See alsoNeonatal and Infantile Acne, p. 574.Cautions Topical retinoids should be avoided in severeacne involving large areas. Contact with eyes, nostrils,mouth and mucous membranes, eczematous, broken orsunburned skin should be avoided. Topical retinoidsshould be used with caution on sensitive areas such asthe neck, and accumulation in angles of the nose shouldbe avoided. Exposure to UV light (including sunlight,solariums) should be avoided; if sun exposure is unavoidable,an appropriate sunscreen (section 13.8.1) orprotective clothing should be used. Use of retinoids withabrasive cleaners, comedogenic or astringent cosmeticsshould be avoided. Allow peeling (resulting from otherirritant treatments) to subside before using a topicalretinoid; alternating a preparation that causes peelingwith a topical retinoid may give rise to contactdermatitis (reduce frequency of retinoid application).Pregnancy Topical retinoids are contra-indicated inpregnancy; females of child-bearing age must use effectivecontraception (oral progestogen-only contraceptivesnot considered effective).Side-effects Local reactions include burning, erythema,stinging, pruritus, dry or peeling skin (discontinue ifsevere). Increased sensitivity to UVB light or sunlightoccurs. Temporary changes of skin pigmentation withtretinoin have been reported. Eye irritation and oedema,and blistering or crusting of skin have been reportedrarely.ADAPALENECautions see notes abovePregnancy see notes aboveBreast-feeding amount of drug in milk probably toosmall to be harmful; ensure infant does not come incontact with treated areasSide-effects see notes aboveLicensed use not licensed for use in infantile acneIndication and doseInfantile acneChild 1 month–2 years apply thinly once daily atnightMild to moderate acne vulgarisChild 12–18 years apply thinly once daily in theevening; reduce frequency or suspend treatment ifirritation occursDifferin c (Galderma) ACream, adapalene 0.1%, net price 45 g = £11.40.Label: 11Excipients include disodium edetate, hydroxybenzoates (parabens)Gel, adapalene 0.1%, net price 45 g = £11.40.Label: 11Excipients include disodium edetate, hydroxybenzoates (parabens),propylene glycol

BNFC 2011–2012 13.6.1 Topical preparations for acne 577With benzoyl peroxideEpiduo c (Galderma) AGel, adapalene 0.1%, benzoyl peroxide 2.5%, net price45 g = £17.91. Label: 11Excipients include disodium edetate, polysorbate 80, propylene glycolDoseAcne vulgarisChild 12–18 years apply thinly once daily in the evening;reduce frequency or suspend treatment if irritationoccursNote May bleach clothing and hairISOTRETINOINNote Isotretinoin is an isomer of tretinoinImportant For prescribing information on isotretinoin whengiven by mouth, see p. 579Cautions (topical application only) see notes above;also personal or familial history of non-melanomaskin cancerContra-indications (topical application only) rosacea;perioral dermatitisPregnancy (topical application only) see notes aboveBreast-feeding avoidSide-effects (topical application only) see notesaboveIndication and doseAcne vulgarisApply thinly 1–2 times dailyIsotrex c (Stiefel) AGel, isotretinoin 0.05%, net price 30 g = £5.94.Label: 11Excipients include butylated hydroxytolueneWith antibacterialIsotrexin c (Stiefel) AGel, isotretinoin 0.05%, erythromycin 2% in ethanolicbasis, net price 30 g = £7.47. Label: 11Excipients include butylated hydroxytolueneTRETINOINNote Tretinoin is the acid form of vitamin ACautions see notes aboveContra-indications personal or familial history ofnon-melanoma skin cancer; rosacea; perioraldermatitisPregnancy see notes aboveBreast-feeding amount of drug in milk after topicalapplication probably too small to be harmful; ensureinfant does not come into contact with treated areasSide-effects see notes aboveLicensed use Retin-A c not licensed for use ininfantile acneIndication and doseSee under preparationsMalignant disease section 8.1.5Retin-A c (Janssen) AGel, tretinoin 0.01%, net price 60 g = £5.28; 0.025%,60 g = £5.28. Label: 11Excipients include butylated hydroxytolueneDoseInfantile acneApply 0.01% gel thinly 1–2 times daily; increase to0.025% gel if necessaryAcne vulgaris, particularly that associated with oilyskinApply thinly 1–2 times dailyWith antibacterialAknemycin Plus c (Almirall) ASolution, tretinoin 0.025%, erythromycin 4% in analcoholic basis, net price 25 mL = £7.05. Label: 11Excipients none as listed in section 13.1.3DoseAcne (all forms), particularly that associated with oilyskinApply thinly 1–2 times dailyOther topical preparations for acneSalicylic acid is available in various preparations forsale direct to the public for the treatment of mild acne.Other products are more suitable for acne; salicylic acidis used mainly for its keratolytic effect.A topical preparation of nicotinamide is available forinflammatory acne.NICOTINAMIDECautions avoid contact with eyes and mucous membranes(including nose and mouth); reduce frequencyof application if excessive dryness, irritation or peelingSide-effects dryness of skin; also pruritus, erythema,burning and irritationLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseInflammatory acne vulgaris see under preparationsbelowNicam c (Dermal)Gel, nicotinamide 4%, net price 60 g = £7.10Excipients none as listed in section 13.1.3DoseApply twice daily; reduce to once daily or on alternatedays if irritation occursSALICYLIC ACID UCautions risk of significant systemic absorption inneonates; avoid contact with mouth, eyes, mucousmembranes; systemic effects after excessive useSalicylate toxicity Salicylate toxicity can occur particularlyif applied on large areas of skin or on neonatal skinSide-effects local irritationLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseAcne vulgaris see under preparationPsoriasis section 13.5.2Warts and calluses section 13.7Fungal nail infections section 13.10.213 Skin

578 13.6.2 Oral preparations for acne BNFC 2011–2012Acnisal c (Alliance) UTopical solution, salicylic acid 2% in a detergent andemollient basis, net price 177 mL = £3.39.Excipients include benzyl alcoholNote may be difficult to obtainDoseApply up to 3 times daily13.6.2 Oral preparations for acneVenous thromboembolism occurs more frequentlyin women taking co-cyprindiol than those taking alow-dose combined oral contraceptive. Co-cyprindiolis licensed for use in women with severe acnethat has not responded to oral antibacterials and formoderately severe hirsutism; it should not be usedsolely for contraception. It is contra-indicated inthose with a personal or close family history ofvenous thromboembolism. Women with severeacne or hirsutism may have an inherently increasedrisk of cardiovascular disease.13 SkinOral antibacterials for acneOral antibacterials may be used in moderate to severeinflammatory acne when topical treatment is not adequatelyeffective or is inappropriate. Concomitant anticomedonaltreatment with topical benzoyl peroxide orazelaic acid may also be required (section 13.6.1).Tetracyclines should not be given to children under 12years. In children over 12 years, either oxytetracyclineor tetracycline (section 5.1.3) is usually given for acnein a dose of 500 mg twice daily. If there is no improvementafter the first 3 months another oral antibacterialshould be used. Maximum improvement usually occursafter 4 to 6 months but in more severe cases treatmentmay need to be continued for 2 years or longer.Doxycycline and lymecycline (section 5.1.3) are alternativesto tetracycline in children over 12 years. Doxycyclinecan be used in a dose of 100 mg daily.Lymecycline is given in a dose of 408 mg daily.Although minocycline is as effective as other tetracyclinesfor acne, it is associated with a greater risk oflupus erythematosus-like syndrome. Minocycline sometimescauses irreversible pigmentation; it is given in adose of 100 mg once daily or 50 mg twice daily.Erythromycin (section 5.1.5) in a dose of 500 mg twicedaily for children over 12 years is an alternative for themanagement of moderate to severe acne with inflamedlesions, but propionibacteria strains resistant to erythromycinare becoming widespread and this may explainpoor response. Infants with acne requiring oral treatmentwith erythromycin should be given 250 mg oncedaily or 125 mg twice daily; in cases of erythromycinresistantP. acnes in infants, oral isotretinoin may beused on the advice of a consultant dermatologist.Concomitant use of different topical and systemic antibacterialsis undesirable owing to the increased likelihoodof the development of bacterial resistance.Hormone treatment for acneCo-cyprindiol (cyproterone acetate with ethinylestradiol)contains an anti-androgen. It is no more effectivethan an oral broad-spectrum antibacterial but is usefulin females of childbearing age who also wish to receiveoral contraception.Improvement of acne with co-cyprindiol probablyoccurs because of decreased sebum secretion which isunder androgen control. Some females with moderatelysevere hirsutism may also benefit because hair growth isalso androgen-dependent. Contra-indications of cocyprindiolinclude pregnancy and a predisposition tothrombosis.CO-CYPRINDIOLA mixture of cyproterone acetate and ethinylestradiol in themass proportions 2000 parts to 35 parts, respectivelyCautions see under Combined Hormonal Contraceptives,section 7.3.1Contra-indications see under Combined HormonalContraceptives, section 7.3.1Hepatic impairment see under Combined HormonalContraceptives, section 7.3.1Pregnancy avoid—risk of feminisation of male fetuswith cyproteroneBreast-feeding manufacturer advises avoid; possibilityof anti-androgen effects in neonate with cyproteroneSide-effects see under Combined Hormonal Contraceptives,section 7.3.1Licensed use licensed for use in females of childbearingageIndication and doseSevere acne in females of childbearing agerefractory to prolonged oral antibacterial therapy(but see notes above), moderately severehirsutism. By mouth1 tablet daily for 21 days starting on day 1 ofmenstrual cycle and repeated after a 7-day interval,usually for several months; withdraw 3–4months after acne or hirsutism completelyresolved (repeat courses may be given if recurrence);long-term treatment may be necessary forsevere symptomsCo-cyprindiol (Non-proprietary) ATablets, co-cyprindiol 2000/35 (cyproterone acetate2 mg, ethinylestradiol 35 micrograms), net price 63-tab pack = £4.70Brands include Acnocin c , Cicafem c , Clairette cDianette c (Bayer Schering) ATablets, beige, s/c, co-cyprindiol 2000/35 (cyproteroneacetate 2 mg, ethinylestradiol 35 micrograms),net price 63-tab pack = £7.71Oral retinoid for acneThe retinoid isotretinoin reduces sebum secretion. It isused for the systemic treatment of nodulo-cystic andconglobate acne, severe acne, acne with scarring, or foracne which has not responded to an adequate course ofa systemic antibacterial. Isotretinoin is used for thetreatment of severe infantile acne resistant to erythromycin.Isotretinoin is a toxic drug that should be prescribedonly by, or under the supervision of, a consultant

BNFC 2011–2012 13.6.2 Oral preparations for acne 579dermatologist. It is given for at least 16 weeks; repeatcourses are not normally required.Side-effects of isotretinoin include severe dryness of theskin and mucous membranes, nose bleeds, and jointpains. The drug is teratogenic and must not be given tofemales of child-bearing age unless they practise effectivecontraception (oral progestogen-only contraceptivesnot considered effective) and then only afterdetailed assessment and explanation by the physician.They must also be registered with a pregnancy preventionprogramme (see under Cautions below).Although a causal link between isotretinoin use andpsychiatric changes (including suicidal ideation) hasnot been established, the possibility should be consideredbefore initiating treatment; if psychiatric changesoccur during treatment, isotretinoin should be stopped,the prescriber informed, and specialist psychiatricadvice should be sought.ISOTRETINOINNote Isotretinoin is an isomer of tretinoinCautions see notes above; also avoid blood donationduring treatment and for at least 1 month after treatment;history of depression; monitor all patients fordepression; measure hepatic function and serumlipids before treatment, 1 month after starting andthen every 3 months (reduce dose or discontinue iftransaminase or serum lipids persistently raised);discontinue if uncontrolled hypertriglyceridaemia orpancreatitis; diabetes; dry eye syndrome (associatedwith risk of keratitis); avoid keratolytics; interactions:Appendix 1 (retinoids)Pregnancy prevention In women of child-bearing potential,exclude pregnancy up to 3 days before treatment (starttreatment on day 2 or 3 of menstrual cycle), every monthduring treatment (unless there are compelling reasons toindicate that there is no risk of pregnancy), and 5 weeks afterstopping treatment—perform pregnancy test in the first 3days of the menstrual cycle. Women must practise effectivecontraception for at least 1 month before starting treatment,during treatment, and for at least 1 month after stoppingtreatment. Women should be advised to use at least 1method of contraception, but ideally they should use 2methods of contraception. Oral progestogen-only contraceptivesare not considered effective. Barrier methodsshould not be used alone, but can be used in conjunctionwith other contraceptive methods. Each prescription forisotretinoin should be limited to a supply of up to 30 days’treatment and dispensed within 7 days of the date stated onthe prescription. Women should be advised to discontinuetreatment and to seek prompt medical attention if theybecome pregnant during treatment or within 1 month ofstopping treatment.Counselling Warn patient to avoid wax epilation (risk ofepidermal stripping), dermabrasion, and laser skin treatments(risk of scarring) during treatment and for at least 6months after stopping; patient should avoid exposure to UVlight (including sunlight) and use sunscreen and emolient(including lip balm) preparations from the start of treatmentContra-indications hypervitaminosis A, hyperlipidaemiaHepatic impairment avoid—further impairment mayoccurRenal impairment in severe impairment, reduceinitial dose and increase gradually, if necessary, up to1 mg/kg daily as toleratedPregnancy avoid—teratogenic; effective contraceptionmust be used—see Pregnancy PreventionaboveBreast-feeding avoidSide-effects dryness of skin (with dermatitis, scaling,thinning, erythema, pruritus), epidermal fragility(trauma may cause blistering), dryness of lips (sometimescheilitis), dryness of eyes (with blepharitis andconjunctivitis), dryness of pharyngeal mucosa (withhoarseness), dryness of nasal mucosa (with epistaxis),headache, myalgia and arthralgia, raised plasma-triglycerideconcentration (risk of pancreatitis if triglyceridesabove 9 mmol/litre), raised serum-cholesterolconcentration (with reduced high-densitylipoprotein concentration), raised blood-glucose concentration,raised serum-transaminase concentration,haematuria and proteinuria, thrombocytopenia,thrombocytosis, neutropenia and anaemia; rarelymood changes (depression, aggressive behaviour,anxiety, and very rarely psychosis and suicidal ideation)—expertreferral required, skin reactions(including reports of Stevens-Johnson syndrome andtoxic epidermal necrolysis), alopecia; very rarelynausea, hepatitis, inflammatory bowel disease, gastrointestinalhaemorrhage, haemorrhagic diarrhoea(discontinue treatment), benign intracranial hypertension(avoid concomitant tetracyclines), convulsions,malaise, drowsiness, dizziness, diabetesmellitus, lymphadenopathy, hyperuricaemia, glomerulonephritis,tendinitis, arthritis, raised serum-creatinekinase concentration, bone changes (includingreduced bone density, early epiphyseal closure, andskeletal hyperstosis) and calcification of tendons andligaments following long-term administration, visualdisturbances (papilloedema, corneal opacities, cataracts,decreased night vision, photophobia, blurredvision, colour blindness)—expert referral requiredand consider withdrawal, decreased tolerance tocontact lenses, keratitis, impaired hearing, Grampositiveinfections of skin and mucous membranes,exacerbation of acne, acne fulminans, allergic vasculitisand granulomatous lesions, paronychia, hirsutism,nail dystrophy, skin hyperpigmentation, photosensitivity,increased sweatingLicensed use not licensed for use in infantile acneIndication and doseAcne vulgaris under supervision of consultant dermatologist,see notes above. By mouthChild 12–18 years 500 micrograms/kg daily (in1–2 divided doses), increased if necessary to1 mg/kg daily, for 16–24 weeks (repeat treatmentcourse after a period of at least 8 weeks if failure orrelapse after first course); max. cumulative dose150 mg/kg per courseSevere infantile acne under supervision of a consultantdermatologist, see p. 574. By mouthChild 1 month–2 years 200 micrograms/kg daily(in 1–2 divided doses), increased if necessary to1 mg/kg daily, for 16–24 weeks; max. cumulativedose 150 mg/kg per courseIsotretinoin (Non-proprietary) ACapsules, isotretinoin 5 mg, net price 56-cap pack =£14.99; 20 mg, 56-cap pack = £39.99. Label: 10,patient information leaflet, 11, 21Roaccutane c (Roche) ACapsules, isotretinoin 10 mg (brown-red), net price30-cap pack = £14.54; 20 mg (brown-red/white), 30-13 Skin

580 13.7 Preparations for warts and calluses BNFC 2011–201213 Skincap pack = £20.02. Label: 10, patient informationcard, 11, 21Extemporaneous formulations available seeExtemporaneous Preparations, p. 613.7 Preparations for wartsand callusesWarts (verruca vulgaris) are common, benign, self-limiting,and usually asymptomatic. They are caused by ahuman papillomavirus, which most frequently affectsthe hands, feet (plantar warts), and the anogenital region(see below); treatment usually relies on local tissuedestruction and is required only if the warts are painful,unsightly, persistent, or cause distress. In immunocompromisedchildren, warts may be more difficult to eradicate.Preparations of salicylic acid, formaldehyde, gluteraldehydeor silver nitrate are used for the removal ofwarts on hands and feet. Salicylic acid is a usefulkeratolytic which may be considered first-line in thetreatment of warts; it is also suitable for the removal ofcorns and calluses. Preparations of salicylic acid in acollodion basis are available but some children maydevelop an allergy to colophony in the formulation;collodion should be avoided in children allergic toelastic adhesive plaster. Cryotherapy causes pain, swelling,and blistering, and may be no more effective thantopical salicylic acid in the treatment of warts.SALICYLIC ACIDCautions significant peripheral neuropathy, patientswith diabetes at risk of neuropathic ulcers; protectsurrounding skin and avoid broken skin; not suitablefor application to face, anogenital region, or largeareasSide-effects skin irritation, see notes aboveLicensed use not licensed for use in children under 2yearsIndication and doseWarts on hands and feet (plantar)For dose see preparations; apply carefully to wartand protect surrounding skin (e.g. with soft paraffinor specially designed plaster); rub wart surfacegently with file or pumice stone once weekly;treatment may need to be continued for up to 3monthsPsoriasis section 13.5.2Acne section 13.6.1Fungal nail infections section 13.10.2Cuplex c (Crawford)Gel, salicylic acid 11%, lactic acid 4%, in a collodionbasis, net price 5 g = £2.23. Label: 15DoseApply twice dailyNote Contains colophony (see notes above)Duofilm c (GSK)Paint, salicylic acid 16.7%, lactic acid 16.7%, in flexiblecollodion, net price 15 mL (with applicator) =£2.25. Label: 15DoseApply dailyOcclusal c (Alliance)Cutaneous solution, salicylic acid 26% in polyacrylicsolution, net price 10 mL (with applicator) = £3.56.Label: 15DoseApply dailySalactol c (Dermal)Paint, salicylic acid 16.7%, lactic acid 16.7%, in flexiblecollodion, net price 10 mL (with applicator) =£1.71. Label: 15DoseApply dailyNote Contains colophony (see notes above)Salatac c (Dermal)Gel, salicylic acid 12%, lactic acid 4% in a collodionbasis, net price 8 g (with applicator) = £2.98. Label: 15DoseApply dailyVerrugon c (Ransom)Ointment, salicylic acid 50% in a paraffin basis, netprice 6 g = £3.12DoseApply dailyFORMALDEHYDECautions see under Salicylic AcidSide-effects see under Salicylic AcidLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseWarts, particularly plantar warts for dose seepreparation belowVeracur c (Typharm)Gel, formaldehyde 0.75% in a water-miscible gelbasis, net price 15 g = £2.41.DoseApply twice dailyGLUTARALDEHYDECautions protect surrounding skin; not for applicationto face, mucosa, or anogenital areasSide-effects rashes, skin irritation (discontinue ifsevere); stains skin brownLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseWarts, particularly plantar wartsApply twice dailyGlutarol c (Dermal)Solution (= application), glutaraldehyde 10%, netprice 10 mL (with applicator) = £2.07

BNFC 2011–2012 13.7 Preparations for warts and calluses 581SILVER NITRATECautions protect surrounding skin and avoid brokenskin; not suitable for application to face, ano-genitalregion, or large areasSide-effects chemical burns on surrounding skin;stains skin and fabricLicensed use no age range specified by manufacturerIndication and doseCommon warts and verrucasApply moistened caustic pencil tip for 1–2 minutes;repeat after 24 hours up to max. 3 applications forwarts or max. 6 applications for verrucasInstructions in proprietary packs generally incorporateadvice to remove dead skin before use by gentle filingand to cover with adhesive dressing after applicationIndication and doseExternal genital and perianal warts (for use underspecialist supervision only)Apply thinly 3 times a week at night until lesionsresolve (max. 16 weeks)Important Should be rubbed in and allowed to stay onthe treated area for 6–10 hours then washed off with mildsoap and water (uncircumcised males treating wartsunder foreskin should wash the area daily). The creamshould be washed off before sexual contactAldara c (Meda) ACream, imiquimod 5%, net price 12-sachet pack =£48.34. Label: 10, patient information leafletExcipients include benzyl alcohol, cetyl alcohol, hydroxybenzoates(parabens), polysorbate 60, stearyl alcoholCondoms may damage latex condoms and diaphragmsUmbilical granulomasApply moistened caustic pencil tip (usually containingsilver nitrate 40%) for 1–2 minutes whileprotecting surrounding skin with soft paraffinSilver nitrate (Non-proprietary)Caustic pencil, tip containing silver nitrate 40%,potassium nitrate 60%, net price = 93pAVOCA c (Bray)Caustic pencil, tip containing silver nitrate 95%,potassium nitrate 5%, net price, treatment pack(including emery file, 6 adhesive dressings and protectorpads) = £1.94.Anogenital wartsAnogenital warts (condylomata acuminata) in childrenare often asymptomatic and require only a simplebarrier preparation. If treatment is required it shouldbe supervised by a hospital specialist. Persistent wartson genital skin may require treatment with cryotherapyor other forms of physical ablation under general anaesthesia.Podophyllotoxin (the major active ingredient of podophyllum),or imiquimod are used to treat external anogenitalwarts; these preparations can cause considerableirritation of the treated area and are therefore suitableonly for children who are able to cooperate with thetreatment.IMIQUIMODCautions avoid normal or broken skin and openwounds; not suitable for internal genital warts; uncircumcisedmales (risk of phimosis or stricture of foreskin);autoimmune disease; immunosuppressedpatientsPregnancy no evidence of teratogenicity or toxicity inanimal studies; manufacturer advises cautionBreast-feeding no information availableSide-effects local reactions (including itching, burningsensation, erythema, erosion, oedema, excoriation,and scabbing); headache; influenza-like symptoms;myalgia; less commonly local ulceration andalopecia; rarely Stevens-Johnson syndrome andcutaneous lupus erythematosus-like effect; very rarelydysuria in females; permanent hypopigmentation orhyperpigmentation reportedLicensed use not licensed for use in childrenPODOPHYLLOTOXINCautions see notes above; avoid normal skin and openwounds; keep away from face; very irritant to eyesPregnancy avoidBreast-feeding avoidSide-effects local irritationLicensed use not licensed for use in childrenIndication and doseSee under preparations (for use under specialistsupervision only)Condyline c (Nycomed) ASolution, podophyllotoxin 0.5% in alcoholic basis, netprice 3.5 mL (with applicators) = £14.49. Label: 15DoseCondylomata acuminata affecting the penis or thefemale external genitaliaChild 2–18 years (see notes above) apply twice daily for3 consecutive days; treatment may be repeated at weeklyintervals if necessary for a total of five 3-day treatmentcourses; direct medical supervision for lesions in thefemale and for lesions greater than 4 cm 2 in the male;max. 50 single applications (‘loops’) per session (consultproduct literature)Warticon c (GSK) ACream, podophyllotoxin 0.15%, net price 5 g (withmirror) = £14.86Excipients include butylated hydroxyanisole, cetyl alcohol, hydroxybenzoates(parabens), sorbic acid, stearyl alcoholDoseCondylomata acuminata affecting the penis or thefemale external genitaliaChild 2–18 years (see notes above) apply twice daily for3 consecutive days; treatment may be repeated at weeklyintervals if necessary for a total of four 3-day treatmentcourses; direct medical supervision for lesions greaterthan 4 cm 2Solution, blue, podophyllotoxin 0.5% in alcoholicbasis, net price 3 mL (with applicators) = £12.38.Label: 15DoseCondylomata acuminata affecting the penis or thefemale external genitaliaChild 2–18 years (see notes above) apply twice daily for3 consecutive days; treatment may be repeated at weeklyintervals if necessary for a total of four 3-day treatmentcourses; direct medical supervision for lesions greaterthan 4 cm 2 ; max. 50 single applications (‘loops’) persession (consult product literature)13 Skin

582 13.8 Sunscreens and camouflagers BNFC 2011–201213 Skin13.8 Sunscreens andcamouflagers13.8.1 Sunscreen preparations13.8.2 Camouflagers13.8.1 Sunscreen preparationsSolar ultraviolet irradiation can be harmful to the skin. Itis responsible for disorders such as polymorphic lighteruption, solar urticaria, and it provokes the variouscutaneous porphyrias. It also provokes (or at leastaggravates) skin lesions of lupus erythematosus andmay aggravate some other dermatoses. Certain drugs,such as demeclocycline, phenothiazines, or amiodarone,can cause photosensitivity. All these conditions (as wellas sunburn) may occur after relatively short periods ofexposure to the sun. Solar ultraviolet irradiation mayprovoke attacks of recurrent herpes labialis (but it is notknown whether the effect of sunlight exposure is local orsystemic).The effects of exposure over longer periods includeageing changes and more importantly the initiation ofskin cancer.Solar ultraviolet radiation is approximately 200–400 nmin wavelength. The medium wavelengths (290–320 nm,known as UVB) cause sunburn. The long wavelengths(320–400 nm, known as UVA) are responsible for manyphotosensitivity reactions and photodermatoses. BothUVA and UVB contribute to long-term photodamageand to the changes responsible for skin cancer andageing.Sunscreen preparations contain substances that protectthe skin against UVA and UVB radiation, but they are nosubstitute for covering the skin and avoiding sunlight.Protective clothing and sun avoidance (rather than theuse of sunscreen preparations) are recommended forchildren under 6 months of age.The sun protection factor (SPF, usually indicated in thepreparation title) provides guidance on the degree ofprotection offered against UVB; it indicates the multiplesof protection provided against burning, comparedwith unprotected skin; for example, an SPF of 8 shouldenable a child to remain 8 times longer in the sunwithout burning. However, in practice users do notapply sufficient sunscreen product and the protectionis lower than that found in experimental studies. Somemanufacturers use a star rating system to indicate theprotection against UVA relative to protection againstUVB for sunscreen products. However, the usefulness ofthe star rating system remains controversial. The EUCommission (September 2006) has recommended thatthe UVA protection factor for a sunscreen should be atleast one-third of the sun protection factor (SPF); productsthat achieve this requirement will be labelled witha UVA logo alongside the SPF classification. Preparationsthat also contain reflective substances, such astitanium dioxide, provide the most effective protectionagainst UVA.Sunscreen preparations may rarely cause allergic reactions.For optimum photoprotection, sunscreen preparationsshould be applied thickly and frequently(approximately 2 hourly). In photodermatoses,they should be used from spring to autumn. Asmaximum protection from sunlight is desirable, preparationswith the highest SPF should be prescribed.Ingredient nomenclature in sunscreenpreparationsrINN INCIamiloxate isoamyl p-methoxycinnamateavobenzone butyl methoxydibenzoylmethanebemotrizinol bis-ethylhexyloxyphenol methoxyphenyltriazinebisoctrizole methylene bis-benzotriazolyl tetramethylbutylphenolecamsule terephthalylidene dicamphor sulfonic acidensulizole phenylbenzimidazole sulfonic acidenzacamene 4-methylbenzylidene camphoroctinoxate octyl (or ethylhexyl) methoxycinnamateoctocrilene octocryleneoxybenzone benzophenone-3The European Commission Cosmetic Products Regulation(EC) 1223/2009 requires the use of INCI (InternationalNomenclature of Cosmetic Ingredients) for cosmetics andsunscreens. This table includes the rINN and the INCIsynonym for the active ingredients of sunscreen preparationsin BNFCBorderline substances The preparations marked‘ACBS’ cannot be prescribed on the NHS except forskin protection against ultraviolet radiation in abnormalcutaneous photosensitivity resulting from genetic disordersor photodermatoses, including vitiligo and thoseresulting from radiotherapy; chronic or recurrent herpessimplex labialis. Preparations with SPF less than 30should not normally be prescribed. See also Appendix 2.Anthelios c (L’Oréal Active)XL SPF 50+ Melt-in cream (UVA and UVB protection; UVB-SPF 50+), avobenzone 3.5%, bemotrizinol 3%, drometrizoletrisiloxane 0.5%, ecamsule 1%, octocrilene 2.5%, titaniumdioxide 4.2%, net price 50 mL = £3.63. ACBSExcipients include disodium edetate, stearyl alcoholNote For INCI synonyms, see table aboveDelph c (Fenton)Lotion (UVA and UVB protection; UVB-SPF 30), octinoxate4.8%, oxybenzone 1.5%, titanium dioxide 2%, net price200 mL = £3.57. ACBSExcipients include cetostearyl alcohol, fragrance, hydroxybenzoates(parabens), imidureaNote For INCI synonyms, see table aboveSunsense c Ultra (Crawford)Lotion (UVA and UVB protection; UVB-SPF 50+), avobenzone2%, ensulizole 2%, enzacamene 4%, octinoxate 6%,oxybenzone 2%, titanium dioxide 3%, net price 50-mL bottlewith roll-on applicator = £4.11, 125 mL = £6.86, 500-mLpump pack = £15.54. ACBSExcipients include butylated hydroxytoluene, cetyl alcohol, fragrance,hydroxybenzoates (parabens), propylene glycolNote For INCI synonyms, see table above

BNFC 2011–2012 13.8.2 Camouflagers 583Uvistat c (LPC)Cream (UVA and UVB protection; UVB-SPF 30), avobenzone5%, bisoctrizole 1.5%, octinoxate 7.5%, octocrilene 4%,titanium dioxide 5.2%, net price 125 mL = £7.45. ACBSExcipients include disodium edetate, hydroxybenzoates (parabens),propylene glycolNote For INCI synonyms, see table aboveCream (UVA and UVB protection; UVB-SPF 50), amiloxate2%, avobenzone 5%, bisoctrizole 6%, octinoxate 10%,octocrilene 4%, titanium dioxide 4.8%, net price 125 mL =£8.45. ACBSExcipients include disodium edetate, polysorbate 60, propylene glycolNote For INCI synonyms, see table aboveLipscreen (UVA and UVB protection; UVB-SPF 50), avobenzone5%, bemotrizinol 3%, octinoxate 10%, octocrilene4%, titanium dioxide 3%, net price 5 g = £2.99. ACBSExcipients include butylated hydroxytoluene, hydroxybenzoates (parabens)Note For INCI synonyms, see table abovePhotodamageActinic keratoses occur very rarely in healthy children;actinic cheilitis may occur on the lips of adolescentsfollowing excessive sun exposure.Diclofenac gel (Solaraze c ) and fluorouracil cream arelicensed for the treatment of actinic keratoses but theyare not licensed for use in children.In children with photosensitivity disorders, such aserythropoietic protoporphyria, specialists may usebetacarotene, mepacrine, chloroquine or hydroxychloroquine(section 10.1.3) to reduce skin reactions.BETACAROTENENote Betacarotene is a precursor to vitamin ACautions monitor vitamin A intake; interactions:Appendix 1 (vitamins)Hepatic impairment avoidRenal impairment use with cautionPregnancy partially converted to vitamin A, but doesnot give rise to abnormally high serum concentration;manufacturer advises use only if potential benefitoutweighs riskBreast-feeding use with caution—present in milkSide-effects loose stools; yellow discoloration of skin;rarely, bruising, arthralgiaLicensed use not licensed for use in UKIndication and doseManagement of photosensitivity reactions inerythropoietic protoporphyria (specialist useonly). By mouthChild 1–5 years 60–90 mg daily in single ordivided dosesChild 5–9 years 90–120 mg daily in single ordivided dosesChild 9–12 years 120–150 mg daily in single ordivided dosesChild 12–16 years 150–180 mg daily in single ordivided dosesChild 16–18 years 180–300 mg daily in single ordivided dosesNote Protection not total—avoid strong sunlight and usesunscreen preparations; generally 2–6 weeks of treatment(resulting in yellow coloration of palms and soles) necessarybefore increasing exposure to sunlight; dose should beadjusted according to level of exposure to sunlightBetacarotene (Non-proprietary)Capsules, 15 mg, 25 mg are available from ‘specialorder’manufacturers or specialist importing companies,see p. 809. Label: 2113.8.2 CamouflagersDisfigurement of the skin can be very distressing andmay have a marked psychological effect, especially inchildren. Cosmetic preparations may be used to camouflageunsightly scars, skin deformities, and pigmentabnormalities, such as vitiligo and birthmarks.Opaque cover foundation or cream is used to mask skinpigment abnormalities; careful application using a combinationof dark- and light-coloured cover creams setwith powder helps to minimise the appearance of skindeformities.Borderline substances The preparations marked‘ACBS’ cannot be prescribed on the NHS for postoperativescars and other deformities except as adjunctivetherapy in the relief of emotional disturbances due todisfiguring skin disease, such as vitiligo.Covermark c (Derma UK)Classic foundation (masking cream), net price 15 g (10shades) = £11.32. ACBSExcipients include beeswax, hydroxybenzoates (parabens), fragranceFinishing powder, net price 25 g = £11.32. ACBSExcipients include beeswax, hydroxybenzoates (parabens), fragranceDermacolor c (Fox)Camouflage creme, (100 shades), net price 25 mL = £9.96.ACBSExcipients include beeswax, butylated hydroxytoluene, fragrance, propyleneglycol, stearyl alcohol, wool fatFixing powder, (7 shades), net price 60 g = £8.45. ACBSExcipients include fragranceKeromask c (Lornamead)Masking cream, (9 shades), net price 15 mL = £5.68. ACBSExcipients include butylated hydroxyanisole, hydroxybenzoates (parabens),wool fat, propylene glycolFinishing powder, net price 20 g = £5.68. ACBSExcipients include butylated hydroxytoluene, hydroxybenzoates (parabens)Veil c (Thomas Blake)Cover cream (40 shades), net price 19 g = £20.63, 44 g =£30.68, 70 g = £38.74. ACBSExcipients include hydroxybenzoates (parabens), wool fat derivativeFinishing powder, translucent, net price 35 g = £22.62. ACBSExcipients include butylated hydroxyanisole, hydroxybenzoates (parabens)13.9 Shampoos and otherpreparations for scalpconditionsThe detergent action of shampoo removes grease(sebum) from hair. Prepubertal children produce verylittle grease and require shampoo less frequently thanadults. Shampoos can be used as vehicles for medicinalproducts, but their usefulness is limited by the short time13 Skin

584 13.9 Shampoos and other preparations for scalp conditions BNFC 2011–201213 Skinthe product is in contact with the scalp and by theirirritant nature.Oils and ointments are very useful for scaly, dry scalpconditions; if a greasy appearance is cosmetically unacceptable,the preparation may be applied at night andwashed out in the morning. Alcohol-based lotions arerarely used in children; alcohol causes painful stingingon broken skin and the fumes may exacerbate asthma.Itchy, inflammatory, eczematous scalp conditions maybe relieved by a simple emollient oil such as olive oil orcoconut oil (arachis oil (ground nut oil, peanut oil) isbest avoided in children under 5 years). In more severecases a topical corticosteroid (section 13.4) may berequired. Preparations containing coal tar are used forthe common scaly scalp conditions of childhood includingseborrhoeic dermatitis, dandruff (a mild form ofseborrhoeic dermatitis), and psoriasis (section 13.5.2);salicylic acid is used as a keratolytic in some scalppreparations.Shampoos containing antimicrobials such as seleniumsulphide or ketoconazole are used for seborrhoeicdermatitis and dandruff in which yeast infection hasbeen implicated, and for tinea capitis (ringworm of thescalp, section 13.10.2). Bacterial infection affecting thescalp (usually secondary to eczema, head lice, or ringworm)may be treated with shampoos containing antimicrobialssuch as pyrithione zinc, cetrimide, orpovidone–iodine.In neonates and infants, cradle cap (which is also a formof seborrhoeic eczema) can be treated by massagingcoconut oil or olive oil into the scalp; a bland emollientsuch as emulsifying ointment can be rubbed onto theaffected area once or twice daily before bathing and amild shampoo used.Shampoos1Ketoconazole (Non-proprietary) ACream—section 13.10.2Shampoo, ketoconazole 2%, net price 120 mL =£3.53Excipients include imidureaBrands include Dandrazol c 2% Shampoo, Nizoral cDoseSeborrhoeic dermatitis and dandruffTreatment, apply twice weekly for 2–4 weeks; prophylaxis,apply once every 1–2 weeks; leave preparation onfor 3–5 minutes before rinsingPityriasis versicolorTreatment, apply once daily for max. 5 days; prophylaxis,apply once daily for up to 3 days before sun exposure;leave preparation on for 3–5 minutes before rinsing1. Can be sold to the public for the prevention and treatment ofdandruff and seborrhoeic dermatitis of the scalp as ashampoo formulation containing ketoconazole max. 2%, in apack containing max. 120 mL and labelled to show a max.frequency of application of once every 3 daysAlphosyl 2 in 1 c (GSK Consumer Healthcare)Shampoo, alcoholic coal tar extract 5%, net price125 mL = £1.81, 250 mL = £3.43Excipients include hydroxybenzoates (parabens), fragranceDoseDandruffUse once or twice weekly as necessaryPsoriasis, seborrhoeic dermatitis, scaling and itchingUse every 2–3 daysCapasal c (Dermal)Shampoo, coal tar 1%, coconut oil 1%, salicylic acid0.5%, net price 250 mL = £4.69Excipients none as listed in section 13.1.3DoseScaly scalp disorders including psoriasis, seborrhoeicdermatitis, dandruff, and cradle capApply daily as necessaryCeanel Concentrate c (Ferndale)Shampoo, cetrimide 10%, undecenoic acid 1%, netprice 150 mL = £3.40, 500 mL = £9.80Excipients none as listed in section 13.1.3DoseScalp psoriasis, seborrhoeic dermatitis, dandruffApply 3 times in first week then twice weeklyDermax c (Dermal)Shampoo, benzalkonium chloride 0.5%, net price250 mL = £5.69Excipients none as listed in section 13.1.3DoseSeborrhoeic scalp conditions associated with dandruffand scalingApply as necessaryMeted c (Alliance)Shampoo, salicylic acid 3%, sulphur 5%, net price120 mL = £3.80Excipients include fragranceNote may be difficult to obtainDoseScaly scalp disorders including psoriasis, seborrhoeicdermatitis, and dandruffApply at least twice weeklyPentrax c (Alliance)Shampoo, coal tar 4.3%, net price 120 mL = £3.80Excipients none as listed in section 13.1.3Note may be difficult to obtainDoseScaly scalp disorders including psoriasis, seborrhoeicdermatitis, and dandruffApply at least twice weeklyPsoriderm c (Dermal)Scalp lotion (= shampoo), coal tar 2.5%, lecithin0.3%, net price 250 mL = £4.74Excipients include disodium edetateDoseScalp psoriasisUse as necessarySelsun c (Chattem UK)Shampoo, selenium sulphide 2.5%, net price 50 mL =£1.44, 100 mL = £1.96, 150 mL = £2.75Excipients include fragranceCautions avoid using 48 hours before or after applying haircolouring, straightening or waving preparationsDoseSeborrhoeic dermatitis and dandruffChild 5–18 years apply twice weekly for 2 weeks thenonce weekly for 2 weeks and then as necessaryPityriasis versicolor [unlicensed indication]Child 5–18 years apply to affected area and leave on for10 minutes before rinsing off; apply once daily for 7 days;repeat course if necessaryNote diluting with a small amount of water prior toapplication can reduce irritation

BNFC 2011–2012 13.10 Anti-infective skin preparations 585T/Gel c (J&J)Shampoo, coal tar extract 2%, net price 125 mL =£3.18, 250 mL = £4.78Excipients include fragrance, hydroxybenzoates (parabens), imidurea,tetrasodium edetateDoseScalp psoriasis, seborrhoeic dermatitis, dandruffApply 2–3 times weeklyOther scalp preparationsCocois cSection 13.5.2Polytar c (Stiefel)Liquid, arachis (peanut) oil extract of coal tar 0.3%,cade oil 0.3%, coal tar solution 0.1%, oleyl alcohol 1%,tar 0.3%, net price 250 mL = £2.23Excipients include fragrance, imidurea, polysorbate 80DoseScalp disorders including psoriasis, seborrhoea,eczema, pruritus, and dandruffApply 1–2 times weeklyPolytar Plus c (Stiefel)Liquid, ingredients as Polytar c liquid with hydrolysedanimal protein 3%, net price 500 mL = £3.91Excipients include fragrance, imidurea, polysorbate 80DoseScalp disorders including psoriasis, seborrhoea,eczema, pruritus, and dandruffApply 1–2 times weekly13.10 Anti-infective skinpreparations13.10.1 Antibacterial preparations13.10.2 Antifungal preparations13.10.3 Antiviral preparations13.10.4 Parasiticidal preparations13.10.5 Preparations for minor cuts andabrasions13.10.1 AntibacterialpreparationsTopical antibacterial preparations are used to treatlocalised bacterial skin infections caused by Gram-positiveorganisms (particularly by staphylococci or streptococci).Systemic antibacterial treatment (Table 1, section5.1) is more appropriate for deep-seated skininfections.Problems associated with the use of topical antibacterialsinclude bacterial resistance, contact sensitisation,and superinfection. In order to minimise the developmentof resistance, antibacterials used systemically (e.g.fusidic acid) should not generally be chosen for topicaluse. Resistant organisms are more common in hospitals,and whenever possible swabs should be taken for bacteriologicalexamination before beginning treatment.Neomycin applied topically may cause sensitisationand cross-sensitivity with other aminoglycoside antibacterialssuch as gentamicin may occur. Topical antibacterialsapplied over large areas can cause systemictoxicity; ototoxicity with neomycin and with polymyxinsis a particular risk for neonates and children withrenal impairment.Superficial bacterial infection of the skin may be treatedwith a topical antiseptic such as povidine–iodine (section13.11.4) which also softens crusts, or hydrogenperoxide 1% cream (section 13.11.6).Bacterial infections such as impetigo and folliculitis canbe treated with a short course of topical fusidic acid;mupirocin should be used only to treat meticillin-resistantStaphylococcus aureus.For extensive or long-standing impetigo, an oral antibacterialsuch as flucloxacillin (or clarithromycin inchildren with penicillin-allergy), Table 1, section 5.1,should be used. A mild antiseptic may help to softencrusts. Mild antiseptics may be useful in reducing thespread of infection, but there is little evidence to supportthe use of topical antiseptics alone in the treatment ofimpetigo.Cellulitis, a rapidly spreading deeply seated inflammationof the skin and subcutaneous tissue, requires systemicantibacterial treatment (see Table 1, section 5.1).Lower leg infections or infections spreading aroundwounds are almost always cellulitis. Erysipelas, a superficialinfection with clearly defined edges (and oftenaffecting the face), is also treated with a systemic antibacterial(see Table 1, section 5.1).Staphylococcal scalded-skin syndrome requires urgenttreatment with a systemic antibacterial, such as flucloxacillin(see Table 1, section 5.1).Mupirocin is not related to any other antibacterial inuse; it is effective for skin infections, particularly thosedue to Gram-positive organisms but it is not indicatedfor pseudomonal infection. Although Staphylococcusaureus strains with low-level resistance to mupirocinare emerging, it is generally useful in infections resistantto other antibacterials. To avoid the development ofresistance, mupirocin or fusidic acid should not beused for longer than 10 days and local microbiologyadvice should be sought before using it in hospital. Inthe presence of mupirocin-resistant MRSA infection, atopical antiseptic, such as povidone–iodine, chlorhexidine,or alcohol, can be used (section 13.11); their useshould be discussed with the local microbiologist.Mupirocin ointment contains macrogols; extensiveabsorption of macrogols through the mucous membranesor through application to thin or damaged skinmay result in renal toxicity, especially in neonates.Mupirocin nasal ointment is formulated in a paraffinbase and may be more suitable for the treatment ofMRSA-infected open wound in neonates.Metronidazole gel is used topically in children toreduce the odour associated with anaerobic infectionsand for the treatment of periorificial rosacea (section13.6); oral metronidazole (section 5.1.11) is used to treatwounds infected with anaerobic bacteria.Retapamulin can be used for impetigo and other superficialbacterial skin infections caused by Staphylococcusaureus and Streptococcus pyogenes that are resistant tofirst-line topical antibacterials. However, it is not effectiveagainst MRSA. The Scottish Medicines Consortium13 Skin

586 13.10.1 Antibacterial preparations BNFC 2011–201213 Skin(p. 3) has advised (March 2008) that retapamulin(Altargo c ) is not recommended for use within NHSScotland for the treatment of superficial skin infections.Silver sulfadiazine is licensed for the prevention andtreatment of infection in burns but the use of appropriatedressings may be more effective. Systemic effectsmay occur following extensive application of silversulfadiazine; its use is not recommended in neonates.13.10.1.1 Antibacterial preparations onlyused topicallyMUPIROCINRenal impairment manufacturer advises cautionwhen Bactroban c ointment used in moderate orsevere impairment because it contains macrogols(polyethylene glycols)Pregnancy manufacturer advises avoid unless potentialbenefit outweighs risk—no information availableBreast-feeding no information availableSide-effects local reactions including urticaria, pruritus,burning sensation, rashLicensed use Bactroban c ointment licensed for usein children (age range not specified by manufacturer);Bactroban c cream not recommended foruse in children under 1 yearIndication and doseBacterial skin infections (see also notes above)Child 1 month–18 years apply up to 3 times dailyfor up to 10 daysBactroban c (GSK) ACream, mupirocin (as mupirocin calcium) 2%, netprice 15 g = £4.38Excipients include benzyl alcohol, cetyl alcohol, stearyl alcoholOintment, mupirocin 2%, net price 15 g = £4.38Excipients none as listed in section 13.1.3Nasal ointment—section 12.2.3NEOMYCIN SULPHATECautions large areas—if large areas of skin are beingtreated ototoxicity may be a hazard in children, particularlyin those with renal impairmentContra-indications neonatesRenal impairment see Cautions aboveSide-effects sensitisation (see also notes above)Licensed use Neomycin Cream BPC—no informationavailableIndication and doseBacterial skin infections see under preparationNeomycin Cream BPC AUCream, neomycin sulphate 0.5%, cetomacrogolemulsifying ointment 30%, chlorocresol 0.1%,disodium edetate 0.01%, in freshly boiled and cooledpurified water, net price 15 g = £2.17Excipients include cetostearyl alcohol, edetic acid (EDTA)DoseApply up to 3 times daily (short-term use)POLYMYXINSCautions large areas—if large areas of skin are beingtreated nephrotoxicity and neurotoxicity may be ahazard, particularly in children with renal impairmentRenal impairment see Cautions aboveSide-effects sensitisation (see also notes above)Licensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseBacterial skin infections see under preparationPolyfax c (TEVA UK) AOintment, polymyxin B sulphate 10 000 units, bacitracinzinc 500 units/g, net price 4 g = £3.26, 20 g =£4.62Excipients none as listed in section 13.1.3DoseApply twice daily or more frequently if requiredRETAPAMULINContra-indications contact with eyes and mucousmembranesSide-effects local reactions including irritation,erythema, pain, contact dermatitis, and pruritusIndication and doseSuperficial bacterial skin infections (but see alsonotes above)Child 9 months–18 years apply thinly twice dailyfor 5 days; max. area of skin treated 2% of bodysurface area; review treatment if no responsewithin 2–3 daysAltargo c (GSK) TAOintment, retapamulin 1%, net price 5 g = £7.89.Label: 28Excipients include butylated hydroxytolueneSILVER SULFADIAZINE(Silver sulphadiazine)Cautions G6PD deficiency; may inactivate enzymaticdebriding agents—concomitant use may be inappropriate;interactions: Appendix 1 (sulfonamides)Large areas Plasma-sulfadiazine concentrations mayapproach therapeutic levels with side-effects and interactionsas for sulfonamides (see section 5.1.8) if large areas of skinare treated. Owing to the association of sulfonamides withsevere blood and skin disorders, treatment should bestopped immediately if blood disorders or rashes develop—but leucopenia developing 2–3 days after starting treatmentof burns patients is reported usually to be self-limiting andsilver sulfadiazine need not usually be discontinued providedblood counts are monitored carefully to ensure return tobaseline within a few days. Argyria may also occur if largeareas of skin are treated (or if application is prolonged).Contra-indications sensitivity to sulfonamides; notrecommended for neonatesHepatic impairment manufacturer advises caution ifsignificant impairment; see also Large areas, aboveRenal impairment manufacturer advises caution ifsignificant impairment; see also Large areas, abovePregnancy risk of neonatal haemolysis andmethaemoglobinaemia in third trimesterBreast-feeding small risk of kernicterus in jaundicedinfants and of haemolysis in G6PD deficient infantsSide-effects allergic reactions including burning,itching and rashes; argyria reported following pro-

BNFC 2011–2012 13.10.1 Antibacterial preparations 587longed use; leucopenia reported (monitor bloodcount)Licensed use no age range specified by manufacturerbut see contra-indications, aboveIndication and doseProphylaxis and treatment of infection in burnwounds, for conservative management of finger-tipinjuries see under preparation belowAdjunct to short-term treatment of infection inpressure sores, adjunct to prophylaxis ofinfection in skin graft donor sites and extensiveabrasions consult product literature for detailsFlamazine c (S&N Hlth.) ACream, silver sulfadiazine 1%, net price 20 g = £2.91,50 g = £3.85, 250 g = £10.32, 500 g = £18.27Excipients include cetyl alcohol, polysorbates, propylene glycolDoseBurnsChild 1 month–18 years apply daily or more frequentlyif very exudativeFinger-tip injuriesChild 1 month–18 years apply every 2–3 daysNote apply with sterile applicator13.10.1.2 Antibacterial preparations alsoused systemicallySodium fusidate is a narrow-spectrum antibacterialused for staphylococcal infections. For the role of sodiumfusidate in the treatment of impetigo see p. 585.Metronidazole is used topically to treat rosacea and toreduce the odour associated with anaerobic infections;oral metronidazole (section 5.1.11) is used to treatwounds infected with anaerobic bacteria.Angular cheilitis An ointment containing sodiumfusidate is used in the fissures of angular cheilitiswhen associated with staphylococcal infection. Forfurther information on angular cheilitis, see p. 545.FUSIDIC ACIDCautions see notes above; avoid contact with eyesSide-effects rarely hypersensitivity reactionsLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseStaphylococcal skin infectionsApply 3–4 times daily, usually for 7 daysPenicillin-resistant staphylococcal infectionssection 5.1.7Staphylococcal eye infectionssection 11.3.1Fucidin c (LEO) ACream, fusidic acid 2%, net price 15 g = £1.92, 30 g =£3.64Excipients include butylated hydroxyanisole, cetyl alcoholOintment, sodium fusidate 2%, net price 15 g = £2.23,30 g = £3.79Excipients include cetyl alcohol, wool fatDental prescribing on NHS May be prescribed as SodiumFusidate ointmentMETRONIDAZOLECautions avoid exposure to strong sunlight or UV lightSide-effects skin irritationLicensed use Acea c and Anabact c not licensed foruse in children under 12 years; Noritate c notlicensed for use in children under 16 years;Metrogel c , Metrosa c , Rosiced c , Rozex c , andZyomet c not licensed for use in childrenIndication and doseMalodorous tumours and woundsFor dose see preparationsRosacea (see also section 13.6)For dose see preparationsHelicobacter pylori eradicationsection 1.3Anaerobic infectionssection 5.1.11 and section 7.2.2Protozoal infectionssection 5.4.2Acea c (Ferndale) AGel, metronidazole 0.75%, net price 40 g = £9.95Excipients include disodium edetate, hydroxybenzoates (parabens)DoseAcute inflammatory exacerbations of rosaceaChild 1–18 years apply thinly twice dailyAnabact c (CHS) AGel, metronidazole 0.75%, net price 15 g = £4.47, 30 g= £7.89Excipients include hydroxybenzoates (parabens), propylene glycolDoseMalodorous fungating tumours and skin ulcersApply to clean wound 1–2 times daily and cover withnon-adherent dressingMetrogel c (Galderma) AGel, metronidazole 0.75%, net price 40 g = £6.86Excipients include hydroxybenzoates (parabens), propylene glycolDoseAcute inflammatory exacerbations of rosaceaChild 1–18 years apply thinly twice dailyMalodorous fungating tumoursApply to clean wound 1–2 times daily and cover withnon-adherant dressingMetrosa c (Linderma) AGel, metronidazole 0.75%, net price 40 g = £19.90Excipients include propylene glycolDoseAcute exacerbation of rosaceaChild 1–18 years apply thinly twice daily13 Skin

588 13.10.2 Antifungal preparations BNFC 2011–201213 SkinRosiced c (Fabre) ACream, metronidazole 0.75%, net price 30 g = £7.50Excipients include propylene glycolDoseInflammatory papules and pustules of rosaceaChild 1–18 years apply twice daily for 6 weeks (longer ifnecessary)Rozex c (Galderma) ACream, metronidazole 0.75%, net price 40 g = £6.86Excipients include benzyl alcohol, isopropyl palmitateGel, metronidazole 0.75%, net price 40 g = £6.86Excipients include disodium edetate, hydroxybenzoates (parabens),propylene glycolDoseInflammatory papules, pustules and erythema ofrosaceaChild 1–18 years apply twice dailyZyomet c (Goldshield) AGel, metronidazole 0.75%, net price 30 g = £12.00Excipients include benzyl alcohol, disodium edetate, propylene glycolDoseAcute inflammatory exacerbations of rosaceaChild 1–18 years apply thinly twice daily13.10.2 Antifungal preparationsMost localised fungal infections are treated with topicalpreparations. To prevent relapse, local antifungal treatmentshould be continued for 1–2 weeks after thedisappearance of all signs of infection. Systemic therapy(section 5.2) is necessary for nail or scalp infection or ifthe skin infection is widespread, disseminated or intractable.Specimens of scale, nail or hair should be sent formycological examination before starting treatment,unless the diagnosis is certain.Dermatophytoses Ringworm infection can affect thescalp (tinea capitis), body (tinea corporis), groin (tineacruris), hand (tinea manuum), foot (tinea pedis, athlete’sfoot), or nail (tinea unguium, onychomycosis). Tineacapitis is a common childhood infection that requiressystemic treatment with an oral antifungal (section 5.2);additional application of a topical antifungal, during theearly stages of treatment, may reduce the risk of transmission.A topical antifungal can also be used to treatasymptomatic carriers of scalp ringworm.Tinea corporis and tinea pedis infections in childrenrespond to treatment with a topical imidazole (clotrimazole,econazole, ketoconazole, or miconazole) or terbinafinecream. Nystatin is less effective against tinea.Compound benzoic acid ointment (Whitfield’s ointment)has been used for ringworm infections but it iscosmetically less acceptable than proprietary preparations.Antifungal dusting powders are of little therapeuticvalue in the treatment of fungal skin infections andmay cause skin irritation; they may have some role inpreventing re-infection.Antifungal treatment may not be necessary in asymptomaticchildren with tinea infection of the nails. If treatmentis necessary, a systemic antifungal (section 5.2) ismore effective than topical therapy. However, topicalapplication of tioconazole may be useful for treatingearly onychomycosis when involvement is limited tomild distal disease in up to 2 nails, or for superficialwhite onychomycosis, or where there are contra-indicationsto systemic therapy. Chronic paronychia on thefingers (usually due to a candidal infection) should betreated with topical clotrimazole or nystatin, but thesepreparations should be used with caution in childrenwho suck their fingers. Chronic paronychia of the toes(usually due to dermatophyte infection) can be treatedwith topical terbinafine.Pityriasis versicolor Pityriasis (tinea) versicolor canbe treated with ketoconazole shampoo or seleniumsulphide shampoo (section 13.9). Topical imidazoleantifungals such as clotrimazole, econazole, ketoconazole,and miconazole, or topical terbinafine are alternatives,but large quantities may be required.If topical therapy fails, or if the infection is widespread,pityriasis versicolor is treated systemically with an azoleantifungal (section 5.2). Relapse is common, especiallyin the immunocompromised.Candidiasis Candidal skin infections can be treatedwith topical imidazole antifungals clotrimazole, econazole,ketoconazole, or miconazole; topical terbinafineis an alternative. Topical application of nystatin isalso effective for candidiasis but it is ineffective againstdermatophytosis. Refractory candidiasis requires systemictreatment (section 5.2.1) generally with a triazolesuch as fluconazole; systemic treatment with griseofulvinor terbinafine is not appropriate for refractorycandidiasis. For the treatment of oral candiasis seesection 12.3.2 and for the management of nappy rashsee section 13.2.2.Angular cheilitis Miconazole cream is used in thefissures of angular cheilitis when associated with Candida.For further information on angular cheilitis, seep. 545.Cautions Contact with eyes and mucous membranesshould be avoided.Side-effects Occasional local irritation and hypersensitivityreactions include mild burning sensation,erythema, and itching. Treatment should be discontinuedif symptoms are severe.Compound topical preparations Combination of animidazole and a mild corticosteroid (such as hydrocortisone1%) (section 13.4) may be of value in the treatmentof eczematous intertrigo and, in the first few days only,of a severely inflamed patch of ringworm. Combinationof a mild corticosteroid with either an imidazole ornystatin may be of use in the treatment of intertriginouseczema associated with candida.AMOROLFINECautions see notes above; also avoid contact withears; use with caution in child likely to suck affecteddigitsPregnancy systemic absorption very low, but manufactureradvises avoid—no information availableBreast-feeding manufacturer advises avoid—noinformation availableSide-effects see notes aboveLicensed use not licensed for use in children under12 years

BNFC 2011–2012 13.10.2 Antifungal preparations 589Indication and doseFungal nail infectionsApply to infected nails 1–2 times weekly after filingand cleansing; allow to dry (approx. 3 minutes);treat finger nails for 6 months, toe nails for 9–12months (review at intervals of 3 months); avoid nailvarnish or artificial nails during treatmentLoceryl c (Galderma) ANail lacquer, amorolfine (as hydrochloride) 5%, netprice 5-mL pack (with nail files, spatulas, and cleansingswabs) = £18.17. Label: 10, patient informationleafletExcipients none as listed in section 13.1.3BENZOIC ACIDLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseRingworm (tinea) but see notes above; dose underpreparationWith salicylic acidFor prescribing information on salicylic acid, seep. 571Benzoic Acid Ointment, Compound, BP(Whitfield’s ointment)Ointment, benzoic acid 6%, salicylic acid 3%, inemulsifying ointmentExcipients include cetostearyl alcoholDoseChild 1 month–18 years apply twice dailyCLOTRIMAZOLECautions see notes abovePregnancy minimal absorption from skin; not knownto be harmfulSide-effects see notes aboveLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseFungal skin infectionsApply 2–3 times dailyVaginal candidiasis section 7.2.2Otitis externa section 12.1.1Clotrimazole (Non-proprietary)Cream, clotrimazole 1%, net price 20 g = £1.52Canesten c (Bayer Consumer Care)Cream, clotrimazole 1%, net price 20 g = £2.14, 50 g =£3.50Excipients include benzyl alcohol, cetostearyl alcohol, polysorbate 60Solution, clotrimazole 1% in macrogol 400 (polyethyleneglycol 400), net price 20 mL = £2.43. Forhairy areasExcipients none as listed in section 13.1.3Spray, clotrimazole 1%, in 30% isopropyl alcohol, netprice 40-mL atomiser = £4.99. Label: 15. For large orhairy areasExcipients include propylene glycolECONAZOLE NITRATECautions see notes abovePregnancy minimal absorption from skin; not knownto be harmfulSide-effects see notes aboveLicensed use Pevaryl c , no age range specified bymanufacturerIndication and doseFungal skin infectionsApply twice dailyFungal nail infectionsApply once daily under occlusive dressingVaginal candidiasis section 7.2.2Pevaryl c (Janssen)Cream, econazole nitrate 1%, net price 30 g = £2.65Excipients include butylated hydroxyanisole, fragranceKETOCONAZOLECautions see notes above; do not use within 2 weeksof a potent topical corticosteroid for seborrhoeicdermatitis—risk of skin sensitisationSide-effects see notes aboveIndication and doseTinea pedisApply twice dailyOther fungal infectionsApply 1–2 times dailySystemic or resistant fungal infections section5.2.2Vulval candidiasis section 7.2.2Nizoral c (Janssen) A1Cream, ketoconazole 2%, net price 30 g = £3.40Excipients include cetyl alcohol, polysorbates, propylene glycol, stearylalcoholNote A 15-g tube is available for sale to the public for thetreatment of tinea pedis, tinea cruris, and candidal intertrigoShampoo—section 13.91. D except for seborrhoeic dermatitis and pityriasisversicolor and endorsed ‘SLS’MICONAZOLE NITRATECautions see notes aboveSide-effects see notes aboveLicensed use Licensed for use in children (age rangenot specified by manufacturer)Indication and doseFungal skin infectionsNeonate apply twice daily continuing for 10 daysafter lesions have healedChild 1 month–18 years apply twice daily continuingfor 10 days after lesions have healedFungal nail infectionsApply 1–2 times daily13 Skin

590 13.10.2 Antifungal preparations BNFC 2011–2012Oral and intestinal fungal infections section12.3.2Vaginal candidiasis section 7.2.2Miconazole (Non-proprietary)Cream, miconazole nitrate 2%, net price 20 g = £2.05,45 g = £1.97Dental prescribing on NHS Miconazole cream may beprescribedDaktarin c (Janssen)Cream, miconazole nitrate 2%, net price 30 g = £1.82Excipients include butylated hydroxyanisoleNYSTATINCautions see notes aboveSide-effects see notes aboveLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseSkin infections due to Candida spp. for dose, seepreparationOral fungal infections section 12.3.2Nystaform c (Typharm) ACream, nystatin 100 000 units/g, chlorhexidinehydrochloride 1%, net price 30 g = £2.62Excipients include benzyl alcohol, cetostearyl alcohol, polysorbate 60DoseApply 2–3 times daily continuing for 7 days after lesionshave healed.Breast-feeding manufacturer advises avoid—presentin milk, but less than 5% of the dose is absorbed aftertopical application of terbinafine; avoid application tomother’s chestSide-effects see notes aboveLicensed use not licensed for use in childrenIndication and doseFungal skin infectionsApply thinly 1–2 times daily for up to 1 week intinea pedis, 1–2 weeks in tinea corporis and tineacruris, 2 weeks in cutaneous candidiasis and pityriasisversicolor; review after 2 weeksSystemic therapy section 5.2.51Terbinafine (Non-proprietary) ACream, terbinafine hydrochloride 1%, net price 15 g =£5.10, 30 g = £2.691. Can be sold to the public for external use in children over 16years for the treatment of tinea pedis and tinea cruris as acream containing terbinafine hydrochloride max. 1% in apack containing max. 15 g; also for the treatment of tineapedis, tinea cruris, and tinea corporis as a spray containingterbinafine hydrochloride max. 1% in a pack containing max.30 mL or as a gel containing terbinafine hydrochloride max.1% in a pack containing max. 30 gLamisil c (Novartis Consumer Health) ACream, terbinafine hydrochloride 1%, net price 15 g =£4.86, 30 g = £8.76Excipients include benzyl alcohol, cetyl alcohol, polysorbate 60, stearylalcohol13 SkinSALICYLIC ACIDCautions avoid broken or inflammed skinSalicylate toxicity Salicylate toxicity can occur particularlyif applied on large areas of skinSide-effects see notes aboveIndication and doseFungal nail infections, particularly tineaChild 5–18 years apply twice daily and afterwashingNote Use with caution in child likely to suck affecteddigitsHyperkeratotic skin disorders section 13.5.2Acne vulgaris section 13.6.1Warts and calluses section 13.7Phytex c (Wynlit) UPaint, salicylic acid 1.46% (total combined), tannicacid 4.89% and boric acid 3.12% (as borotanniccomplex), in a vehicle containing alcohol and ethylacetate, net price 25 mL (with brush) = £2.81Excipients none as listed in section 13.1.3Note FlammableTERBINAFINECautions avoid contact with eyesPregnancy manufacturer advises use only if potentialbenefit outweighs risk—animal studies suggest noadverse effectsTIOCONAZOLECautions see notes above; also use with caution ifchild likely to suck affected digitsPregnancy manufacturer advises avoidSide-effects see notes above; also local oedema, dryskin, nail discoloration, periungual inflammation, nailpain, rash, exfoliationLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseFungal nail infectionsApply to nails and surrounding skin twice daily forup to 6 months (may be extended to 12 months)Trosyl c (Pfizer) ACutaneous solution, tioconazole 28%, net price12 mL (with applicator brush) = £27.38Excipients none as listed in section 13.1.3UNDECENOATESSide-effects see notes aboveLicensed use Monphytol c not licensed for use inchildren under 12 years; Mycota c licensed for usein children (age range not specified by manufacturer)Indication and doseSee under preparations

BNFC 2011–2012 13.10.3 Antiviral preparations 591Mycota c (Thornton & Ross)Cream, zinc undecenoate 20%, undecenoic acid 5%,net price 25 g = £1.64Excipients include fragranceDoseTreatment of athlete’s footApply twice daily continuing for 7 days after lesions havehealedPrevention of athlete’s footApply once dailyPowder, zinc undecenoate 20%, undecenoic acid 2%,net price 70 g = £2.22Excipients include fragranceDoseTreatment of athlete’s footApply twice daily continuing for 7 days after lesions havehealedPrevention of athlete’s footApply once dailySpray application, undecenoic acid 3.9%, dichlorophen0.4% (pressurised aerosol pack), net price100 mL = £2.46Excipients include fragranceDoseTreatment of athlete’s footApply twice daily continuing for 7 days after lesions havehealedPrevention of athlete’s footApply once daily13.10.3 Antiviral preparationsSee section 12.3.2 for drugs used in herpetic stomatitis,section 13.5.1 for eczema herpeticum, and section11.3.3 for viral infections of the eye.Aciclovir cream is used for the treatment of initial andrecurrent labial, cutaneous, and genital herpes simplexinfections in children; treatment should begin as early aspossible. Systemic treatment is necessary for buccal orvaginal infections or if cold sores recur frequently (fordetails of systemic use see section 5.3.2.1).Herpes labialis Aciclovir cream can be used for thetreatment of initial and recurrent labial herpes simplexinfections (cold sores). It is best applied at the earliestpossible stage, usually when prodromal changes ofsensation are felt in the lip and before vesicles appear.Penciclovir cream is also licensed for the treatment ofherpes labialis; it needs to be applied more frequentlythan aciclovir cream. These creams should not be usedin the mouth.ACICLOVIR(Acyclovir)Cautions avoid contact with eyes and mucous membranesPregnancy not known to be harmful—manufacturersadvise use only when potential benefit outweighs risk;limited absorption from topical aciclovir preparationsSide-effects transient stinging or burning; occasionallyerythema, itching or drying of the skinLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseHerpes simplex infectionsApply to lesions every 4 hours (5 times daily) for 5–10 days, starting at first sign of attackHerpes simplex and varicella–zoster infectionssection 5.3.2.1Eye infections section 11.3.31Aciclovir (Non-proprietary) ACream, aciclovir 5%, net price 2 g = £1.10, 10 g =£1.81Excipients include propylene glycolBrands include Zuvogen c (excipients include cetyl alcohol,propylene glycol)Dental prescribing on NHS Aciclovir Cream may beprescribed1. A 2-g tube and a pump pack are on sale to the public for thetreatment of cold soresZovirax c (GSK) ACream, aciclovir 5%, net price 2 g = £4.63, 10 g =£13.96Excipients include cetostearyl alcohol, propylene glycolPENCICLOVIRCautions avoid contact with eyes and mucous membranesSide-effects transient stinging, burning, numbness;hypersensitivity reactions also reportedLicensed use not licensed for use in children under12 yearsVectavir c (Novartis Consumer Health) ACream, penciclovir 1%, net price 2 g = £4.20Excipients include cetostearyl alcohol, propylene glycolDoseHerpes labialisApply to lesions every 2 hours during waking hours for 4days, starting at first sign of attackDental prescribing on NHS May be prescribed as PenciclovirCream13.10.4 Parasiticidal preparationsSuitable quantities of parasiticidal preparationsScalp (headlice)Skin Lotions Cream rinsescreams— 50–100 mL 50–100 mLBody (scabies) 30–60 g 100 mL —Body (crab lice) 30–60 g 100 mL —These amounts are usually suitable for a child 12–18years for single application13 Skin

592 13.10.4 Parasiticidal preparations BNFC 2011–201213 SkinScabiesPermethrin is used for the treatment of scabies (Sarcoptesscabiei); malathion can be used if permethrin isinappropriate.Benzyl benzoate is an irritant and should be avoided inchildren; it is less effective than malathion and permethrin.Ivermectin (available from ‘special-order’ manufacturersor specialist importing companies, see p. 809),is used in combination with topical drugs, for the treatmentof hyperkeratotic (crusted or ‘Norwegian’) scabiesthat does not respond to topical treatment alone.Application Although acaricides have traditionallybeen applied after a hot bath, this is not necessaryand there is even evidence that a hot bath may increaseabsorption into the blood, removing them from their siteof action on the skin.All members of the affected household should be treatedsimultaneously. Treatment should be applied to thewhole body including the scalp, neck, face, and ears.Particular attention should be paid to the webs of thefingers and toes and lotion brushed under the ends ofnails. Malathion and permethrin should be appliedtwice, one week apart. It is important to warn users toreapply treatment to the hands if they are washed.Children with hyperkeratotic scabies may require 2 or3 applications of acaricide on consecutive days toensure that enough penetrates the skin crusts to killall the mites.Itching The itch and eczema of scabies persists forsome weeks after the infestation has been eliminatedand treatment for pruritus and eczema (section 13.5.1)may be required. Application of crotamiton can be usedto control itching after treatment with more effectiveacaricides. A topical corticosteroid (section 13.4) mayhelp to reduce itch and inflammation after scabies hasbeen treated successfully; however, persistent symptomssuggest failure of scabies eradication. Oral administrationof a sedating antihistamine (section 3.4.1) atnight may also be useful.Head liceDimeticone is effective against head lice (Pediculushumanus capitis) and acts on the surface of the organism.Malathion, an organophosphorous insecticide, isan alternative but resistance has been reported. Benzylbenzoate is licensed for the treatment of head lice but itis not recommended for use in children.Head lice infestation (pediculosis) should be treatedusing lotion or liquid formulations only if live lice arepresent. Shampoos are diluted too much in use to beeffective. A contact time of 8–12 hours or overnighttreatment is recommended for lotions and liquids; a 2-hour treatment is not sufficient to kill eggs.In general, a course of treatment for head lice should be2 applications of a parasiticidal product 7 days apart tokill lice emerging from any eggs that survive the firstapplication. All affected individuals in a householdshould be treated at the same time.Wet combing methods Head lice can be mechanicallyremoved by combing wet hair meticulously with aplastic detection comb (probably for at least 30 minuteseach time) over the whole scalp at 4-day intervals for aminimum of 2 weeks and continued until no lice arefound on 3 consecutive sessions; hair conditioner orvegetable oil can be used to facilitate the process.Several devices for the removal of head lice, such ascombs and topical solutions, are available and some areprescribable on the NHS (consult Drug Tariff—seeAppliances and Reagents, p. 797 for links to onlineDrug Tariffs).Crab licePermethrin and malathion are used to eliminate crablice (Pthirus pubis); permethrin is not licensed for treatmentof crab lice in children under 18 years. An aqueouspreparation should be applied, allowed to dry naturallyand washed off after 12 hours; a second treatment isneeded after 7 days to kill lice emerging from survivingeggs. All surfaces of the body should be treated, includingthe scalp, neck, and face (paying particular attentionto the eyebrows and other facial hair). A differentinsecticide should be used if a course of treatment fails.Parasiticidal preparationsDimeticone coats head lice and interferes with waterbalance in lice by preventing excretion of water; it is lessactive against eggs and treatment should be repeatedafter 7 days.Malathion is recommended for scabies, head lice andcrab lice (see notes above). The risk of systemic effectsassociated with 1–2 applications of malathion is consideredto be very low; however, except in the treatmentof hyperkeratotic scabies (see notes above), applicationsof malathion liquid repeated at intervals of less than 1week or application for more than 3 consecutive weeksshould be avoided since the likelihood of eradication oflice is not increased.Permethrin is effective for scabies. It is active againsthead lice but the formulation and licensed methods ofapplication of the current products make them unsuitablefor the treatment of head lice. Permethrin is alsoeffective against crab lice but it is not licensed for thispurpose in children under 18 years.DIMETICONECautions avoid contact with eyesSide-effects skin irritationLicensed use not licensed for use in children under 6months except under medical supervisionIndication and doseHead liceRub into dry hair and scalp, allow to dry naturally,shampoo after 8 hours (or overnight); repeatapplication after 7 daysHedrin c (Thornton & Ross)Lotion, dimeticone 4%, net price 50 mL = £2.98, 120-mL spray pack = £7.13, 150 mL = £6.92Note Patients should be told to keep their hair away from fireand flames during treatment

BNFC 2011–2012 13.10.5 Preparations for minor cuts and abrasions 593MALATHIONCautions avoid contact with eyes; do not use onbroken or secondarily infected skin; do not use lotionmore than once a week for 3 consecutive weeks;alcoholic lotions not recommended for head lice inchildren with severe eczema or asthma, or for scabiesor crab lice (see notes above)Side-effects skin irritation and hypersensitivity reactions;chemical burns also reportedLicensed use not licensed for use in children under 6months except under medical supervisionIndication and doseSee notes above and under preparationsPermethrin (Non-proprietary)Cream, permethrin 5%, net price 30 g = £5.43Lyclear c Creme Rinse (Chefaro UK) UCream rinse, permethrin 1% in basis containing isopropylalcohol 20%, net price 59 mL = £2.38, 2 59-mL pack = £4.32Excipients include cetyl alcoholNote Use not recommended, therefore no dose stated (producttoo diluted in use and insufficient contact time)Lyclear c Dermal Cream (Chefaro UK)Dermal cream, permethrin 5%, net price 30 g = £5.71.Label: 10, patient information leafletExcipients include butylated hydroxytoluene, wool fat derivativeHead liceRub into dry hair and scalp, allow to dry naturally,remove by washing after 12 hours; repeat applicationafter 7 days (see also notes above)Crab liceApply over whole body, allow to dry naturally,wash off after 12 hours or overnight; repeatapplication after 7 daysScabiesApply over whole body, and wash off after 24hours; if hands are washed with soap within 24hours, they should be retreated; see also notesabove; repeat application after 7 daysNote For scabies, manufacturer recommends application tothe body but not necessarily to the head and neck. However,application should be extended to the scalp, neck, face, andearsDerbac-M c (SSL)Liquid, malathion 0.5% in an aqueous basis, net price50 mL = £2.37, 200 mL = £5.93Excipients include cetostearyl alcohol, fragrance, hydroxybenzoates(parabens)For crab lice, head lice, and scabiesPERMETHRINCautions avoid contact with eyes; do not use onbroken or secondarily infected skinSide-effects pruritus, erythema, and stinging; rarelyrashes and oedemaLicensed use Dermal Cream (scabies), not licensedfor use in children under 2 months; children aged 2months–2 years, medical supervison required; notlicensed for treatment of crab lice in children under18 years; Creme Rinse (head lice) not licensed foruse in children under 6 months except under medicalsupervisionIndication and doseSee notes aboveScabiesApply 5% preparation over whole body includingface, neck, scalp and ears; wash off after 8–12hours; if hands washed with soap within 8 hours ofapplication, they should be treated again withcream (see notes above); repeat application after 7daysNote Manufacturer recommends application to the bodybut to exclude head and neck. However, applicationshould be extended to the scalp, neck, face, and ears13.10.5 Preparations for minorcuts and abrasionsCetrimide cream is used to treat minor cuts and abrasions.Proflavine cream may be used to treat infectedwounds or burns, but has now been largely supersededby other antiseptics or suitable antibacterials.Cetrimide Cream, BPCream, cetrimide 0.5% in a suitable water-misciblebasis such as cetostearyl alcohol 5%, liquid paraffin50% in freshly boiled and cooled purified water, netprice 50 g = £1.11Proflavine Cream, BPCCream, proflavine hemisulphate 0.1%, yellow beeswax2.5%, chlorocresol 0.1%, liquid paraffin 67.3%,freshly boiled and cooled purified water 25%, wool fat5%, net price 100 mL = £1.59Excipients include beeswax, wool fatNote Stains clothingCollodionFlexible collodion may be used to seal minor cuts andwounds that have partially healed.Collodion, Flexible, BPCollodion, castor oil 2.5%, colophony 2.5% in a collodionbasis, prepared by dissolving pyroxylin (10%) ina mixture of 3 volumes of ether and 1 volume ofalcohol (90%), net price 10 mL = 38p. Label: 15Contra-indications allergy to colophony in elastic adhesiveplasters and tapeSkin tissue adhesiveTissue adhesives are used for closure of minor skinwounds and for additional suture support. They shouldbe applied by an appropriately trained healthcare professional.Skin tissue adhesives may cause skin sensitisation.Dermabond ProPen c (Ethicon)Topical skin adhesive, sterile, octyl 2-cyanoacrylate,net price 0.5 mL = £18.38Epiglu c (Schuco)Tissue adhesive, sterile, ethyl-2-cyanoacrylate954.5 mg/g, polymethylmethacrylate, net price 4 3-g vials = £149.50 (with dispensing pipettes and pallete)13 Skin

594 13.11.1 Alcohols and saline BNFC 2011–2012Histoacryl c (Braun)Tissue adhesive, sterile, enbucrilate, net price 5 200-mg unit (blue) = £32.00, 10 200-mg unit (blue)= £67.20, 5 500-mg unit (clear or blue) = £34.65, 10 500-mg unit (blue) = £69.30LiquiBand c (MedLogic)Tissue adhesive, sterile, enbucrilate, net price 0.5-gamp = £5.5013.11 Skin cleansers,antiseptics, andpreparations forpromotion of woundhealing13.11.1 Alcohols and salineALCOHOLCautions flammable; avoid broken skin; patients havesuffered severe burns when diathermy has been precededby application of alcoholic skin disinfectantsContra-indications neonates, see section 13.1Indication and doseSkin preparation before injectionApply to skin as necessaryIndustrial Methylated Spirit, BPSolution, 19 volumes of ethanol and 1 volumeapproved wood naphtha, net price ‘66 OP’ (containing95% by volume alcohol) 100 mL = 39p; ‘74 OP’(containing 99% by volume alcohol) 100 mL = 39p.Label: 15Surgical Spirit, BPSpirit, methyl salicylate 0.5 mL, diethyl phthalate 2%,castor oil 2.5%, in industrial methylated spirit, netprice 100 mL = 20p. Label: 1513 Skin13.11.1 Alcohols and saline13.11.2 Chlorhexidine salts13.11.3 Cationic surfactants and soaps13.11.4 Iodine13.11.5 Phenolics13.11.6 Oxidisers and dyes13.11.7 Preparations for promotion of woundhealingSoap or detergent is used with water to cleanse intactskin but they can irritate infantile skin; emollient preparationssuch as aqueous cream or emulsifying ointment(section 13.2.1) that do not irritate the skin arebest used in place of soap or detergent for cleansing dryor irritated skin.An antiseptic is used for skin that is infected or that issusceptible to recurrent infection. Detergent preparationscontaining chlorhexidine or povidone–iodine,which should be thoroughly rinsed off, are used. Emollientsmay also contain antiseptics (section 13.2.1).Antiseptics such as chlorhexidine or povidone–iodineare used on intact skin before surgical procedures; theirantiseptic effect is enhanced by an alcoholic solvent.Antiseptic solutions containing cetrimide can be used ifa detergent effect is also required.Preparations containing alcohol and regular use ofpovidone iodine should be avoided on neonatal skin(see section 13.1).Hydrogen peroxide, an oxidising agent, is available as acream and can be used for superficial bacterial skininfections.For irrigating ulcers or wounds, lukewarm sterile sodiumchloride 0.9% solution is used but tap water isoften appropriate.Potassium permanganate solution 1 in 10 000, a mildantiseptic with astringent properties, can be used as asoak for exudative eczematous areas (section 13.5.1);treatment should be stopped when the skin becomesdry. Potassium permanganate can stain skin and nailsespecially with prolonged use.SODIUM CHLORIDEIndication and doseSee notes aboveNebuliser diluent section 3.1.5Sodium depletion section 9.2.1.2Electrolyte imbalance section 9.2.2.1Eye section 11.8.1Oral hygiene section 12.3.4Sodium Chloride (Non-proprietary)Solution (sterile), sodium chloride 0.9%, net price 25 20-mL unit = £5.50, 200–mL can = £2.65, 1 litre =97pFlowfusor c (Fresenius Kabi)Solution (sterile), sodium chloride 0.9%, net price120-mL Bellows Pack = £1.53Irriclens c (ConvaTec)Solution in aerosol can (sterile), sodium chloride0.9%, net price 240-mL can = £3.30Irripod c (C D Medical)Solution (sterile), sodium chloride 0.9%, net price 25 20-mL sachet = £5.50Miniversol c (Aguettant)Solution (sterile), sodium chloride 0.9%, net price 30 45-mL unit = £13.20; 30 100-mL unit = £19.50Normasol c (Mölnlycke)Solution (sterile), sodium chloride 0.9%, net price 25 25-mL sachet = £6.14; 10 100-mL sachet = £7.47Stericlens c (C D Medical)Solution in aerosol can (sterile), sodium chloride0.9%, net price 100-mL can = £1.94, 240-mL can =£2.95

BNFC 2011–2012 13.11.2 Chlorhexidine salts 595Steripod c Sodium Chloride (Medlock)Solution (sterile), sodium chloride 0.9%, net price 25 20-mL sachet = £7.5713.11.2 Chlorhexidine saltsCHLORHEXIDINECautions avoid contact with eyes, brain, meninges andmiddle ear; not for use in body cavities; alcoholicsolutions not suitable before diathermy or for use onneonatal skinSide-effects occasional sensitivityIndication and doseSee under preparationsBladder irrigation and catheter patency solutionssection 7.4.4Chlorhexidine 0.05% (Baxter)2000 Solution (sterile), pink, chlorhexidine acetate0.05%, net price 500 mL = 72p, 1000 mL = 77pFor cleansing and disinfecting wounds and burnsCepton c (LPC)Skin wash (= solution), red, chlorhexidine gluconate1%, net price 150 mL = £2.48For use as skin wash in acneLotion, blue, chlorhexidine gluconate 0.1%, net price150 mL = £2.48For skin disinfection in acneChloraPrep c (CareFusion)Cutaneous solution, sterile, chlorhexidine gluconate2% in isopropyl alcohol 70%, net price (all with singleapplicator) 0.67 mL (with SEPP c applicator) = 30p,1.5 mL (with FREPP c applicator) = 55p, 1.5 mL =78p, 3 mL = 85p, 10.5 mL = £2.92, 26 mL = £6.50; (allwith single applicator, with tint) 3 mL = 90p, 10.5 mL= £3.07, 26 mL = £6.83For skin disinfection before invasive procedures; Child under 2months not recommendedNote FlammableCX Antiseptic Dusting Powder c (Ecolab)Dusting powder, sterile, chlorhexidine acetate 1%,net price 15 g = £3.40For skin disinfectionHibiscrub c (Mölnlycke)Cleansing solution, red, chlorhexidine gluconate 4%,perfumed, in a surfactant solution, net price 250 mL =£4.25, 500 mL = £5.25, 5 litres = £24.00Excipients include fragranceUse instead of soap for pre-operative hand and skin preparationand for general hand and skin disinfectionHibi c Liquid Hand Rub+ (Mölnlycke)Solution, chlorhexidine gluconate 0.5%, in isopropylalcohol 70% with emollients, net price 500 mL = £5.25To be used undiluted for hand and skin disinfectionHibitane Obstetric c (Derma UK)Cream, chlorhexidine gluconate solution 5% (: 1%chlorhexidine gluconate), in a pourable water-misciblebasis, net price 250 mL = £4.44For use in obstetrics and gynaecology as an antiseptic andlubricant (for application to skin around vulva and perineum andto hands of midwife or doctor)Hydrex c (Ecolab)Solution, chlorhexidine gluconate solution 2.5% (:chlorhexidine gluconate 0.5%), in an alcoholic solution,net price 600 mL (clear) = £2.72; 600 mL (pink) =£2.72, 200-mL spray = £1.77, 500-mL spray = £3.01;600 mL (blue) = £2.26Note FlammableFor pre-operative skin disinfectionSurgical scrub, chlorhexidine gluconate 4% in a surfactantsolution, net price 250 mL = £2.44, 500 mL =£2.58For pre-operative hand and skin preparation and for general handdisinfectionUnisept c (Medlock)Solution (sterile), pink, chlorhexidine gluconate0.05%, net price 25 25-mL sachet = £5.40; 10 100-mL sachet = £6.67For cleansing and disinfecting wounds and burns and swabbing inobstetricsWith cetrimideTisept c (Medlock)Solution (sterile), yellow, chlorhexidine gluconate0.015%, cetrimide 0.15%, net price 25 25-mLsachet = £5.20; 10 100-mL sachet = £6.68To be used undiluted for general skin disinfection and woundcleansingTravasept 100 c (Baxter)Solution (sterile), yellow, chlorhexidine acetate0.015%, cetrimide 0.15%, net price 500 mL = 72p,1 litre = 77pTo be used undiluted in skin disinfection such as wound cleansingand obstetricsConcentratesHibitane c Plus 5% Concentrate (Mölnlycke)Solution, red, chlorhexidine gluconate 5%, in a perfumedaqueous solution, net price 5 litres = £14.50DosePre-operative skin preparationDilute 1 in 10 (0.5%) with alcohol 70%General skin disinfectionDilute 1 in 100 (0.05%) with waterNote Alcoholic solutions not suitable for use before diathermy(see Alcohol, p. 594) or on neonatal skin13.11.3 Cationic surfactants andsoapsCETRIMIDECautions avoid contact with eyes; avoid use in bodycavitiesSide-effects skin irritation and occasionally sensitisationIndication and doseSkin disinfectionPreparationsIngredient of Tisept c and Travasept c 100, see above13 Skin

596 13.11.4 Iodine BNFC 2011–201213.11.4 Iodine13.11.6 Oxidisers and dyes13 SkinPOVIDONE–IODINECautions broken skin (see below)Large open wounds The application of povidone–iodine tolarge wounds or severe burns may produce systemic adverseeffects such as metabolic acidosis, hypernatraemia, andimpairment of renal functionContra-indications preterm neonate gestational ageunder 32 weeks; infants body-weight under 1.5 kg;regular use in neonates; thyroid disorders; concomitantlithium treatmentRenal impairment avoid regular application toinflamed or broken skin or mucosaPregnancy sufficient iodine may be absorbed to affectthe fetal thyroid in the second and third trimesterBreast-feeding avoid regular or excessive useSide-effects rarely sensitivity; may interfere withthyroid function testsIndication and doseSkin disinfection see preparationsBetadine c (Mölnlycke)Dry powder spray, povidone–iodine 2.5% in a pressurisedaerosol unit, net price 150-g unit = £2.63For skin disinfection, particularly minor wounds and infections;child under 2 years not recommendedNote Not for use in serous cavitiesSavlon c Dry (Novartis Consumer Health)Powder spray, povidone–iodine 1.14% in a pressurisedaerosol unit, net price 50-mL unit = £2.39For minor woundsVidene c (Ecolab)Alcoholic tincture, povidone–iodine 10%, net price500 mL = £3.46DoseApply undiluted in pre-operative skin disinfectionNote Flammable—caution in procedures involving hot wirecautery and diathermy; avoid use in neonatesAntiseptic solution, povidone–iodine 10% inaqueous solution, net price 500 mL = £3.46DoseApply undiluted in pre-operative skin disinfection andgeneral antisepsisSurgical scrub, povidone–iodine 7.5% in aqueoussolution, net price 500 mL = £3.46DoseUse as a pre-operative scrub for hand and skin disinfection13.11.5 PhenolicsTriclosan has been used for disinfection of the handsand wounds, and for disinfection of the skin beforesurgery.HYDROGEN PEROXIDECautions large or deep wounds; avoid on healthy skinand eyes; bleaches fabric; incompatible with productscontaining iodine or potassium permanganateLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseSuperficial bacterial skin infection see underpreparation belowCrystacide c (GP Pharma)Cream, hydrogen peroxide 1%, net price 25 g = £8.07,40 g = £11.62DoseSuperficial bacterial skin infectionApply 2–3 times daily for up to 3 weeksExcipients include edetic acid (EDTA), propylene glycolPOTASSIUM PERMANGANATECautions irritant to mucous membranesIndication and doseCleansing and deodorising suppurating eczematousreactions (section 13.5.1) and woundsFor wet dressings or baths, use approx. 0.01% (1 in10 000) solutionNote Stains skin and clothingPotassium Permanganate SolutionSolution, potassium permanganate 0.1% (1 in 1000)in waterNote to be diluted 1 in 10 to provide a 0.01% (1 in 10 000)solutionPermitabs c (Alliance)Solution tablets, for preparation of topical solution,potassium permanganate 400 mg, net price 30-tabpack = £9.85Note 1 tablet dissolved in 4 litres of water provides a 0.01%(1 in 10 000) solution13.11.7 Preparations forpromotion of woundhealingDesloughing agents Alginate, hydrogel, and hydrocolloiddressings (see BNF appendix on wound management)are effective in wound debridement. Sterile larvae(maggots) (LarvE c , Zoobiotic) are also used formanaging sloughing wounds and are prescribable onthe NHS.Desloughing solutions and creams are of little clinicalvalue. Substances applied to an open area are easilyabsorbed and perilesional skin is easily sensitised.Growth factor A topical preparation of becaplermin(recombinant human platelet-derived growth factor) isused as an adjunct treatment of full-thickness, neuropathic,diabetic ulcers. It enhances the formulation ofgranulation tissue, thereby promoting wound healing.

BNFC 2011–2012 13.12 Antiperspirants 597For further information on wound management productsand elastic hosiery, see the relevant BNF appendix.BECAPLERMIN(Recombinant human platelet-derived growthfactor)Cautions avoid on sites with infection or peripheralarteriopathyContra-indications malignant diseaseSide-effects pain; infections including cellulitis andosteomyelitis, local reactions including erythema;rarely bullous eruption, oedema, and hypertrophicgranulationLicensed use not licensed for use in childrenIndication and doseFull-thickness, neuropathic, diabetic ulcers (nolarger than 5 cm 2 )Apply thin layer daily and cover with gauze dressingmoistened with physiological saline; max.duration of treatment 20 weeks (reassess if nohealing after first 10 weeks)Regranex c (Janssen) AGel, becaplermin (recombinant human plateletderivedgrowth factor) 0.01%, net price 15 g = £240.92Excipients include hydroxybenzoates (parabens)13.12 AntiperspirantsAluminium chloride is a potent antiperspirant used inthe treatment of axillary, palmar, and plantar hyperhidrosis.Aluminium salts are also incorporated in preparationsused for minor fungal skin infections associatedwith hyperhidrosis.In more severe cases specialists use tap water or glycopyrroniumbromide (as a 0.05% solution) in the iontophoretictreatment of hyperhidrosis of palms and soles.Botox c contains botulinum toxin type A complex(section 4.9.3) and is available for use intradermallyfor severe hyperhidrosis of the axillae unresponsive totopical antiperspirant or other antihidrotic treatment;intradermal treatment is unlikely to be tolerated by mostchildren and should be administered under hospitalspecialist supervision.Hyperhidrosis, bromidrosis, intertrigo, andprevention of tinea pedis and related conditionsApply powder to dry skinAnhydrol c Forte (Dermal)Solution (= application), aluminium chloride hexahydrate20% in an alcoholic basis, net price 60-mLbottle with roll-on applicator = £2.51. Label: 15Excipients none as listed in section 13.1.31Driclor c (Stiefel)Application, aluminium chloride hexahydrate 20% inan alcoholic basis, net price 75-mL bottle with roll-onapplicator = £3.01. Label: 15Excipients none as listed in section 13.1.31. A 30-mL pack is on sale to the publicZeaSORB c (Stiefel)Dusting powder, aldioxa 0.22%, chloroxylenol 0.5%,net price 50 g = £2.61Excipients include fragranceGLYCOPYRRONIUM BROMIDECautions see section 15.1.3 (but poorly absorbed andsystemic effects unlikely)Contra-indications see section 15.1.3 (but poorlyabsorbed and systemic effects unlikely), infectionsaffecting the treatment siteSide-effects see section 15.1.3 (but poorly absorbedand systemic effects unlikely), tingling at administrationsiteLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseIontophoretic treatment of hyperhidrosisConsult product literature; only 1 site to be treatedat a time, max. 2 sites treated in any 24 hours,treatment not to be repeated within 7 daysOther indications section 15.1.3Robinul c (Goldshield) APowder, glycopyrronium bromide, net price 3 g =£175.0013 SkinALUMINIUM SALTSCautions avoid contact with eyes or mucous membranes;avoid use on broken or irritated skin; do notshave axillae or use depilatories within 12 hours ofapplication; avoid contact with clothingSide-effects skin irritationLicensed use licensed for use in children (age rangenot specified by manufacturer)Indication and doseHyperhidrosis affecting axillae, hands or feetApply liquid formulation at night to dry skin, washoff the following morning, initially apply daily thenreduce frequency as condition improves—do notbathe immediately before use13.13 Topical circulatorypreparationsThese preparations are used to improve circulation inconditions such as bruising and superficial thrombophlebitisbut are of little value. First aid measures suchas rest, ice, compression, and elevation should be used.Topical preparations containing heparinoids should notbe used on large areas of skin, broken or sensitive skin,or mucous membranes. Chilblains are best managed byavoidance of exposure to cold; neither systemic nortopical vasodilator therapy is established as being effective.

598 13.13 Topical circulatory preparations BNFC 2011–2012Hirudoid c (Genus) UCream, heparinoid 0.3% in a vanishing-cream basis,net price 50 g = £3.99Excipients include cetostearyl alcohol, hydroxybenzoates (parabens)DoseSuperficial thrombophlebitis, bruising, and haematomaChild 5–18 years apply up to 4 times dailyGel, heparinoid 0.3%, net price 50 g = £3.99Excipients include propylene glycol, fragranceDoseSuperficial thrombophlebitis, bruising, and haematomaChild 5–18 years apply up to 4 times daily13 Skin

BNFC 2011–2012 59914 Immunological productsand vaccines14.1 Active immunity 59914.2 Passive immunity 60214.3 Storage and use 60214.4 Vaccines and antisera 60214.5 Immunoglobulins 62214.5.1 Normal Immunoglobulin 62214.5.2 Disease-specific immunoglobulins62414.5.3 Anti-D (Rh 0 ) immunoglobulin 62614.6 International travel 62614.1 Active immunityActive immunity can be acquired by natural disease orby vaccination. Vaccines stimulate production of antibodiesand other components of the immune mechanism;they consist of either:1. a live attenuated form of a virus (e.g. measles,mumps, and rubella vaccine) or bacteria (e.g. BCGvaccine), or2. inactivated preparations of a virus (e.g. influenzavaccine) or bacteria, or3. detoxified exotoxins produced by a micro-organism(e.g. tetanus vaccine), or4. extracts of a micro-organism, which may be derivedfrom the organism (e.g. pneumococcal vaccine) orproduced by recombinant DNA technology (e.g.hepatitis B vaccine).Live attenuated vaccines usually produce durableimmunity but not always as long-lasting as that resultingfrom natural infection.Inactivated vaccines may require a primary series ofinjections of vaccine to produce an adequate antibodyresponse, and in most cases booster (reinforcing) injectionsare required; the duration of immunity varies frommonths to many years. Some inactivated vaccines areadsorbed onto an adjuvant (such as aluminium hydroxide)to enhance the antibody response.Advice in this chapter reflects that in the handbookImmunisation against Infectious Disease (2006),which in turn reflects the guidance of the JointCommittee on Vaccination and Immunisation(JCVI).Chapters from the handbook are available atwww.dh.gov.uk/immunisationThe advice in this chapter also incorporates changesannounced by the Chief Medical Officer and HealthDepartment Updates.Cautions Most children can safely receive the majorityof vaccines. Vaccination may be postponed if the child issuffering from an acute illness; however, it is not necessaryto postpone immunisation in children with minorillnesses without fever or systemic upset. See also Predispositionto Neurological Problems, below. For individualswith bleeding disorders, see Route of Administration,below. If alcohol or disinfectant is used forcleansing the skin it should be allowed to evaporatebefore vaccination to prevent possible inactivation oflive vaccines.When 2 or more vaccines are required (and are notavailable as a combined preparation), they should begiven simultaneously at different sites, preferably in adifferent limb; if more than one injection is to be given inthe same limb, they should be administered at least2.5 cm apart (but see also BCG Vaccines, p. 603).When 2 live vaccines cannot be given at the sametime, they should be separated by an interval of atleast 4 weeks. For interactions see Appendix I (vaccines).See also Cautions under individual vaccines.Contra-indications Vaccines are contra-indicated inchildren who have a confirmed anaphylactic reaction toa preceding dose of a vaccine containing the sameantigens or vaccine component (such as antibacterialsin viral vaccines). The presence of the following excipientsin vaccines and immunological products has beennoted under the relevant entries:GelatinGentamicinKanamycinNeomycinPenicillinsPolymyxin BStreptomycinThiomersalHypersensitivity to egg with evidence of previous anaphylacticreaction, contra-indicates influenza vaccine(prepared in hens’ eggs), tick-borne encephalitisvaccine, and yellow fever vaccine. See also Cautionsunder MMR vaccine.See also Vaccines and HIV infection, below.Live vaccines may be contra-indicated temporarily inchildren who are:. immunosuppressed (see Impaired ImmuneResponse, below);. pregnant (see Pregnancy and Breast-feeding,below).See also Contra-indications under individual vaccines.Impaired immune response Immune response to vaccinesmay be reduced in immunosuppressed childrenand there is also a risk of generalised infection with livevaccines. Severely immunosuppressed children shouldnot be given live vaccines (including those with severeprimary immunodeficiency). Specialist advice should besought for children being treated with high doses ofcorticosteroids (dose equivalents of prednisolone: children,2 mg/kg (or more than 40 mg) daily for at least 1week or 1 mg/kg daily for 1 month), or other immuno-14 Immunological products and vaccines

600 14.1 Active immunity BNFC 2011–201214 Immunological products and vaccinessuppressive drugs 1 , and for children with malignantconditions undergoing chemotherapy or generalisedradiotherapy 1;2 . For special reference to HIV infection,see below.The Royal College of Paediatrics and Child Health hasproduced a statement, Immunisation of the ImmunocompromisedChild (2002) (available atwww.rcpch.ac.uk).Pregnancy Live vaccines should not be administeredroutinely during pregnancy because of the theoreticalrisk of fetal infection but where there is a significant riskof exposure to disease (e.g. to yellow fever), the need forvaccination usually outweighs any possible risk to thefetus. Termination of pregnancy following inadvertentimmunisation is not recommended. There is no evidenceof risk from vaccinating pregnant women withinactivated viral or bacterial vaccines or toxoids. For useof specific vaccines during pregnancy, see under individualvaccines.Breast-feeding Although there is a theoretical risk oflive vaccine being present in breast milk, vaccination isnot contra-indicated for women who are breast-feedingwhen there is significant risk of exposure to disease.There is no evidence of risk from vaccinating womenwho are breast-feeding, with inactivated viral or bacterialvaccines or toxoids. For use of specific vaccinesduring breast-feeding, see under individual vaccines.Side-effects Injection of a vaccine may be followed bylocal reactions such as pain, inflammation, redness, andlymphangitis. An induration or sterile abscess maydevelop at the injection site. Gastro-intestinal disturbances,fever, headache, irritability, loss of appetite,fatigue, myalgia, and malaise are among the most commonlyreported side-effects. Other side-effects includeinfluenza-like symptoms, dizziness, paraesthesia, asthenia,drowsiness, arthralgia, rash, and lymphadenopathy.Hypersensitivity reactions, such as bronchospasm,angioedema, urticaria, and anaphylaxis, are very rarebut can be fatal (see section 3.4.3 for management ofallergic emergencies).Oral vaccines, such as cholera, live poliomyelitis, rotavirus,and live typhoid, can also cause gastro-intestinaldisturbances such as nausea, vomiting, abdominal painand cramps, and diarrhoea.See also Predisposition to Neurological Problems,below.Some vaccines (e.g. poliomyelitis) produce very fewreactions, while others (e.g. measles, mumps and rubella)may cause a very mild form of the disease.Occasionally more serious adverse reactions canoccur—these should always be reported to the CHM(see Adverse Reactions to Drugs, p. 12).See also Preterm Birth, p. 601.1. Live vaccines should be postponed until at least 3 monthsafter stopping high-dose systemic corticosteroids and atleast 6 months after stopping other immunosuppressivedrugs or generalised radiotherapy (at least 12 months afterdiscontinuing immunosuppressants following bone-marrowtransplantation).2. Use of normal immunoglobulin should be considered afterexposure to measles (see p. 623) and varicella–zosterimmunoglobulin considered after exposure to chickenpoxor herpes zoster (see p. 625).Predisposition to neurological problemsWhen there is a personal or family history of febrileconvulsions, there is an increased risk of theseoccurring during fever from any cause includingimmunisation, but this is not a contra-indication toimmunisation. In children who have had a seizureassociated with fever without neurological deterioration,immunisation is recommended; advice on themanagement of fever (see Post-immunisationPyrexia in Infants, below) should be given beforeimmunisation. When a child has had a convulsionnot associated with fever, and the neurological conditionis not deteriorating, immunisation is recommended.Children with stable neurological disorders (e.g.spina bifida, congenital brain abnormality, andperi-natal hypoxic-ischaemic encephalopathy)should be immunised according to the recommendedschedule.When there is a still evolving neurological problem,including poorly controlled epilepsy, immunisationshould be deferred and the child referred to aspecialist. Immunisation is recommended if acause for the neurological disorder is identified. Ifa cause is not identified, immunisation should bedeferred until the condition is stable.Post-immunisation pyrexia in infantsThe parent should be advised that if pyrexia developsafter childhood immunisation and the infantseems distressed, a dose of paracetamol can begiven and, if necessary, a second dose can begiven 6 hours later; ibuprofen may be used if paracetamolis unsuitable. The parent should be warnedto seek medical advice if the pyrexia persists.For post-immunisation pyrexia in an infant aged 2–3months, the dose of paracetamol is 60 mg; the doseof ibuprofen is 50 mg (on a doctor’s advice). An oralsyringe can be obtained from any pharmacy to givethe small volume required.Further information on adverse effects associated withspecific vaccines can be found under individual vaccines.Vaccines and HIV infection HIV-positive childrenwith or without symptoms can receive the following livevaccines:MMR (but avoid if immunity significantly impaired),varicella-zoster (but avoid if immunity significantlyimpaired—consult product literature); 2and the following inactivated vaccines:anthrax, cholera (oral), diphtheria, haemophilusinfluenzae type b, hepatitis A, hepatitis B, humanpapilloma virus, influenza, meningococcal, pertussis,pneumococcal, poliomyelitis 3 , rabies,tetanus, tick-borne encephalitis, typhoid (injection).HIV-positive children should not receive:BCG, typhoid (oral), yellow fever 4Note The above advice differs from that for other immunocompromisedchildren; Immunisation of HIV-infected Childrenissued by Children’s HIV Association (CHIVA) are available atwww.chiva.org.uk3. Inactivated poliomyelitis vaccine is now used instead oforal poliomyelitis vaccine for routine immunisation ofchildren.4. If yellow fever risk is unavoidable, specialist advice shouldbe sought.

BNFC 2011–2012 14.1 Active immunity 601Immunisation scheduleVaccines for the childhood immunisation schedule should be obtained from local health organisations or from ImmForm(www.immform.dh.gov.uk)—not to be prescribed on FP10 (HS21 in Northern Ireland; GP10 in Scotland; WP10 in Wales).Preterm birthBabies born preterm should receive all routine immunisations based on their actual date of birth. The risk ofapnoea following vaccination is increased in preterm babies, particularly in those born at or before 28 weekspostmenstrual age. If babies at risk of apnoea are in hospital at the time of their first immunisation, theyshould be monitored for 48 hours after immunisation. If a baby develops apnoea, bradycardia, or desaturationafter the first immunisation, the second immunisation should also be given in hospital with similarmonitoring. Seroconversion may be unreliable in babies born earlier than 28 weeks’ gestation or in babiestreated with corticosteroids for chronic lung disease; consideration should be given to testing for antibodiesagainst Haemophilus influenzae (type b), meningococcal C, and hepatitis B after primary immunisation.When to immunise (for prematureinfants—see noteabove)Neonates at risk onlyVaccine given and dose schedule (for details of dose, see under individual vaccines). BCG VaccineSee section 14.4, BCG Vaccines. Hepatitis B VaccineSee section 14.4, Hepatitis B Vaccine2 months . Diphtheria, Tetanus, Pertussis (Acellular, Component), Poliomyelitis (Inactivated), andHaemophilus Type b Conjugate Vaccine (Adsorbed)First dose. Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed)First dose3 months . Diphtheria, Tetanus, Pertussis (Acellular, Component), Poliomyelitis (Inactivated), andHaemophilus Type b Conjugate Vaccine (Adsorbed)Second dose. Meningococcal Group C Conjugate VaccineFirst dose4 months . Diphtheria, Tetanus, Pertussis (Acellular, Component), Poliomyelitis (Inactivated), andHaemophilus Type b Conjugate Vaccine (Adsorbed)Third dose. Meningococcal Group C Conjugate VaccineSecond dose. Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed)Second dose12 –13 months . Measles, Mumps and Rubella Vaccine, Live (MMR)First dose. Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed)Single booster dose. Haemophilus Type b Conjugate Vaccine and Meningococcal Group C Conjugate VaccineSingle booster doseBetween 3 years and 4months, and 5 years. Adsorbed Diphtheria [low dose], Tetanus, Pertussis (Acellular, Component) and Poliomyelitis(Inactivated) VaccineorAdsorbed Diphtheria, Tetanus, Pertussis (Acellular, Component) and Poliomyelitis(Inactivated) VaccineSingle booster doseNote: Preferably allow interval of at least 3 years after completing primary course. Measles, Mumps and Rubella Vaccine, Live (MMR)Second dose12–13 years (females only) . Human Papilloma Virus Vaccine3 doses; second dose 1–2 months, and third dose 6 months after first dose 113–18 years . Adsorbed Diphtheria [low dose], Tetanus, and Poliomyelitis (Inactivated) VaccineSingle booster doseDuring adult life, women ofchild-bearing age susceptibleto rubella. Measles, Mumps and Rubella Vaccine, Live (MMR)Women of child-bearing age who have not received 2 doses of a rubella-containingvaccine or who do not have a positive antibody test for rubella should be offered rubellaimmunisation (using the MMR vaccine)—exclude pregnancy before immunisation, but seealso section 14.4, Measles, Mumps and Rubella Vaccine1. The two human papilloma virus vaccines are not interchangeable and one vaccine product should be used for the entirecourse; however, Department of Health (November 2008) states for individuals with previous incomplete vaccination withGardasil c , who are eligible for HPV vaccination under the national programme, Cervarix c can be used to complete thevaccination course if necessary; the individual must be informed that Cervarix c does not protect against genital warts.14 Immunological products and vaccines

602 14.2 Passive immunity BNFC 2011–201214 Immunological products and vaccinesVaccines and asplenia The following vaccines arerecommended for asplenic children or those with splenicdysfunction:haemophilus influenzae type b; influenza; meningococcalA, C, W135, and Y conjugate; pneumococcal.For antibiotic prophylaxis in asplenia see p. 255.Route of administration Vaccines should not begiven intravenously. Most vaccines are given by theintramuscular route; some vaccines are given by otherroutes—the intradermal route for BCG vaccine, deepsubcutaneous route for Japanese encephalitis and varicellavaccines, and the oral route for cholera, live poliomyelitis,rotavirus, and live typhoid vaccines. The intramuscularroute should not be used in children withbleeding disorders such as haemophilia or thrombocytopenia;vaccines usually given by the intramuscularroute should be given by deep subcutaneous injectioninstead.Note The Department of Health has advised against the use ofjet guns for vaccination owing to the risk of transmitting bloodborneinfections, such as HIV.High-risk groupsFor information on high-risk groups, see section 14.4under individual vaccinesBCG Vaccines, p. 603Hepatitis A Vaccine, p. 607Hepatitis B Vaccine, p. 608Influenza Vaccine, p. 611Pneumococcal Vaccines, p. 616Tetanus Vaccines, p. 619Children with unknown or incompleteimmunisation historyFor children born in the UK who present with aninadequate or unknown immunisation history, investigationinto immunisations received should be carriedout. Outstanding doses should be administered wherethe routine childhood immunisation schedule has notbeen completed.For advice on the immunisation of children coming tothe UK, consult the handbook Immunisation againstInfectious Disease (2006) (available at www.dh.gov.uk)14.2 Passive immunityImmunity with immediate protection against certaininfective organisms can be obtained by injecting preparationsmade from the plasma of immune individualswith adequate levels of antibody to the disease for whichprotection is sought (see under Immunoglobulins, section14.5). The duration of this passive immunity variesaccording to the dose and the type of immunoglobulin.Passive immunity may last only a few weeks; whennecessary, passive immunisation can be repeated.Antibodies of human origin are usually termed immunoglobulins.The term antiserum is applied to materialprepared in animals. Because of serum sickness andother allergic-type reactions that may follow injectionsof antisera, this therapy has been replaced wheneverpossible by the use of immunoglobulins. Reactions aretheoretically possible after injection of human immunoglobulins,but reports of such reactions are very rare.14.3 Storage and useCare must be taken to store all vaccines and otherimmunological products under the conditions recommendedin the product literature, otherwise the preparationmay become ineffective. Refrigerated storage isusually necessary; many vaccines and immunoglobulinsneed to be stored at 2–88C and not allowed to freeze.Vaccines and immunoglobulins should be protectedfrom light. Reconstituted vaccines and opened multidosevials must be used within the period recommendedin the product literature. Unused vaccines should bedisposed of by incineration at a registered disposalcontractor.Particular attention must be paid to instructions on theuse of diluents. Vaccines which are liquid suspensions orare reconstituted before use should be adequatelymixed to ensure uniformity of the material to beinjected.14.4 Vaccines and antiseraAvailability Anthrax and yellow fever vaccines, botulismantitoxin, diphtheria antitoxin, and snake and spidervenom antitoxins are available from local designatedholding centres.For antivenom, see Emergency Treatment of Poisoning,p. 34.Enquiries for vaccines not available commercially canalso be made to:Immunisation Policy, Monitoring and SurveillanceDepartment of HealthWellington House133–155 Waterloo RoadLondon, SE1 8UGvaccine.supply@dh.gsi.gov.ukIn Scotland information about availability of vaccinescan be obtained from a Specialist in PharmaceuticalPublic Health. In Wales enquiries for vaccines notcommercially available should be directed to:Welsh Medicines Information CentreUniversity Hospital of WalesCardiff, CF14 4XWTel: (029) 2074 2979and in Northern Ireland:Pharmacy and Medicines Management CentreBeech HouseAntrim Hospital SiteNorthern Health and Social Care TrustBush RoadAntrim, BT41 2RLrphps.admin@northerntrust.hscni.netFor further details of availability, see under individualvaccines.

BNFC 2011–2012 14.4 Vaccines and antisera 603Anthrax vaccineAnthrax vaccine is rarely required for children. Forfurther information see BNF section 14.4.BCG vaccinesBCG (Bacillus Calmette-Guérin) is a live attenuatedstrain derived from Mycobacterium bovis which stimulatesthe development of hypersensitivity to M. tuberculosis.BCG vaccine should be given intradermally byoperators skilled in the technique (see below).The expected reaction to successful BCG vaccination isinduration at the site of injection followed by a locallesion which starts as a papule 2 or more weeks aftervaccination; the lesion may ulcerate then subside overseveral weeks or months, leaving a small flat scar. A drydressing may be used if the ulcer discharges, but airshould not be excluded.All children of 6 years and over being considered forBCG immunisation must first be given a skin test forhypersensitivity to tuberculoprotein (see under Diagnosticagents, below). A skin test is not necessary fora child under 6 years, provided that the child has notstayed for longer than 3 months in a country with anincidence 1 of tuberculosis greater than 40 per 100 000,the child has not had contact with a person with tuberculosis,and there is no family history of tuberculosiswithin the last 5 years.BCG is recommended for the following groups of childrenif BCG immunisation has not previously beencarried out and they are negative for tuberculoproteinhypersensitivity:. neonates with a family history of tuberculosis in thelast 5 years;. all neonates and infants (0–12 months) born in areaswhere the incidence 1 of tuberculosis is greater than40 per 100 000;. neonates, infants, and children under 16 years witha parent or grandparent born in a country with anincidence 1 of tuberculosis greater than 40 per100 000;. new immigrants aged under 16 years who wereborn in, or lived for more than 3 months in acountry with an incidence 1 of tuberculosis greaterthan 40 per 100 000;. new immigrants aged 16–18 years from Sub-SaharanAfrica or a country 1 with an incidence of tuberculosisgreater than 500 per 100 000;. contacts of those with active respiratory tuberculosis;. children under 16 years intending to live with localpeople for more than 3 months in a country with anincidence 1 of tuberculosis greater than 40 per100 000 (section 14.6).BCG vaccine can be given simultaneously with anotherlive vaccine (see also section 14.1), but if they are notgiven at the same time, an interval of 4 weeks shouldnormally be allowed between them. When BCG is givento infants, there is no need to delay routine primaryimmunisations. No further vaccination should be given1. List of countries or primary care trusts where the incidenceof tuberculosis is greater than 40 cases per 100 000 isavailable at www.hpa.org.ukin the arm used for BCG vaccination for at least 3months because of the risk of regional lymphadenitis.For advice on chemoprophylaxis against tuberculosis,see section 5.1.9; for treatment of infection followingvaccination, seek expert advice.BACILLUS CALMETTE-GUÉRINVACCINEBCG vaccineCautions see section 14.1; interactions: Appendix 1(vaccines)Contra-indications see section 14.1; also neonate inhousehold contact with known or suspected case ofactive tuberculosis; generalised septic skin conditions(for children with eczema, lesion-free site should beused)Pregnancy see p. 600Breast-feeding see p. 600Side-effects see section 14.1 and notes above; also atthe injection-site, subcutaneous abscess, prolongedulceration; rarely disseminated complications such asosteitis or osteomyelitisIndication and doseImmunisation against tuberculosis. By intradermal injectionNeonate 0.05 mLChild 1 month–1 year 0.05 mLChild 1–18 years 0.1 mLIntradermal injection technique Skin is stretched betweenthumb and forefinger and needle (size 25G or 26G) inserted(bevel upwards) for about 3 mm into superficial layers ofdermis (almost parallel with surface). Needle should be shortwith short bevel (can usually be seen through epidermisduring insertion). Tense raised blanched bleb showing tips ofhair follicles is sign of correct injection; 7 mm bleb : 0.1 mLinjection, 3 mm bleb : 0.05 mL injection; if considerableresistance not felt, needle is too deep and should be removedand reinserted before giving more vaccine.To be injected at insertion of deltoid muscle onto humerus(keloid formation more likely with sites higher on arm); tip ofshoulder should be avoided.IntradermalBacillus Calmette-Guérin Vaccine ABCG Vaccine, Dried/Tub/BCGInjection, (powder for suspension), freeze-dried preparationof live bacteria of a strain derived from thebacillus of Calmette and GuérinAvailable from health organisations or from ImmForm (SSI brand,multidose vial with diluent)Diagnostic agentsThe Mantoux test is recommended for tuberculin skintesting, but no licensed preparation is currently available.Guidance for healthcare professionals is availableat www.dh.gov.uk/immunisation.In the Mantoux test, the diagnostic dose is administeredby intradermal injection of Tuberculin Purified ProteinDerivative (PPD).The Heaf test (involving the use of multiple-punctureapparatus) is no longer available.Note Response to tuberculin may be suppressed by live viralvaccines, viral infection, sarcoidosis, corticosteroid therapy, orimmunosuppression due to disease or treatment. Tuberculintesting should not be carried out within 4 weeks of receiving alive viral vaccine14 Immunological products and vaccines

604 14.4 Vaccines and antisera BNFC 2011–201214 Immunological products and vaccinesTwo interferon gamma release assay (IGRA) tests arealso available as an aid in the diagnosis of tuberculosisinfection: QuantiFERON c -TB Gold and T-SPOT c .TB.Both tests measure T-cell mediated immune response tosynthetic antigens. For further information on the use ofinterferon gamma release assay tests for tuberculosis,see www.hpa.org.uk.Tuberculin Purified Protein Derivative A(Tuberculin PPD)Injection, heat-treated products of growth and lysis ofappropriate Mycobacterium spp. 20 units/mL(2 units/0.1-mL dose) (for routine use), 1.5-mL vial;100 units/mL (10 units/0.1-mL dose), 1.5-mL vialDoseMantoux test. By intradermal injection2 units (0.1 mL of 20 units/mL strength) for routineMantoux test; if first test is negative and a further test isconsidered appropriate 10 units (0.1 mL of 100 units/mLstrength)Available from ImmForm (SSI brand)Important The strength of tuberculin PPD in this productmay be different to the strengths of products used previouslyfor the Mantoux test; care is required to select the correctstrengthBotulism antitoxinA polyvalent botulism antitoxin is available for the postexposureprophylaxis of botulism and for the treatmentof children thought to be suffering from botulism. Itspecifically neutralises the toxins produced by Clostridiumbotulinum types A, B, and E. It is not effectiveagainst infantile botulism as the toxin (type A) is seldom,if ever, found in the blood in this type of infection.Hypersensitivity reactions are a problem. It is essentialto read the contra-indications, warnings, and details ofsensitivity tests on the package insert. Prior to treatmentchecks should be made regarding previous administrationof any antitoxin and history of any allergic condition,e.g. asthma, hay fever, etc. All children should betested for sensitivity (diluting the antitoxin if history ofallergy).Botulism Antitoxin AA preparation containing the specific antitoxic globulinsthat have the power of neutralising the toxinsformed by types A, B, and E of Clostridium botulinum.Note The BP title Botulinum Antitoxin is not used becausethe preparation currently in use may have a different specificationDoseProphylaxisConsult product literatureAvailable from local designated centres, for details see TOXBASE(requires registration) www.toxbase.org. For supplies outsideworking hours apply to other designated centres or to the dutydoctor at the Health Protection Agency (Tel (020) 8200 6868). Formajor incidents, obtain supplies from the local blood bankCholera vaccineCholera vaccine (oral) contains inactivated Inaba(including El-Tor biotype) and Ogawa strains of Vibriocholerae, serotype O1 together with recombinant B-subunit of the cholera toxin produced in Inaba strainsof V.cholerae, serotype O1.Oral cholera vaccine is licensed for travellers to endemicor epidemic areas on the basis of current recommendations(see also section 14.6). Immunisationshould be completed at least 1 week before potentialexposure. However, there is no requirement for choleravaccination for international travel.Immunisation with cholera vaccine does not providecomplete protection and all travellers to a countrywhere cholera exists should be warned that scrupulousattention to food, water, and personal hygiene is essential.Injectable cholera vaccine provides unreliable protectionand is no longer available in the UK.CHOLERA VACCINECautions see section 14.1 and notes aboveContra-indications see section 14.1; also acute gastro-intestinalillnessPregnancy see p. 600Breast-feeding see p. 600Side-effects see section 14.1; also rarely respiratorysymptoms such as rhinitis and cough; very rarely sorethroat, insomniaIndication and doseSee notes above. By mouthChild 2–6 years 3 doses each separated by aninterval of 1–6 weeksChild 6–18 years 2 doses separated by an intervalof 1–6 weeksNote If more than 6 weeks have elapsed between doses,the primary course should be restartedA single booster dose can be given 2 years afterprimary course for children 6–18 years, and 6months after primary course for children 2–6 years.If more than 2 years have elapsed since the lastvaccination, the primary course should be repeatedAdministration Dissolve effervescent sodium bicarbonategranules in a glassful of water (approximately150 mL). For child over 6 years, add vaccine suspensionto make one dose. For child 2–6 years, discardhalf (approximately 75 mL) of the solution, then addvaccine suspension to make one dose. Drink within 2hours. Food, drink and other oral medicines should beavoided for 1 hour before and after vaccinationDukoral c (Crucell) AOral suspension, for dilution with solution of effervescentsodium bicarbonate granules, heat- andformaldehyde-inactivated Inaba (including El-Torbiotype) and Ogawa strains of Vibrio cholerae bacteriaand recombinant cholera toxin B-subunit producedin V. cholerae, net price 2-dose pack = £23.42.Counselling, administrationDiphtheria VaccinesDiphtheria vaccines are prepared from the toxin ofCorynebacterium diphtheriae and adsorption on aluminiumhydroxide or aluminium phosphate improvesantigenicity. The vaccine stimulates the production ofthe protective antitoxin. The quantity of diphtheria

BNFC 2011–2012 14.4 Vaccines and antisera 605toxoid in a preparation determines whether the vaccineis defined as ‘high dose’ or ‘low dose’. Vaccines containingthe higher dose of diphtheria toxoid are used forprimary immunisation of children under 10 years of age.Vaccines containing the lower dose of diphtheria toxoidare used for primary immunisation in children over 10years. Single-antigen diphtheria vaccine is not availableand adsorbed diphtheria vaccine is given as a combinationproduct containing other vaccines.For primary immunisation of children aged between 2months and 10 years vaccination is recommendedusually in the form of 3 doses (separated by 1-monthintervals) of diphtheria, tetanus, pertussis (acellular,component), poliomyelitis (inactivated) and haemophilustype b conjugate vaccine (adsorbed) (seeImmunisation schedule, section 14.1). In unimmunisedchildren aged over 10 years the primary course comprisesof 3 doses of adsorbed diphtheria [low dose],tetanus and poliomyelitis (inactivated) vaccine.A booster dose should be given 3 years after the primarycourse (this interval can be reduced to a minimum of 1year if the primary course was delayed). Children under10 years should receive either adsorbed diphtheria,tetanus, pertussis (acellular, component) and poliomyelitis(inactivated) vaccine or adsorbed diphtheria[low dose], tetanus, pertussis (acellular, component)and poliomyelitis (inactivated) vaccine. Childrenaged over 10 years should receive adsorbed diphtheria[low dose], tetanus, and poliomyelitis (inactivated)vaccine.A second booster dose, of adsorbed diphtheria [lowdose], tetanus and poliomyelitis (inactivated) vaccine,should be given 10 years after the previous booster dose(this interval can be reduced to a minimum of 5 years ifprevious doses were delayed). For children who havebeen vaccinated following a tetanus-prone wound, seeTetanus vaccines, p. 619.Travel Children travelling to areas with a risk of diphtheriainfection should be fully immunised according tothe UK schedule (see also section 14.6). If more than 10years have lapsed since completion of the UK schedule,a dose of adsorbed diphtheria [low dose], tetanus andpoliomyelitis (inactivated) vaccine should be administered.Contacts Advice on the management of cases ofdiphtheria, carriers, contacts and outbreaks must besought from health protection units. The immunisationhistory of infected children and their contacts should bedetermined; those who have been incompletely immunisedshould complete their immunisation and fullyimmunised individuals should receive a reinforcingdose. For advice on antibacterial treatment to preventa secondary case of diphtheria in a non-immune child,see Table 2, section 5.1.DIPHTHERIA-CONTAINING VACCINESCautions see section 14.1; see also individual componentsof vaccinesContra-indications see section 14.1; see also individualcomponents of vaccinesPregnancy see p. 600Breast-feeding see p. 600Side-effects see section 14.1; also restlessness, sleepdisturbances, and unusual crying in infants;Licensed use Infanrix-IPV + Hib c not licensed foruse in children over 36 months; Pediacel c notlicensed in children over 4 years but Department ofHealth recommends that these be used for childrenup to 10 yearsIndication and doseSee notes above and under preparationsDiphtheria-containing vaccines for childrenunder 10 yearsImportant Not recommended for children aged 10 years orover (see Diphtheria vaccines for children over 10)Diphtheria, Tetanus, Pertussis (Acellular, Component),Poliomyelitis (Inactivated) and HaemophilusType b Conjugate Vaccine (Adsorbed) AInjection, suspension of diphtheria toxoid, tetanustoxoid, acellular pertussis, inactivated poliomyelitisand Haemophilus influenzae type b (conjugated totetanus protein), net price 0.5-mL prefilled syringe =£19.94Excipients may include neomycin, polymyxin B and streptomycinDosePrimary immunisation. By intramuscular injectionChild 2 months–10 years 3 doses each of 0.5 mLseparated by intervals of 1 month; see also notes onbooster doses, aboveAvailable as part of childhood immunisation schedule, from healthorganisations or ImmFormBrands include Pediacel cAdsorbed Diphtheria, Tetanus, Pertussis (Acellular,Component) and Poliomyelitis (Inactivated)Vaccine AInjection, suspension of diphtheria toxoid, tetanustoxoid, acellular pertussis and inactivated poliomyelitisvaccine components adsorbed on a mineral carrier,net price 0.5-mL prefilled syringe = £17.56Excipients may include neomycin and polymyxin BDoseFirst booster dose. By intramuscular injectionChild 3–10 years 0.5 mL 3 years after primaryimmunisation; see also notes on booster doses, aboveAvailable as part of childhood immunisation schedule, from healthorganisations or ImmFormBrands include Infanrix-IPV cAdsorbed Diphtheria [low dose], Tetanus, Pertussis(Acellular, Component) and Poliomyelitis(Inactivated) Vaccine AInjection, suspension of diphtheria toxoid [low dose],tetanus toxoid, acellular pertussis and inactivatedpoliomyelitis vaccine components adsorbed on amineral carrier, net price 0.5-mL prefilled syringe =£11.98Excipients may include neomycin, polymyxin B and streptomycinDoseFirst booster dose. By intramuscular injectionChild 3–10 years 0.5 mL 3 years after primaryimmunisation; see also notes on booster doses, aboveAvailable as part of childhood immunisation schedule, from healthorganisations or ImmFormBrands include Repevax c14 Immunological products and vaccines

606 14.4 Vaccines and antisera BNFC 2011–201214 Immunological products and vaccinesDiphtheria-containing vaccines for children over10 yearsA low dose of diphtheria toxoid is sufficient to recallimmunity in older children previously immunisedagainst diphtheria but whose immunity may havediminished with time; it is insufficient to cause seriousreactions in a child who is already immune. Preparationscontaining low dose diphtheria should be usedfor children over 10 years, both for primary immunisationand booster doses.Adsorbed Diphtheria [low dose], Tetanus andPoliomyelitis (Inactivated) Vaccine AInjection, suspension of diphtheria toxoid [low dose],tetanus toxoid and inactivated poliomyelitis vaccinecomponents adsorbed on a mineral carrier, net price0.5-mL prefilled syringe = £6.35Excipients may include neomycin, polymyxin B and streptomycinDosePrimary immunisation. By intramuscular injectionChild 10–18 years 3 doses each of 0.5 mL separated byintervals of 1 month; second booster dose, 0.5 mL given10 years after first booster dose (may also be used as firstbooster dose in those over 10 years who have receivedonly 3 previous doses of a diphtheria-containingvaccine); see also notes on booster doses, aboveAvailable as part of childhood schedule, from health organisationsor ImmFormBrands include Revaxis cDiphtheria antitoxinDiphtheria antitoxin is used for passive immunisationin suspected cases of diphtheria only (withoutwaiting for bacteriological confirmation); tests forhypersensitivity should be first carried out. It isderived from horse serum, and reactions are commonafter administration; resuscitation facilities should beavailable immediately.It is no longer used for prophylaxis because of the riskof hypersensitivity; unimmunised contacts should bepromptly investigated and given antibacterial prophylaxis(Table 2, section 5.1) and vaccine (see Contactsabove, p. 605).Diphtheria Antitoxin ADip/SerDoseProphylaxisNot recommended therefore no dose stated (see notesabove)Immunisation schedule, section 14.1). For infantsunder 1 year, the course consists of 3 doses of a vaccinecontaining haemophilus influenzae type b component,with an interval of 1 month between doses. A boosterdose of haemophilus influenzae type b vaccine (combinedwith meningococcal group C conjugate vaccine)should be given at around 12–13 months of age.Children 1–10 years who have not been immunisedagainst Haemophilus influenzae type b need to receiveonly 1 dose of the vaccine (combined with meningococcalgroup C conjugate vaccine). However, if a primarycourse of immunisation has not been completed,these children should be given 3 doses of diphtheria,tetanus, pertussis (acellular, component), poliomyelitis(inactivated) and haemophilus type b conjugate vaccine(adsorbed). The risk of infection falls sharply in olderchildren and the vaccine is not normally required forchildren over 10 years.Haemophilus influenzae type b vaccine may be given tothose over 10 years who are considered to be atincreased risk of invasive H. influenzae type b disease(such as those with sickle-cell disease or complementdeficiency, or those receiving treatment for malignancy).For use of rifampicin in the prevention of secondarycases of Haemophilus influenza type b disease, seeTable 2, section 5.1Asplenia, splenic dysfunction, or complementdeficiency Children diagnosed with asplenia, splenicdysfunction, or complement deficiency at:. under 2 years of age should be vaccinated accordingto the Immunisation Schedule (section 14.1).The booster dose of haemophilus influenzae type bvaccine (combined with meningococcal group Cconjugate vaccine), given at 12–13 months of age,should be followed at least 1 month later by onedose of meningococcal A, C, W135, and Y conjugatevaccine. An additional dose of haemophilusinfluenzae type b vaccine (combined with meningococcalgroup C conjugate vaccine) should be givenafter the second birthday;. over 2 years of age should receive one dose ofhaemophilus influenzae type b vaccine (combinedwith meningococcal group C conjugate vaccine),followed 1 month later by one dose of meningococcalA, C, W135, and Y conjugate vaccine.TreatmentConsult product literatureAvailable from Centre for Infections (Tel (020) 8200 6868) or inNorthern Ireland from Public Health Laboratory, Belfast CityHospital (Tel (028) 9032 9241).Haemophilus type B conjugate vaccineHaemophilus influenzae type b (Hib) vaccine is madefrom capsular polysaccharide; it is conjugated with aprotein such as tetanus toxoid to increase immunogenicity,especially in young children. Haemophilus influenzaetype b vaccine is given in combination with diphtheria,tetanus, pertussis (acellular, component) andpoliomyelitis (inactivated) vaccine, (see under Diphtheriacontaining Vaccines) as a component of theprimary course of childhood immunisation (seeHAEMOPHILUS TYPE B CONJUGATEVACCINECautions see section 14.1Contra-indications see section 14.1Pregnancy see p. 600Breast-feeding see p. 600Side-effects see section 14.1; also, atopic dermatitis,hypotoniaLicensed use Menitorix c is not licensed for use inchildren over 2 yearsIndication and doseSee notes above and under preparationPrimary immunisation, see under Diphtheriacontainingvaccines

BNFC 2011–2012 14.4 Vaccines and antisera 607Menitorix c (GSK) AInjection, powder for reconstitution, capsular polysaccharideof Haemophilus influenzae type b andcapsular polysaccharide of Neisseria meningitidisgroup C (both conjugated to tetanus protein), netprice single dose vial (with syringe containing 0.5 mLdiluent) = £39.87Dose. By intramuscular injectionCHILD 1–10 year 0.5 mLCHILD over 1 year with asplenia or splenic dysfunction(see notes above), 0.5 mLAvailable as part of the childhood immunisation schedule fromImmFormCombined vaccinesSee also Diphtheria-containing vaccinesHepatitis A vaccineHepatitis A vaccine is prepared from formaldehydeinactivatedhepatitis A virus grown in human diploidcells.Immunisation is recommended for:. residents of homes for those with severe learningdifficulties;. children with haemophilia or other conditions treatedwith plasma-derived clotting factors;. children with severe liver disease;. children travelling to high-risk areas (see p. 626);. adolescents who are at risk due to their sexualbehaviour;. parenteral drug abusers.Immunisation should be considered for:. children with chronic liver disease including chronichepatitis B or chronic hepatitis C;. prevention of secondary cases in close contacts ofconfirmed cases of hepatitis A, within 14 days ofexposure to the primary case (within 8 weeks ofexposure to the primary case where there is morethan 1 contact in the household).A booster dose of hepatitis A vaccine is usually given 6–12 months after the initial dose. A second booster dosecan be given 20 years after the previous booster dose tothose who continue to be at risk. Specialist adviceshould be sought on re-immunisation of immunocompromisedindividuals.Post-exposure prophylaxis is not required for healthychildren under 1 year of age, so long as all thoseinvolved in nappy changing are vaccinated againsthepatitis A. However, children 2–12 months of agecan be given a dose of hepatitis A vaccine if it is notpossible to vaccinate their carers, or if the childbecomes a source of infection to others [unlicenseduse]; in these cases, if the child goes on to requirelong-term protection against hepatitis A after the firstbirthday, the full course of 2 doses should be given.In children under 16 years, a single dose of the combinedvaccine Ambirix c can be used to provide rapidprotection against hepatitis A.Intramuscular normal immunoglobulin (section14.5.1) is recommended for use in addition to HepatitisA vaccine for close contacts (of confirmed cases ofhepatitis A) who have chronic liver disease or HIVinfection, or who are immunosuppressed.HEPATITIS A VACCINECautions section 14.1Contra-indications section 14.1Pregnancy see p. 600Breast-feeding see p. 600Side-effects section 14.1; for combination vaccines,see also Typhoid vaccines, p. 620Indication and doseImmunisation against hepatitis A infectionFor dose, see under preparationsSingle componentAvaxim c (Sanofi Pasteur) AInjection, suspension of formaldehyde-inactivatedhepatitis A virus (GBM grown in human diploid cells)320 antigen units/mL adsorbed onto aluminiumhydroxide, net price 0.5-mL prefilled syringe = £18.10Excipients include neomycinDose. By intramuscular injection(see note below)Child 16–18 years 0.5 mL as a single dose; booster dose0.5 mL 6–12 months after initial doseNote Booster dose may be delayed by up to 3 years if notgiven after recommended interval following primarydose with Avaxim c . The deltoid region is the preferredsite of injection; not to be injected into the buttock(vaccine efficacy reduced). The subcutaneous route maybe used for children with bleeding disordersEpaxal c (Crucell) AInjection, suspension of formaldehyde-inactivatedhepatitis A virus (RG-SB grown in human diploid cells)at least 48 units/mL, net price 0.5-mL prefilledsyringe = £23.81Dose. By intramuscular injection(see note below)Child 1–18 years 0.5 mL as a single dose; booster dose0.5 mL 6–12 months after initial dose (1–6 months ifsplenectomised)Note Booster dose may be delayed by up to 4 years if notgiven after recommended interval following primarydose. The deltoid region is the preferred site of injection.The subcutaneous route may be used for children withbleeding disordersImportant Epaxal c contains influenza virus haemagglutiningrown in the allantoic cavity of chick embryos, and is thereforecontra-indicated in those hypersensitive to eggs or chickenprotein.Havrix Monodose c (GSK) AInjection, suspension of formaldehyde-inactivatedhepatitis A virus (HM 175 grown in human diploidcells) 1440 ELISA units/mL adsorbed onto aluminiumhydroxide, net price 1-mL prefilled syringe = £22.14,0.5-mL (720 ELISA units) prefilled syringe (HavrixJunior Monodose c ) = £16.77Excipients include neomycinDose. By intramuscular injection(see note below)Child 1–15 years 0.5 mL as a single dose; booster dose0.5 mL 6–12 months after initial dose14 Immunological products and vaccines

608 14.4 Vaccines and antisera BNFC 2011–201214 Immunological products and vaccinesChild 16–18 years 1 mL as a single dose; booster dose1 mL 6–12 months after initial doseNote Booster dose may be delayed by up to 3 years if notgiven after recommended interval following primarydose with Havrix Monodose c . The deltoid region is thepreferred site of injection. The subcutaneous route maybe used for children with bleeding disordersVaqta c Paediatric (Sanofi Pasteur) AInjection, suspension of formaldehyde-inactivatedhepatitis A virus (grown in human diploid cells)50 antigen units/mL adsorbed onto aluminiumhydroxyphosphate sulphate, net price 0.5-mL prefilledsyringe = £14.74Excipients include neomycinDose. By intramuscular injection(see note below)Child 1–18 years 0.5 mL as a single dose; booster dose0.5 mL 6–18 months after initial doseNote The deltoid region is the preferred site of injection.The subcutaneous route may be used for children withbleeding disorders (but immune response may bereduced)With hepatitis B vaccineAmbirix c (GSK) TAInjection, suspension of inactivated hepatitis A virus(grown in human diploid cells) 720 ELISA units/mLabsorbed onto aluminium hydroxide, and recombinant(DNA) hepatitis B surface antigen (grown in yeastcells) 20 micrograms/mL adsorbed onto aluminiumhydroxide and aluminium phosphate, net price 1-mLprefilled syringe = £31.18Excipients include neomycinDose. By intramuscular injection(see note below)Child 1–15 years primary course, 2 doses of 1 mL, thesecond 6–12 months after initial doseNote Primary course should be completed with Ambirix c(single component vaccines given at appropriate intervalsmay be used for booster dose); the deltoid region is thepreferred site of injection in older children; anterolateralthigh is the preferred site in infants; not to be injected intothe buttock (vaccine efficacy reduced); subcutaneous routeused for children with bleeding disorders (but immuneresponse may be reduced)Important Ambirix c not recommended for post-exposureprophylaxis following percutaneous (needle-stick), ocular, ormucous membrane exposure to hepatitis B virusTwinrix c (GSK) AInjection, inactivated hepatitis A virus (grown inhuman diploid cells) 720 ELISA units/mL adsorbedonto aluminium hydroxide, and recombinant (DNA)hepatitis B surface antigen (grown in yeast cells)20 micrograms/mL adsorbed onto aluminium phosphate,net price 1-mL prefilled syringe (Twinrix cAdult) = £27.76, 0.5-mL prefilled syringe (Twinrix cPaediatric) = £20.79Excipients include neomycinDose. By intramuscular injection(see note below)Child 1–15 years primary course 3 doses of 0.5 mL(Twinrix c Paediatric), the second 1 month and the third6 months after first doseChild 16–18 years primary course, 3 doses of 1 mL(Twinrix c Adult), the second 1 month and the third 6months after first doseAccelerated schedule (e.g. for travellers departing within1 month) for child over 16 years, second dose given 7days after first dose, third dose after further 14 days andfourth dose 12 months after the first doseNote Primary course should be completed with Twinrix c(single component vaccines given at appropriate intervalsmay be used for booster dose); the deltoid region is thepreferred site of injection in older children; anterolateralthigh is the preferred site in infants; not to be injected intothe buttock (vaccine efficacy reduced); subcutaneous routeused for children with bleeding disorders (but immuneresponse may be reduced).Important Twinrix c not recommended for post-exposureprophylaxis following percutaneous (needle-stick), ocular ormucous membrane exposure to hepatitis B virus.With typhoid vaccineHepatyrix c (GSK) AInjection, suspension of inactivated hepatitis A virus(grown in human diploid cells) 1440 ELISA units/mLadsorbed onto aluminium hydroxide, combined withtyphoid vaccine containing 25 micrograms/mL virulencepolysaccharide antigen of Salmonella typhi, netprice 1-mL prefilled syringe = £32.08Excipients include neomycinDose. By intramuscular injection(see note below)Child 15–18 years 1 mL as a single dose; booster doses,see under single component hepatitis A vaccine (above)and under polysaccharide typhoid vaccine, p. 620Note The deltoid region is the preferred site of injection;not to be injected into the buttock (vaccine efficacyreduced). The subcutaneous route may be used forchildren with bleeding disordersViATIM c (Sanofi Pasteur) AInjection, suspension of inactivated hepatitis A virus(grown in human diploid cells) 160 antigen units/mLadsorbed onto aluminium hydroxide, combined withtyphoid vaccine containing 25 micrograms/mL virulencepolysaccharide antigen of Salmonella typhi, netprice 1-mL prefilled syringe = £29.80Dose. By intramuscular injection(see note below)Child 16–18 years 1 mL as a single dose; booster doses,see under single component hepatitis A vaccine (above)and under polysaccharide typhoid vaccine, p. 620Note The deltoid region is the preferred site of injection;not to be injected into the buttock (vaccine efficacyreduced). The subcutaneous route may be used forchildren with bleeding disordersHepatitis B vaccineHepatitis B vaccine contains inactivated hepatitis Bvirus surface antigen (HBsAg) adsorbed on to aluminiumhydroxide adjuvant. It is made biosyntheticallyusing recombinant DNA technology. The vaccine isused in individuals at high risk of contracting hepatitis B.In the UK, high-risk groups include:. parenteral drug misusers, their sexual partners, andhousehold contacts; other drug misusers who arelikely to ‘progress’ to injecting;. adolescents who are at risk from their sexual behaviour;

BNFC 2011–2012 14.4 Vaccines and antisera 609. close family contacts of an individual with chronichepatitis B infection;. babies whose mothers have had acute hepatitis Bduring pregnancy or are positive for hepatitis Bsurface antigen (regardless of e-antigen markers);hepatitis B vaccination is started immediately ondelivery and hepatitis B immunoglobulin (seep. 624) given at the same time (but at a differentsite). Babies whose mothers are positive for hepatitisB surface antigen and for e-antigen antibodyshould receive the vaccine only (but babies weighing1.5 kg or less should also receive the immunoglobulinregardless of the mother’s e-antigen antibodystatus);. children with haemophilia, those receiving regularblood transfusions or blood products, and carersresponsible for the administration of such products;. children with chronic renal failure including thoseon haemodialysis. Children receiving haemodialysisshould be monitored for antibodies annually and reimmunisedif necessary. Home carers (of dialysispatients) should be vaccinated;. children with chronic liver disease;. patients of day-care or residential accommodationfor those with severe learning difficulties;. children in custodial institutions;. children travelling to areas of high or intermediateprevalence who are at increased risk or who plan toremain there for lengthy periods (see p. 626);. families adopting children from countries with ahigh or intermediate prevalence of hepatitis B;. foster carers and their families.Different immunisation schedules for hepatitis Bvaccine are recommended for specific circumstances(see under individual preparations); an ‘acceleratedschedule’ is recommended for pre-exposure prophylaxisin high–risk groups where rapid protection is required,and for post-exposure prophylaxis (see below). Generally,three or four doses are required for primaryimmunisation. Immunisation may take up to 6 monthsto confer adequate protection; the duration of immunityis not known precisely, but a single booster 5 years afterthe primary course may be sufficient to maintain immunityfor those who continue to be at risk.Immunisation does not eliminate the need for commonsenseprecautions for avoiding the risk of infection fromknown carriers by the routes of infection which havebeen clearly established, consult Guidance for ClinicalHealth Care Workers: Protection against Infection withBlood-borne Viruses (available at www.dh.gov.uk). Accidentalinoculation of hepatitis B virus-infected bloodinto a wound, incision, needle-prick, or abrasion maylead to infection, whereas it is unlikely that indirectexposure to a carrier will do so.Following significant exposure to hepatits B, an acceleratedschedule, with the second dose given 1 month,and the third dose 2 months after the initial dose, isrecommended. For those at continued risk, a fourthdose should be given 12 months after the first dose.More detailed guidance is given in the Immunisationagainst Infectious Disease handbook, see p. 599Specific hepatitis B immunoglobulin (‘HBIG’) is availablefor use with the vaccine in those accidentallyinoculated and in neonates at special risk of infection(section 14.5.2).A combined hepatitis A and hepatitis B vaccine is alsoavailable.HEPATITIS B VACCINECautions section 14.1Contra-indications section 14.1Pregnancy see p. 600Breast-feeding see p. 600Side-effects section 14.1Indication and doseImmunisation against hepatitis B infectionFor dose see under preparationsSingle componentEngerix B c (GSK) AInjection, suspension of hepatitis B surface antigen(prepared from yeast cells by recombinant DNAtechnique) 20 micrograms/mL adsorbed onto aluminiumhydroxide, net price 0.5-mL (paediatric) prefilledsyringe = £9.67, 1-mL vial = £12.34, 1-mLprefilled syringe = £12.99Dose. By intramuscular injection(see note below)Neonate (except if born to hepatitis B surface antigenpositivemother, see below), 3 doses of 10 micrograms,second dose 1 month and third dose 6 months after firstdoseChild 1 month–16 years 3 doses of 10 micrograms,second dose 1 month and third dose 6 months after firstdoseChild 16–18 years 3 doses of 20 micrograms, seconddose 1 month and third dose 6 months after first doseAccelerated schedule (all age groups), second dose 1month after first dose, third dose 2 months after first doseand fourth dose 12 months after first doseAlternative schedule for Child 11–15 years, 2 doses of20 micrograms, the second dose 6 months after the firstdose (this schedule not suitable if high risk of infectionbetween doses or if compliance with second doseuncertain)Infant born to hepatitis B surface antigen-positivemother (see also notes above). By intramuscular injection(see note below)Neonate 4 doses of 10 micrograms, first dose at birthwith hepatitis B immunoglobulin injection (separate site)the second 1 month, the third 2 months and the fourth 12months after first doseRenal insufficiency (including haemodialysispatients). By intramuscular injection(see note below)Neonate (except if born to hepatitis B surface antigenpositive mother, see above), 3 doses of 10 micrograms,second dose 1 month and third dose 6 months after firstdose or accelerated schedule, 4 doses of 10 micrograms,second dose 1 month, third dose 2 months, and fourthdose 12 months after first dose; immunisation scheduleand booster doses may need to be adjusted in those withlow antibody concentrationChild 1 month–16 years 3 doses of 10 micrograms,second dose 1 month and third dose 6 months after firstdose or accelerated schedule, 4 doses of 10 micrograms,second dose 1 month, third dose 2 months, and fourthdose 12 months after first dose; immunisation schedule14 Immunological products and vaccines

610 14.4 Vaccines and antisera BNFC 2011–201214 Immunological products and vaccinesand booster doses may need to be adjusted in those withlow antibody concentrationChild 16–18 years 4 doses of 40 micrograms, the second1 month, the third 2 months and the fourth 6 monthsafter the first dose; immunisation schedule and boosterdoses may need to be adjusted in those with low antibodyconcentrationNote Deltoid muscle is preferred site of injection in olderchildren; anterolateral thigh is preferred site in neonates,infants and young children; not to be injected into thebuttock (vaccine efficacy reduced)Fendrix c (GSK) AInjection, suspension of hepatitis B surface antigen(prepared from yeast cells by recombinant DNAtechnique) 40 micrograms/mL adsorbed onto aluminiumphosphate, net price 0.5-mL prefilled syringe= £38.10Excipients include traces of thiomersalDoseRenal insufficiency patients (including pre-haemodialysisand haemodialysis patients). By intramuscular injection(see note below)Child 15–18 years 4 doses of 20 micrograms, the second1 month, the third 2 months and the fourth 6 monthsafter the first dose; immunisation schedule and boosterdoses may need to be adjusted in those with low antibodyconcentrationNote Deltoid muscle is preferred site of injection; not tobe injected into the buttock (vaccine efficacy reduced)HBvaxPRO c (Sanofi Pasteur) AInjection, suspension of hepatitis B surface antigen(prepared from yeast cells by recombinant DNAtechnique) 10 micrograms/mL adsorbed onto aluminiumhydroxyphosphate sulphate, net price 0.5-mL(5-microgram) prefilled syringe = £8.95, 1-mL (10-microgram) prefilled syringe = £12.20; 40 micrograms/mL,1-mL (40-microgram) vial = £27.60Dose. By intramuscular injection(see note below)Neonate (except if born to hepatitis B surface antigenpositivemother, see below), 3 doses of 5 micrograms,second dose 1 month and third dose 6 months after firstdoseChild 1 month–16 years 3 doses of 5 micrograms,second dose 1 month and third dose 6 months after firstdoseChild 16–18 years 3 doses of 10 micrograms, seconddose 1 month and third dose 6 months after first doseAccelerated schedule (all age groups), second dose 1month after first dose, third dose 2 months after first dosewith fourth dose at 12 monthsBooster doses may be required in immunocompromisedpatients with low antibody concentrationInfant born to hepatitis B surface antigen-positivemother (see also notes above). By intramuscular injection(see note below)Neonate 5 micrograms, first dose at birth with hepatitis Bimmunoglobulin injection (separate site), the second 1month, the third 2 months and the fourth 12 months afterthe first doseChronic haemodialysis patients. By intramuscular injection(see note below)Child 16–18 years 3 doses of 40 micrograms, seconddose 1 month and third dose 6 months after first dose;booster doses may be required in those with low antibodyconcentrationNote Deltoid muscle is preferred site of injection in olderchildren; anterolateral thigh is preferred site in neonates andinfants; not to be injected into the buttock (vaccine efficacyreduced)With hepatitis A vaccineSee Hepatitis A VaccineHuman papilloma virus vaccinesHuman papilloma virus vaccine is available as abivalent vaccine (Cervarix c ) or a quadrivalent vaccine(Gardasil c ). Cervarix c is licensed for use in females forthe prevention of cervical cancer and other precancerouslesions caused by human papilloma virustypes 16 and 18. Gardasil c is licensed for use in femalesfor the prevention of cervical cancer, genital warts andpre-cancerous lesions caused by human papilloma virustypes 6, 11, 16 and 18. The vaccines may also providelimited protection against disease caused by other typesof human papilloma virus. The two vaccines are notinterchangeable and one vaccine product should beused for an entire course. However, the Department ofHealth (November 2008) states for individuals withprevious incomplete vaccination with Gardasil c , whoare eligible for HPV vaccination under the nationalprogramme, Cervarix c can be used to complete thevaccination course if necessary; the individual must beinformed that Cervarix c does not protect againstgenital warts.Human papilloma virus vaccine will be most effective ifgiven before sexual activity starts. The first dose is givento females aged 12 to 13 years, the second and thirddoses are given 1–2 and 6 months after the first dose(see Immunisation schedule, section 14.1); all 3 dosesshould be given within a 12-month period. If the courseis interrupted, it should be resumed but not repeated,allowing the appropriate interval between the remainingdoses. Where there are significant challenges in schedulingvaccination, or a high likelihood that the thirddose will not be given, the third dose of Cervarix c canbe given 3 months after the second dose; if this is notpossible and the second dose was given late, inexceptional circumstances, the third dose can be givenat least 1 month after the second dose. Under thenational programme in England, females remain eligibleto receive the vaccine up to the age of 18 years if theydid not receive the vaccine when scheduled. Whereappropriate, immunisation with human papillomavirusvaccine should be offered to females coming into theUK as they may not have been offered protection intheir country of origin. The duration of protection hasnot been established, but current studies suggest thatprotection is maintained for at least 6 years aftercompletion of the primary course.HUMAN PAPILLOMA VIRUSVACCINESCautions see section 14.1Contra-indications see section 14.1Pregnancy not known to be harmful, but vaccinationshould be postponed until completion of pregnancyBreast-feeding see p. 600Side-effects see section 14.1

BNFC 2011–2012 14.4 Vaccines and antisera 611Indication and doseSee notes above and under preparationsNote To avoid confusion, prescribers should specify thebrand to be dispensedCervarix c (GSK) AInjection, suspension of virus-like particles of humanpapilloma virus type 16 (40 micrograms/mL), type 18(40 micrograms/mL) capsid protein (prepared byrecombinant DNA technique using a Baculovirusexpression system) in monophosphoryl lipid A adjuvantadsorbed onto aluminium hydroxide, net price0.5-mL prefilled syringe = £80.50Note To avoid confusion, prescribers should specify the brandto be dispensedDosePrevention of premalignant genital lesions and cervicalcancer (see notes above). By intramuscular injection into deltoid regionChild 10–18 years 3 doses of 0.5 mL, the second 1month and the third 6 months after the first doseAlternative schedule for Child 10–18 years, 3 doses of0.5 mL, the second 1–2.5 months, and the third 5–12months after the first doseGardasil c (Sanofi Pasteur) TAInjection, suspension of virus-like particles of humanpapilloma virus type 6 (40 micrograms/mL), type 11(80 micrograms/mL), type 16 (80 micrograms/mL),type 18 (40 micrograms/mL) capsid protein (preparedfrom yeast cells by recombinant DNA technique)adsorbed onto aluminium hydroxyphosphate sulphate,net price 0.5-mL prefilled syringe = £86.50Note To avoid confusion, prescribers should specify the brandto be dispensedDosePrevention of premalignant genital lesions, cervicalcancer and genital warts (see notes above). By intramuscular injection preferably into deltoidregion or higher anterolateral thighChild 9–18 years 3 doses of 0.5 mL, the second 2months and the third 6 months after the first doseAlternative schedule for Child 9–18 years, 3 doses of0.5 mL, the second at least 1 month and the third at least4 months after the first dose; schedule should be completedwithin 12 months. chronic liver disease;. chronic renal disease;. chronic neurological disease;. diabetes mellitus;. immunosuppression because of disease (includingasplenia or splenic dysfunction) or treatment(including prolonged corticosteroid treatment [forover 1 month at dose equivalents of prednisolone:1 mg/kg or more daily or 20 mg or more daily] andchemotherapy);. HIV infection (regardless of immune status).Seasonal influenza vaccine is also recommended for allpregnant women, for children living in long-stay facilities,and for carers of children whose welfare may be atrisk if the carer falls ill. Influenza immunisation shouldalso be considered for household contacts of immunocompromisedindividuals.Monovalent influenza A(H1N1)v vaccinesPandemrix c and Celvapan c are monovalent vaccineslicensed against the influenza A(H1N1)v (swine flu)strain.Pandemrix c is recommended for children aged 6months–5 years who have not received the monovalentvaccine previously and who are in the risk groupsprioritised for seasonal influenza vaccine. Pandemrix cis also recommended for all immunocompromisedpatients over 6 months of age who have not receivedthe monovalent vaccine previously. Seasonal influenzavaccine should continue to be offered as normal.Pandemrix c can be given at the same time as the firstdose of seasonal influenza vaccine; however,Pandemrix c should be given 4 weeks before theseasonal influenza vaccine to immunocompromisedpatients who only require one dose of seasonal influenzavaccine.Further information on pandemic influenza, avian influenzaand swine influenza may be found atwww.dh.gov.uk/pandemicflu and at www.hpa.org.uk.Influenza vaccineWhile most viruses are antigenically stable, the influenzaviruses A and B (especially A) are constantlyaltering their antigenic structure as indicated bychanges in the haemagglutinins (H) and neuraminidases(N) on the surface of the viruses. It is essential thatinfluenza vaccines in use contain the H and N componentsof the prevalent strain or strains recommendedeach year by the World Health Organization.Seasonal influenza vaccines Seasonal influenzavaccines will not control epidemics — immunisation isrecommended only for persons at high risk. Annualimmunisation is strongly recommended for children(including infants that were preterm or low birth-weight)aged over 6 months with the following conditions:. chronic respiratory disease (includes asthma treatedwith continuous or repeated use of inhaled orsystemic corticosteroids or asthma with previousexacerbations requiring hospital admission);. chronic heart disease;INFLUENZA VACCINESCautions see section 14.1; interactions: Appendix 1(vaccines)Contra-indications see section 14.1; avoid Enzira c orpreparations marketed by Pfizer, Wyeth or CSLBiotherapies in child under 5 years—increased risk offebrile convulsionsPregnancy not known to be harmfulBreast-feeding not known to be harmfulSide-effects see section 14.1; also reported, febrileconvulsions and transient thrombocytopeniaLicensed use Inactivated Influenza Vaccine (SurfaceAntigen) and Fluvirin c are not licensed for use inchildren under 4 yearsIndication and doseAnnual immunisation against seasonal influenza. By intramuscular injectionChild 6 months–3 years 0.25–0.5 mL (repeatedafter 4–6 weeks in children who have not receivedseasonal influenza vaccine previously)14 Immunological products and vaccines

612 14.4 Vaccines and antisera BNFC 2011–201214 Immunological products and vaccinesChild 3–13 years 0.5 mL (repeated after 4–6weeks in children who have not received seasonalinfluenza vaccine previously)Child 13–18 years 0.5 mL as a single doseInfluenza A(HINI)vSee under Celvapan c and Pandemrix c belowSeasonal influenza vaccinesInactivated Influenza Vaccine (Split Virion) AFluInjection, suspension of formaldehyde-inactivatedinfluenza virus (split virion) grown in fertilised hens’eggs, net price 0.25-mL prefilled syringe = £6.29, 0.5-mL prefilled syringe = £6.29Excipients may include neomycin and polymyxinAvailable from Sanofi PasteurContra-indications avoid preparations marketed by Pfizer,Wyeth, or CSL Biotherapies in child under 5 years—increased riskof febrile convulsionsInactivated Influenza Vaccine (Surface Antigen)AFlu or Flu(adj)Injection, suspension of propiolactone-inactivatedinfluenza virus (surface antigen) grown in fertilisedhens’ eggs, net price 0.5-mL prefilled syringe = £4.15Excipients may include neomycin, polymyxin B and traces of thiomersalAvailable from Novartis VaccinesAgrippal c (Novartis Vaccines) AInjection, suspension of formaldehyde-inactivatedinfluenza virus (surface antigen) grown in fertilisedhens’ eggs, net price 0.5-mL prefilled syringe = £5.85Excipients include kanamycin and neomycinBegrivac c (Novartis Vaccines) AInjection, suspension of formaldehyde-inactivatedinfluenza virus (split virion) grown in fertilised hens’eggs, net price 0.5-mL prefilled syringe = £5.85Excipients include polymyxin BEnzira c (Pfizer) AInjection, suspension of inactivated influenza virus(split virion) grown in fertilised hens’ eggs, net price0.5-mL prefilled syringe = £6.33Excipients include neomycin and polymyxin BContra-indications child under 5 years—increased risk of febrileconvulsionsFluarix c (GSK) AInjection, suspension of formaldehyde-inactivatedinfluenza virus (split virion) grown in fertilised hens’eggs, net price 0.5-mL prefilled syringe = £5.39Excipients include gentamicinFluvirin c (Novartis Vaccines) AInjection, suspension of formaldehyde-inactivatedinfluenza virus (surface antigen) grown in fertilisedhens’ eggs, net price 0.5 mL prefilled syringe = £5.55Excipients include neomycin, polymyxin B, and traces of thiomersalImuvac c (Abbott Healthcare) AInjection, suspension of formaldehyde-inactivatedinfluenza virus (surface antigen) grown in fertilisedhens’ eggs, net price 0.5-mL prefilled syringe = £6.59Excipients include gentamicinInfluvac Sub-unit c (Abbott Healthcare) AInjection, suspension of formaldehyde-inactivatedinfluenza virus (surface antigen) grown in fertilisedhens’ eggs, net price 0.5-mL prefilled syringe = £5.22Excipients include gentamicinMastaflu c (MASTA) AInjection, suspension of formaldehyde-inactivatedinfluenza virus (surface antigen) grown in fertilisedhens’ eggs, net price 0.5-mL prefilled syringe = £6.50Excipients include gentamicinViroflu c (Crucell) AInjection, suspension of inactivated influenza virus(surface antigen, virosome) grown in fertilised hens’eggs, net price 0.5-mL prefilled syringe = £6.33Excipients include neomycin and polymyxin BMonovalent influenza A(H1N1)v vaccinesCelvapan c (Baxter) TAInjection, suspension of formaldehyde-inactivatedinfluenza A(H1N1)v virus (whole virion, grown in verocells), 15 micrograms/mL, 5-mL multidose vial contains10 doses of 0.5 mLDosePrevention of influenza A(H1N1)v. By intramuscular injectionChild 6 months–18 years 2 doses each of 0.5 mLseparated by an interval of at least 3 weeksNote Celvapan c is not interchangeable withPandemrix cPandemrix c (GSK) TAInjection, suspension of inactivated influenzaA(H1N1)v virus (split virion, grown in fertilised hens’eggs) 7.5 micrograms/mL when mixed with emulsionof adjuvant, 5 mL of mixed multidose vial contains 10doses of 0.5 mLExcipients include gentamicin and thiomersalDosePrevention of influenza A(H1N1)v. By intramuscular injectionChild 6 months–10 years 0.25 mL as a single doseChild 10–18 years 0.5 mL as a single doseNote Pandemrix c is not interchangeable withCelvapan cMeasles vaccineMeasles vaccine has been replaced by a combined livemeasles, mumps and rubella vaccine (MMR vaccine).MMR vaccine may be used in the control of outbreaks ofmeasles (see under MMR Vaccine).Single antigen vaccineNo longer available in the UKCombined vaccinesSee MMR vaccine, belowMeasles, Mumps and Rubella (MMR)vaccineA combined live measles, mumps, and rubellavaccine (MMR vaccine) aims to eliminate measles,mumps and rubella (and congenital rubella syndrome).Every child should receive two doses of MMR vaccineby entry to primary school, unless there is a validcontra-indication (see section 14.1). MMR vaccineshould be given irrespective of previous measles,mumps, or rubella infection or vaccination.The first dose of MMR vaccine is given to children aged12–13 months. A second dose is given before starting

BNFC 2011–2012 14.4 Vaccines and antisera 613school at 3–5 years of age (see Immunisation schedule,section 14.1).When protection against measles is required urgently(e.g. during a measles outbreak), the second dose ofMMR vaccine can be given 1 month after the first dose;if the second dose is given before 18 months of age, thenchildren should still receive the routine dose beforestarting school at 3–5 years of age.Children presenting for pre-school booster who havenot received the first dose of MMR vaccine should begiven a dose of MMR vaccine followed 3 months later bya second dose. At school-leaving age or at entry intofurther education, MMR immunisation should beoffered to individuals of both sexes who have notreceived 2 doses during childhood. In a young adultwho has received only a single dose of MMR in childhood,a second dose is recommended to achieve fullprotection. If 2 doses of MMR vaccine are required, thesecond dose should be given one month after the initialdose.MMR vaccine should be used to protect against rubellain seronegative females of child-bearing age (seeImmunisation schedule, section 14.1). MMR vaccinemay also be offered to previously unimmunised andseronegative post-partum mothers—vaccination a fewdays after delivery is important because about 60% ofcongenital abnormalities from rubella infection occur inbabies of mothers who have borne more than one child.Immigrants arriving after the age of school immunisationare particularly likely to require immunisation.Contacts MMR vaccine may also be used in thecontrol of outbreaks of measles and should be offeredto susceptible children including babies aged over 6months who are contacts of a case, within 3 days ofexposure to infection; these children should still receiveroutine MMR vaccinations at the recommended ages.Children aged under 9 months for whom avoidance ofmeasles infection is particularly important (such asthose with history of recent severe illness) can begiven normal immunoglobulin (section 14.5, p. 622)after exposure to measles; routine MMR immunisationshould then be given after at least 3 months at theappropriate age.MMR vaccine is not suitable for prophylaxis followingexposure to mumps or rubella since the antibodyresponse to the mumps and rubella components is tooslow for effective prophylaxis.Children with impaired immune response should notreceive live vaccines (for advice on HIV see section14.1). If they have been exposed to measles infectionthey should be given normal immunoglobulin (section14.5).Travel Unimmunised children over 6 months of agetravelling to areas where measles is endemic or epidemicshould receive MMR vaccine. Children immunisedbefore 12 months of age should still receive twodoses of MMR at the recommended ages. If one dose ofMMR has already been given to a child, then the seconddose should be brought forward to at least one monthafter the first, to ensure complete protection. If the childis under 18 months of age and the second dose is givenwithin 3 months of the first, then the routine dose,before starting school at 3–5 years, should still be given.Side-effects See section 14.1. Also malaise, fever, or arash can occur after the first dose of MMR vaccine, mostcommonly about a week after vaccination and lastingabout 2 to 3 days. Leaflets are available for parents onadvice for reducing fever (including the use of paracetamol).Febrile seizures occur rarely 6 to 11 days afterMMR vaccination; the incidence of febrile seizures islower than that following measles infection. Parotidswelling occurs occasionally, usually in the third week,and rarely, arthropathy 2 to 3 weeks after immunisation.Adverse reactions are considerably less frequent afterthe second dose of MMR vaccine than after the firstdose.Idiopathic thrombocytopenic purpura has occurredrarely following MMR vaccination, usually within 6weeks of the first dose. The risk of idiopathic thrombocytopenicpurpura after MMR vaccine is much less thanthe risk after infection with wild measles or rubella virus.Children who develop idiopathic thrombocytopenicpurpura within 6 weeks of the first dose of MMR shouldundergo serological testing before the second dose isdue; if the results suggest incomplete immunity againstmeasles, mumps or rubella then a second dose of MMRis recommended. The Specialist and Reference MicrobiologyDivision, Health Protection Agency offers freeserological testing for children who develop idiopathicthrombocytopenic purpura within 6 weeks of the firstdose of MMR.Post-vaccination aseptic meningitis was reported (rarelyand with complete recovery) following vaccination withMMR vaccine containing Urabe mumps vaccine, whichhas now been discontinued; no cases have been confirmedin association with the currently used Jeryl Lynnmumps vaccine. Children with post-vaccination symptomsare not infectious.Reviews undertaken on behalf of the CSM, theMedical Research Council, and the Cochrane Collabaration,have not found any evidence of a linkbetween MMR vaccination and bowel disease orautism. The Chief Medical Officers have advisedthat the MMR vaccine is the safest and best way toprotect children against measles, mumps, and rubella.Information (including fact sheets and a list ofreferences) may be obtained from:www.dh.gov.uk/immunisationMEASLES, MUMPS AND RUBELLAVACCINE, LIVECautions see section 14.1; also after immunoglobulinadministration or blood transfusion, leave an intervalof at least 3 months before MMR immunisation asantibody response to measles component may bereduced; interactions: Appendix 1 (vaccines)Hypersensitivity to egg There is increasing evidence thatMMR vaccine can be given safely even when the child hashad an anaphylactic reaction to food containing egg (dislikeof egg or refusal to eat egg is not a contra-indication). Forchildren with a confirmed anaphylactic reaction to eggcontainingfood, MMR vaccine may be administered in ahospital setting.Contra-indications see section 14.1Pregnancy avoid pregnancy for at least 1 month aftervaccination; see also, p. 600Breast-feeding see p. 60014 Immunological products and vaccines

614 14.4 Vaccines and antisera BNFC 2011–201214 Immunological products and vaccinesSide-effects see section 14.1 and notes above; alsoless commonly sleep disturbance, unusual crying ininfants, also reported peripheral and optic neuritis.Licensed use not licensed for use in children under 9monthsIndication and doseImmunisation against measles, mumps, andrubella. By intramuscular or deep subcutaneous injectionCHILD 6 months–18 years primary immunisation,2 doses each of 0.5 mL, see Immunisationschedule, section 14.1, p. 601; see also notes abovefor use in outbreaks, for contacts of cases, and fortravelCombined vaccinesMMRvaxPro c (Sanofi Pasteur) TAInjection, powder for reconstitution, live attenuated,measles virus (Enders’ Edmonston strain) and mumpsvirus (Jeryl Lynn [Level B] strain) prepared in chickembryo cells, and rubella virus (Wistar RA 27/3strain); single-dose vial (with syringe containing solvent)Excipients include gelatin and neomycinOnly available as part of childhood immunisation schedule fromhealth organisations or ImmFormPriorix c (GSK) AInjection, powder for reconstitution, live attenuated,measles virus (Schwarz strain) and mumps virus (RIT4385 strain) prepared in chick embryo cells, and rubellavirus (Wistar RA 27/3 strain), net price singledosevial (with syringe containing solvent) = £6.37Excipients include neomycinAlso available as part of childhood immunisation schedule fromhealth organisations or ImmFormMeningococcal vaccinesAlmost all childhood meningococcal disease in the UKis caused by Neisseria meningitidis serogroups B and C.Meningococcal Group C conjugate vaccine protectsonly against infection by serogroup C. The risk ofmeningococcal disease declines with age—immunisationis not generally recommended after the age of25 years.Tetravalent meningococcal vaccines that cover serotypesA, C, W135, and Y are available. Although theduration of protection has not been established, themeningococcal A, C, W135, and Y conjugate vaccineis likely to provide longer-lasting protection than theunconjugated meningococal polysaccharide vaccine.The antibody response to serotype C in unconjugatedmeningococcal polysaccharide vaccines in young childrenmay be suboptimal.Childhood immunisation Meningococcal Group Cconjugate vaccine provides long-term protectionagainst infection by serogroup C of Neisseria meningitidis.Immunisation consists of 2 doses given at 3months and 4 months of age; a booster dose shouldbe given at 12–13 months of age, usually combined withhaemophilus influenzae type b vaccine (see ImmunisationSchedule, section 14.1, p. 601).It is recommended that meningococcal group C conjugatevaccine be given to anyone aged under 25 yearswho has not been vaccinated previously with thisvaccine; those over 1 year receive a single dose. Childrenwith confirmed serogroup C disease, who havepreviously been immunised with meningococcal groupC vaccine, should be offered meningococcal group Cconjugate vaccine before discharge from hospital.Asplenia, splenic dysfunction, or complementdeficiency See p. 606.Travel Individuals travelling to countries of risk (seebelow) should be immunised with meningococcal A, C,W135, and Y conjugate vaccine, even if they havepreviously received meningitis C conjugate vaccine. Ifan individual has recently received meningococcalgroup C conjugate vaccine, an interval of at least 4weeks should be allowed before administration of thetetravalent (A, C, W135, and Y) vaccine.Vaccination is particularly important for those livingwith local people or visiting an area of risk duringoutbreaks.Immunisation recommendations and requirements forvisa entry for individual countries should be checkedbefore travelling, particularly to countries in Sub-SaharanAfrica, Asia, and the Indian sub-continent whereoutbreaks and epidemics of meningococcal infectionare reported. Country-by-country information is availablefrom the National Travel Health Network andCentre (www.nathnac.org).Proof of vaccination with the tetravalent (A, C, W135and Y) meningococcal vaccine is required for thosetravelling to Saudi Arabia during the Hajj and Umrahpilgrimages (where outbreaks of the W135 strain haveoccurred).Contacts For advice on the immunisation of laboratoryworkers and close contacts of cases of meningococcaldisease in the UK and on the role of the vaccinein the control of local outbreaks, consult Guidelines forPublic Health Management of Meningococcal Diseasein the UK at www.hpa.org.uk. See Table 2, section 5.1for antibacterial prophylaxis for prevention of secondarycases of meningococcal meningitis.MENINGOCOCCAL VACCINESCautions see section 14.1Contra-indications see section 14.1Pregnancy see p. 600Breast-feeding see p. 600Side-effects see section 14.1; also rarely symptoms ofmeningitis reported (but no evidence that vaccinecauses meningococcal C meningitis)Licensed use Menveo c not licensed for use inchildren under 11 yearsIndication and doseImmunisation against Neisseria meningitidisfor dose, see under preparationsMeningococcal Group C conjugate vaccineMeningitec c (Wyeth) AInjection, suspension of capsular polysaccharideantigen of Neisseria meningitidis group C (conjugatedto Corynebacterium diphtheriae protein), adsorbed

BNFC 2011–2012 14.4 Vaccines and antisera 615onto aluminium phosphate, net price 0.5-mL prefilledsyringe = £7.50Dose. By intramuscular injectionChild 2 months–1 year for routine immunisation,0.5 mL, see notes above and Immunisation schedule,section 14.1Child 1–18 years 0.5 mL as a single doseNote Subcutaneous route used for children with bleedingdisordersAvailable as part of childhood immunisation schedule fromImmFormMenjugate Kit c (Sanofi Pasteur) AInjection, powder for reconstitution, capsular polysaccharideantigen of Neisseria meningitidis group C(conjugated to Corynebacterium diphtheriae protein),adsorbed onto aluminium hydroxide, single-dose vialsDose. By intramuscular injectionChild 2 months–1 year for routine immunisation,0.5 mL, see notes above and Immunisation schedule,section 14.1Child 1–18 years 0.5 mL as a single doseNote Subcutaneous route used for children with bleedingdisordersAvailable as part of childhood immunisation schedule fromImmFormNeisVac-C c (Baxter) AInjection, suspension of polysaccharide antigen ofNeisseria meningitidis group C (conjugated to tetanustoxoid protein), adsorbed onto aluminium hydroxide,0.5-mL prefilled syringeDose. By intramuscular injectionChild 2 months–1 year for routine immunisation,0.5 mL, see notes above and Immunisation schedule,section 14.1Child 1–18 years 0.5 mL as a single doseAvailable as part of childhood immunisation schedule fromImmFormMeningococcal Group C conjugate vaccine withHaemophilus Influenzae type B vaccineSee Haemophilus Influenzae type B vaccineMeningococcal A, C, W135, and Y conjugatevaccineMenveo c (Novartis Vaccines) TAInjection, powder for reconstitution, capsular oligosaccharideantigens of Neisseria meningitidis groupsA, C, W135, and Y (conjugated to Corynebacteriumdiphtheriae protein), net price single-dose vial (withsyringe containing diluent) = £40.01Dose. By intramuscular injection preferably into deltoidregionChild 3 months–1 year 2 doses of 0.5 mL separated byan interval of 1 monthChild 1–18 years 0.5 mL as a single doseMeningococcal polysaccharide A, C, W135 and YvaccineACWY Vax c (GSK) TAInjection, powder for reconstitution, capsular polysaccharideantigens of Neisseria meningitidis groupsA, C, W135 and Y, net price single-dose vial (withsyringe containing diluent) = £16.73Dose. By deep subcutaneous injectionChild 5–18 years 0.5 mL as a single dose; booster dosefor those at continued risk, 0.5mL 5 years after initialdoseMumps vaccineSingle antigen vaccineNo longer available in the UKCombined vaccinesSee MMR Vaccine, p. 612Pertussis vaccinePertussis vaccine is given as a combination preparationcontaining other vaccines (see Diphtheria Vaccines).Acellular vaccines are derived from highly purifiedcomponents of Bordetella pertussis. Primaryimmunisation against pertussis (whooping cough)requires 3 doses of an acellular pertussis-containingvaccine (see Immunisation schedule, section 14.1,p. 601), given at intervals of 1 month from the age of2 months.All children up to the age of 10 years should receiveprimary immunisation with diphtheria, tetanus, pertussis(acellular, component), poliomyelitis (inactivated)and haemophilus type b conjugate vaccine (adsorbed).A booster dose of an acellular pertussis-containingvaccine should ideally be given 3 years after the primarycourse, although, the interval can be reduced to 1 year ifthe primary course was delayed.Children aged 1–10 years who have not received apertussis-containing vaccine as part of their primaryimmunisation schedule should be offered 1 dose of asuitable pertussis-containing vaccine; after an interval ofat least 1 year, a booster dose of a suitable pertussiscontainingvaccine should be given. Immunisationagainst pertussis is not routinely recommended in individualsover 10 years of age.Contacts Vaccination against pertussis should beconsidered for close contacts of cases with pertussiswho have been offered antibacterial prophylaxis (Table2, section 5.1). Unimmunised or partially immunisedcontacts under 10 years of age should complete theirvaccination against pertussis. A booster dose of anacellular pertussis-containing vaccine is recommendedfor contacts aged 10–18 years who have not received apertussis-containing vaccine in the last 10 years andwho have not received adsorbed diphtheria [low dose],tetanus, and poliomyelitis (inactivated) vaccine in thelast month.Cautions Section 14.1Contra-indications Section 14.1Pregnancy see p. 600Breast-feeding see p. 60014 Immunological products and vaccines

616 14.4 Vaccines and antisera BNFC 2011–201214 Immunological products and vaccinesSide effects See also section 14.1. The incidence oflocal and systemic effects is generally lower with vaccinescontaining acellular pertussis components thanwith the whole-cell pertussis vaccine used. However,compared with primary vaccination, booster doses withvaccines containing acellular pertussis are reported toincrease the risk of injection-site reactions (some ofwhich affect the entire limb); local reactions do notcontra-indicate further doses (see below).The vaccine should not be withheld from children with ahistory to a preceding dose of:. fever, irrespective of severity;. persistent crying or screaming for more than 3hours;. severe local reaction, irrespective of extent.Combined vaccinesCombined vaccines, see under Diphtheria vaccinesPneumococcal vaccinesPneumococcal vaccines protect against infection withStreptococcus pneumoniae (pneumococcus); the vaccinescontain polysaccharide from capsular pneumococci,Pneumococcal polysaccharide vaccine containspurified polysaccharide from 23 capsular types ofpneumococci, whereas pneumococcal polysaccharideconjugate vaccine (adsorbed) contains polysaccharidefrom either 10 capsular types (Synflorix c ) or 13capsular types (Prevenar 13 c ) with the polysaccharidebeing conjugated to protein.The 13-valent conjugate vaccine is used for childhoodimmunisation. The recommended schedule consists of 3doses, the first at 2 months of age, the second at 4months, and the third at 12–13 months (see ImmunisationSchedule, section 14.1).Pneumococcal vaccination is recommended for individualsat increased risk of pneumococcal infection asfollows:. child under 5 years with a history of invasivepneumococcal disease;. asplenia or splenic dysfunction (including homozygoussickle cell disease and coeliac disease whichcould lead to splenic dysfunction);. chronic respiratory disease (includes asthma treatedwith continuous or frequent use of a systemiccorticosteroid);. chronic heart disease;. chronic renal disease;. chronic liver disease;. diabetes mellitus;. immune deficiency because of disease (e.g. HIVinfection) or treatment (including prolonged systemiccorticosteroid treatment);. presence of cochlear implant;. conditions where leakage of cerebrospinal fluidcould occur.Where possible, the vaccine should be given at least 2weeks before splenectomy, cochlear implant surgery,and chemotherapy; children and carers should begiven advice about increased risk of pneumococcalinfection. Prophylactic antibacterial therapy againstpneumococcal infection (Table 2, section 5.1, p. 255)should not be stopped after immunisation. A patientcard and information leaflet for patients with aspleniaare available from the Department of Health or in Scotlandfrom the Scottish Executive, Public Health Division1 (Tel (0131) 244 2501).Choice of vaccine Children under 2 years at increasedrisk of pneumococcal infection (see list above) shouldreceive the 13-valent pneumococcal polysaccharideconjugate vaccine (adsorbed) at the recommendedages, followed by a single dose of the 23-valent pneumococcalpolysaccharide vaccine after their second birthday(see below). Children at increased risk of pneumococcalinfection presenting late for vaccination shouldreceive 2 doses (separated by at least 1 month) of the13-valent pneumococcal polysaccharide conjugatevaccine (adsorbed) before the age of 12 months, and athird dose at 12–13 months. Children over 12 monthsand under 5 years (who have not been vaccinated or notcompleted the primary course) should receive a singledose of 13-valent pneumococcal polysaccharide conjugatevaccine (adsorbed) (2 doses separated by an intervalof 2 months in the immunocompromised or thosewith asplenia or splenic dysfunction). All children under5 years at increased risk of pneumococcal infectionshould receive a single dose of the 23-valent pneumococcalpolysaccharide vaccine after their second birthdayand at least 2 months after the final dose of the 13-valent pneumococcal polysaccharide conjugate vaccine(adsorbed).Children over 5 years who are at increased risk ofpneumococcal disease should receive a single dose ofthe 23-valent unconjugated pneumococcal polysaccharidevaccine.Revaccination In individuals with higher concentrationsof antibodies to pneumococcal polysaccharides,revaccination with the 23-valent pneumococcal polysaccharidevaccine more commonly produces adversereactions. Revaccination is therefore not recommended,except every 5 years in individuals in whom the antibodyconcentration is likely to decline rapidly (e.g.asplenia, splenic dysfunction and nephrotic syndrome).If there is doubt, the need for revaccination should bediscussed with a haematologist, immunologist, ormicrobiologist.PNEUMOCOCCAL VACCINESCautions see section 14.1Contra-indications see section 14.1Pregnancy see p. 600Breast-feeding see p. 600Side-effects see section 14.1; also Revaccination,aboveIndication and doseImmunisation against pneumococcal infectionFor dose see under preparationsPneumococcal polysaccharide vaccinesPneumovax c II (Sanofi Pasteur) AInjection, polysaccharide from each of 23 capsulartypes of pneumococcus, net price 0.5-mL vial = £8.32Dose. By subcutaneous or intramuscular injectionChild 2–18 years 0.5 mL; revaccination, see notes above

BNFC 2011–2012 14.4 Vaccines and antisera 617Pneumococcal polysaccharide conjugate vaccine(adsorbed)Prevenar 13 c (Wyeth) TAInjection, polysaccharide from each of 13 capsulartypes of pneumococcus (conjugated to carrier protein)adsorbed onto aluminium phosphate, net price0.5-mL prefilled syringe = £49.10Dose. By intramuscular injectionChild 2 months–5 years 0.5 mL (see notes above andImmunisation schedule, section 14.1)Note Deltoid muscle is preferred site of injection inyoung children; anterolateral thigh is preferred site ininfantsThe dose in BNF for Children may differ from that inproduct literatureAvailable as part of childhood immunisation schedule fromImmFormSynflorix c (GSK) TAInjection, polysaccharide from each of 10 capsulartypes of pneumococcus (conjugated to carrier proteins)adsorbed onto aluminium phosphate, net price0.5-mL prefilled syringe = £27.60Dose. By intramuscular injectionChild 6 weeks–2 years consult product literatureNote Deltoid muscle is preferred site of injection in youngchildren; anterolateral thigh is preferred site in infantsPoliomyelitis vaccinesTwo types of poliomyelitis vaccine (containing strains ofpoliovirus types 1, 2, and 3) are available, inactivatedpoliomyelitis vaccine (for injection) and live (oral) poliomyelitisvaccine. Inactivated poliomyelitis vaccine,only available in combined preparation (see under Diphtheriavaccines, combined), is recommended for routineimmunisation; it is given by injection and containsinactivated strains of human poliovirus types 1, 2 and 3.A course of primary immunisation consists of 3 doses ofa combined preparation containing inactivated poliomyelitisvaccine starting at 2 months of age with intervalsof 1 month between doses (see Immunisationschedule, section 14.1). A course of 3 doses shouldalso be given to all unimmunised children; no childshould remain unimmunised against poliomyelitis.Two booster doses of a preparation containing inactivatedpoliomyelitis vaccine are recommended, the firstbefore school entry and the second before leavingschool (see Immunisation schedule, section 14.1).Further booster doses should be given every 10 yearsonly to individuals at special risk.Preparations containing inactivated poliomyelitisvaccine can be used to complete an immunisationcourse initiated with the live (oral) poliomyelitis vaccine.Live (oral) poliomyelitis vaccine is available only foruse during outbreaks. The live (oral) vaccine poses avery rare risk of vaccine-associated paralytic poliobecause the attenuated strain of the virus can revertto a virulent form. For this reason the live (oral) vaccinemust not be used for immunosuppressed individuals ortheir household contacts. The use of inactivated poliomyelitisvaccine removes the risk of vaccine-associatedparalytic polio altogether.Travel Unimmunised travellers to areas with a highincidence of poliomyelitis should receive a full 3–dosecourse of a preparation containing inactivated poliomyelitisvaccine. Those who have not been vaccinatedin the last 10 years should receive a booster dose ofadsorbed diphtheria [low dose], tetanus and poliomyelitis(inactivated) vaccine. Information aboutcountries with a high incidence of poliomyelitis can beobtained from www.travax.nhs.uk or from the NationalTravel Health Network and Centre, p. 627(www.nathnac.org).POLIOMYELITIS VACCINESCautions see section 14.1; also for live vaccine,interactions: Appendix 1 (vaccines)Contra-indications see notes above and section 14.1Pregnancy see p. 600Breast-feeding see p. 600Side-effects see notes above and section 14.1Indication and doseSee under preparationsCombined vaccinesSee under Diphtheria-containing VaccinesInactivated (Salk) VaccineSee under Diphtheria-containing VaccinesLive (oral) (Sabin) vaccinePoliomyelitis Vaccine, Live (Oral) (GSK) AOPVA suspension of suitable live attenuated strains ofpoliomyelitis virus, types 1, 2, and 3. Available insingle-dose and 10-dose containersExcipients include neomycin and polymyxin BDoseControl of outbreaks. By mouthChild 1 month–18 years 3 drops; may be given on alump of sugar; not to be given with foods which containpreservativesNote Live poliomyelitis vaccine loses potency once thecontainer has been opened—any vaccine remaining at theend of an immunisation session should be discarded;whenever possible sessions should be arranged to avoidundue wastage.Rabies vaccineRabies vaccine contains inactivated rabies virus cultivatedin either human diploid cells or purified chickembryo cells; vaccines are used for pre- and postexposureprophylaxis.Pre-exposure prophylaxis Immunisation should beoffered to children at high risk of exposure to rabies—where there is limited access to prompt medical care forthose living in areas where rabies is enzootic, for thosetravelling to such areas for longer than 1 month, and forthose on shorter visits who may be exposed to unusualrisk. Transmission of rabies by humans has not beenrecorded but it is advised that those caring for childrenwith the disease should be vaccinated.Immunisation against rabies is indicated duringpregnancy if there is substantial risk of exposure to14 Immunological products and vaccines

618 14.4 Vaccines and antisera BNFC 2011–201214 Immunological products and vaccinesrabies and rapid access to post-exposure prophylaxis islikely to be limited.Up-to-date country-by-country information on the incidenceof rabies can be obtained from the NationalTravel Health Network and Centre (www.nathnac.org)and, in Scotland, from Health Protection Scotland(www.hps.scot.nhs.uk).Immunisation against rabies requires 3 doses of rabiesvaccine, with further booster doses for those whoremain at continued risk.Post-exposure management Following potentialexposure to rabies, the wound or site of exposure (e.g.mucous membrane) should be cleansed under runningwater and washed for several minutes with soapy wateras soon as possible after exposure. Disinfectant and asimple dressing can be applied, but suturing should bedelayed because it may increase the risk of introducingrabies virus into the nerves.Post-exposure prophylaxis against rabies depends onthe level of risk in the country, the nature of exposure,and the individual’s immunity. In each case, expert riskassessment and advice on appropriate managementshould be obtained from the Health Protection AgencyVirus Reference Department, Colindale, London (tel.(020) 8200 4400) or the Centre for Infections (tel.(020) 8200 6868), in Scotland from Health ProtectionScotland (tel. (0141) 300 1100), in Northern Ireland fromthe Public Health Laboratory, Belfast City Hospital (tel.(028) 9032 9241).There are no specific contra-indications to the use ofrabies vaccine for post-exposure prophylaxis and its useshould be considered whenever a child has beenattacked by an animal in a country where rabies isenzootic, even if there is no direct evidence of rabiesin the attacking animal. Because of the potential consequencesof untreated rabies exposure and becauserabies vaccination has not been associated with fetalabnormalities, pregnancy is not considered a contraindicationto post-exposure prophylaxis.For post-exposure prophylaxis of fully immunised individuals(who have previously received pre-exposure orpost-exposure prophylaxis with cell-derived rabiesvaccine), 2 doses of cell-derived vaccine, given on day0 and day 3, are likely to be sufficient. Rabies immunoglobulinis not necessary in such cases.Post-exposure treatment for unimmunised individuals(or those whose prophylaxis is possibly incomplete)comprises 5 doses of rabies vaccine given over 1month (on days 0, 3, 7, 14, and 30); also, dependingon the level of risk (determined by factors such as thenature of the bite and the country where it was sustained),rabies immunoglobulin (section 14.5.2) is givenon day 0. The immunisation course can be discontinuedif it is proved that the child was not at risk.RABIES VACCINECautions see section 14.1Contra-indications see section 14.1; but see also PostexposureManagement in notes abovePregnancy see p. 600Breast-feeding see p. 600Side-effects see section 14.1; also reported paresisIndication and dosePre-exposure immunisation against rabies. By intramuscular injection in deltoid region oranterolateral thigh in infantsChild 1 month–18 years 1 mL on days 0, 7, and21 or 28; for those at continued risk give a singlereinforcing dose 1 year after the primary course iscompleted and booster doses every 3–5 years; forthose at intermittent risk give booster doses every2–5 yearsPost-exposure immunisation against rabies. By intramuscular injection in deltoid region oranterolateral thigh in infantsChild 1 month–18 years 1 mL (see notes above)Rabies Vaccine (Sanofi Pasteur) ARabInjection, powder for reconstitution, freeze-driedinactivated Wistar rabies virus strain PM/WI 38 1503-3M cultivated in human diploid cells, net price singledosevial with syringe containing diluent = £31.90Excipients include neomycinRabipur c (Novartis Vaccines) AInjection, powder for reconstitution, freeze-driedinactivated Flury LEP rabies virus strain cultivated inchick embryo cells, net price single-dose vial = £28.80Excipients include neomycinRotavirus vaccineRotavirus vaccine is a live, oral vaccine licensed forimmunisation of infants over 6 weeks of age for protectionagainst gastro-enteritis caused by rotavirus infection.The vaccine is not included in the childhoodimmunisation schedule.The rotavirus vaccine virus is excreted in the stool andmay be transmitted to close contacts; the vaccineshould be used with caution in those with immunosuppressedclose contacts. Carers of a recently vaccinatedbaby should be advised of the need to wash their handsafter changing the baby’s nappies.ROTAVIRUS VACCINECautions see section 14.1; also diarrhoea or vomiting(postpone vaccination); immunosuppressed closecontacts (see notes above); interactions: Appendix 1(vaccines)Contra-indications see section 14.1; also predispositionto, or history of, intussusceptionSide-effects see section 14.1Indication and doseImmunisation against gastro-enteritis causedby rotavirus infection. By mouthChild over 6 weeks 2 doses of 1.5 mL, separatedby an interval of at least 4 weeks; course should becompleted before 24 weeks of age (preferablybefore 16 weeks)Rotarix c (GSK) TAOral suspension, live attenuated rotavirus (RIX4414strain), net price 1.5 mL prefilled oral syringe = £41.38

BNFC 2011–2012 14.4 Vaccines and antisera 619Rubella vaccineA combined measles, mumps and rubella vaccine (MMRvaccine) aims to eliminate rubella (German measles)and congenital rubella syndrome. MMR vaccine is usedfor childhood vaccination as well as for vaccinatingadults (including women of child-bearing age) who donot have immunity against rubella the combined livemeasles, mumps and rubella vaccine is a suitable alternative.Single antigen vaccineNo longer available in the UK; see MMR vaccine,p. 612Combined vaccinessee MMR vaccineSmallpox vaccineLimited supplies of smallpox vaccine are held at theSpecialist and Reference Microbiology Division, HealthProtection Agency (Tel. (020) 8200 4400) for the exclusiveuse of workers in laboratories where pox viruses(such as vaccinia) are handled.If a wider use of the vaccine is being considered, Guidelinesfor smallpox response and management in thepost-eradication era should be consulted atwww.dh.gov.ukTetanus vaccinesTetanus vaccine contains a cell-free purified toxin ofClostridium tetani adsorbed on aluminium hydroxide oraluminium phosphate to improve antigenicity.Primary immunisation for children under 10 years consistsof 3 doses of a combined preparation containingadsorbed tetanus vaccine (see Diphtheria-containingVaccines), with an interval of 1 month between doses.Following routine childhood vaccination, 2 boosterdoses of a preparation containing adsorbed tetanusvaccine are recommended, the first before schoolentry and the second before leaving school. (seeImmunisation schedule, section 14.1).The recommended schedule of tetanus vaccination notonly gives protection against tetanus in childhood butalso gives the basic immunity for subsequent boosterdoses. In most circumstances, a total number of 5 dosesof tetanus vaccine is considered sufficient for long-termprotection.For primary immunisation of children over 10 yearspreviously unimmunised against tetanus, 3 doses ofadsorbed diphtheria [low dose], tetanus and poliomyelitis(inactivated) vaccine are given with an intervalof 1 month between doses (see Diphtheria-containingVaccines).Cautions See also Section 14.1. When a child presentsfor a booster dose but has been vaccinated following atetanus-prone wound, the vaccine preparation administeredat the time of injury should be determined. If thisis not possible, the booster should still be given toensure adequate protection against all antigens in thebooster vaccine.Very rarely, tetanus has developed after abdominalsurgery; carers of children awaiting elective surgeryshould be asked about the child’s tetanus immunisationstatus and the child should be immunised if necessary.Parenteral drug abuse is also associated with tetanus;those abusing drugs by injection should be vaccinated ifunimmunised—booster doses should be given if there isany doubt about their immunisation status.Travel recommendations see section 14.6.Contra-indications See section 14.1Pregnancy see p. 600Breast-feeding see p. 600Side-effects See section 14.1Wounds Wounds are considered to be tetanus-prone ifthey are sustained more than 6 hours before surgicaltreatment or at any interval after injury and are puncture-type(particularly if contaminated with soil or manure)or show much devitalised tissue or are septic or arecompound fractures or contain foreign bodies. Allwounds should receive thorough cleansing.. For clean wounds: fully immunised individuals(those who have received a total of 5 doses of atetanus-containing vaccine at appropriate intervals)and those whose primary immunisation is complete(with boosters up to date), do not require tetanusvaccine; individuals whose primary immunisation isincomplete or whose boosters are not up to daterequire a reinforcing dose of a tetanus-containingvaccine (followed by further doses as required tocomplete the schedule); non-immunised individuals(or those whose immunisation status is not knownor who have been fully immunised but are nowimmunocompromised) should be given a dose ofthe appropriate tetanus-containing vaccine immediately(followed by completion of the full course ofthe vaccine if records confirm the need).. For tetanus-prone wounds: management is as forclean wounds with the addition of a dose of tetanusimmunoglobulin (section 14.5.2) given at a differentsite; in fully immunised individuals and those whoseprimary immunisation is complete (with boostersup to date) the immunoglobulin is needed only if therisk of infection is especially high (e.g. contaminationwith manure). Antibacterial prophylaxis (withbenzylpenicillin, co-amoxiclav, or metronidazole)may also be required for tetanus-prone wounds.Combined vaccinesSee Diphtheria-containing VaccinesTick-borne encephalitis vaccineTick-borne encephalitis vaccine contains inactivatedtick-borne encephalitis virus cultivated in chick embyrocells. It is recommended for immunisation of thoseliving in or visiting high-risk areas (see InternationalTravel, section 14.6). Children walking or camping inwarm forested areas of Central and Eastern Europe,Scandinavia, Northern and Eastern China, and someparts of Japan, particularly from April to Novemberwhen ticks are most prevalent, are at greatest risk of14 Immunological products and vaccines

620 14.4 Vaccines and antisera BNFC 2011–201214 Immunological products and vaccinestick-borne encephalitis. For full protection, 3 doses ofthe vaccine are required; booster doses are requiredevery 3–5 years for those still at risk. Ideally, immunisationshould be completed at least one month beforetravel.TICK-BORNE ENCEPHALITISVACCINE, INACTIVATEDCautions see section 14.1Contra-indications see section 14.1Pregnancy see p. 600Breast-feeding see p. 600Side-effects see section 14.1Indication and doseImmunisation against tick-borne encephalitis. By intramuscular injection in deltoid region oranterolateral thigh in infantsChild 1–16 years initial immunisation, 3 doses of0.25 mL, second dose after 1–3 months and thirddose after a further 5–12 monthsChild 16–18 years 3 doses each of 0.5 mL, seconddose after 1–3 months and third dose afterfurther 5–12 monthsImmunocompromised (including those receivingimmunosuppressants), antibody concentrationmay be measured 4 weeks after second dose anddose repeated if protective levels not achievedNote To achieve more rapid protection, second dose maybe given 14 days after first dose.Booster doses, give first dose within 3 years afterinitial course, then every 3–5 yearsTicoVac c (MASTA) AInjection, suspension, formaldehyde-inactivatedNeudörfl tick-borne encephalitis virus strain, (cultivatedin chick embryo cells) adsorbed onto hydratedaluminium hydroxide, net price 0.25-mL prefilledsyringe (TicoVac Junior c ) = £28.00, 0.5-mL prefilledsyringe = £32.00Excipients include gentamicin and neomycinTyphoid vaccinesTyphoid vaccine is available as Vi capsular polysaccharideinjectable vaccine (from Salmonella typhi) forinjection; and as live attenuated Salmonella typhivaccine for oral use.Typhoid immunisation is advised for children travellingto:. areas where typhoid is endemic, especially if stayingwith or visiting local people. endemic areas where frequent or prolonged exposureto poor sanitation and poor food hygiene islikelyTyphoid vaccination is not a substitute for scrupulouspersonal hygiene (see p. 627).Capsular polysaccharide typhoid vaccine is usuallygiven by intramuscular injection. Children under 2years may respond suboptimally to the vaccine, butchildren aged between 1–2 years should be immunisedif the risk of typhoid fever is considered high (immunisationis not recommended for infants under 12months). Booster doses are needed every 3 years oncontinued exposure.Oral typhoid vaccine is a live attenuated vaccinecontained in an enteric-coated capsule. One capsuletaken on alternate days for a total of 3 doses, providesprotection 7–10 days after the last dose. Protection maypersist for up to 3 years in those constantly (or repeatedly)exposed to Salmonella typhi, but occasional travellersrequire further courses at intervals of 1 year.interactions Oral typhoid vaccine is inactivated byconcomitant administration of antibacterials or antimalarials:. Antibacterials should be avoided for 3 days beforeand after oral typhoid vaccination;. Mefloquine should be avoided for at least 12 hoursbefore or after oral typhoid;. For other antimalarials, vaccination with oral typhoidvaccine should be completed at least 3 daysbefore the first dose of the antimalarial (exceptproguanil hydrochloride with atovaquone, whichmay be given concomitantly).TYPHOID VACCINECautions section 14.1; interactions: see above andAppendix 1 (vaccines)Contra-indications section 14.1; also for oral vaccine,acute gastro-intestinal illnessPregnancy see p. 600Breast-feeding see p. 600Side-effects section 14.1Indication and doseImmunisation against typhoid feverFor dose see under preparationsTyphoid polysaccharide vaccine for injectionTypherix c (GSK) AInjection, Vi capsular polysaccharide typhoidvaccine, 50 micrograms/mL virulence polysaccharideantigen of Salmonella typhi, net price 0.5-mL prefilledsyringe = £9.93Dose. By intramuscular injectionChild under 2 years [unlicensed use], 0.5 mL, at least 2weeks before potential exposure to typhoid infection;response may be suboptimal (see notes above)Child 2–18 years 0.5 mL, at least 2 weeks beforepotential exposure to typhoid infectionTyphim Vi c (Sanofi Pasteur) AInjection, Vi capsular polysaccharide typhoidvaccine, 50 micrograms/mL virulence polysaccharideantigen of formaldehyde-inactivated Salmonellatyphi, net price 0.5-mL prefilled syringe = £9.00Dose. By intramuscular injectionChild under 2 years [unlicensed use], 0.5 mL, at least 2weeks before potential exposure to typhoid infection;response may be suboptimal (see notes above)Child 2–18 years 0.5 mL, at least 2 weeks beforepotential exposure to typhoid infectionPolysaccharide vaccine with hepatitis A vaccineSee Hepatitis A Vaccine

BNFC 2011–2012 14.4 Vaccines and antisera 621Typhoid vaccine, live (oral)Vivotif c (Crucell) ACapsules, e/c, live attenuated Salmonella typhi(Ty21a), net price 3-cap pack = £14.77. Label: 23, 25,counselling, administrationDose. By mouthChild 6–18 years 1 capsule on days 1, 3, and 5Counselling Swallow as soon as possible after placing inmouth with a cold or lukewarm drink; it is important tostore capsules in a refrigeratorin human diploid cells, net price 0.5-mL vial (withdiluent) = £30.28Excipients include gelatin and neomycinDose. By intramuscular or subcutaneous injection intodeltoid region (or higher anterolateral thigh in youngchildren)Child 1–13 years (see notes above) 2 doses of 0.5 mLseparated by an interval of at least 4 weeks (2 dosesseparated by 12 weeks in children with asymptomaticHIV infection)Child 13–18 years 2 doses of 0.5 mL separated by 4–8weeksVaricella–zoster vaccineVaricella–zoster vaccine (live) is licensed for immunisationagainst varicella in seronegative individuals. It isnot recommended for routine use in children but can begiven to seronegative healthy children over 1 year whocome into close contact with individuals at high risk ofsevere varicella infections.Rarely, the varicella–zoster vaccine virus has beentransmitted from the vaccinated individual to closecontacts. Therefore, contact with the following shouldbe avoided if a vaccine-related cutaneous rash developswithin 4–6 weeks of the first or second dose:. varicella-susceptible pregnant females;. individuals at high risk of severe varicella, includingthose with immunodeficiency or those receivingimmunosuppressive therapy.Varicella–zoster immunoglobulin is used to protectsusceptible children at increased risk of varicella infection,see p. 625.VARICELLA–ZOSTER VACCINESCautions see section 14.1; also post-vaccination closecontactwith susceptible individuals (see notes above):interactions: Appendix 1 (vaccines)Contra-indications see section 14.1Pregnancy avoid pregnancy for 3 months aftervaccination; see also p. 600Breast-feeding see p. 600Side-effects see section 14.1; also varicella-like rash;rarely thrombocytopeniaIndication and doseImmunisation against varicella infection (seenotes above)For dose, see under preparationsVarilrix c (GSK) AInjection, powder for reconstitution, live attenuatedvaricella–zoster virus (Oka strain) propagated inhuman diploid cells, net price 0.5-mL vial (with diluent)= £27.31Excipients include neomycinDose. By subcutaneous injection preferably into deltoidregionChild 1–18 years (see notes above), 2 doses of 0.5 mLseparated by an interval of at least 6 weeks (minimum 4weeks)Varivax c (Sanofi Pasteur) TAInjection powder for reconstitution, live attenuatedvaricella-zoster virus (Oka/Merck strain) propagatedYellow fever vaccineLive yellow fever vaccine is indicated for those travellingto or living in areas where infection is endemic (seep. 626). Infants under 6 months of age should not bevaccinated because there is a small risk of encephalitis;infants aged 6–9 months should be vaccinated only ifthe risk of yellow fever is high and unavoidable (seekexpert advice). The immunity which probably lasts forlife is officially accepted for 10 years starting from 10days after primary immunisation and for a further 10years immediately after revaccination.Very rarely vaccine-associated adverse effects havebeen reported, such as viscerotropic disease (yellowfever vaccine-associated viscerotropic disease, YEL-AVD), a syndrome which may include metabolic acidosis,muscle and liver cytolysis, and multi-organ failure.Neurological disorders (yellow fever vaccine-associatedneurotropic disease, YEL-AND) such as encephalitishave also been reported. These very rare adverse effectshave usually occured after the first dose of yellow fevervaccine in those with no previous immunity.Pregnancy Live yellow fever vaccine should not begiven during pregnancy, but if a significant risk ofexposure cannot be avoided then vaccination shouldbe delayed to the third trimester if possible (but the needfor immunisation usually outweighs risk to the fetus).Breast-feeding Vaccination should be considered inbreast-feeding women when there is a real risk to themother from yellow fever disease.YELLOW FEVER VACCINECautions see section 14.1; also see interactions:Appendix 1 (vaccines)Contra-indications see section 14.1 and notes above;also children under 6 months; history of thymusdysfunctionPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see section 14.1; also reported neurotropicdisease, and viscerotropic disease (see notesabove)Indication and doseImmunisation against yellow fever. By deep subcutaneous injectionChild 9 months–18 years 0.5 mL (see also notesabove)14 Immunological products and vaccines

622 14.5 Immunoglobulins BNFC 2011–201214 Immunological products and vaccinesYellow Fever Vaccine, Live AYel(live)Injection, powder for reconstitution, live, attenuated17D-204 strain of yellow fever virus, cultivated inchick embryos; single dose vial with syringe containing0.5 mL diluentAvailable (only to designated Yellow Fever Vaccination centres) asStamaril c14.5 Immunoglobulins14.5.1 Normal Immunoglobulin14.5.2 Disease-specific immunoglobulins14.5.3 Anti-D (Rh 0 ) immunoglobulinTwo types of human immunoglobulin preparation areavailable, normal immunoglobulin and disease-specificimmunoglobulins.Human immunoglobulin is a sterile preparation of concentratedantibodies (immune globulins) recoveredfrom pooled human plasma or serum obtained fromoutside the UK, tested and found non-reactive for hepatitisB surface antigen and for antibodies against hepatitisC virus and human immunodeficiency virus (types 1 and2). A global shortage of human immunoglobulin and therapidly increasing range of clinical indications for treatmentwith immunoglobulins has resulted in the need fora Demand Management programme in the UK (forfurther information consult www.ivig.nhs.uk and ClinicalGuidelines for Immunoglobulin Use,www.dh.gov.uk.Immunoglobulins of animal origin (antisera) were frequentlyassociated with hypersensitivity reactions andare no longer used.Further information on the use of immunoglobulins isincluded in the Health Protection Agency’s ImmunoglobulinHandbook: www.hpa.org.uk and in the Departmentof Health’s publication, Immunisation againstInfectious Disease, www.dh.gov.uk.Availability Normal immunoglobulin for intramuscularadministration is available from some regionalHealth Protection Agencies and microbiology laboratoriesfor protection of contacts and the control ofoutbreaks of hepatitis A, measles, and rubella only. Forother indications, subcutaneous or intravenous normalimmunoglobulin should be purchased from the manufacturer.Disease-specific immunoglobulins (section 14.5.2)are available from some regional Health ProtectionAgencies and microbiology laboratories with the exceptionof tetanus immunoglobulin which is availablefrom BPL, hospital pharmacies, or blood transfusiondepartments. Rabies immunoglobulin is availablefrom the Specialist and Reference Microbiology Division,Health Protection Agency. Hepatitis B immunoglobulinrequired by transplant centres should beobtained commercially.In Scotland all immunoglobulins are available from theScottish National Blood Transfusion Service (SNBTS)14.5.1 Normal ImmunoglobulinHuman normal immunoglobulin (‘HNIG’) is preparedfrom pools of at least 1000 donations of human plasma;it contains immunoglobulin G (IgG) and antibodies tohepatitis A, measles, mumps, rubella, varicella, andother viruses that are currently prevalent in the generalpopulation.Normal immunoglobulin may interfere with theimmune response to live virus vaccines which shouldtherefore only be given at least 3 weeks before or 3months after an injection of normal immunoglobulin(this does not apply to yellow fever vaccine sincenormal immunoglobulin does not contain antibody tothis virus).Uses Normal immunoglobulin (containing 10–18%protein) is administered by intramuscular injection forthe protection of susceptible contacts against hepatitisA virus (infectious hepatitis), measles and, to a lesserextent, rubella. Injection of immunoglobulin producesimmediate protection lasting for several weeks.Normal immunoglobulin (containing 3–12% protein) forintravenous administration is used as replacement therapyfor children with congenital agammaglobulinaemiaand hypogammaglobulinaemia, and for the short-termtreatment of idiopathic thrombocytopenic purpura andKawasaki syndrome; it is also used for the prophylaxis ofinfection following bone-marrow transplantation and inchildren with symptomatic HIV infection who haverecurrent bacterial infections. Normal immunoglobulinfor replacement therapy may also be given intramuscularlyor subcutaneously, but intravenous formulationsare normally preferred. Intravenous immunoglobulin isalso used in the treatment of Guillain-Barré syndrome asan alternative to plasma exchange.The dose of normal immunoglobulin used as replacementtherapy in patients with immunodeficiencies is notthe same as the dose required for treatment of acuteconditions. For Kawasaki syndrome a single dose of 2 g/kg by intravenous infusion should be given with concomitantaspirin (see section 2.9) within 10 days of onsetof symptoms (but children with a delayed diagnosis mayalso benefit).For guidance on the use of intravenous normal immunoglobulinsand alternative therapies for other conditions,consult Clinical Guidelines for ImmunoglobulinUse (www.dh.gov.uk).Hepatitis A Hepatitis A vaccine is preferred forchildren at risk of infection (see p. 607) includingthose visiting areas where the disease is highly endemic(all countries excluding Northern and Western Europe,North America, Japan, Australia, and New Zealand). Inunimmunised children, transmission of hepatitis A isreduced by good hygiene. Intramuscular normalimmunoglobulin is no longer recommended for routineprophylaxis in travellers, but it may be indicated forimmunocompromised patients if their antibodyresponse to the vaccine is unlikely to be adequate.Intramuscular normal immunoglobulin is recommendedfor prevention of infection in close contacts (of confirmedcases of hepatitis A) who have chronic liverdisease or HIV infection, or who are immunosup-

BNFC 2011–2012 14.5.1 Normal Immunoglobulin 623pressed; normal immunoglobulin should be given assoon as possible, preferably within 14 days of exposureto the primary case. However, normal immunoglobulincan still be given to contacts at risk of severe disease upto 28 days after exposure to the primary case. HepatitisA vaccine can be given at the same time, but it should begiven at a separate injection site.Measles Intravenous or subcutaneous normalimmunoglobulin may be given to prevent or attenuatean attack of measles in children with compromisedimmunity. Children with compromised immunity whohave come into contact with measles should receiveintravenous or subcutaneous normal immunoglobulinas soon as possible after exposure. It is most effective ifgiven within 72 hours but can be effective if given within6 days.Subcutaneous or intramuscular normal immunoglobulinshould also be considered for the following individuals ifthey have been in contact with a confirmed case ofmeasles or with a person associated with a local outbreak:. non-immune pregnant women. infants under 9 monthsFurther advice should be sought from the Centre forInfections, Health Protection Agency (tel. (020) 82006868).Children with normal immunity who are not in theabove categories and who have not been fully immunisedagainst measles, can be given MMR vaccine(section 14.4) for prophylaxis following exposure tomeasles.Rubella Intramuscular immunoglobulin after exposureto rubella does not prevent infection in non-immunecontacts and is not recommended for protection ofpregnant females exposed to rubella. It may, however,reduce the likelihood of a clinical attack which maypossibly reduce the risk to the fetus. Risk of intrauterinetransmission is greatest in the first 11 weeks ofpregnancy, between 16 and 20 weeks there is a minimalrisk of deafness only, after 20 weeks there is noincreased risk. Intramuscular normal immunoglobulinshould be used only if termination of pregnancy wouldbe unacceptable to the pregnant individual—it shouldbe given as soon as possible after exposure. Serologicalfollow-up of recipients is essential.For routine prophylaxis, see MMR vaccine (p. 612).NORMAL IMMUNOGLOBULINCautions hypo- or agammaglobulinaemia with orwithout IgA deficiency; interference with live virusvaccines—see p. 622Intravenous use Thrombophilic disorders, or risk factors forarterial or venous thromboembolic events; obesity; ensureadequate hydration, renal insufficiencyContra-indications patients with selective IgA deficiencywho have known antibody against IgARenal impairment monitor for acute renal failure;consider discontinuation if renal function deteriorates.Intravenous preparations with added sucrose havebeen associated with cases of renal dysfunction andacute renal failureSide-effects nausea, diarrhoea, chills, fever, headache,dizziness, arthralgia, myalgia, muscle spasms,low back pain; rarely hypotension, anaphylaxis,cutaneous skin reactions, aseptic meningitis, acuterenal failure; also reported with intravenous use,injection site reactions, abdominal pain and distension,blood pressure fluctuations, haemolytic anaemia,thromboembolic events including myocardialinfarction, stroke, pulmonary embolism, and deepvein thrombosisNote Adverse reactions are more likely to occur in patientsreceiving normal immunoglobulin for the first time, or followinga prolonged period between treatments, or when adifferent brand of normal immunoglobulin is administered.Side-effectsNote Adverse reactions are more likely to occur in patientsreceiving normal immunoglobulin for the first time, or followinga prolonged period between treatments, or when adifferent brand of normal immunoglobulin is administeredIndication and doseSee under preparationsNote Antibody titres can vary widely between normalimmunoglobulin preparations from different manufacturers—formulationsare not interchangeable; patientsshould be maintained on the same formulation throughoutlong-term treatment to avoid adverse effectsFor intramuscular useNormal Immunoglobulin ANormal immunoglobulin injection. 250-mg vial; 750-mg vialDoseTo control outbreaks of hepatitis A (see notes above). By deep intramuscular injectionChild under 10 years 250 mgChild 10–18 years 500 mgRubella in pregnancy, prevention of clinical attack. By deep intramuscular injection750 mgAvailable from the Centre for Infections and other regional HealthProtection Agency offices (for contacts and control of outbreaksonly, see above)For subcutaneous useNote Preparations for subcutaneous use may be administeredby intramuscular injection if subcutaneous route notpossible; intramuscular route not recommended for patientswith thrombocytopenia or other bleeding disordersGammanorm c (Octapharma) TANormal immunoglobulin (protein 16.5%) injection,net price 10-mL vial = £113.85, 20-mL vial = £227.70Electrolytes Electrolytes: Na + 1.09 mmol/10-mL vialDoseAntibody deficiency syndromes. By subcutaneous infusionConsult product literatureSubcuvia c (Baxter) ANormal immunoglobulin (protein 16%) injection, netprice 5-mL vial = £32.56, 10-mL vial = £65.12DoseAntibody deficiency syndromes. By subcutaneous infusionConsult product literature (not licensed for use in childrenunder 12 years)14 Immunological products and vaccines

624 14.5.2 Disease-specific immunoglobulins BNFC 2011–201214 Immunological products and vaccinesSubgam c (BPL) ANormal immunoglobulin (protein 14–18%) injection,net price 250-mg vial = £11.20, 750-mg vial = £28.50,1.5-g vial = £57.00DoseAntibody deficiency syndromes. By subcutaneous infusionConsult product literatureHepatitis A prophylaxis (see also notes above). By intramuscular injectionChild under 10 years 500 mgChild 10–18 years 750 mgRubella prophylaxis in pregnancy (see also notes above). By intramuscular injection750 mgNote Subgam c is not licensed for prophylactic use, but due todifficulty in obtaining suitable immunoglobulin products, theHealth Protection Agency recommends intramuscular use forprophylaxis against Hepatitis A, or rubellaVivaglobin c (CSL Behring) ANormal immunoglobulin (protein 16%) injection, netprice 3-mL vial £17.76, 10-mL vial = £59.20, 20-mLvial = £118.40Cautions risk factors for arterial or venous thromboembolicevents; ensure adequate hydrationSide-effects rarely thromboembolic eventsDoseAntibody deficiency syndromes. By subcutaneous infusionConsult product literatureFor intravenous useNote Dose recommendation for Kawasaki Sydrome, seesection 14.5.1; other indications—consult product literaturefor dosage regimensFlebogamma c DIF (Grifols) TAIntravenous infusion, human normal immunoglobulin(protein 5%), net price 0.5 g (10 mL) = £30.00, 2.5 g(50 mL) = £150.00; 5 g (100 mL) = £300.00, 10 g(200 mL) = £600.00, 20 g (400 mL) = £1200.00Note Contains sorbitol 50 mg/mL; contra-indicated inpatients with hereditary fructose intoleranceGammagard S/D c (Baxter) AIntravenous infusion, powder for reconstitution,human normal immunoglobulin (providing protein 5%or 10%), net price 0.5 g (with diluent) = £20.05, 2.5 g(with diluent) = £100.25, 5 g (with diluent) = £200.50,10 g (with diluent) = £401.00Gammaplex c (BPL) TAIntravenous infusion, human normal immunoglobulin(protein 5%), net price 2.5 g (50 mL) = £85.00, 5 g(100 mL) = £170.00, 10 g (200 mL) = £340.00Note Contains sorbitol 50 mg/mL; contra-indicated inpatients with hereditary fructose intoleranceIntratect c (Biotest UK) AIntravenous infusion, human normal immunoglobulin(protein 5%), net price 1 g (20 mL) = £45.00, 2.5 g(50 mL) = £112.50, 5 g (100 mL) = £225.00, 10 g(200 mL) = £450.00Kiovig c (Baxter) AIntravenous infusion, human normal immunoglobulin(protein 10%), net price 1 g (10 mL) = £49.00, 2.5 g(25 mL) = £122.50, 5 g (50 mL) = £245.00, 10 g(100 mL) = £490.00, 20 g (200 mL) = £980.00Note Use Glucose 5% intravenous infusion, if dilution priorto administration is requiredPrivigen c (CSL Behring) TAIntravenous infusion, human normal immunoglobulin(protein 10%), net price 2.5 g (25 mL) = £135.00,5 g (50 mL) = £270.00, 10 g (100 mL) = £540.00, 20 g(200 mL) = £1080.00Note Contains L-proline; contra-indicated in patients withhyperprolinaemiaVigam c (BPL) TAIntravenous infusion, human normal immunoglobulin(protein 5%), net price 2.5 g (50 mL) = £95.00, 5 g(100 mL) = £190.00, 10 g (200 mL) = £380.00Note Contains sucrose (see Renal Impairment above)14.5.2 Disease-specificimmunoglobulinsSpecific immunoglobulins are prepared by pooling theplasma of selected human donors with high levels of thespecific antibody required. For further information, seeImmunoglobulin Handbook (www.hpa.org.uk).There are no specific immunoglobulins for hepatitis A,measles, or rubella—normal immunoglobulin, section14.5.1 is used in certain circumstances. There is nospecific immunoglobulin for mumps; neither normalimmunoglobulin nor MMR vaccine is effective as postexposureprophylaxis.Hepatitis BDisease-specific hepatitis B immunoglobulin (‘HBIG’)is available for use in association with hepatitis Bvaccine for the prevention of infection in infants bornto mothers who have become infected with this virus inpregnancy or who are high-risk carriers (see Hepatitis BVaccine, p. 608). Hepatitis B immunoglobulin will notinhibit the antibody response when given at the sametime as hepatitis B vaccine, but should be given atdifferent sites.An intravenous preparation of hepatitis B-specificimmunoglobulin is licensed for the prevention of hepatitisB recurrence in HBV-DNA negative patients whohave undergone liver transplantation for liver failurecaused by the virus.HEPATITIS B IMMUNOGLOBULINCautions IgA deficiency; interference with live virusvaccines—see under Normal Immunoglobulin, p. 622Side-effects injection site swelling and pain, arthralgia;rarely anaphylaxis chest tightness, dyspnoea;also reported tremor, dizziness, facial oedema, glossitis,and buccal ulceration; for side-effects associatedwith intravenous immunoglobulins, see section 14.5.1Indication and doseSee under preparations and see also notes aboveHepatitis B Immunoglobulin AInjection, hepatitis B-specific immunoglobulin,100 units/mL. Vials containing 200 units or 500 units,available from selected Health Protection Agency and

BNFC 2011–2012 14.5.2 Disease-specific immunoglobulins 625NHS laboratories (except for Transplant Centres, seep. 622), also available from BPLDoseProphylaxis against hepatitis B infection. By intramuscular injection(as soon as possible after exposure; ideally within 48hours, but no later than 7 days after exposure)Child 1 month–5 years 200 unitsChild 5–10 years 300 unitsChild 10–18 years 500 unitsPrevention of transmitted infection at birth. By intramuscular injectionNeonate 200 units as soon as possible after birth; for fulldetails consult Immunisation against Infectious Disease(www.dh.gov.uk)Hepatect c CP (Biotest UK) AIntravenous infusion, hepatitis B-specific immunoglobulin50 units/mL, net price 500 units (10 mL) =£300.00, 2000 units (40 mL) = £1100.00DoseFollowing exposure to hepatitis B virus-contaminatedmaterial (as soon as possible after exposure, but nolater than 72 hours); prevention of transmittedinfection at birth; prophylaxis against re-infection oftransplanted liverConsult product literatureRabiesFollowing exposure of an unimmunised child to ananimal in or from a country where the risk of rabies ishigh, the site of the bite should be washed with soapywater and specific rabies immunoglobulin of humanorigin should be administered. All of the dose should beinjected around the site of the wound; if this is difficult orthe wound has completely healed it can be given in theanterolateral thigh (remote from the site used for vaccination).Rabies vaccine should also be given intramuscularlyat a different site (for details see Rabies Vaccine,p. 617).Rabies Immunoglobulin A(Antirabies Immunoglobulin Injection)See notes aboveAvailable from Specialist and Reference Microbiology Division,Health Protection Agency (see section 14.5 under Availability)(also from BPL)TetanusTetanus immunoglobulin, together with metronidazole(section 5.1.11) and wound cleansing, should also beused for the treatment of established cases of tetanus.For the management of tetanus-prone wounds, tetanusimmunoglobulin of human origin should be used inaddition to wound cleansing and, where appropriate,antibacterial prophylaxis and a tetanus-containingvaccine (see Diphtheria-containing Vaccines, section14.4).TETANUS IMMUNOGLOBULINCautions IgA deficiency; interference with live virusvaccines—see, p. 622Side-effects injection site swelling and pain; rarelyanaphylaxis; buccal ulceration; glossitis, chest tightness,dyspnoea, tremor, dizziness, arthralgia, andfacial oedema also reportedIndication and dosePost-exposure prophylaxis. By intramuscular injection250 units, increased to 500 units if more than 24hours have elapsed or there is risk of heavy contaminationor following burnsTreatment of tetanus infection. By intramuscular injection150 units/kg (multiple sites)Tetanus Immunoglobulin A(Antitetanus Immunoglobulin Injection)Available from BPLNote May be difficult to obtainRABIES IMMUNOGLOBULINCautions IgA deficiency; interference with live virusvaccines—see p. 622 under Normal ImmunoglobulinSide-effects injection site swelling and pain; rarelyanaphylaxis; buccal ulceration, glossitis, chest tightness,dyspnoea, tremor, dizziness, arthralgia, andfacial oedema also reportedIndication and dosePost-exposure prophylaxis against rabiesinfection. By intramuscular injection20 units/kg, by infiltration in and around thecleansed wound; if the wound not visible or healedor if infiltration of whole volume not possible, giveremainder by intramuscular injection into anterolateralthigh (remote from vaccination site)Note The potency of individual batches of rabies immunoglobulinfrom the manufacturer may vary; potency may alsobe described differently by different manufacturers. It istherefore critical to know the potency of the batch to be usedand the weight of the patient in order to calculate the specificvolume required to provide the necessary doseVaricella–zosterVaricella–zoster immunoglobulin (VZIG) is recommendedfor individuals who are at increased risk ofsevere varicella and who have no antibodies to varicella–zostervirus and who have significant exposure tochickenpox or herpes zoster. Those at increased riskinclude:. neonates whose mothers develop chickenpox in theperiod 7 days before to 7 days after delivery;. susceptible neonates exposed in the first 7 days oflife;. susceptible neonates or infants exposed whilstrequiring intensive or prolonged special care nursing;. susceptible women exposed at any stage ofpregnancy (but when supplies of VZIG are short,may only be issued to those exposed in the first 20weeks’ gestation or to those near term) providingVZIG is given within 10 days of contact;14 Immunological products and vaccines

626 14.5.3 Anti-D (Rh 0 ) immunoglobulin BNFC 2011–201214 Immunological products and vaccines. immunocompromised individuals including thosewho have received corticosteroids in the previous3 months at the following dose equivalents of prednisolone:children 2 mg/kg daily (or more than40 mg) for at least 1 week or 1 mg/kg daily for 1month.Important: for full details consult Immunisationagainst Infectious Disease. Varicella–zoster vaccineis available—see section 14.4.For treatment of varicella–zoster infections and attenuationof infection if varicella–zoster immunoglobulin notindicated, see section 5.3.2.1VARICELLA–ZOSTERIMMUNOGLOBULINCautions IgA deficiency; interference with live virusvaccines—see p. 622 under Normal ImmunoglobulinsSide-effects injection site swelling and pain; rarelyanaphylaxisIndication and doseProphylaxis against varicella infection (as soonas possible—not later than 10 days afterexposure). By deep intramuscular injectionNeonate 250 mgChild 1 month–6 years 250 mgChild 6–11 years 500 mgChild 11–15 years 750 mgChild 15–18 years 1gGive second dose if further exposure occurs morethan 3 weeks after first doseNote No evidence that effective in treatment of severedisease.Normal immunoglobulin for intravenous use (section 14.5.1)may be used in those unable to receive intramuscularinjection.Varicella–Zoster Immunoglobulin A(Antivaricella–zoster Immunoglobulin)Available from selected Health Protection Agency and NHSlaboratories (see section 14.5 under Availability) (also fromBPL)14.5.3 Anti-D (Rh 0 )immunoglobulinThis section is not included in BNF for Children. SeeBNF for use of Anti-D (Rh 0 ) immunoglobulin14.6 International travelNote For advice on malaria chemoprophylaxis, see section5.4.1.No special immunisation is required for travellers to theUnited States, Europe, Australia, or New Zealandalthough all travellers should have immunity to tetanusand poliomyelitis (and childhood immunisations shouldbe up to date); see also Tick-borne Encephalitis, p. 619.Certain precautions are required in Non-European areassurrounding the Mediterranean, in Africa, the MiddleEast, Asia, and South America.Travellers to areas that have a high incidence of poliomyelitisor tuberculosis should be immunised with theappropriate vaccine; in the case of poliomyelitis previouslyimmunised adults may be given a booster doseof a preparation containing inactivated poliomyelitisvaccine. BCG immunisation is recommended for travellersaged under 16 years proposing to stay for longerthan 3 months (or in close contact with the localpopulation) in countries with an incidence 1 of tuberculosisgreater than 40 per 100 000; it should preferablybe given three months or more before departure.Monovalent influenza A(H1N1)v vaccine (see p. 612)can be offered to travellers visiting countries in thesouthern hemisphere during their influenza season.Yellow fever immunisation is recommended for travelto the endemic zones of Africa and South America.Many countries require an International Certificate ofVaccination from individuals arriving from, or who havebeen travelling through, endemic areas, whilst othercountries require a certificate from all entering travellers(consult the Department of Health handbook, HealthInformation for Overseas Travel, www.dh.gov.uk).Immunisation against meningococcal meningitis isrecommended for a number of areas of the world (fordetails, see p. 614).Protection against hepatitis A is recommended fortravellers to high-risk areas outside Northern and WesternEurope, North America, Japan, Australia and NewZealand. Hepatitis A vaccine (see p. 607) is preferredand it is likely to be effective even if given shortly beforedeparture; normal immunoglobulin is no longer givenroutinely but may be indicated in the immunocompromised(see p. 622). Special care must also be taken withfood hygiene (see below).Hepatitis B vaccine (see p. 608) is recommended forthose travelling to areas of high prevalence who plan toremain there for lengthy periods and who may thereforebe at increased risk of acquiring infection as the result ofmedical or dental procedures carried out in those countries.Short-term tourists are not generally at increasedrisk of infection but may place themselves at risk bytheir sexual behaviour when abroad.Prophylactic immunisation against rabies (see p. 617) isrecommended for travellers to enzootic areas on longjourneys or to areas out of reach of immediate medicalattention.Travellers who have not had a tetanus booster in thelast 10 years and are visiting areas where medicalattention may not be accessible should receive a boosterdose of adsorbed diphtheria [low dose], tetanus andinactivated poliomyelitis vaccine (see p. 604), even ifthey have received 5 doses of a tetanus-containingvaccine previously.Typhoid vaccine is indicated for travellers to countrieswhere typhoid is endemic, but the vaccine is no substitutefor personal precautions (see below).There is no requirement for cholera vaccination as acondition for entry into any country, but oral choleravaccine (see p. 604) should be considered for backpackersand those travelling to situations where the1. List of countries where the incidence of tuberculosis isgreater than 40 cases per 100 000 is available atwww.hpa.org.uk

BNFC 2011–2012 14.6 International travel 627risk is greatest (e.g. refugee camps). Regardless ofvaccination, travellers to areas where cholera is endemicshould take special care with food hygiene (seebelow).Advice on diphtheria, on Japanese encephalitis 1(vaccine available on named-patient basis fromMASTA) and on tick-borne encephalitis is includedin Health Information for Overseas Travel, see below.Food hygiene In areas where sanitation is poor, goodfood hygiene is important to help prevent hepatitis A,typhoid, cholera, and other diarrhoeal diseases (includingtravellers’ diarrhoea). Food should be freshly preparedand hot, and uncooked vegetables (includinggreen salads) should be avoided; only fruits which canbe peeled should be eaten. Only suitable bottled water,or tap water that has been boiled, or treated withsterilising tablets should be used for drinking.Information on health advice for travellersHealth professionals and travellers can find the latestinformation on immunisation requirements and precautionsfor avoiding disease while travelling from:www.nathnac.orgThe handbook, Health Information for OverseasTravel (2010), which draws together essential informationfor healthcare professionals regarding healthadvice for travellers, can also be obtained here.Immunisation requirements change from time to time,and information on the current requirements for anyparticular country may be obtained from the embassy orlegation of the appropriate country or from:National Travel Health Network and CentreUCLH NHS Foundation trust5th Floor West250 Euston RoadLondon, NW1 2PGTel: 0845 602 6712(9 a.m.–noon, 2–4.30 p.m. weekdays for healthcareprofessionals only)www.nathnac.orgTravel Medicine TeamHealth Protection ScotlandClifton HouseClifton PlaceGlasgow, G3 7LNTel: (0141) 300 1130(2 p.m.–4 p.m. weekdays)www.travax.nhs.uk (registration required. Annualfee may be payable for users outside NHS Scotland)Welsh Assembly GovernmentTel: (029) 2082 5397(9 a.m.–5.30 p.m. weekdays)Department of Health and Social ServicesCastle BuildingsStormontBelfast, BT4 3PPTel: (028) 9052 2118(weekdays)1. Japanese encephalitis vaccine not prescribable on theNHS; health authorities may investigate circumstancesunder which vaccine prescribed14 Immunological products and vaccines

628 BNFC 2011–201215 Anaesthesia15.1 General anaesthesia 62815.1.1 Intravenous anaesthetics 62915.1.2 Inhalational anaesthetics 63215.1.3 Antimuscarinic drugs 63515.1.4 Sedative and analgesic perioperativedrugs 63715.1.4.1 Anxiolytics 63715.1.4.2 Non-opioid analgesics 63915.1.4.3 Opioid analgesics 64015.1.5 Neuromuscular blocking drugs 64215.1.6 Drugs for reversal of neuromuscularblockade 64615.1.7 Antagonists for central andrespiratory depression 64715.1.8 Drugs for malignant hyperthermia64815.2 Local anaesthesia 64915.1 General anaesthesia15.1.1 Intravenous anaesthetics15.1.2 Inhalational anaesthetics15.1.3 Antimuscarinic drugs15.1.4 Sedative and analgesic peri-operativedrugs15.1.5 Neuromuscular blocking drugs15.1.6 Drugs for reversal of neuromuscularblockade15.1.7 Antagonists for central andrespiratory depression15.1.8 Drugs for malignant hyperthermiaImportantThe drugs in section 15.1 should be used by experiencedpersonnel only and when resuscitation equipmentis available.15 AnaesthesiaSeveral different types of drug are given together duringgeneral anaesthesia. Anaesthesia is induced with eithera volatile drug given by inhalation (section 15.1.2) orwith an intravenously administered drug (section15.1.1); anaesthesia is maintained with an intravenousor inhalational anaesthetic. Analgesics (section 15.1.4),usually short-acting opioids, are also used. The use ofneuromuscular blocking drugs (section 15.1.5) necessitatesintermittent positive-pressure ventilation. Followingsurgery, anticholinesterases (section 15.1.6) can begiven to reverse the effects of neuromuscular blockingdrugs; specific antagonists (section 15.1.7) can be usedto reverse central and respiratory depression caused bysome drugs used in surgery. A topical local anaesthetic(section 15.2) can be used to reduce pain at the injectionsite.Individual requirements vary considerably and therecommended doses are only a guide. Smaller dosesare indicated in ill, shocked, or debilitated children andin significant hepatic impairment, while robust individualsmay require larger doses. The required dose ofinduction agent may be less if the patient has beenpremedicated with a sedative agent (section 15.1.4) orif an opioid analgesic has been used.Surgery and long-term medication The risk oflosing disease control on stopping long-term medicationbefore surgery is often greater than the risk posed bycontinuing it during surgery. It is vital that the anaesthetistknows about all drugs that a child is (or has been)taking.Children with adrenal atrophy resulting from long-termcorticosteroid use (section 6.3.2) may suffer a precipi-

BNFC 2011–2012 15.1.1 Intravenous anaesthetics 629tous fall in blood pressure unless corticosteroid cover isprovided during anaesthesia and in the immediate postoperativeperiod. Anaesthetists must therefore knowwhether a child is, or has been, receiving corticosteroids(including high-dose inhaled corticosteroids).Other drugs that should normally not be stopped beforesurgery include drugs for epilepsy, asthma, immunosuppression,and metabolic, endocrine and cardiovasculardisorders (but see potassium sparing diuretics, below).Expert advice is required for children receiving antiviralsfor HIV infection. For general advice on surgery inchildren with diabetes, see section 6.1.1.Children taking antiplatelet medication or an oral anticoagulantpresent an increased risk for surgery. In thesecircumstances, the anaesthetist and surgeon shouldassess the relative risks and decide jointly whether theantiplatelet or the anticoagulant drug should be stoppedor replaced with unfractionated or low molecular weightheparin therapy.Drugs that should be stopped before surgery includecombined oral contraceptives (see Surgery, section 7.3.1for details). If antidepressants need to be stopped, theyshould be withdrawn gradually to avoid withdrawalsymptoms. Tricyclic antidepressants need not bestopped, but there may be an increased risk of arrhythmiasand hypotension (and dangerous interactions withvasopressor drugs); therefore, the anaesthetist should beinformed if they are not stopped. Lithium should bestopped 24 hours before major surgery but the normaldose can be continued for minor surgery (with carefulmonitoring of fluids and electrolytes). Potassium-sparingdiuretics may need to be withheld on the morning ofsurgery because hyperkalaemia may develop if renalperfusion is impaired or if there is tissue damage.Anaesthesia and skilled tasks Children and theircarers should be very carefully warned about the risk ofundertaking skilled tasks after the use of sedatives andanalgesics during minor outpatient procedures. Forintravenous benzodiazepines and for a short generalanaesthetic the risk extends to at least 24 hours afteradministration. Responsible persons should be availableto take children home. The dangers of taking alcoholshould also be emphasised.Prophylaxis of acid aspiration Regurgitation andaspiration of gastric contents (Mendelson’s syndrome)can be a complication of general anaesthesia, particularlyin obstetrics and in gastro-oesophageal reflux disease;prophylaxis against acid aspiration is not routinelyused in children but may be required in high-risk cases.An H 2 -receptor antagonist (section 1.3.1) or a protonpump inhibitor (section 1.3.5), such as omeprazole, canbe used before surgery to increase the pH and reducethe volume of gastric fluid. They do not affect the pH offluid already in the stomach and this limits their value inemergency procedures; oral H 2 -receptor antagonistscan be given 1–2 hours before the procedure, but omeprazolemust be given at least 12 hours earlier.Anaesthesia, sedation, andresuscitation in dental practiceFor details see A Conscious Decision: A review ofthe use of general anaesthesia and conscious sedationin primary dental care; report by a groupchaired by the Chief Medical Officer and ChiefDental Officer, July 2000 and associated documents.Further details can also be found in Conscious Sedationin the Provision of Dental Care; report of anExpert Group on Sedation for Dentistry (commissionedby the Department of Health), 2003. Bothdocuments are available at www.dh.gov.uk.Guidance is also included in Standards for DentalProfessionals, London, General Dental Council, May2005 (and as amended subsequently) and ConsciousSedation in Dentistry: Dental Clinical Guidance,Scottish Dental Clinical Effectiveness Programme,May 2006.15.1.1 Intravenous anaestheticsImportantThe drugs in this section should be used by experiencedpersonnel only and when resuscitation equipmentis available.Intravenous anaesthetics may be used either to induceanaesthesia or for maintenance of anaesthesia throughoutsurgery. Intravenous anaesthetics nearly all producetheir effect in one arm-brain circulation time and cancause apnoea and hypotension, and so adequate resuscitativefacilities must be available. They are contraindicatedif the anaesthetist is not confident of beingable to maintain the airway. Extreme care is required insurgery of the mouth, pharynx, or larynx and in childrenwith acute circulatory failure (shock) or fixed cardiacoutput.To facilitate tracheal intubation, induction is usuallyfollowed by a neuromuscular blocking drug (section15.1.5) or a short-acting opioid (section 15.1.4.3).The doses of all intravenous anaesthetic drugs shouldbe titrated according to response (except when using‘rapid sequence induction’). The doses and rates ofadministration should be reduced in those with hypovolaemiaor cardiovascular disease; reduced doses mayalso be required in premedicated children.Total intravenous anaesthesia This is a techniquein which surgery is carried out with all drugs givenintravenously. Respiration can be spontaneous, or controlledwith oxygen-enriched air. Neuromuscular blockingdrugs can be used to provide relaxation and preventreflex muscle movements. The main problem to beovercome is the assessment of depth of anaesthesia.Target Controlled Infusion (TCI) systems can be used totitrate intravenous anaesthetic infusions to predictedplasma-drug concentrations; specific models with paediatricpharmacokinetic data should be used for children.Anaesthesia and skilled tasks See section 15.1.15 Anaesthesia

630 15.1.1 Intravenous anaesthetics BNFC 2011–201215 AnaesthesiaDrugs used for intravenous anaesthesia Propofol,the most widely used intravenous anaesthetic, canbe used for induction or maintenance of anaesthesia inchildren, but it is not commonly used in neonates.Propofol is associated with rapid recovery and lesshangover effect than other intravenous anaesthetics. Itcauses pain on intravenous injection which can bereduced by intravenous lidocaine. Significant extraneousmuscle movements can occur. Rarely, convulsions,anaphylaxis, and delayed recovery from anaesthesiacan occur after propofol administration; the onsetof convulsions can be delayed. Propofol is associatedwith bradycardia, occasionally profound; intravenousadministration of an antimuscarinic drug is used totreat this.Propofol can be used for sedation during diagnosticprocedures but is contra-indicated in children under16 years receiving intensive care because of the risk ofpropofol infusion syndrome (potentially fatal effects,including metabolic acidosis, cardiac failure, rhabdomyolysis,hyperlipidaemia, and hepatomegaly).Thiopental sodium is a barbiturate that is used forinduction of anaesthesia, but it has no analgesic properties.Induction is generally smooth and rapid, but doserelatedcardiorespiratory depression can occur. Awakeningfrom a moderate dose of thiopental is rapidbecause the drug redistributes into other tissues, particularlyfat. However, metabolism is slow and sedativeeffects can persist for 24 hours. Repeated doses have acumulative effect particularly in neonates, and recoveryis much slower.Etomidate is an intravenous agent associated with rapidrecovery without a hangover effect. Etomidate causesless hypotension than thiopental and propofol duringinduction. It produces a high incidence of extraneousmuscle movements, which can be minimised by anopioid analgesic or a short-acting benzodiazepinegiven just before induction. Pain on injection can bereduced by injecting into a larger vein or by giving anopioid analgesic just before induction. Etomidate suppressesadrenocortical function, particularly on continuousadministration, and it should not be used formaintenance of anaesthesia.Ketamine causes less hypotension than thiopental andpropofol during induction. It is sometimes used inchildren requiring repeat anaesthesia (such as for serialburns dressings), however recovery is relatively slowand there is a high incidence of extraneous musclemovements. Ketamine can cause hallucinations, nightmares,and other transient psychotic effects; these canbe reduced by a benzodiazepine, such as diazepam ormidazolam.ETOMIDATECautions see notes above; avoid in acute porphyria(section 9.8.2); interactions: Appendix 1 (anaesthetics,general)Contra-indications see notes aboveHepatic impairment reduce dose in liver cirrhosisPregnancy may depress neonatal respiration if usedduring deliveryBreast-feeding breast-feeding can be resumed assoon as mother has recovered sufficiently fromanaesthesiaSide-effects see notes above; also nausea, vomiting,hypotension, apnoea, hyperventilation, stridor, rash;less commonly hypersalivation, bradycardia, arrhythmias,hypertension, hiccups, cough, phlebitis; AVblock, cardiac arrest, respiratory depression, seizures,shivering, and Stevens-Johnson syndrome alsoreportedIndication and doseSee under preparationsEtomidate-Lipuro c (Braun) AInjection (emulsion), etomidate 2 mg/mL, net price10-mL amp = £1.53DoseInduction of anaesthesia. By slow intravenous injectionChild 1 month–18 years 150–300 micrograms/kg; childunder 10 years may need up to 400 micrograms/kgHypnomidate c (Janssen) AInjection, etomidate 2 mg/mL, net price 10-mL amp= £1.38Excipients include propylene glycol (see Excipients, p. 2)DoseInduction of anaesthesia. By slow intravenous injectionChild 1 month–18 years 300 micrograms/kg (max.total dose 60 mg)KETAMINECautions see notes above; dehydration; hypertension;respiratory tract infection; increased cerebrospinalfluid pressure; predisposition to seizures, hallucinations,or nightmares; psychotic disorders; head injuryor intracranial mass lesions; thyroid dysfunction;raised intraocular pressure; interactions: Appendix 1(anaesthetics, general)Contra-indications see notes above; hypertension,pre-eclampsia or eclampsia, severe cardiac disease,stroke; raised intracranial pressure; head trauma;acute porphyria (section 9.8.2)Hepatic impairment consider dose reductionPregnancy may depress neonatal respiration if usedduring deliveryBreast-feeding avoid for at least 12 hours after lastdoseSide-effects see notes above; also nausea, vomiting,tachycardia, hypertension, arrhythmias, hypotension,bradycardia, hypersalivation, laryngospasm, anxiety,insomnia, diplopia, nystagmus, raised intra-ocularpressure; rashes, apnoea, and respiratory depressionalso reportedIndication and doseSedation prior to invasive or painful procedures. By intravenous injectionChild 1 month–18 years 1–2 mg/kg as a singledoseInduction and maintenance of anaesthesia(short procedures). By intravenous injection over at least 60 secondsNeonate 1–2 mg/kg produces 5–10 minutes ofsurgical anaesthesia, adjusted according toresponse

BNFC 2011–2012 15.1.1 Intravenous anaesthetics 631Child 1 month–12 years 1–2 mg/kg produces 5–10 minutes of surgical anaesthesia, adjustedaccording to responseChild 12–18 years 1–4.5 mg/kg adjustedaccording to response (2 mg/kg usually produces5–10 minutes of surgical anaesthesia). By intramuscular injectionNeonate 4 mg/kg usually produces 15 minutes ofsurgical anaesthesia, adjusted according toresponseChild 1 month–18 years 4–13 mg/kg (4 mg/kgsufficient for some diagnostic procedures),adjusted according to response; 10 mg/kg usuallyproduces 12–25 minutes of surgical anaesthesiaInduction and maintenance of anaesthesia(longer procedures). By intravenous administrationNeonate initially 0.5–2 mg/kg by intravenousinjection, followed by a continuous intravenousinfusion of 8 micrograms/kg/minute adjustedaccording to response; up to 30 micrograms/kg/minute may be used to produce deep anaesthesiaChild 1 month–18 years initially 0.5–2 mg/kg byintravenous injection followed by a continuousintravenous infusion of 10–45 micrograms/kg/minute adjusted according to responseAdministration for continuous intravenous infusion,dilute to a concentration of 1 mg/mL with Glucose 5%or Sodium Chloride 0.9%; use microdrip infusion formaintenance of anaesthesiaFor intravenous injection, dilute 100 mg/mL strengthto a concentration of not more than 50 mg/mL withGlucose 5% or Sodium Chloride 0.9%Ketalar c (Pfizer) KInjection, ketamine (as hydrochloride) 10 mg/mL, netprice 20-mL vial = £5.06; 50 mg/mL, 10-mL vial =£8.77; 100 mg/mL, 10-mL vial = £16.10PROPOFOLCautions see notes above; cardiac impairment; respiratoryimpairment; hypovolaemia; epilepsy; hypotension;raised intracranial pressure; monitor bloodlipidconcentration if risk of fat overload or if sedationlonger than 3 days; interactions: Appendix 1(anaesthetics, general)Contra-indications see notes aboveHepatic impairment use with cautionRenal impairment use with cautionPregnancy may depress neonatal respiration if usedduring delivery; max. dose for maintenance ofanaesthesia, 6 mg/kg/hourBreast-feeding breast-feeding can be resumed assoon as mother has recovered sufficiently fromanaesthesiaSide-effects see notes above; also hypotension,tachycardia, flushing; transient apnoea, hyperventilation,coughing, and hiccup during induction; headache;less commonly thrombosis, phlebitis; rarelyarrhythmia, headache, vertigo, shivering, euphoria;very rarely pancreatitis, pulmonary oedema, sexualdisinhibition, and discoloration of urine; serious andsometimes fatal side-effects reported with prolongedinfusion of doses exceeding 5 mg/kg/hour, includingmetabolic acidosis, rhabdomyolysis, hyperkalaemia,and cardiac failure, dystonia and dyskinesia alsoreportedIndication and doseInduction of anaesthesia using 0.5% or 1%injection. By slow intravenous injection or by intravenousinfusionChild 1 month–18 years adjust dose according toage, body-weight, and response; usual dose inchild 1 month–17 years 2.5–4 mg/kg; usual dose inchild 17–18 years 1.5–2.5 mg/kg at a rate of 20–40 mg every 10 seconds until responseInduction of anaesthesia using 2% injection. By intravenous infusionChild 3–18 years adjust dose according to age,body-weight, and response; usual dose in child 3–17 years 2.5–4 mg/kg; usual dose in child 17–18years 1.5–2.5 mg/kg at a rate of 20–40 mg every10 seconds until responseMaintenance of anaesthesia using 1% injection. By continuous intravenous infusionChild 1 month–18 years adjust dose according toage, body-weight, and response; usual dose inchild 1 month–17 years 9–15 mg/kg/hour; usualdose in child 17–18 years 4–12 mg/kg/hour,adjusted according to responseMaintenance of anaesthesia using 2% injection. By continuous intravenous infusionChild 3–18 years adjust dose according to age,body-weight, and response; usual dose in child 3–17 years 9–15 mg/kg/hour; usual dose in child 17–18 years 4–12 mg/kg/hour, adjusted according toresponseSedation of ventilated children in intensive careusing 1% or 2% injection. By continuous intravenous infusionChild 16–18 years 0.3–4 mg/kg/hour, adjustedaccording to responseInduction of sedation for surgical and diagnosticprocedures using 0.5% or 1% injection. By slow intravenous injectionChild 1 month–18 years dose and rate ofadministration adjusted according to desired levelof sedation and response; usual dose in child1 month–17 years 1–2 mg/kg; usual dose in child17–18 years 0.5–1 mg/kg over 1–5 minutesMaintenance of sedation for surgical and diagnosticprocedures using 0.5% injection. By intravenous infusionChild 17–18 years dose and rate of administrationadjusted according to desired level of sedationand response; usual dose 1.5–4.5 mg/kg/hour(additionally, if rapid increase in sedation required,by slow intravenous injection 10–20 mg)15 Anaesthesia

632 15.1.2 Inhalational anaesthetics BNFC 2011–201215 AnaesthesiaMaintenance of sedation for surgical and diagnosticprocedures using 1% injection. By intravenous infusionChild 1 month–18 years dose and rate ofadministration adjusted according to desired levelof sedation and response; usual dose in child1 month–17 years 1.5–9 mg/kg/hour (additionally,if rapid increase in sedation required, by slowintravenous injection, max. 1 mg/kg); usual dosein child 17–18 years 1.5–4.5 mg/kg/hour (additionally,if rapid increase in sedation required, byslow intravenous injection, 10–20 mg)Maintenance of sedation for surgical and diagnosticprocedures using 2% injection. By intravenous infusionChild 3–18 years dose and rate of administrationadjusted according to desired level of sedation andresponse; usual dose in child 3–17 years 1.5–9 mg/kg/hour; usual dose in child 17–18 years 1.5–4.5 mg/kg/hour (additionally, if rapid increase insedation required, by slow intravenous injectionusing 0.5% or 1% injection, 10–20 mg)Administration for continuous intravenous infusion;microbiological filter not recommended; 0.5% or 1%emulsion may be infused undiluted using a suitableinfusion pump; may also be administered via a Y-piece close to injection site co-administered withGlucose 5% or Sodium Chloride 0.9%; alternativelydilute to a concentration not less than 2 mg/mL(1 mg/mL for 0.5% injection) with Glucose 5% (orSodium Chloride 0.9% for Propofol-Lipuro c ,Propoven c , Braun, and Fresenius Kabi brands); useglass or PVC containers (if PVC bag used, it should befull—withdraw volume of infusion fluid equal to thatof propofol to be added); give within 6 hours ofpreparation2% emulsion do not dilute; may be administered via aY-piece close to injection site co-administered withGlucose 5% or Sodium Chloride 0.9%Propofol (Non-proprietary) A0.5% injection (emulsion), propofol 5 mg/mL, netprice 20-mL amp = £3.46Brands include Propofol-Lipuro c1% injection (emulsion), propofol 10 mg/mL, netprice 20-mL amp = £4.18, 50-mL bottle = £10.10, 100-mL bottle = £19.40Brands include Propofol-Lipuro c , Propoven c2% injection (emulsion), propofol 20 mg/mL, netprice 50-mL vial = £21.30Brands include Propofol-Lipuro c , Propoven cDiprivan c (AstraZeneca) A1% injection (emulsion), propofol 10 mg/mL, netprice 20-mL amp = £1.07, 50-mL prefilled syringe (foruse with Diprifusor c TCI system) = £4.722% injection (emulsion), propofol 20 mg/mL, netprice 50-mL prefilled syringe (for use withDiprifusor c TCI system) = £5.27THIOPENTAL SODIUM(Thiopentone sodium)Cautions see notes above; cardiovascular disease;reconstituted solution is highly alkaline—extravasationcauses tissue necrosis and severe pain; avoidintra-arterial injection; interactions: Appendix 1(anaesthetics, general)Contra-indications see notes above; acute porphyria(section 9.8.2); myotonic dystrophyHepatic impairment use with caution—reduce doseRenal impairment caution in severe impairmentPregnancy may depress neonatal respiration if usedduring delivery; dose should not exceed 250 mgBreast-feeding breast-feeding can be resumed assoon as mother has recovered sufficiently fromanaesthesiaSide-effects hypotension, arrhythmias, myocardialdepression, laryngeal spasm, cough, headache,sneezing, hypersensitivity reactions, rashLicensed use not licensed for use in status epilepticus;not licensed for use by intravenous infusionIndication and doseInduction of anaesthesia. By slow intravenous injectionNeonate initially up to 2 mg/kg, then 1 mg/kgrepeated as necessary (max. total dose 4 mg/kg)Child 1 month–18 years initially up to 4 mg/kg,then 1 mg/kg repeated as necessary (max. totaldose 7 mg/kg)Prolonged status epilepticus. By slow intravenous injection and intravenousinfusionNeonate initially up to 2 mg/kg by intravenousinjection, then up to 8 mg/kg/hour by continuousintravenous infusion, adjusted according toresponseChild 1 month–18 years initially up to 4 mg/kgby intravenous injection, then up to 8 mg/kg/hourby continuous intravenous infusion, adjustedaccording to responseAdministration For intravenous injection, dilute to aconcentration of 25 mg/mL with Water for Injections,and give over at least 10–15 seconds; for intravenousinfusion dilute to a concentration of 2.5 mg/mL withSodium Chloride 0.9%Thiopental (Archimedes) AInjection, powder for reconstitution, thiopental sodium,net price 500-mg vial = £3.6815.1.2 Inhalational anaestheticsImportantThe drugs in this section should be used by experiencedpersonnel only and when resuscitation equipmentis available.Inhalational anaesthetics include gases and volatileliquids. Gaseous anaesthetics require suitable equipmentfor administration. Volatile liquid anaestheticsare administered using calibrated vaporisers, using air,oxygen, or nitrous oxide-oxygen mixtures as the carrier

BNFC 2011–2012 15.1.2 Inhalational anaesthetics 633gas. To prevent hypoxia, the inspired gas mixture shouldcontain a minimum of 25% oxygen at all times. Higherconcentrations of oxygen (greater than 30%) are usuallyrequired during inhalational anaesthesia with nitrousoxide, see Nitrous Oxide, p. 634.Anaesthesia and skilled tasks See section 15.1.Volatile liquid anaestheticsVolatile liquid anaesthetics can be used for inductionand maintenance of anaesthesia, and following inductionwith an intravenous anaesthetic (section 15.1.1).Volatile liquid anaesthetics can trigger malignant hyperthermia(section 15.1.8) and are contra-indicated inthose susceptible to malignant hyperthermia. Theycan increase cerebrospinal pressure and should beused with caution in those with raised intracranialpressure. They can also cause hepatotoxicity in thosewho are sensitised to halogenated anaesthetics; halothanehas been associated with severe hepatotoxicity(important: see below). In children with neuromusculardisease, inhalational anaesthetics are very rarely associatedwith hyperkalaemia, resulting in cardiac arrhythmiasand death. Cardiorespiratory depression, hypotension,and arrhythmias are common side-effects ofvolatile liquid anaesthetics.Isoflurane is a volatile liquid anaesthetic. Heart rhythmis generally stable during isoflurane anaesthesia, butheart-rate can rise. Systemic arterial pressure and cardiacoutput can fall, owing to a decrease in systemicvascular resistance. Muscle relaxation occurs and theeffects of muscle relaxant drugs are potentiated. Isofluranecan irritate mucous membranes, causing cough,breath-holding, and laryngospasm. Isoflurane is thepreferred inhalational anaesthetic for use in obstetrics.Desflurane is a rapid-acting volatile liquid anaesthetic;it is reported to have about one-fifth the potency ofisoflurane. Emergence and recovery from anaesthesiaare particularly rapid because of its low solubility. Desfluraneis not recommended for induction of anaesthesiaas it is irritant to the upper respiratory tract;cough, breath-holding, apnoea, laryngospasm, andincreased secretions can occur.Sevoflurane is a rapid-acting volatile liquid anaestheticand is more potent than desflurane. Emergence andrecovery are particularly rapid but slower than desflurane.Sevoflurane is non-irritant and is therefore used forinhalational induction of anaesthesia. Sevoflurane caninteract with carbon dioxide absorbents to form compoundA, a potentially nephrotoxic vinyl ether. However,in spite of extensive use, no cases of sevofluraneinducedpermanent renal injury have been reported andthe carbon dioxide absorbents used in the UK producevery low concentrations of compound A, even in lowflowanaesthetic systems.Halothane is a volatile liquid anaesthetic that has largelybeen superseded by newer agents, but is usedoccasionally by very specialised paediatric anaesthetiststo manage difficult airways (with careful monitoring forcardiorespiratory depression and arrhythmias). Itsadvantages are that it is potent, induction is smooth,and the vapour is non-irritant and seldom inducescoughing or breath-holding.Halothane hepatotoxicitySevere hepatotoxicity can follow halothane anaesthesia.It occurs more frequently after repeatedexposure to halothane and has a high mortality.The risk of severe hepatotoxicity appears to beincreased by repeated exposures within a shorttime interval, but even after a long interval (sometimesof several years), susceptible patients havebeen reported to develop jaundice. Since there isno reliable way of identifying patients at risk, thefollowing precautions are recommended before theuse of halothane:. a careful anaesthetic history should be taken todetermine previous exposure and previous reactionsto halothane;. repeated exposure to halothane within a periodof at least 3 months should be avoided unlessthere are overriding clinical circumstances;. a history of unexplained jaundice or pyrexia in apatient following exposure to halothane is anabsolute contra-indication to its future use inthat patient.DESFLURANECautions see notes above; interactions: Appendix 1(anaesthetics, general)Contra-indications see notes abovePregnancy may depress neonatal respiration if usedduring deliveryBreast-feeding breast-feeding can be resumed assoon as mother has recovered sufficiently fromanaesthesiaSide-effects see notes aboveIndication and doseInduction of anaesthesia. By inhalation through specifically calibratedvaporiserChild 12–18 years 4–11%, but not recommended(see notes above)Maintenance of anaesthesia. By inhalation through specifically calibratedvaporiserNeonate 2–6% in nitrous oxide-oxygen; 2.5–8.5%in oxygen or oxygen-enriched airChild 1 month–18 years 2–6% in nitrous oxideoxygen;2.5–8.5% in oxygen or oxygen-enrichedairHALOTHANECautions see notes above (important: see HalothaneHepatoxicity above); avoid for dental procedures inthose under 18 years unless treated in hospital (highrisk of arrhythmia); avoid in acute porphyria (section9.8.2); interactions: Appendix 1 (anaesthetics, general)Contra-indications see notes aboveHepatic impairment avoid if history of unexplainedpyrexia or jaundice following previous exposure tohalothanePregnancy may depress neonatal respiration if usedduring delivery15 Anaesthesia

634 15.1.2 Inhalational anaesthetics BNFC 2011–201215 AnaesthesiaBreast-feeding breast-feeding can be resumed assoon as mother has recovered sufficiently fromanesthesiaSide-effects see notes aboveIndication and doseInduction of anaesthesia. By inhalation through specifically calibratedvaporiserChild 1 month–18 years initially 0.5% thenincreased gradually according to response to 2–5%in oxygen or nitrous oxide-oxygenMaintenance of anaesthesia. By inhalation through specifically calibratedvaporiserChild 1 month–18 years 0.5–2% in oxygen, oroxygen-air, or nitrous oxide-oxygenISOFLURANECautions see notes above; interactions: Appendix 1(anaesthetics, general)Contra-indications see notes abovePregnancy may depress neonatal respiration if usedduring deliveryBreast-feeding breast-feeding can be resumed assoon as mother has recovered sufficiently fromanaesthesiaSide-effects see notes aboveIndication and doseInduction of anaesthesia. By inhalation through specifically calibratedvaporiserNeonate increased gradually according toresponse from 0.5–3% in oxygen or nitrous oxideoxygenChild 1 month–18 years increased graduallyaccording to response from 0.5–3% in oxygen ornitrous oxide-oxygenMaintenance of anaesthesia. By inhalation through specifically calibratedvaporiserNeonate 1–2.5% in nitrous oxide-oxygen; additional0.5–1% may be required if given with oxygenaloneChild 1 month–18 years 1–2.5% in nitrous oxideoxygen;additional 0.5–1% may be required if givenwith oxygen alone; caesarean section, 0.5–0.75%in nitrous oxide-oxygenSEVOFLURANECautions see notes above; susceptibility to QT-intervalprolongation; interactions: Appendix 1 (anaesthetics,general)Contra-indications see notes aboveRenal impairment use with cautionPregnancy may depress neonatal respiration if usedduring deliveryBreast-feeding breast-feeding can be resumed assoon as mother has recovered sufficiently fromanaesthesiaSide-effects see notes above; also urinary retention,leucopenia, agitation; cardiac arrest, torsade depointes, dystonia, and seizures also reportedIndication and doseInduction of anaesthesia. By inhalation through specifically calibratedvaporiserNeonate up to 4% in oxygen or nitrous oxideoxygen,according to responseChild 1 month–18 years initially 0.5–1% thenincreased gradually up to 8% in oxygen or nitrousoxide-oxygen, according to responseMaintenance of anaesthesia. By inhalation through specifically calibratedvaporiserNeonate 0.5–2% in oxygen or nitrous oxide-oxygen,according to responseChild 1 month–18 years 0.5–3% in oxygen ornitrous oxide-oxygen, according to responseNitrous oxideNitrous oxide is used for maintenance of anaesthesiaand, in sub-anaesthetic concentrations, for analgesia.For anaesthesia it is commonly used in a concentrationof 50 to 66% in oxygen as part of a balanced techniquein association with other inhalational or intravenousagents. Nitrous oxide is unsatisfactory as a sole anaestheticowing to lack of potency, but is useful as part of acombination of drugs since it allows a significant reductionin dosage.For analgesia (without loss of consciousness) a mixtureof nitrous oxide and oxygen containing 50% of each gas(Entonox c , Equanox c ) is used. Self-administrationusing a demand valve may be used in children whoare able to self-regulate their intake (usually over 5 yearsof age) for painful dressing changes, as an aid topostoperative physiotherapy, for wound debridementand in emergency ambulances.Nitrous oxide may have a deleterious effect if used inchildren with an air-containing closed space sincenitrous oxide diffuses into such a space with a resultingincrease in pressure. This effect may be dangerous inthe presence of a pneumothorax, which may enlarge tocompromise respiration, or in the presence of intracranialair after head injury. Hypoxia can occur immediatelyfollowing the administration of nitrous oxide; additionaloxygen should always be given for severalminutes after stopping the flow of nitrous oxide.Exposure of children to nitrous oxide for prolongedperiods, either by continuous or by intermittent administration,may result in megaloblastic anaemia owing tointerference with the action of vitamin B 12; neurologicaltoxic effects can occur without preceding overt haematologicalchanges. For the same reason, exposure oftheatre staff to nitrous oxide should be minimised.Depression of white cell formation may also occur.Assessment of plasma-vitamin B 12 concentration shouldbe considered before nitrous oxide anaesthesia in childrenat risk of deficiency, including children who have apoor or vegetarian diet and children with a history ofanaemia. Nitrous oxide should not be given continuouslyfor longer than 24 hours or more frequently thanevery 4 days without close supervision and haematologicalmonitoring.

BNFC 2011–2012 15.1.3 Antimuscarinic drugs 635NITROUS OXIDECautions see notes above; interactions: Appendix 1(anaesthetics, general)Pregnancy may depress neonatal respiration if usedduring deliveryBreast-feeding breast-feeding can be resumed assoon as mother has recovered sufficiently fromanaesthesiaSide-effects see notes aboveIndication and doseMaintenance of anaesthesia in conjunctionwith other anaesthetic agents. By inhalation using suitable anaesthetic apparatusNeonate 50–66% in oxygenChild 1 month–18 years 50–66% in oxygenAnalgesia. By inhalation using suitable anaesthetic apparatus(see also notes above)Neonate up to 50% in oxygen, according to thechild’s needsChild 1 month–18 years up to 50% in oxygen,according to the child’s needs15.1.3 Antimuscarinic drugsImportantThe drugs in this section should be used by experiencedpersonnel only.Antimuscarinic drugs are used (less commonly nowadays)as premedicants to dry bronchial and salivarysecretions which are increased by intubation, upperairway surgery, or some inhalational anaesthetics, butthey should not be used for this indication in childrenwith cystic fibrosis. Antimuscarinics are also used beforeor with neostigmine (section 15.1.6) to prevent bradycardia,excessive salivation, and other muscarinicactions of neostigmine. They also prevent bradycardiaand hypotension associated with drugs such as halothane,propofol, and suxamethonium.Atropine sulphate is now rarely used for premedicationbut still has an emergency role in the treatment ofvagotonic side-effects. For its role in cardiopulmonaryresuscitation, see section 2.7.3.Hyoscine hydrobromide reduces secretions and alsoprovides a degree of amnesia, sedation and anti-emesis.Unlike atropine it may produce bradycardia rather thantachycardia. In some children hyoscine may cause thecentral anticholinergic syndrome (excitement, ataxia,hallucinations, behavioural abnormalities, and drowsiness).Glycopyrronium bromide reduces salivary secretions.When given intravenously it produces less tachycardiathan atropine. It is widely used with neostigmine forreversal of non-depolarising muscle relaxants (section15.1.5).Glycopyrronium or hyoscine hydrobromide are alsoused to control excessive secretions in upper airwaysor hypersalivation in palliative care and in childrenunable to control posture or with abnormal swallowingreflex; effective dose varies and tolerance may develop.The intramuscular route should be avoided if possible.Hyoscine transdermal patches may also be used (section4.6).ATROPINE SULPHATECautions see notes in section 1.2Duration of action Since atropine has a shorter duration ofaction than neostigmine, late unopposed bradycardia mayresult; close monitoring of the patient is necessaryContra-indications see notes in section 1.2Pregnancy not known to be harmful; use with cautionBreast-feeding small amount present in milk—usewith cautionSide-effects see notes in section 1.2Licensed use not licensed for use by oral route; notlicensed for use in children under 12 years for intraoperativebradycardia; not licensed for use in childrenunder 12 years by intravenous route for premedication;not licensed for the control of muscarinicside-effects of edrophonium in reversal ofcompetitive neuromuscular blockIndication and dosePremedication. By mouth 1–2 hours before induction ofanaesthesiaNeonate 20–40 micrograms/kgChild 1 month–18 years 20–40 micrograms/kg(max. 900 micrograms). By intravenous injection immediately beforeinduction of anaesthesiaNeonate 10 micrograms/kgChild 1 month–12 years 20 micrograms/kg(minimum 100 micrograms, max. 600 micrograms)Child 12–18 years 300–600 micrograms. By subcutaneous or intramuscular injection30–60 minutes before induction of anaesthesiaNeonate 10 micrograms/kgChild 1 month–12 years 10–30 micrograms/kg(minimum 100 micrograms, max. 600 micrograms)Child 12–18 years 300–600 microgramsIntra-operative bradycardia. By intravenous injectionNeonate 10–20 micrograms/kgChild 1 month–12 years 10–20 micrograms/kgChild 12–18 years 300–600 micrograms (largerdoses in emergencies)Control of muscarinic side-effects of neostigmine50 micrograms/kg in reversal of competitiveneuromuscular block. By intravenous injectionNeonate 20 micrograms/kgChild 1 month–12 years 20 micrograms/kg(max. 1.2 mg)Child 12–18 years 0.6–1.2 mg15 Anaesthesia

636 15.1.3 Antimuscarinic drugs BNFC 2011–201215 AnaesthesiaControl of muscarinic side-effects of edrophoniumin reversal of competitive neuromuscularblock. By intravenous injectionChild 1 month–18 years 7 micrograms/kg (max.600 micrograms)Cycloplegia, anterior uveitis (section 11.5)Administration for administration by mouth, injectionsolution may be given orally1Atropine (Non-proprietary) AInjection, atropine sulphate 600 micrograms/mL, netprice 1-mL amp = 62pNote Other strengths also availableInjection, prefilled disposable syringe, atropine sulphate100 micrograms/mL, net price 5 mL = £4.58,10 mL = £5.39, 30 mL = £8.95Injection, prefilled disposable syringe, atropine sulphate200 micrograms/mL, net price 5 mL = £5.91;300 micrograms/mL, 10 mL = £5.91; 600 micrograms/mL,1 mL = £5.91Oral solution, atropine sulphate 100 micrograms/mLavailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809TabletsU, atropine sulphate 600 micrograms, netprice 28-tab pack = £17.591. A restriction does not apply where administration is forsaving life in emergency1Minijet c Atropine (UCB Pharma) AInjection, atropine sulphate 100 micrograms/mL, netprice 5 mL = £5.04, 10 mL = £5.93, 30 mL = £9.851. A restriction does not apply where administration is forsaving life in emergencyGLYCOPYRRONIUM BROMIDE(Glycopyrrolate)Cautions section 1.2Contra-indications section 1.2Side-effects section 1.2Licensed use not licensed for use in control of upperairways secretion and hypersalivationIndication and dosePremedication at induction. By intravenous or intramuscular injectionNeonate 5 micrograms/kgChild 1 month–12 years 4–8 micrograms/kg(max. 200 micrograms)Child 12–18 years 200–400 micrograms or 4–5 micrograms/kg (max. 400 micrograms)Intra-operative bradycardia. By intravenous injectionNeonate 10 micrograms/kg, repeated if necessaryChild 1 month–18 years 4–8 micrograms/kg(max. 200 micrograms), repeated if necessaryControl of muscarinic side-effects of neostigminein reversal of competitive neuromuscularblock. By intravenous injectionNeonate 10 micrograms/kgChild 1 month–12 years 10 micrograms/kg(max. 500 micrograms)Child 12–18 years 200 micrograms per 1 mg ofneostigmine, or 10–15 micrograms/kgControl of upper airways secretion and hypersalivation. By mouthChild 1 month–18 years 40–100 micrograms/kg(max. 2 mg) 3–4 times daily, adjusted according toresponse. By subcutaneous infusionChild 1 month–12 years 12–40 micrograms/kg/24 hours (max. 1.2 mg)Child 12–18 years 0.6–1.2 mg/24 hours. By subcutaneous injection or intramuscularinjection or intravenous injection (but seenotes above)Child 1 month–12 years 4–10 micrograms/kg(max. 200 micrograms) 4 times a day whenrequiredChild 12–18 years 200 micrograms every 4 hourswhen requiredAdministration for administration by mouth, injectionsolution may be given or crushed tablets suspended inwaterGlycopyrronium bromide (Non-proprietary)Injection, glycopyrronium bromide 200 micrograms/mL, net price 1-mL amp = 54p, 3-mL amp = 91pTablets, glycopyrronium bromide 1 mg and 2 mgAvailable on a named-patient basis from specialist importingcompanies, p. 809With neostigmine metilsulphateSection 15.1.6HYOSCINE HYDROBROMIDE(Scopolamine hydrobromide)Cautions see notes in section 1.2 and notes above;also epilepsyContra-indications see notes in section 1.2Hepatic impairment see Hyoscine Hydrobromide,section 4.6Renal impairment see Hyoscine Hydrobromide, section4.6Pregnancy see Hyoscine Hydrobromide, section 4.6Breast-feeding see Hyoscine Hydrobromide, section4.6Side-effects see notes in section 1.2Indication and dosePremedication. By subcutaneous or intramuscular injection30–60 minutes before inductionChild 1–12 years 15 micrograms/kg (max.600 micrograms)Child 12–18 years 200–600 microgramsNote Same dose may be given by intravenous injectionimmediately before induction

BNFC 2011–2012 15.1.4 Sedative and analgesic peri-operative drugs 637Motion sickness, excessive respiratory secretions,hypersalivation associated with clozapinetherapy section 4.6Hyoscine (Non-proprietary) AInjection, hyoscine hydrobromide 400 micrograms/mL, net price 1-mL amp = £2.80; 600 micrograms/mL, 1-mL amp = £2.94PreparationsFor transdermal and oral preparations see section 4.615.1.4 Sedative and analgesicperi-operative drugs15.1.4.1 Anxiolytics15.1.4.2 Non-opioid analgesics15.1.4.3 Opioid analgesicsImportantThe drugs in this section should be used by experiencedpersonnel only.Premedication Fear and anxiety before a procedure(including the night before) can be minimised by using asedative drug, usually a benzodiazepine. Premedicationmay also augment the action of anaestheticsand provide some degree of pre-operative amnesia.The choice of drug depends on the individual child,the nature of the procedure, the anaesthetic to be used,and other prevailing circumstances such as outpatients,obstetrics, and recovery facilities. The choice also variesbetween elective and emergency procedures. Oraladministration is preferred if possible; the rectal routeshould only be used in exceptional circumstances. Sedativepremedication should be avoided in children with acompromised airway, CNS depression, or a history ofsleep apnoea.Premedicants can be given the night before majorsurgery; a further, smaller dose may be required thefollowing morning if any delay in starting surgery isanticipated. Alternatively, the first dose may be given onthe day of procedure.Oral midazolam is the most common premedicant forchildren; temazepam may be used in older children.The antihistamine alimemazine (section 3.4.1) is occasionallyused orally, but when given alone it may causepostoperative restlessness in the presence of pain.Sedation for clinical procedures Sedation of childrenduring diagnostic and therapeutic procedures isused to reduce fear and anxiety, to control pain, and tominimise excessive movement. The choice of sedativedrug will depend upon the intended procedure andwhether the child is cooperative; some procedures aresafer and more successful under anaesthesia. The childshould be monitored carefully; monitoring shouldbegin as soon as the sedative is given or when thechild becomes drowsy, and should be continued untilthe child wakes up.Midazolam and chloral hydrate (section 4.1.1) aresuitable for sedating children for painless procedures,such as imaging. For painful procedures, alternativechoices include nitrous oxide (section 15.1.2), localanaesthesia (section 15.2), ketamine (section 15.1.1),or concomitant use of sedation with opioid or nonopioidanalgesia (section 4.7).Dental procedures Sedation for dental proceduresshould be limited to conscious sedation whenever possible.Nitrous oxide (section 15.1.2) alone and midazolamare effective for many children. For furtherinformation on hypnotics used for dental procedures,see p. 170.Anaesthesia and skilled tasks See section 15.1.15.1.4.1 AnxiolyticsBenzodiazepinesBenzodiazepines possess useful properties for premedicationincluding relief of anxiety, sedation, and amnesia;short-acting benzodiazepines taken by mouth are themost common premedicants. Benzodiazepines are alsoused for sedation prior to clinical procedures and forsedation in intensive care.Benzodiazepines may occasionally cause marked respiratorydepression and facilities for its treatment areessential; flumazenil (section 15.1.7) is used to antagonisethe effects of benzodiazepines.Midazolam, a water-soluble benzodiazepine, is the preferredbenzodiazepine for premedication and for sedationfor clinical procedures in children. It has a fast onsetof action, and recovery is faster than for other benzodiazepines.Recovery may be longer in children with alow cardiac output, or after repeated dosing.Midazolam can be given by mouth [unlicensed], but itsbitter acidic taste may need to be disguised. It can alsobe given buccally [unlicensed] or intranasally [unlicensed].Midazolam is associated with profound sedationwhen high doses are given or when it is used withcertain other drugs. It can cause severe disinhibition andrestlessness in some children. Midazolam is not recommendedfor prolonged sedation in neonates; drug accumulationis likely to occurOverdosage with midazolamThere have been reports of overdosage in adultswhen high strength midazolam injection has beenused for conscious sedation. The use of highstrength midazolam (5 mg/mL in 2 mL and 10 mLampoules, or 2 mg/mL in 5 mL ampoules) should berestricted to general anaesthesia, intensive care,palliative care, or other situations where the riskhas been assessed. It is advised that flumazenil(section 15.1.7) is available where midazolam isused, to reverse the effects if necessary.Temazepam is given by mouth for premedication inolder children and has a short duration of action. Anxio-15 Anaesthesia

638 15.1.4 Sedative and analgesic peri-operative drugs BNFC 2011–201215 Anaesthesialytic and sedative effects last about 90 minutes, althoughthere may be residual drowsiness. Temazepam is rarelyused for dental procedures in children.Lorazepam produces more prolonged sedation thantemazepam and it has marked amnesic effects.Peri-operative use of diazepam is not recommended inchildren; onset and magnitude of response are unreliable,and paradoxical effects may occur. Diazepam isnot used for dental procedures in children.LORAZEPAMCautions see notes above and section 4.8.2; interactions:Appendix 1 (anxiolytics and hypnotics)Contra-indications see Diazepam, section 4.8.2Hepatic impairment see Benzodiazepines, section4.8.1Renal impairment see Benzodiazepines, section 4.8.1Pregnancy see Benzodiazepines, section 4.8.1Breast-feeding see Benzodiazepines, section 4.8.1Side-effects see notes above and Diazepam, section4.8.2Licensed use not licensed for use in children under 5years by mouth; not licensed for use in childrenunder 12 years by intravenous injectionIndication and dosePremedication. By mouthChild 1 month–12 years 50–100 micrograms/kg(max. 4 mg) at least 1 hour before procedureChild 12–18 years 1–4 mg at least 1 hour beforeprocedureNote Same dose may be given the night before procedurein addition to, or to replace, dose before procedure. By intravenous injectionChild 1 month–18 years 50–100 micrograms/kg(max. 4 mg)Note Give intravenous injection 30–45 minutes beforeprocedureStatus epilepticus section 4.8.2Administration for intravenous injection, diluteinjection solution with an equal volume of SodiumChloride 0.9%; give over 3–5 minutes; max. rate50 micrograms/kg over 3 minutesLorazepam (Non-proprietary) KTablets, lorazepam 1 mg, net price 28-tab pack =£5.42; 2.5 mg, 28-tab pack = £7.11. Label: 2 or 19Injection, lorazepam 4 mg/mL, net price 1-mL amp =35pExcipients include benzyl alcohol (avoid in neonates unless there is nosafer alternative available, see Excipients, p. 2), propylene glycolBrands include Ativan cExtemporaneous formulations available seeExtemporaneous Preparations, p. 6MIDAZOLAMCautions see notes above; cardiac disease; respiratorydisease; myasthenia gravis; neonates; history of drugor alcohol abuse; reduce dose if debilitated; risk ofsevere hypotension in children with hypovolaemia,vasoconstriction, hypothermia; avoid prolongeduse (and abrupt withdrawal thereafter); interactions:Appendix 1 (anxiolytics and hypnotics)Contra-indications marked neuromuscular respiratoryweakness including unstable myasthenia gravis;severe respiratory depression; acute pulmonaryinsufficiencyHepatic impairment use with caution; can precipitatecomaRenal impairment start with small doses in severeimpairment; increased cerebral sensitivityPregnancy avoid regular use (risk of neonatal withdrawalsymptoms); use only if clear indication such asseizure control (high doses during late pregnancy orlabour may cause neonatal hypothermia, hypotonia,and respiratory depression)Breast-feeding present in milk—avoid breast-feedingfor 24 hours after administrationSide-effects see notes above; gastro-intestinal disturbances,increased appetite, jaundice; hypotension,cardiac arrest, heart rate changes, anaphylaxis,thrombosis; laryngospasm, bronchospasm, respiratorydepression and respiratory arrest (particularlywith high doses or on rapid injection); drowsiness,confusion, ataxia, amnesia, headache, euphoria, hallucinations,convulsions (more common in neonates),fatigue, dizziness, vertigo, involuntary movements,paradoxical excitement and aggression, dysarthria;urinary retention, incontinence; blood disorders;muscle weakness; visual disturbances; salivationchanges; skin reactions; injection-site reactions; withintranasal administration burning sensation, lacrimation,and severe irritation of nasal mucosaLicensed use not licensed for use in children under 6months for premedication and conscious sedation;not licensed for use by mouth, or by buccaladministrationIndication and doseConscious sedation for procedures (but see notesabove). By mouthChild 1 month–18 years 500 micrograms/kg(max. 20 mg) 30–60 minutes before procedure. By buccal administrationChild 6 months–10 years 200–300 micrograms/kg (max. 5 mg)Child 10–18 years 6–7 mg (max. 8 mg if 70 kg orover). By rectumChild 6 months–12 years 300–500 micrograms/kg 15–30 minutes before procedure. By intravenous injection over 2–3 minutes 5–10 minutes before procedureChild 1 month–6 years initially 25–50 micrograms/kg,increased if necessary in small steps(max. total dose 6 mg)Child 6–12 years initially 25–50 micrograms/kg,increased if necessary in small steps (max. totaldose 10 mg)Child 12–18 years initially 25–50 micrograms/kg, increased if necessary in small steps (max. totaldose 7.5 mg)

BNFC 2011–2012 15.1.4 Sedative and analgesic peri-operative drugs 639Premedication (but see notes above). By mouthChild 1 month–18 years 500 micrograms/kg(max. 20 mg) 15–30 minutes before the procedure. By rectumChild 6 months–12 years 300–500 micrograms/kg 15–30 minutes before inductionInduction of anaesthesia (but rarely used). By slow intravenous injectionChild 7–18 years initially 150 micrograms/kg(max. 7.5 mg) given in steps of 50 micrograms/kg(max. 2.5 mg) over 2–5 minutes; wait for 2–5minutes then give additional doses of 50 micrograms/kg(max. 2.5 mg) every 2 minutes ifnecessary; max. total dose 500 micrograms/kg(not exceeding 25 mg)Sedation in intensive care. By intravenous injection and continuous intravenousinfusionNeonate less than 32 weeks gestational age60 micrograms/kg/hour by continuous intravenousinfusion, reduced after 24 hours to30 micrograms/kg/hour; adjusted according toresponse; max. treatment duration 4 daysNeonate over 32 weeks gestational age60 micrograms/kg/hour by continuous intravenousinfusion adjusted according to response;max. treatment duration 4 daysChild 1–6 months 60 micrograms/kg/hour bycontinuous intravenous infusion adjusted accordingto responseChild 6 months–12 years initially 50–200 micrograms/kgby slow intravenous injection over atleast 3 minutes followed by 30–120 micrograms/kg/hour by continuous intravenous infusionadjusted according to responseChild 12–18 years initially 30–300 micrograms/kg by slow intravenous injection given in steps of1–2.5 mg every 2 minutes followed by 30–200 micrograms/kg/hour by continuous intravenousinfusion adjusted according to responseNote Initial dose may not be required and lower maintenancedoses needed if opioid analgesics also used;reduce dose (or reduce or omit initial dose) in hypovolaemia,vasoconstriction, or hypothermiaStatus epilepticus section 4.8.2Administration for administration by mouth, injectionsolution may be diluted with apple or black currantjuice, chocolate sauce, or colaFor buccal administration, administer half of the dosebetween the upper lip and gum on each side of themouth using an oral syringe; retain in the mouth for atleast 5 minutes then swallowFor continuous intravenous infusion, dilute with Glucose5% or Sodium Chloride 0.9%Neonatal intensive care, dilute 15 mg/kg body-weightto a final volume of 50 mL with infusion fluid; anintravenous infusion rate of 0.1 mL/hour provides adose of 30 micrograms/kg/hourFor rectal administration of the injection solution,attach a plastic applicator onto the end of a syringe; ifthe volume to be given rectally is too small, dilute withWater for InjectionsMidazolam (Non-proprietary) 3Oral liquid, midazolam 2.5 mg/mL, 100 mLAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Buccal liquid, midazolam 5 mg/mL, 0.5-mL (2.5 mg)prefilled syringe, 1-mL (5 mg) prefilled syringe, 1.5-mL(7.5 mg) prefilled syringe, 2-mL (10 mg) prefilledsyringe; 10 mg/mL, 5-mL pack and 25-mL packAvailable from ‘special-order’ manufacturers or specialistimporting companies, see p. 809Injection, midazolam (as hydrochloride) 1 mg/mL,net price 2-mL amp = 50p, 5-mL amp = 60p, 50-mLvial = £7.87; 2 mg/mL, 5-mL amp = 65p; 5 mg/mL, 2-mL amp = 58p, 10-mL amp = £2.50Hypnovel c (Roche) 3Injection, midazolam (as hydrochloride) 2 mg/mL,net price 5-mL amp = 85p; 5 mg/mL, 2-mL amp =72pTEMAZEPAMCautions see notes above and Diazepam, section4.8.2; interactions: Appendix 1 (anxiolytics and hypnotics)Contra-indications see Diazepam, section 4.8.2Hepatic impairment see Benzodiazepines, section4.8.1Renal impairment see Benzodiazepines, section 4.8.1Pregnancy see Benzodiazepines, section 4.8.1Breast-feeding see Benzodiazepines, section 4.8.1Side-effects see notes above and Diazepam, section4.8.2Licensed use tablets not licensed for use in childrenIndication and dosePremedication. By mouthChild 12–18 years 10–20 mg 1 hour before procedureTemazepam (Non-proprietary) 3Tablets, temazepam 10 mg, net price 28-tab pack =£3.42; 20 mg, 28-tab pack = £2.24. Label: 19Dental prescribing on NHS Temazepam Tablets may beprescribedOral solution, temazepam 10 mg/5 mL, net price300 mL = £33.44. Label: 19Note Sugar-free versions are available and can be ordered byspecifying ‘sugar-free’ on the prescriptionDental prescribing on NHS Temazepam Oral Solution maybe prescribedNote See p. 9 for prescribing requirements of controlled drugs15.1.4.2 Non-opioid analgesicsSince non-steroidal anti-inflammatory drugs (NSAIDs)do not depress respiration, do not impair gastro-intestinalmotility, and do not cause dependence, they maybe useful alternatives or adjuncts to opioids for the reliefof postoperative pain. NSAIDs may be inadequate forthe relief of severe pain.15 Anaesthesia

640 15.1.4 Sedative and analgesic peri-operative drugs BNFC 2011–2012Diclofenac, ibuprofen (section 10.1.1), paracetamol(section 4.7.1), and ketorolac are used to relieve postoperativepain in children; diclofenac and paracetamolcan be given parenterally and rectally as well as bymouth. Ketorolac is given by mouth or by intravenousinjection.Toradol c (Roche) ATablets, ivory, f/c, ketorolac trometamol 10 mg, netprice 20-tab pack = £5.45. Label: 17, 21Injection, ketorolac trometamol 10 mg/mL, net price1-mL amp = 89p; 30 mg/mL, 1-mL amp = £1.0815 AnaesthesiaKETOROLAC TROMETAMOLCautions section 10.1.1; avoid in acute porphyria(section 9.8.2); interactions: Appendix 1 (NSAIDs)Contra-indications section 10.1.1; also complete orpartial syndrome of nasal polyps; haemorrhagic diatheses(including coagulation disorders) and followingoperations with high risk of haemorrhage or incompletehaemostasis; confirmed or suspected cerebrovascularbleeding; hypovolaemia or dehydrationHepatic impairment section 10.1.1Renal impairment max. 60 mg daily by intravenousinjection; avoid if serum creatinine greater than160 micromol/litre; see also section 10.1.1Pregnancy section 10.1.1Breast-feeding amount too small to be harmfulSide-effects section 10.1.1; also gastro-intestinal disturbances,taste disturbances, dry mouth; flushing,bradycardia, palpitation, chest pain, hypertension,pallor; dyspnoea, asthma; malaise, euphoria, psychosis,paraesthesia, convulsions, abnormal dreams,hyperkinesia, confusion, hallucinations, urinary frequency,thirst, sweating; hyponatraemia, hyperkalaemia,myalgia; visual disturbances (including opticneuritis); purpura, pain at injection siteLicensed use not licensed for use in children under16 yearsIndication and doseShort-term management of moderate to severeacute postoperative pain only. By mouthChild 16–18 years 10 mg every 4–6 hours asrequired; max. 40 mg daily; max. duration oftreatment 7 days. By intravenous injection over at least 15 secondsChild 6 months–16 years initially 0.5–1 mg/kg(max. 15 mg), then 500 micrograms/kg (max.15 mg) every 6 hours as required; max. 60 mgdaily; max. duration of treatment 2 days. By intravenous injection over at least 15 secondsChild 16–18 years initially 10 mg, then 10–30 mgevery 4–6 hours as required (up to every 2 hoursduring initial postoperative period); max. 90 mgdaily (children weighing less than 50 kg max.60 mg daily); max. duration of treatment 2 daysNote When converting from parenteral to oral administration,total combined dose on the day of convertingshould not exceed 90 mg (60 mg in children weighing lessthan 50 kg) of which the oral component should notexceed 40 mgKetorolac (Non-proprietary) AInjection, ketorolac trometamol 30 mg/mL, net price1-mL amp = £1.1015.1.4.3 Opioid analgesicsOpioid analgesics are now rarely used as premedicants;they are more likely to be administered at induction.Pre-operative use of opioid analgesics is generally limitedto children who require control of existing pain. Themain side-effects of opioid analgesics are respiratorydepression, cardiovascular depression, nausea, andvomiting; for general notes on opioid analgesics andtheir use in postoperative pain, see section 4.7.2.For the management of opioid-induced respiratorydepression, see section 15.1.7.Intra-operative analgesia Opioid analgesics given insmall doses before or with induction reduce the doserequirement of some drugs used during anaesthesia.Alfentanil, fentanyl, and remifentanil are particularlyuseful because they act within 1–2 minutes and haveshort durations of action. The initial doses of alfentanilor fentanyl are followed either by successive intravenousinjections or by an intravenous infusion; prolongedinfusions increase the duration of effect.Repeated intra-operative doses of alfentanil or fentanylshould be given with care since the resulting respiratorydepression can persist postoperatively and occasionallyit may become apparent for the first time postoperativelywhen monitoring of the child might be less intensive.Alfentanil, fentanyl, and remifentanil can causemuscle rigidity, particularly of the chest wall muscle orjaw muscle, which can be managed by the use of neuromuscularblocking drugs.In contrast to other opioids which are metabolised in theliver, remifentanil undergoes rapid metabolism by nonspecificblood and tissue esterases; its short duration ofaction allows prolonged administration at high dosage,without accumulation, and with little risk of residualpostoperative respiratory depression. Remifentanilshould not be given by intravenous injection intraoperatively,but it is well suited to continuous infusion;a supplementary analgesic is given before stopping theinfusion of remifentanil.Neonates The half-life of fentanyl and alfentanil isprolonged in neonates and accumulation is likely withprolonged use.ALFENTANILCautions section 4.7.2 and notes aboveContra-indications section 4.7.2Hepatic impairment section 4.7.2Renal impairment section 4.7.2Pregnancy section 4.7.2Breast-feeding present in milk—withhold breastfeedingfor 24 hours

BNFC 2011–2012 15.1.4 Sedative and analgesic peri-operative drugs 641Side-effects section 4.7.2 and notes above; alsohypertension, myoclonic movements; less commonlyarrhythmias, hiccup, laryngospasm; rarely epistaxis;also reported cardiac arrest, cough, convulsions, andpyrexiaIndication and doseTo avoid excessive dosage in obese children, dose mayneed to be calculated on the basis of ideal weight forheightAnalgesia especially during short procedures;enhancement of anaesthesia. By intravenous injection over 30 seconds (withassisted ventilation)Neonate initially 5–20 micrograms/kg; supplementaldoses up to 10 micrograms/kgChild 1 month–18 years initially 10–20 micrograms/kg;supplemental doses up to 10 micrograms/kg. By intravenous infusion (with assisted ventilation)Neonate initially 10–50 micrograms/kg over 10minutes followed by 0.5–1 micrograms/kg/minuteChild 1 month–18 years initially 50–100 micrograms/kgover 10 minutes followed by 0.5–1 micrograms/kg/minuteAdministration for continuous or intermittent intravenousinfusion dilute in Glucose 5% or SodiumChloride 0.9%Alfentanil (Non-proprietary) 2Injection, alfentanil (as hydrochloride) 500 micrograms/mL,net price 2-mL amp = 70p, 10-mL amp =£3.20Intensive care injection, alfentanil (as hydrochloride)5 mg/mL, net price 1-mL amp = £2.50Note To be diluted before useRapifen c (Janssen) 2Injection, alfentanil (as hydrochloride) 500 micrograms/mL,net price 2-mL amp = 64p; 10-mL amp =£2.90Intensive care injection, alfentanil (as hydrochloride)5 mg/mL, net price 1-mL amp = £2.32Note To be diluted before useFENTANYLCautions see Fentanyl, section 4.7.2 and notes aboveContra-indications see notes in section 4.7.2Hepatic impairment see notes in section 4.7.2Renal impairment see notes in section 4.7.2Pregnancy see notes in section 4.7.2Breast-feeding see Fentanyl, section 4.7.2Side-effects see Fentanyl, section 4.7.2 and notesabove; also myoclonic movements; less commonlylaryngospasm; rarely asystole, insomniaLicensed use not licensed for use in children under 2years; infusion not licensed for use in children under12 yearsIndication and doseTo avoid excessive dosage in obese children, dose mayneed to be calculated on the basis of ideal weight forheightSpontaneous respiration: analgesia duringoperation, enhancement of anaesthesia. By intravenous injection over at least 30 secondsChild 1 month–12 years initially 1–3 micrograms/kg,then 1 microgram/kg as requiredChild 12–18 years initially 50–100 micrograms(max. 200 micrograms on specialist advice), then25–50 micrograms as requiredAssisted ventilation: analgesia during operation,enhancement of anaesthesia. By intravenous injection over at least 30 secondsNeonate initially 1–5 micrograms/kg, then 1–3 micrograms/kg as requiredChild 1 month–12 years initially 1–5 micrograms/kg,then 1–3 micrograms/kg as requiredChild 12–18 years initially 1–5 micrograms/kg,then 50–200 micrograms as requiredAssisted ventilation: analgesia and respiratorydepression in intensive care. By intravenous administrationNeonate initially by intravenous injection 1–5 micrograms/kg, then by intravenous infusion,1.5 micrograms/kg/hour adjusted according toresponseChild 1 month–18 years initially by intravenousinjection 1–5 micrograms/kg, then by intravenousinfusion, 1–6 micrograms/kg/hour adjustedaccording to responseAnalgesia in other situations section 4.7.2Administration for intravenous infusion, injectionsolution may be diluted in Glucose 5% or SodiumChloride 0.9%Fentanyl (Non-proprietary) 2Injection, fentanyl (as citrate) 50 micrograms/mL, netprice 2-mL amp = 30p, 10-mL amp = 64pSublimaze c (Janssen) 2Injection, fentanyl (as citrate) 50 micrograms/mL, netprice 10-mL amp = £1.31REMIFENTANILCautions section 4.7.2 and notes aboveContra-indications section 4.7.2 and notes above; leftventricular dysfunction; analgesia in consciouspatientsHepatic impairment section 4.7.2Pregnancy no information available; see also section4.7.2Breast-feeding avoid breast-feeding for 24 hours afteradministration—present in milk in animal studiesSide-effects section 4.7.2 and notes above; alsohypertension; less commonly hypoxia; rarely asystole;AV block and convulsions also reported15 Anaesthesia

642 15.1.5 Neuromuscular blocking drugs BNFC 2011–201215 AnaesthesiaLicensed use not licensed for use in children under 1yearIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightEnhancement and maintenance of anaesthesiain ventilated patients. By intravenous administrationNeonate by intravenous infusion 0.4–1 micrograms/kg/minute;additional doses of 1 microgram/kgcan be given by intravenous injectionduring the intravenous infusionChild 1 month–12 years initially by intravenousinjection 0.1–1 micrograms/kg over at least 30seconds (omitted if not required) then by intravenousinfusion 0.05–1.3 micrograms/kg/minuteaccording to anaesthetic technique and adjustedaccording to response; additional doses can begiven by intravenous injection during the intravenousinfusionChild 12–18 years initially by intravenous injection0.1–1 micrograms/kg over at least 30 seconds(omitted if not required) then by intravenousinfusion 0.05–2 micrograms/kg/minute accordingto anaesthetic technique and adjusted according toresponse; additional doses can be given by intravenousinjection during the intravenous infusionAdministration for intravenous injection, reconstituteto a concentration of 1 mg/mL; for continuous intravenousinfusion, dilute further with Glucose 5% orSodium Chloride 0.9% to a concentration of 20–25 micrograms/mL for Child 1–12 years or 20–250 micrograms/mL (usually 50 micrograms/mL) forChild 12–18 yearsUltiva c (GSK) 2Injection, powder for reconstitution, remifentanil (ashydrochloride), net price 1-mg vial = £5.12; 2-mg vial= £10.23; 5-mg vial = £25.5815.1.5 Neuromuscular blockingdrugsImportantThe drugs in this section should be used by experiencedpersonnel only.Neuromuscular blocking drugs used in anaesthesia arealso known as muscle relaxants. By specific blockadeof the neuromuscular junction they enable light anaesthesiato be used with adequate relaxation of the musclesof the abdomen and diaphragm. They also relax thevocal cords and allow the passage of a tracheal tube.Their action differs from the muscle relaxants used inmusculoskeletal disorders (section 10.2.2) that act onthe spinal cord or brain.Children who have received a neuromuscular blockingdrug should always have their respiration assisted orcontrolled until the drug has been inactivated or antagonised(section 15.1.6). They should also receive sufficientconcomitant inhalational or intravenous anaestheticor sedative drugs to prevent awareness.Non-depolarising neuromuscularblocking drugsNon-depolarising neuromuscular blocking drugs (alsoknown as competitive muscle relaxants) compete withacetylcholine for receptor sites at the neuromuscularjunction and their action can be reversed with anticholinesterases,such as neostigmine (section 15.1.6).Non-depolarising neuromuscular blocking drugs can bedivided into the aminosteroid group, comprising pancuronium,rocuronium, and vecuronium, and the benzylisoquinoliniumgroup, which includes atracurium,cisatracurium, and mivacurium.Non-depolarising neuromuscular blocking drugs have aslower onset of action than suxamethonium. Thesedrugs can be classified by their duration of action asshort-acting (15–30 minutes), intermediate-acting (30–40 minutes), and long-acting (60–120 minutes),although duration of action is dose-dependent. Drugswith a shorter or intermediate duration of action, suchas atracurium and vecuronium, are more widely usedthan those with a longer duration of action, such aspancuronium.Non-depolarising neuromuscular blocking drugs haveno sedative or analgesic effects and are not consideredto trigger malignant hyperthermia.For children receiving intensive care and who requiretracheal intubation and mechanical ventilation, a nondepolarisingneuromuscular blocking drug is chosenaccording to its onset of effect, duration of action, andside-effects. Rocuronium, with a rapid onset of effect,may facilitate intubation. Atracurium or cisatracuriummay be suitable for long-term neuromuscular blockadesince their duration of action is not dependent onelimination by the liver or the kidneys.Cautions Allergic cross-reactivity between neuromuscularblocking drugs has been reported; caution isadvised in cases of hypersensitivity to these drugs. Theiractivity is prolonged in children with myasthenia gravisand in hypothermia, therefore lower doses are required.Non-depolarising neuromuscular blocking drugs shouldbe used with great care in those with other neuromusculardisorders and those with fluid and electrolytedisturbances, as response in these children is unpredictable.Resistance may develop in children with burnswho may require increased doses; low plasma cholinesteraseactivity in these children requires dose titrationfor mivacurium. The rate of administration of neuromuscularblocking drugs should be reduced in childrenwith cardiovascular disease. Interactions: Appendix 1(muscle relaxants).Pregnancy Non-depolarising neuromuscular blockingdrugs are highly ionised at physiological pH and aretherefore unlikely to cross the placenta in significantamounts.Breast-feeding Because they are ionised at physiologicalpH, non-depolarising neuromuscular blockingdrugs are unlikely to be present in milk in significantamounts. Breast-feeding may be resumed once themother has recovered from neuromuscular block.

BNFC 2011–2012 15.1.5 Neuromuscular blocking drugs 643Side-effects Benzylisoquinolinium non-depolarisingneuromuscular blocking drugs (except cisatracurium)are associated with histamine release, which cancause skin flushing, hypotension, tachycardia, bronchospasm,and very rarely, anaphylactoid reactions. Mostaminosteroid neuromuscular blocking drugs produceminimal histamine release. Drugs with vagolytic activitycan counteract any bradycardia that occurs duringsurgery. Acute myopathy has also been reported afterprolonged use in intensive care.Atracurium, a mixture of 10 isomers, is a benzylisoquinoliniumneuromuscular blocking drug with an intermediateduration of action. It undergoes non-enzymaticmetabolism which is independent of liver and kidneyfunction, thus allowing its use in children with hepatic orrenal impairment. Cardiovascular effects are associatedwith significant histamine release. Neonates may bemore sensitive to the effects of atracurium and lowerdoses may be required.Cisatracurium is a single isomer of atracurium. It ismore potent and has a slightly longer duration of actionthan atracurium and provides greater cardiovascularstability because cisatracurium lacks histamine-releasingeffects. In children aged 1 month to 12 years,cisatracurium has a shorter duration of action andproduces faster spontaneous recovery.Mivacurium, a benzylisoquinolinium neuromuscularblocking drug, has a short duration of action. It ismetabolised by plasma cholinesterase and muscleparalysis is prolonged in individuals deficient in thisenzyme. It is not associated with vagolytic activity organglionic blockade although histamine release canoccur, particularly with rapid injection. In childrenunder 12 years mivacurium has a faster onset, shorterduration of action, and produces more rapid spontaneousrecovery.Pancuronium, an aminosteroid neuromuscular blockingdrug, has a long duration of action and is often usedin children receiving long-term mechanical ventilationin intensive care units. It lacks a histamine-releasingeffect, but vagolytic and sympathomimetic effects cancause tachycardia and hypertension. The half-life ofpancuronium is prolonged in neonates; neonates shouldreceive postoperative intermittent positive pressureventilation.Rocuronium exerts an effect within 2 minutes and hasthe most rapid onset of any of the non-depolarisingneuromuscular blocking drugs. It is an aminosteroidneuromuscular blocking drug with an intermediateduration of action. It is reported to have minimal cardiovasculareffects; high doses produce mild vagolyticactivity. In children under 12 years, rocuronium has afaster onset and shorter duration of action.Vecuronium, an aminosteroid neuromuscular blockingdrug, has an intermediate duration of action. It does notgenerally produce histamine release and lacks cardiovasculareffects. In neonates and infants, vecuroniumhas a faster onset and a longer duration of action;recovery is longer in these children. Unexpected sustainedneuromuscular blockade may occur in neonates.ATRACURIUM BESILATE(Atracurium besylate)Cautions see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; seizures also reportedLicensed use not licensed for use in neonatesIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightNeuromuscular blockade (short to intermediateduration) for surgery. By intravenous administrationNeonate initially by intravenous injection 300–500 micrograms/kg followed either by intravenousinjection, 100–200 micrograms/kg repeated asnecessary or by intravenous infusion, 300–400 micrograms/kg/hour adjusted according toresponseChild 1 month–18 years initially by intravenousinjection 300–600 micrograms/kg then 100–200 micrograms/kg repeated as necessary orinitially by intravenous injection 200–600 micrograms/kgfollowed by intravenous infusion, 300–600 micrograms/kg/hour adjusted according toresponseNeuromuscular blockade during intensive care. By intravenous administrationNeonate initially by intravenous injection 300–500 micrograms/kg followed either by intravenousinjection, 100–200 micrograms/kg repeated asnecessary or by intravenous infusion, 300–400 micrograms/kg/hour adjusted according toresponse; higher doses may be necessaryChild 1 month–18 years initially by intravenousinjection 300–600 micrograms/kg (optional) thenby intravenous infusion, 270–1770 micrograms/kg/hour (usual dose 650–780 micrograms/kg/hour)Administration for continuous intravenous infusion,dilute to a concentration of 0.5–5 mg/mL with Glucose5% or Sodium Chloride 0.9%; stability varieswith diluent.Neonatal intensive care, dilute 60 mg/kg body-weightto a final volume of 50 mL with Glucose 5% or SodiumChloride 0.9%; minimum concentration of 500 micrograms/mL,max. concentration of 5 mg/mL; anintravenous infusion rate of 0.1 mL/hour provides adose of 120 micrograms/kg/hourAtracurium (Non-proprietary) AInjection, atracurium besilate 10 mg/mL, net price2.5-mL amp = £1.85; 5-mL amp = £3.37; 25-mL vial=£14.45Tracrium c (GSK) AInjection, atracurium besilate 10 mg/mL, net price2.5-mL amp = £1.66; 5-mL amp = £3.00; 25-mL vial =£12.91CISATRACURIUMCautions see notes abovePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes above; also bradycardia15 Anaesthesia

644 15.1.5 Neuromuscular blocking drugs BNFC 2011–201215 AnaesthesiaIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightNeuromuscular blockade (intermediate duration)during surgery. By intravenous injectionChild 1 month–2 years initially 150 micrograms/kg, then 30 micrograms/kg repeated approx. every20 minutes as necessaryChild 2–12 years initially 150 micrograms/kg(80–100 micrograms/kg if not for intubation), then20 micrograms/kg repeated approx. every 10minutes as necessaryChild 12–18 years initially 150 micrograms/kg,then 30 micrograms/kg repeated approx. every 20minutes as necessary. By intravenous administrationChild 2–18 years initially 150 micrograms/kg byintravenous injection, then by intravenous infusion180 micrograms/kg/hour, reduced to 60–120 micrograms/kg/hour according to responseAdministration for continuous intravenous infusion,dilute to a concentration of 0.1–2 mg/mL with Glucose5% or Sodium Chloride 0.9%; solutions of 2 mg/mL and 5 mg/mL may be infused undilutedNimbex c (GSK) AInjection, cisatracurium (as besilate) 2 mg/mL, netprice 10-mL amp = £7.55Forte injection, cisatracurium (as besilate) 5 mg/mL,net price 30-mL vial = £31.09MIVACURIUMCautions see notes above; low plasma cholinesteraseactivityHepatic impairment reduce dose in severe impairmentRenal impairment clinical effect prolonged in renalfailure—reduce dose according to responsePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightNeuromuscular blockade (short duration) duringsurgery. By intravenous administrationChild 2–6 months by intravenous injection initially150 micrograms/kg, then either by intravenousinjection 100 micrograms/kg repeatedevery 6–9 minutes as necessary or by intravenousinfusion, 8–10 micrograms/kg/minute, adjusted ifnecessary every 3 minutes by 1 microgram/kg/minute to usual dose 11–14 micrograms/kg/minuteChild 6 months–12 years by intravenous injectioninitially 200 micrograms/kg, then either byintravenous injection 100 micrograms/kgrepeated every 6–9 minutes as necessary or byintravenous infusion, 8–10 micrograms/kg/minute,adjusted if necessary every 3 minutes by1 microgram/kg/minute to usual dose 11–14 micrograms/kg/minuteChild 12–18 years by intravenous injection initially70–250 micrograms/kg, then either by intravenousinjection 100 micrograms/kg repeatedevery 15 minutes as necessary or by intravenousinfusion, 8–10 micrograms/kg/minute, adjusted ifnecessary every 3 minutes by 1 microgram/kg/minute to usual dose of 6–7 micrograms/kg/minuteAdministration for intravenous injection, give undilutedor dilute in Glucose 5% or Sodium Chloride0.9%. Doses up to 150 micrograms/kg may be givenover 5–15 seconds, higher doses should be given over30 seconds. In asthma, cardiovascular disease or inthose sensitive to reduced arterial blood pressure,give over 60 seconds.Mivacron c (GSK) AInjection, mivacurium (as chloride) 2 mg/mL, netprice 5-mL amp = £2.79; 10-mL amp = £4.51PANCURONIUM BROMIDECautions see notes aboveHepatic impairment possibly slower onset, higherdose requirement, and prolonged recovery timeRenal impairment use with caution; prolonged durationof blockPregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightNeuromuscular blockade (long duration) duringsurgery. By intravenous injectionNeonate initially 100 micrograms/kg, then50 micrograms/kg repeated as necessaryChild 1 month–18 years initially 100 micrograms/kg,then 20 micrograms/kg repeated asnecessaryAdministration for intravenous injection, give undilutedor dilute in Glucose 5% or Sodium Chloride0.9%Pancuronium (Non-proprietary) AInjection, pancuronium bromide 2 mg/mL, net price2-mL amp = £1.20ROCURONIUM BROMIDECautions see notes aboveHepatic impairment reduce doseRenal impairment reduce maintenance dose; prolongedparalysisPregnancy see notes aboveBreast-feeding see notes above

BNFC 2011–2012 15.1.5 Neuromuscular blocking drugs 645Side-effects see notes aboveLicensed use not licensed for use in children forassisted ventilation in intensive careIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightNeuromuscular blockade (intermediate duration)during surgery. By intravenous administrationChild 1 month–18 years initially by intravenousinjection 600 micrograms/kg, then either byintravenous injection, 150 micrograms/kgrepeated as required or by intravenous infusion,300–600 micrograms/kg/hour adjusted accordingto responseAssisted ventilation in intensive care. By intravenous administrationChild 1 month–18 years initially by intravenousinjection 600 micrograms/kg (optional), then byintravenous infusion, 300–600 micrograms/kg/hour for first hour, then adjusted according toresponseAdministration for continuous intravenous infusionor via drip tubing, may be diluted with Glucose 5% orSodium Chloride 0.9%Rocuronium (Non-proprietary) AInjection, rocuronium bromide 10 mg/mL, net price5-mL vial = £3.00, 10-mL vial = £6.00Esmeron c (Organon) AInjection, rocuronium bromide 10 mg/mL, net price5-mL vial = £2.90, 10-mL vial = £5.79VECURONIUM BROMIDECautions see notes aboveHepatic impairment caution in significant impairmentRenal impairment caution in renal failurePregnancy see notes aboveBreast-feeding see notes aboveSide-effects see notes aboveLicensed use not licensed for assisted ventilation inintensive careIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightNeuromuscular blockade (intermediate duration)during surgery. By intravenous administrationNeonate by intravenous injection initially80 micrograms/kg, then 30–50 micrograms/kgadjusted according to responseChild 1 month–18 years by intravenous injectioninitially 80–100 micrograms/kg, then either byintravenous injection, 20–30 micrograms/kgrepeated as required or by intravenous infusion,0.8–1.4 micrograms/kg/minute, adjusted accordingto responseAssisted ventilation in intensive care. By intravenous injectionNeonate initially 80 micrograms/kg, then 30–50 micrograms/kg adjusted according to response. By intravenous administrationNeonate by intravenous injection 80 micrograms/kg, then by intravenous infusion, 0.8–1.4 micrograms/kg/minute,adjusted according toresponse (risk of accumulation—consider interruptionof infusion)Child 1 month–18 years initially by intravenousinjection 80–100 micrograms/kg (optional), thenby intravenous infusion 0.8–1.4 micrograms/kg/minute, adjusted according to response; up to3 micrograms/kg/minute may be requiredAdministration reconstitute each vial with 5 mLWater for Injections to give 2 mg/mL solution; alternativelyreconstitute with up to 10 mL Glucose 5% orSodium Chloride 0.9% or Water for Injections—unsuitable for further dilution if not reconstituted withWater for Injections.For continuous intravenous infusion, dilute reconstitutedsolution to a concentration up to 40 micrograms/mLwith Glucose 5% or Sodium Chloride0.9%; reconstituted solution can also be given via driptubing.Neonatal intensive care, reconstitute each vial with5 mL Water for Injections to give a 2 mg/mL solution.Dilute 5 mg/kg body-weight to a final volume of50 mL with Glucose 5% or Sodium Chloride 0.9%; anintravenous infusion rate of 0.5 mL/hour provides adose of 50 micrograms/kg/hour; minimum concentrationof 40 micrograms/mLNorcuron c (Organon) AInjection, powder for reconstitution, vecuroniumbromide, net price 10-mg vial = £3.38 (with water forinjections)Depolarising neuromuscular blockingdrugsSuxamethonium has the most rapid onset of action ofany of the neuromuscular blocking drugs and is ideal iffast onset and brief duration of action are required e.g.with tracheal intubation. Neonates and young childrenare less sensitive to suxamethonium and a higher dosemay be required.Suxamethonium acts by mimicking acetylcholine at theneuromuscular junction but hydrolysis is much slowerthan for acetylcholine; depolarisation is therefore prolonged,resulting in neuromuscular blockade. Unlike thenon-depolarising neuromuscular blocking drugs, itsaction cannot be reversed and recovery is spontaneous;anticholinesterases such as neostigmine potentiate theneuromuscular block.Suxamethonium should be given after anaestheticinduction because paralysis is usually preceded by painfulmuscle fasciculations. Bradycardia may occur; premedicationwith atropine (section 15.1.3) reducesbradycardia as well as the excessive salivation associatedwith suxamethonium use.Prolonged paralysis may occur in dual block, whichoccurs with high or repeated doses of suxamethonium15 Anaesthesia

646 15.1.6 Drugs for reversal of neuromuscular blockade BNFC 2011–201215 Anaesthesiaand is caused by the development of a non-depolarisingblock following the initial depolarising block; edrophonium(section 15.1.6) may be used to confirm the diagnosisof dual block. Children with myasthenia gravis areresistant to suxamethonium but can develop dual blockresulting in delayed recovery. Prolonged paralysis mayalso occur in those with low or atypical plasma cholinesterase.Assisted ventilation should be continued untilmuscle function is restored.SUXAMETHONIUM CHLORIDE(Succinylcholine chloride)Cautions see notes above; hypersensitivity to otherneuromuscular blocking drugs; patients with cardiac,respiratory or neuromuscular disease; raised intraocularpressure (avoid in penetrating eye injury);severe sepsis (risk of hyperkalaemia); interactions:Appendix 1 (muscle relaxants)Contra-indications family history of malignanthyperthermia, hyperkalaemia; major trauma, severeburns, neurological disease involving acute wasting ofmajor muscle, prolonged immobilisation—risk ofhyperkalaemia; personal or family history of congenitalmyotonic disease, Duchenne muscular dystrophy;low plasma-cholinesterase activity (includingsevere liver disease, see below)Hepatic impairment prolonged apnoea may occur insevere liver disease because of reduced hepaticsynthesis of pseudocholinesterasePregnancy mildly prolonged neuromuscular blockademay occurBreast-feeding unlikely to be present in breast milk insignificant amounts (ionised at physiological pH);breast-feeding may be resumed once the motherrecovered from neuromuscular blockSide-effects see notes above; also increased gastricpressure; hyperkalaemia; postoperative muscle pain,myoglobinuria, myoglobinaemia; increased intraocularpressure; flushing, rash; rarely arrhythmias, cardiacarrest; bronchospasm, apnoea, prolonged respiratorydepression; limited jaw mobility; very rarelyanaphylactic reactions, malignant hyperthermia; alsoreported hypertension, hypotension, rhabdomyolysisIndication and doseNeuromuscular blockade (short duration) duringsurgery. By intravenous injectionNeonate 2 mg/kg produces 5–10 minutes neuromuscularblockadeChild 1 month–1 year 2 mg/kgChild 1–18 years 1 mg/kg. By intramuscular injection (onset in 2–3 minutes)Neonate up to 4 mg/kg produces 10–30 minutesneuromuscular blockadeChild 1 month–1 year up to 4–5 mg/kgChild 1–12 years up to 4 mg/kg; max. 150 mgAdministration for intravenous injection, give undilutedor dilute with Glucose 5% or Sodium Chloride0.9%Suxamethonium Chloride (Non-proprietary) AInjection, suxamethonium chloride 50 mg/mL, netprice 2-mL amp = 58p, 2-mL prefilled syringe = £8.45Anectine c (GSK) AInjection, suxamethonium chloride 50 mg/mL, netprice 2-mL amp = 71p15.1.6 Drugs for reversal ofneuromuscular blockadeImportantThe drugs in this section should be used by experiencedpersonnel only.AnticholinesterasesAnticholinesterases reverse the effects of the non-depolarising(competitive) neuromuscular blocking drugssuch as pancuronium, but they prolong the action ofthe depolarising neuromuscular blocking drug suxamethonium.Edrophonium has a transient action and may be used inthe diagnosis of suspected dual block due to suxamethonium.Atropine (section 15.1.3) is given beforeor with edrophonium to prevent muscarinic effects ofedrophonium; it is also used in the diagnosis of myastheniagravis (section 10.2.1).Neostigmine has a longer duration of action thanedrophonium and is used specifically for reversal ofnon-depolarising (competitive) blockade. It acts withinone minute of intravenous injection and its effects lastfor 20 to 30 minutes; a second dose may then benecessary. Glycopyrronium or alternatively atropine(section 15.1.3), given before or with neostigmine, preventbradycardia, excessive salivation, and other muscariniceffects of neostigmine.EDROPHONIUM CHLORIDECautions section 10.2.1; atropine should also be givenContra-indications section 10.2.1Pregnancy section 10.2.1Breast-feeding section 10.2.1Side-effects section 10.2.1Indication and doseBrief reversal of non-depolarising neuromuscularblockade. By intravenous injection over several minutesChild 1 month–18 years 500–700 micrograms/kg (after or with atropine)Myasthenia gravis section 10.2.1Edrophonium (Non-proprietary) AInjection, edrophonium chloride 10 mg/mL, net price1-mL amp = £19.50NEOSTIGMINE METILSULFATE(Neostigmine methylsulphate)Cautions section 10.2.1; glycopyrronium or atropineshould also be givenContra-indications section 10.2.1Renal impairment section 10.2.1Pregnancy section 10.2.1

BNFC 2011–2012 15.1.7 Antagonists for central and respiratory depression 647Breast-feeding section 10.2.1Side-effects section 10.2.1Indication and doseReversal of non-depolarising muscle block. By intravenous injection over 1 minuteNeonate 50 micrograms/kg, after or with glycopyrroniumor atropine; a further dose of 25 micrograms/kgmay be requiredChild 1 month–12 years 50 micrograms/kg(max. 2.5 mg) after or with glycopyrronium oratropine; a further dose of 25 micrograms/kg maybe requiredChild 12–18 years 50 micrograms/kg (max.2.5 mg) after or with glycopyrronium or atropine; afurther dose of 25 micrograms/kg (max. 2.5 mg)may be requiredMyasthenia gravis section 10.2.1Administration for intravenous injection, give undilutedor dilute with Glucose 5% or Sodium Chloride0.9%Neostigmine (Non-proprietary) AInjection, neostigmine metilsulfate 2.5 mg/mL, netprice 1-mL amp = 58pWith glycopyrroniumGlycopyrronium-Neostigmine (Non-proprietary) AInjection, neostigmine metilsulfate 2.5 mg, glycopyrroniumbromide 500 micrograms/mL, net price 1-mL amp = 91pDoseReversal of non-depolarising neuromuscular blockade. By intravenous injection over 10–30 secondsChild 1 month–18 years 0.02 mL/kg (or 0.2 mL/kg of a1 in 10 dilution), dose may be repeated if required (totalmax. 2 mL)Administration for intravenous injection, may be diluted withSodium Chloride 0.9%Other drugs for reversal ofneuromuscular blockadeSugammadex is a modified gamma cyclodextrin thatcan be used for rapid reversal of neuromuscular blockadeinduced by rocuronium (section 15.1.5). In practice,sugammadex is used mainly for rapid reversal of neuromuscularblockade in an emergency.SUGAMMADEXCautions recurrence of neuromuscular blockade—monitor respiratory function until fully recovered;recovery may be delayed in cardiovascular disease;pre-existing coagulation disorders or use of anticoagulants(unrelated to surgery); wait 24 hours beforere-administering rocuronium; interactions: Appendix1 (sugammadex)Renal impairment avoid if estimated glomerular filtrationrate less then 30 mL/minute/1.73 m 2Pregnancy use with caution—no information availableSide-effects taste disturbances; less commonly allergicreactions; bronchospasm also reportedIndication and doseRoutine reversal of neuromuscular blockadeinduced by rocuronium. By intravenous injectionChild 2–18 years 2 mg/kg (consult product literature)Administration for intravenous injection dose may bediluted to a concentration of 10 mg/mL with SodiumChloride 0.9%Bridion c (Schering-Plough) TAInjection, sugammadex (as sodium salt) 100 mg/mL,net price 2-mL amp = £59.64, 5-mL amp = £149.10Electrolytes Na + 0.42 mmol/mL15.1.7 Antagonists for centraland respiratorydepressionImportantThe drugs in this section should be used by experiencedpersonnel only.Respiratory depression is a major concern with opioidanalgesics and it may be treated by artificial ventilationor be reversed by an opioid antagonist. Naloxone givenintravenously immediately reverses opioid-inducedrespiratory depression but the dose may have to berepeated because of its short duration of action. Intramuscularinjection of naloxone produces a more gradualand prolonged effect but absorption may be erratic.Care is required in children requiring pain relief becausenaloxone also antagonises the analgesic effect ofopioids.Neonates Naloxone is used in newborn infants toreverse respiratory depression and sedation resultingfrom the use of opioids by the mother, usually for painduring labour. In neonates the effects of opioids maypersist for up to 48 hours and in such cases naloxone isoften given by intramuscular injection for its prolongedeffect. In severe respiratory depression after birth,breathing should first be established (using artificialmeans if necessary) and naloxone administered only ifuse of opioids by the mother is thought to cause therespiratory depression; the infant should be monitoredclosely and further doses of naloxone administered asnecessary.Flumazenil is a benzodiazepine antagonist for thereversal of the central sedative effects of benzodiazepinesafter anaesthetic and similar procedures. Flumazenilhas a shorter half-life and duration of action thandiazepam and midazolam, so children may becomeresedated.FLUMAZENILCautions short-acting (repeat doses may be necessary—benzodiazepineeffects may persist for at least24 hours); benzodiazepine dependence (may precipitatewithdrawal symptoms); prolonged benzodiazepinetherapy for epilepsy (risk of convulsions); historyof panic disorders (risk of recurrence); ensure neuromuscularblockade cleared before giving; avoid rapidinjection in high-risk or anxious children and following15 Anaesthesia

648 15.1.8 Drugs for malignant hyperthermia BNFC 2011–201215 Anaesthesiamajor surgery; head injury (rapid reversal of benzodiazepinesedation may cause convulsions)Contra-indications life-threatening condition (e.g.raised intracranial pressure, status epilepticus) controlledby benzodiazepinesHepatic impairment carefully titrate dosePregnancy not known to be harmfulBreast-feeding avoid breast-feeding for 24 hoursSide-effects nausea and vomiting; less commonlypalpitation, anxiety, fear; also reported transienthypertension, tachycardia, flushing, agitation, convulsions(particularly in those with epilepsy), dizziness,sensory disturbance, chills, sweatingLicensed use not licensed for use in children under 1year; not licensed for use by intravenous infusion inchildren; not licensed for use in children in intensivecareIndication and doseReversal of sedative effects of benzodiazepines. By intravenous injection over 15 secondsNeonate 10 micrograms/kg, repeat at 1-minuteintervals if requiredChild 1 month–18 years 10 micrograms/kg(max. 200 micrograms), repeated at 1-minuteintervals if required; max. total dose of 50 micrograms/kg(1 mg) (2 mg in intensive care). By intravenous infusion, if drowsiness recursafter injectionNeonate 2–10 micrograms/kg/hour, adjustedaccording to responseChild 1 month–18 years 2–10 micrograms/kg/hour, adjusted according to response; max.400 micrograms/hourOverdosage with benzodiazipines see EmergencyTreatment of Poisoning p. 30Administration for continuous intravenous infusion,dilute with Glucose 5% or Sodium Chloride 0.9%Flumazenil (Non-proprietary) AInjection, flumazenil 100 micrograms/mL, net price5-mL amp = £14.49Anexate c (Roche) AInjection, flumazenil 100 micrograms/mL, net price5-mL amp = £13.66NALOXONE HYDROCHLORIDECautions cardiovascular disease or those receivingcardiotoxic drugs (serious adverse cardiovasculareffects reported); maternal physical dependence onopioids (may precipitate withdrawal in newborn); pain(see also under Titration of Dose, below); has shortduration of action (see notes above)Titration of dose In postoperative use, the dose should betitrated for each child in order to obtain sufficient respiratoryresponse; however, naloxone antagonises analgesiaPregnancy use only if potential benefit outweighs riskBreast-feeding not orally bioavailableSide-effects nausea, vomiting; hypotension, hypertension,ventricular tachycardia and fibrilation, cardiacarrest; hyperventilation, dyspnoea, pulmonaryoedema; headache, dizziness; less commonly diarrhoea,dry mouth, agitation, excitement, paraesthesia,tremor, sweating; very rarely seizures and erythemamultiformeIndication and doseReversal of respiratory and CNS depression inneonate following maternal opioid use duringlabour. By intramuscular injectionNeonate 200 micrograms (60 micrograms/kg) as asingle dose at birth. By intravenous or subcutaneous injectionNeonate 10 micrograms/kg, repeated every 2–3minutes if requiredReversal of postoperative respiratory depression. By intravenous injectionNeonate 1 microgram/kg, repeated every 2–3minutes if requiredChild 1 month–12 years 1 microgram/kg,repeated every 2–3 minutes if requiredChild 12–18 years 1.5–3 micrograms/kg; ifresponse inadequate, give subsequent doses of100 micrograms every 2 minutesOverdosage with opioids see Emergency Treatmentof Poisoning, p. 28PreparationSee Emergency Treatment of Poisoning, p. 2915.1.8 Drugs for malignanthyperthermiaImportantThe drugs in this section should be used by experiencedpersonnel only.Malignant hyperthermia is a rare but potentially lethalcomplication of anaesthesia. It is characterised by arapid rise in temperature, increased muscle rigidity,tachycardia, and acidosis. The most common triggersof malignant hyperthermia are the volatile anaesthetics.Suxamethonium has also been implicated, but malignanthyperthermia is more likely if it is given following avolatile anaesthetic. Volatile anaesthetics and suxamethoniumshould be avoided during anaesthesia inchildren at high risk of malignant hyperthermia.Dantrolene is used in the treatment of malignant hyperthermia.It acts on skeletal muscle cells by interferingwith calcium efflux, thereby stopping the contractileprocess.DANTROLENE SODIUMCautions avoid extravasation (risk of tissue necrosis);interactions: Appendix 1 (muscle relaxants)Pregnancy use only if potential benefit outweighs riskBreast-feeding present in milk—use only if potentialbenefit outweighs risk

BNFC 2011–2012 15.2 Local anaesthesia 649Side-effects hepatotoxicity, pulmonary oedema, dizziness,weakness, and injection-site reactions includingerythema, rash, swelling, and thrombophlebitisLicensed use not licensed for use in childrenIndication and doseMalignant hyperthermia. By rapid intravenous injectionChild 1 month–18 years initially 2–3 mg/kg, then1 mg/kg repeated as required (total max. dose10 mg/kg)Chronic severe spasticity of voluntary musclesee section 10.2.2Dantrium Intravenous c (SpePharm) AInjection, powder for reconstitution, dantrolene sodium,net price 20-mg vial = £51.00 (hosp. only)15.2 Local anaesthesiaImportantThe drugs in section 15.2 should be used by experiencedpersonnel only and should not be administeredparenterally unless adequate resuscitationequipment is available.The use of local anaesthetics by injection or by applicationto mucous membranes to produce local analgesia isdiscussed in this section.See also section 1.7 (anus), section 11.7 (eye), section12.3 (oropharynx), and section 13.3 (skin).Use of local anaesthetics Local anaesthetic drugsact by causing a reversible block to conduction alongnerve fibres. They vary widely in their potency, toxicity,duration of action, stability, solubility in water, andability to penetrate mucous membranes. These factorsdetermine their application, e.g. topical (surface), infiltration,peripheral nerve block, intravenous regionalanaesthesia (Bier’s block), plexus, epidural (extradural),or spinal (intrathecal or subarachnoid) block. Localanaesthetics may also be used for postoperative painrelief, thereby reducing the need for analgesics such asopioids.Administration The dose of local anaestheticdepends on the injection site and the procedure used.In determining the safe dosage, it is important to takeaccount of the rate of absorption and excretion, and ofthe potency. The child’s age, weight, physique, andclinical condition, and the vascularity of the administrationsite and the duration of administration, must also beconsidered.Uptake of local anaesthetics into the systemic circulationdetermines their duration of action and producestoxicity.Great care must be taken to avoid accidental intravascularinjection; local anaesthetic injections should begiven slowly in order to detect inadvertent intravascularadministration. When prolonged analgesia is required, along-acting local anaesthetic is preferred to minimisethe likelihood of cumulative systemic toxicity. Localanaesthesia around the oral cavity may impair swallowingand therefore increases the risk of aspiration.Following most regional anaesthetic procedures, maximumarterial plasma concentration of anaestheticdevelops within about 10 to 25 minutes, so carefulsurveillance for toxic effects (see Toxicity and Sideeffects,p. 650) is necessary during the first 30 minutesafter injection.Epidural anaesthesia is combined with general anaesthesiafor certain surgical procedures in children.Use of vasoconstrictors Local anaesthetics causedilatation of blood vessels. The addition of a vasoconstrictorsuch as adrenaline (epinephrine) to the localanaesthetic preparation diminishes local blood flow,slowing the rate of absorption and thereby prolongingthe anaesthetic effect. Great care should be taken toavoid inadvertent intravenous administration of a preparationcontaining adrenaline, and it is not advisable togive adrenaline with a local anaesthetic injection indigits or appendages because of the risk of ischaemicnecrosis.Adrenaline must be used in a low concentration whenadministered with a local anaesthetic (but see alsoDental Anaesthesia, below). The total dose of adrenalineshould not exceed 5 micrograms/kg (1 mL/kg of a 1 in200 000 solution) and it is essential not to exceed aconcentration of 1 in 200 000 (5 micrograms/mL) ifmore than 50 mL of the mixture is to be injected. Caremust also be taken to calculate a safe maximum dose oflocal anaesthetic when using combination products. Forprescribing information on adrenaline, see section 2.7.2.For drug interactions of adrenaline, see Appendix 1(sympathomimetics).In children with severe hypertension or unstable cardiacrhythm, the use of adrenaline with a local anaestheticmay be hazardous. For these children an anaestheticwithout adrenaline should be used.Dental anaesthesia Lidocaine is widely used indental procedures; it is most often used in combinationwith adrenaline (epinephrine). Lidocaine 2% combinedwith adrenaline 1 in 80 000 (12.5 micrograms/mL) is asafe and effective preparation; there is no justificationfor using higher concentrations of adrenaline. See alsoUse of Vasoconstrictors, above.The local anaesthetics articaine and mepivacaine arealso used in dentistry; they are available in cartridgessuitable for dental use. Mepivacaine is available with orwithout adrenaline, and articaine is available with adrenaline.In children with severe hypertension or unstable cardiacrhythm, mepivacaine without adrenaline may be used.Alternatively, prilocaine with or without felypressin canbe used but there is no evidence that it is any safer.Felypressin can cause coronary vasoconstriction whenused at high doses; limit dose in children with coronaryartery disease.Cautions of local anaesthetics Local anaestheticsshould be administered with caution in children, especiallyif debilitated (consider dose reduction) or thosewith impaired cardiac conduction, cardiovascular disease,hypovolaemia, shock, impaired respiratory function,epilepsy, or myasthenia gravis. See also Administrationand Use of Vasoconstrictors, above.15 Anaesthesia

650 15.2 Local anaesthesia BNFC 2011–201215 AnaesthesiaContra-indications of local anaesthetics Localanaesthetics should not be injected into inflamed orinfected tissues nor should they be applied to damagedskin. In such circumstances, increased absorption intothe blood increases the possibility of systemic sideeffects,and the local anaesthetic effect may also bereduced by altered local pH. See also Use of Vasoconstrictors,p. 649.Local anaesthetic preparations containing preservativesshould not be used for caudal, epidural, or spinal block,or for intravenous regional anaesthesia (Bier’s block).Local anaesthetics can cause ototoxicity and should notbe applied to the middle ear. They are also contraindicatedin children with complete heart block.Toxicity and side-effects A single application of atopical lidocaine preparation does not generally causesystemic side-effects. Toxic effects after administrationof local anaesthetics are a result of excessively highplasma concentrations; severe toxicity usually resultsfrom inadvertent intravascular injection or too rapidinjection.The systemic toxicity of local anaesthetics mainlyinvolves the central nervous and cardiovascular systems.CNS effects include a feeling of inebriation andlightheadedness followed by drowsiness, numbness ofthe tongue and perioral region, restlessness, paraesthesia(including sensations of hot and cold), dizziness,blurred vision, nausea and vomiting, muscle twitching,tremors, and convulsions. Transient excitation may alsooccur, followed by depression with drowsiness, respiratoryfailure, unconsciousness, and coma. Effects on thecardiovascular system include myocardial depressionand peripheral vasodilatation resulting in hypotensionand bradycardia; arrhythmias and cardiac arrest canoccur.Hypersensitivity reactions occur mainly with the estertypelocal anaesthetics, such as tetracaine; reactions areless frequent with the amide types, such as articaine,bupivacaine, levobupivacaine, lidocaine, mepivacaine,prilocaine, and ropivacaine. Cross-sensitivity reactionsmay be avoided by using the alternative chemical type.ArticaineArticaine is an amide-type local anaesthetic used fordental anaesthesia (see Dental Anaesthesia, p. 649). It isavailable in a preparation that also contains adrenaline(see Use of Vasoconstrictors, p. 649).ARTICAINE HYDROCHLORIDE WITHADRENALINE(Carticaine hydrochloride with adrenaline)Cautions see Cautions of Local Anaesthetics, p. 649and Adrenaline, section 2.7.2Contra-indications see Contra-indications of LocalAnaesthetics, p. 650 and Adrenaline, section 2.7.2Hepatic impairment use with caution; increased riskof side-effects in severe impairmentRenal impairment see Adrenaline, section 2.7.2Pregnancy use only if potential benefit outweighsrisk—no information availableBreast-feeding avoid breast-feeding for 48 hours afteradministrationSide-effects see Toxicity and Side-effects, above andAdrenaline, section 2.7.2; also methaemoglobinaemia(see Prilocaine (p. 653) for treatment)Indication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightInfiltration anaesthesia in dentistryChild 4–18 years consult expert dental sources;important: see also Administration, p. 649Septanest c (Septodont) AInjection, articaine hydrochloride 40 mg/mL, adrenaline1 in 200 000 (5 micrograms/mL), net price2.2-mL cartridge = 41pExcipients include sulphitesInjection, articaine hydrochloride 40 mg/mL, adrenaline1 in 100 000 (10 micrograms/mL), net price2.2-mL cartridge = 41pExcipients include sulphitesBupivacaineBupivacaine has a longer duration of action than otherlocal anaesthetics. It has a slow onset of action, takingup to 30 minutes for full effect. It is often used in lumbarepidural blockade and is particularly suitable for continuousepidural analgesia in labour, or for postoperativepain relief. It is the principal drug used for spinal anaesthesia.Hyperbaric solutions containing glucose may beused for spinal block.BUPIVACAINE HYDROCHLORIDECautions see Cautions of Local Anaesthetics, p. 649;myocardial depression may be more severe and moreresistant to treatment; cardiovascular disease; hypertension;hypotension; cerebral atheroma; interactions:Appendix 1 (bupivacaine)Contra-indications see Contra-indications of LocalAnaesthetics, aboveHepatic impairment use with caution in severeimpairmentRenal impairment use with caution in severe impairmentPregnancy large doses during delivery can causeneonatal respiratory depression, hypotonia, andbradycardia after paracervical or epidural block; uselower doses for intrathecal use during late pregnancyBreast-feeding amount too small to be harmfulSide-effects see Toxicity and Side-effects, aboveIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightAdjusted according to child’s physical status andnature of procedure, seek expert advice—important:see also under Administration, p. 649Bupivacaine (Non-proprietary) AInjection, anhydrous bupivacaine hydrochloride2.5 mg/mL (0.25%), net price 10 mL = 82p; 5 mg/mL(0.5%), 10 mL = 94p

BNFC 2011–2012 15.2 Local anaesthesia 651Infusion, anhydrous bupivacaine hydrochloride1 mg/mL (0.1%), net price 100 mL = £8.41, 250 mL =£10.59; 1.25 mg/mL (0.125%), 250 mL = £10.80Marcain c (AstraZeneca) AInjection, anhydrous bupivacaine hydrochloride2.5 mg/mL (Marcain c 0.25%), net price 10-mLPolyamp c = £1.06; 5 mg/mL (Marcain c 0.5%), 10-mL Polyamp c = £1.21Marcain Heavy c (AstraZeneca) AInjection, anhydrous bupivacaine hydrochloride5 mg/mL (0.5%), glucose 80 mg/mL, net price 4-mLamp = £1.21With adrenalineFor prescribing information on adrenaline, see section2.7.2; see also Use of Vasoconstrictors, p. 649Bupivacaine and Adrenaline (Non-proprietary) AInjection, anhydrous bupivacaine hydrochloride2.5 mg/mL (0.25%), adrenaline 1 in 200 000 (5 micrograms/mL),net price 10-mL amp = £1.40Injection, anhydrous bupivacaine hydrochloride5 mg/mL (0.5%), adrenaline 1 in 200 000 (5 micrograms/mL),net price 10-mL amp = £1.50LevobupivacaineLevobupivacaine, an isomer of bupivacaine, has anaestheticand analgesic properties similar to bupivacainebut is thought to have fewer adverse effects.LEVOBUPIVACAINENote Levobupivacaine is an isomer of bupivacaineCautions see Cautions of Local Anaesthetics, p. 649;cardiovascular disease; interactions: Appendix 1(levobupivacaine)Contra-indications see Contra-indications of LocalAnaesthetics, p. 650Hepatic impairment use with cautionPregnancy large doses during delivery can causeneonatal respiratory depression, hypotonia, andbradycardia after epidural block; avoid if possible infirst trimester—toxicity in animal studies; may causefetal distress syndrome; do not use for paracervicalblock in obstetrics; do not use 7.5 mg/mL strength inobstetricsBreast-feeding amount too small to be harmfulSide-effects see Toxicity and Side-effects, p. 650; alsosweating, pyrexia, anaemiaLicensed use not licensed for use in children exceptfor analgesia by ilioinguinal or iliohypogastric blockIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightAdjusted according to child’s physical status andnature of procedure, seek expert advice—important:see also under Administration, p. 649Chirocaine c (Abbott) AInjection, levobupivacaine (as hydrochloride) 2.5 mg/mL, net price 10-mL amp = £1.42; 5 mg/mL, 10-mLamp = £1.62; 7.5 mg/mL, 10-mL amp = £2.43Note For 1.25 mg/mL concentration dilute standard solutionswith sodium chloride 0.9%Infusion, levobupivacaine (as hydrochloride)625 micrograms/mL, net price 100 mL = £6.63,200 mL = £10.37; 1.25 mg/mL, net price 100 mL =£7.26, 200 mL = £12.20LidocaineLidocaine is effectively absorbed from mucous membranesand is a useful surface anaesthetic in concentrationsup to 10%. Except for surface anaesthesia anddental anaesthesia, solutions should not usually exceed1% in strength. The duration of the block (with adrenaline)is about 90 minutes.Application of a mixture of lidocaine and prilocaine(EMLA c ) under an occlusive dressing provides surfaceanaesthesia for 1–2 hours. EMLA c does not appear tobe effective in providing local anaesthesia for heellancing in neonates.LIDOCAINE HYDROCHLORIDE(Lignocaine hydrochloride)Cautions see Cautions of Local Anaesthetics, p. 649and section 2.3.2; hypertension; topical preparationscan damage plastic cuffs of endotracheal tubesContra-indications see notes above, Contra-indicationsof Local Anaesthetics (p. 650), and section 2.3.2Hepatic impairment section 2.3.2Renal impairment section 2.3.2Pregnancy large doses can cause fetal bradycardia;large doses during delivery can cause neonatal respiratorydepression, hypotonia, or bradycardia afterparacervical or epidural blockBreast-feeding section 2.3.2Side-effects see Toxicity and Side-effects, p. 650 andsection 2.3.2; also methaemoglobinaemia (see Prilocaine(p. 653) for treatment), nystagmus, rash; hypoglycaemiaalso reported following intrathecal orextradural administrationLicensed use EMLA c cream not licensed for use inchildren under 1 yearIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightInfiltration anaesthesia. By injection(see also Administration, p. 649, and Importantwarning below)Neonate according to nature of procedure, up to3 mg/kg (0.3 mL/kg of 1% solution), repeated notmore often than every 4 hoursChild 1 month–12 years according to nature ofprocedure, up to 3 mg/kg (0.3 mL/kg of 1% solution),repeated not more often than every 4 hours15 Anaesthesia

652 15.2 Local anaesthesia BNFC 2011–201215 AnaesthesiaChild 12–18 years according to weight of childand nature of procedure, max. 200 mg, repeatednot more often than every 4 hoursSurface anaesthesia see preparations belowVentricular arrhythmias, neonatal seizures section2.3.2Intravenous regional anaesthesia and nerveblocks seek expert adviceDental anaesthesia seek expert adviceImportantThe licensed doses stated above may not be appropriatein some settings and expert advice should besoughtLidocaine hydrochloride injectionsLidocaine (Non-proprietary) AInjection, lidocaine hydrochloride 5 mg/mL (0.5%),net price 10-mL amp = 35p; 10 mg/mL (1%), 2-mLamp = 25p, 5-mL amp = 26p, 10-mL amp = 39p, 10-mL prefilled syringe = £4.53, 20-mL amp = 75p;20 mg/mL (2%), 2-mL amp = 32p, 5-mL amp = 31pWith adrenalineFor prescribing information on adrenaline see section2.7.2; see also Use of Vasoconstrictors, p. 649.Xylocaine c (AstraZeneca) AInjection, anhydrous lidocaine hydrochloride 10 mg/mL (1%), adrenaline 1 in 200 000 (5 micrograms/mL),net price 20-mL vial = 99pExcipients include sulphitesInjection, anhydrous lidocaine hydrochloride 20 mg/mL (2%), adrenaline 1 in 200 000 (5 micrograms/mL),net price 20-mL vial = £1.04Excipients include sulphitesLidocaine injections for dental useA variety of lidocaine injections with adrenaline areavailable in dental cartridges; brand names includeLignospan Special c , Rexocaine c , and Xylocaine c .For prescribing information on adrenaline see section2.7.2; see also Use of Vasoconstrictors, p. 649.Note Consult expert dental sources for specific advice inrelation to dose of lidocaine for dental anaesthesiaLidocaine for surface anaesthesiaInstillagel c (CliniMed)Gel, lidocaine hydrochloride 2%, chlorhexidinegluconate solution 0.25%, in a sterile lubricant basis indisposable syringe, net price 6-mL syringe = £1.41,11-mL syringe = £1.58Excipients include hydroxybenzoates (parabens)Laryngojet c (UCB Pharma) ASolution, lidocaine hydrochloride 40 mg/mL (4%),net price per unit (4-mL vial and disposable sterilecannula with cover and vial injector) = £5.10DoseAnaesthesia of mucous membranes of oropharynx,trachea, and respiratory tractChild up to 0.075 mL/kg (3 mg/kg) as a single dosesprayed, instilled (if a cavity) or applied with a swab;reduce dose according to size, age, and condition of child,max. 5 mL (200 mg)LMX 4 c (Ferndale)Cream, lidocaine 4 %, net price 5-g tube = £2.98; 5 5-g tube with 10 occlusive dressings = £16.90Excipients include benzyl alcohol and propylene glycolDoseAnaesthesia before venous cannulation or venepunctureChild 1 month–18 years apply thick layer (1–2.5 g; childunder 1 year max. 1 g) to small area (2.5 cm 2.5 cm) ofnon–irritated skin at least 30 minutes before procedure;max. application time 5 hours (child 1–3 months, 60minutes; child 3 months–1 year, 4 hours); remove creamwith gauze and perform procedure after approximately 5minutesXylocaine c (AstraZeneca)Spray, lidocaine 10% (100 mg/g) supplying 10 mglidocaine/dose; 500 spray doses per container, netprice 50-mL bottle = £3.13DoseBronchoscopy, laryngoscopy, oesophagoscopy,endotracheal intubationChild up to 18 years up to 3 mg/kgWith prilocaineFor prescribing information on prilocaine, see p. 653.EMLA c (AstraZeneca)Cream, lidocaine 2.5%, prilocaine 2.5%, net price 5-gtube = £1.73; 30-g tube (surgical pack) = £10.25; 5 5-g tube with 12 occlusive dressings (premedicationpack) = £9.75DoseAnaesthesia before minor skin procedures includingvenepunctureNeonate apply max. 1 g under occlusive dressing formax. 1 hour before procedure; max. 1 dose in 24 hoursChild 1–3 months or body-weight less than 5 kg applymax. 1 g under occlusive dressing for max. 1 hour beforeprocedure; max. 1 dose in 24 hoursChild 3 months–1 year and body-weight over 5 kgapply max. 2 g under occlusive dressing for max. 4 hoursbefore procedure; max. 2 doses in 24 hoursChild 1–18 years apply thick layer under occlusivedressing 1–5 hours before procedure (2–5 hours beforeprocedures on large areas e.g. split skin grafting); max. 2doses in 24 hours for child 1–12 yearsNote Shorter application time of 15–30 minutes is recommendedfor children with atopic dermatitisLidocaine for ear, nose, and oropharyngeal useFor prescribing information on phenylephrine, seesection 2.7.2.Lidocaine with Phenylephrine (Non-proprietary)Topical solution, lidocaine hydrochloride 5%,phenylephrine hydrochloride 0.5%, net price 2.5 mL(with nasal applicator) = £9.98DoseAnaesthesia before nasal surgery, endoscopy, laryngoscopy,or removal of foreign bodies from the noseChild 12–18 years up to max. 8 sprays

BNFC 2011–2012 15.2 Local anaesthesia 653MepivacaineMepivacaine is an amide-type local anaesthetic usedfor dental anaesthesia (see Dental Anaesthesia, p. 649).MEPIVACAINE HYDROCHLORIDECautions see Cautions of Local Anaesthetics, p. 649Contra-indications see Contra-indications of LocalAnaesthetics, p. 650Hepatic impairment use with caution; increased riskof side-effects in severe impairmentRenal impairment use with caution; increased risk ofside-effectsPregnancy use with caution in early pregnancyBreast-feeding use with cautionSide-effects see Toxicity and Side-effects, p. 650Indication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightInfiltration anaesthesia and nerve block indentistryChild 3–18 years consult expert dental sourcesScandonest c 3% Plain (Septodont) AInjection, mepivacaine hydrochloride 30 mg/mL, netprice 2.2-mL cartridge = 36pWith adrenalineFor prescribing information on adrenaline, see section2.7.2; see Use of Vasoconstrictors, p. 649.Scandonest c 2% Special (Septodont) AInjection, mepivacaine hydrochloride 20 mg/mL,adrenaline 1 in 100 000 (10 micrograms/mL), netprice 2.2-mL cartridge = 36pExcipients include sulphitesPrilocainePrilocaine is a local anaesthetic of low toxicity which issimilar to lidocaine. If used in high doses, methaemoglobinaemiamay occur which can be treated with anintravenous injection of methylthioninium chloride1% using a dose of 1–2 mg/kg given over 5 minutes.The dose may be repeated after 30–60 minutes ifnecessary. Neonates and infants under 6 months areparticularly susceptible to methaemoglobinaemia.PRILOCAINE HYDROCHLORIDECautions see Cautions of Local Anaesthetics, p. 649;severe or untreated hypertension; concomitant drugswhich cause methaemoglobinaemia; acute porphyria(section 9.8.2); interactions: Appendix 1 (prilocaine)Contra-indications see Contra-indications of LocalAnaesthetics, p. 650; anaemia, or congenital oracquired methaemoglobinaemiaHepatic impairment use with caution; lower dosesmay be required for intrathecal anaesthesiaRenal impairment use with caution; lower doses maybe required for intrathecal anaesthesiaPregnancy large doses during delivery can causeneonatal respiratory depression, hypotonia, andbradycardia after epidural block; avoid paracervical orpudendal block in obstetrics (neonatal methaemoglobinaemiareported); use lower doses for intrathecaluse during late pregnancyBreast-feeding present in milk but not known to beharmfulSide-effects see notes above and Toxicity and Sideeffects,p. 650; also hypertensionIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightInfiltration anaesthesia (higher strengths fordental use only), nerve blockSee under preparations below, seek expertadvice—important: see also under Administration,p. 649Citanest 1% c (AstraZeneca) AInjection, prilocaine hydrochloride 10 mg/mL, netprice 50-mL multidose vial = £2.01DoseChild 6 months–12 years up to 5 mg/kg adjustedaccording to site of administration and response; max.400 mgChild 12–18 years 100–200 mg/minute, or in incrementaldoses, to max. total dose 400 mg (adjustedaccording to site of administration and response)With lidocaineSee Lidocaine, p. 652For dental useNote Consult expert dental sources for specific advice inrelation to dose of prilocaine for dental anaesthesiaCitanest 3% with Octapressin c (Dentsply) AInjection, prilocaine hydrochloride 30 mg/mL, felypressin0.03 unit/mL, net price 2.2-mL cartridge andself-aspirating cartridge (both) = 47pRopivacaineRopivacaine is an amide-type local anaesthetic agentsimilar to bupivacaine. It is less cardiotoxic than bupivacaine,but also less potent.ROPIVACAINE HYDROCHLORIDECautions see Cautions of Local Anaesthetics, p. 649;also acute porphyria (section 9.8.2); interactions:Appendix 1 (ropivacaine)Contra-indications see Contra-indications of LocalAnaesthetics, p. 650Hepatic impairment use with caution in severeimpairmentRenal impairment use with caution in severe impairment;increased risk of systemic toxicity in chronicrenal failurePregnancy not known to be harmful; do not use forparacervical block in obstetricsBreast-feeding not known to be harmfulSide-effects see Toxicity and Side-effects, p. 650; alsohypertension, pyrexia; less commonly syncope andhypothermia15 Anaesthesia

654 15.2 Local anaesthesia BNFC 2011–2012Licensed use 2 mg/mL strength not licensed for usein children under 12 years except for acute painmanagement by caudal epidural block and continuousepidural infusion; 7.5 mg/mL and 10 mg/mLstrengths not licensed for use in children under 12yearsIndication and doseTo avoid excessive dosage in obese children, doseshould be calculated on the basis of ideal weight forheightAdjust according to child’s physical status andnature of procedure, seek expert advice—important:see also under Administration, p. 649Ropivacaine (Non-proprietary) AInfusion, ropivacaine hydrochloride 2 mg/mL, netprice 200 mL = £14.45Ametop c (S&N Hlth.)Gel, tetracaine 4%, net price 1.5-g tube = £1.08Excipients include hydroxybenzoates (parabens)DoseNeonate apply contents of tube (or appropriate proportion)to site of venepuncture or venous cannulation andcover with occlusive dressing; remove gel and dressingafter 30 minutes for venepuncture and after 45 minutesfor venous cannulationChild 1 month–18 years apply contents of tube (orappropriate proportion) to site of venepuncture orvenous cannulation and cover with occlusive dressing;remove gel and dressing after 30 minutes for venepunctureand after 45 minutes for venous cannulationNote Child 5–18 years, contents of max. 5 tubes appliedat separate sites at a single time, child 1 month–5 years,contents of max. 1 tube applied at separate sites at asingle timeNaropin c (AstraZeneca) AInjection, ropivacaine hydrochloride 2 mg/mL, netprice 10-mL Polyamp c = £1.78; 7.5 mg/mL, 10-mLPolyamp c = £2.65; 10 mg/mL, 10-mL Polyamp c =£3.20Electrolytes Na +

BNFC 2011–2012 655A1InteractionsTwo or more drugs given at the same time may exerttheir effects independently or may interact. The interactionmay be potentiation or antagonism of one drugby another, or occasionally some other effect. Adversedrug interactions should be reported to the Medicinesand Healthcare products Regulatory Agency (MHRA),through the Yellow Card Scheme (see Adverse Reactionsto Drugs, p. 12), as for other adverse drugreactions.Drug interactions may be pharmacodynamic orpharmacokinetic.Pharmacodynamic interactionsThese are interactions between drugs which have similaror antagonistic pharmacological effects or sideeffects.They may be due to competition at receptorsites, or occur between drugs acting on the samephysiological system. They are usually predictablefrom a knowledge of the pharmacology of the interactingdrugs; in general, those demonstrated with one drugare likely to occur with related drugs. They occur to agreater or lesser extent in most patients who receive theinteracting drugs.Pharmacokinetic interactionsThese occur when one drug alters the absorption, distribution,metabolism, or excretion of another, thusincreasing or reducing the amount of drug available toproduce its pharmacological effects. They are not easilypredicted and many of them affect only a small proportionof patients taking the combination of drugs. Pharmacokineticinteractions occurring with one drug cannotbe assumed to occur with related drugs unless theirpharmacokinetic properties are known to be similar.Pharmacokinetic interactions are of several types:Affecting absorption The rate of absorption or thetotal amount absorbed can both be altered by druginteractions. Delayed absorption is rarely of clinicalimportance unless high peak plasma concentrationsare required (e.g. when giving an analgesic). Reductionin the total amount absorbed, however, may result inineffective therapy.Due to changes in protein binding To a variableextent most drugs are loosely bound to plasma proteins.Protein-binding sites are non-specific and one drug candisplace another thereby increasing its proportion freeto diffuse from plasma to its site of action. This onlyproduces a detectable increase in effect if it is anextensively bound drug (more than 90%) that is notwidely distributed throughout the body. Even so displacementrarely produces more than transient potentiationbecause this increased concentration of free drugresults in an increased rate of elimination.Displacement from protein binding plays a part in thepotentiation of warfarin by sulfonamides, and tolbutamidebut the importance of these interactions is duemainly to the fact that warfarin metabolism is alsoinhibited.Affecting metabolism Many drugs are metabolisedin the liver. Induction of the hepatic microsomal enzymesystem by one drug can gradually increase the rate ofmetabolism of another, resulting in lower plasma concentrationsand a reduced effect. On withdrawal of theinducer plasma concentrations increase and toxicitymay occur. Barbiturates, griseofulvin, many antiepileptics,and rifampicin are the most important enzymeinducers. Drugs affected include warfarin and the oralcontraceptives.Conversely when one drug inhibits the metabolism ofanother higher plasma concentrations are produced,rapidly resulting in an increased effect with risk oftoxicity. Some drugs which potentiate warfarin andphenytoin do so by this mechanism.Isoenzymes of the hepatic cytochrome P450 systeminteract with a wide range of drugs. Drugs may besubstrates, inducers or inhibitors of the differentisoenzymes. A great deal of in-vitro information isavailable on the effect of drugs on the isoenzymes;however, since drugs are eliminated by a number ofdifferent metabolic routes as well as renal excretion,the clinical effects of interactions cannot be predictedaccurately from laboratory data on the cytochromeP450 isoenzymes. Except where a combinationof drugs is specifically contra-indicated, theBNF presents only interactions that have beenreported in clinical practice. In all cases the possibilityof an interaction must be considered if toxiceffects occur or if the activity of a drug diminishes.Affecting renal excretion Drugs are eliminatedthrough the kidney both by glomerular filtration andby active tubular secretion. Competition occursbetween those which share active transport mechanismsin the proximal tubule. For example, salicylates andsome other NSAIDs delay the excretion of methotrexate;serious methotrexate toxicity is possible.Relative importance of interactionsMany drug interactions are harmless and many of thosewhich are potentially harmful only occur in a smallproportion of patients; moreover, the severity of aninteraction varies from one patient to another. Drugswith a small therapeutic ratio (e.g. phenytoin) and thosewhich require careful control of dosage (e.g. anticoagulants,antihypertensives, and antidiabetics) are mostoften involved.Patients at increased risk from drug interactions includethose with impaired renal or liver function.Serious interactions The symbol . has been placedagainst interactions that are potentially serious andwhere combined administration of the drugs involvedAppendix 1: Interactions

656 Appendix 1: Interactions BNFC 2011–2012Appendix 1: Interactionsshould be avoided (or only undertaken with caution andappropriate monitoring).Interactions that have no symbol do not usually haveserious consequences.List of drug interactionsThe following is an alphabetical list of drugs and theirinteractions; to avoid excessive cross-referencing eachdrug or group is listed twice: in the alphabetical list andalso against the drug or group with which it interacts.For explanation of symbol . see aboveAbacavirAnalgesics: abacavir possibly reduces plasma concentrationof methadoneAntibacterials: plasma concentration of abacavir possiblyreduced by rifampicinAntiepileptics: plasma concentration of abacavir possiblyreduced by phenobarbital and phenytoin. Antivirals: abacavir possibly reduces effects of.ribavirin; plasma concentration of abacavir reducedby .tipranavirAbataceptAdalimumab: increased risk of side-effects whenabatacept given with adalimumab. Certolizumab pegol: avoid concomitant use of abataceptwith .certolizumab pegol. Etanercept: avoid concomitant use of abatacept with.etanercept. Golimumab: avoid concomitant use of abatacept with.golimumab. Infliximab: avoid concomitant use of abatacept with.infliximab. Vaccines: avoid concomitant use of abatacept with live.vaccines (see p. 599)Acarbose see AntidiabeticsACE InhibitorsAlcohol: enhanced hypotensive effect when ACE inhibitorsgiven with alcoholAldesleukin: enhanced hypotensive effect when ACEinhibitors given with aldesleukinAllopurinol: increased risk of leucopenia and hypersensitivityreactions when ACE inhibitors given withallopurinol especially in renal impairmentAlpha-blockers: enhanced hypotensive effect whenACE inhibitors given with alpha-blockersAnaesthetics, General: enhanced hypotensive effectwhen ACE inhibitors given with general anaestheticsAnalgesics: increased risk of renal impairment whenACE inhibitors given with NSAIDs, also hypotensiveeffect antagonisedAngiotensin-II Receptor Antagonists: increased risk ofhyperkalaemia when ACE inhibitors given withangiotensin-II receptor antagonistsAntacids: absorption of ACE inhibitors possiblyreduced by antacids; absorption of captopril,enalapril and fosinopril reduced by antacidsAntibacterials: plasma concentration of active metaboliteof imidapril reduced by rifampicin (reducedantihypertensive effect); quinapril tablets reduceabsorption of tetracyclines (quinapril tablets containmagnesium carbonate); possible increased risk ofhyperkalaemia when ACE inhibitors given withtrimethoprimAnticoagulants: increased risk of hyperkalaemia whenACE inhibitors given with heparinsAntidepressants: hypotensive effect of ACE inhibitorspossibly enhanced by MAOIsAntidiabetics: ACE inhibitors possibly enhance hypoglycaemiceffect of insulin, metformin and sulfonylureasAntipsychotics: enhanced hypotensive effect whenACE inhibitors given with antipsychoticsAnxiolytics and Hypnotics: enhanced hypotensiveeffect when ACE inhibitors given with anxiolytics andhypnoticsACE Inhibitors (continued)Azathioprine: increased risk of anaemia or leucopeniawhen captopril given with azathioprine especially inrenal impairment; increased risk of anaemia whenenalapril given with azathioprine especially in renalimpairmentBeta-blockers: enhanced hypotensive effect when ACEinhibitors given with beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when ACE inhibitors given with calciumchannelblockersCardiac Glycosides: captopril possibly increasesplasma concentration of digoxin. Ciclosporin: increased risk of hyperkalaemia whenACE inhibitors given with .ciclosporinClonidine: enhanced hypotensive effect when ACEinhibitors given with clonidine; antihypertensiveeffect of captopril possibly delayed by previoustreatment with clonidineCorticosteroids: hypotensive effect of ACE inhibitorsantagonised by corticosteroidsDiazoxide: enhanced hypotensive effect when ACEinhibitors given with diazoxide. Diuretics: enhanced hypotensive effect when ACEinhibitors given with .diuretics; increased risk ofsevere hyperkalaemia when ACE inhibitors givenwith .potassium-sparing diuretics and aldosteroneantagonists (monitor potassium concentration withlow-dose spironolactone in heart failure)Dopaminergics: enhanced hypotensive effect whenACE inhibitors given with levodopa. Gold: flushing and hypotension reported when ACEinhibitors given with .sodium aurothiomalate. Lithium: ACE inhibitors reduce excretion of .lithium(increased plasma concentration)Methyldopa: enhanced hypotensive effect when ACEinhibitors given with methyldopaMoxisylyte: enhanced hypotensive effect when ACEinhibitors given with moxisylyteMoxonidine: enhanced hypotensive effect when ACEinhibitors given with moxonidineMuscle Relaxants: enhanced hypotensive effect whenACE inhibitors given with baclofen or tizanidineNitrates: enhanced hypotensive effect when ACEinhibitors given with nitratesOestrogens: hypotensive effect of ACE inhibitorsantagonised by oestrogens. Potassium Salts: increased risk of severe hyperkalaemiawhen ACE inhibitors given with .potassiumsaltsProbenecid: excretion of captopril reduced by probenecidProstaglandins: enhanced hypotensive effect whenACE inhibitors given with alprostadilVasodilator Antihypertensives: enhanced hypotensiveeffect when ACE inhibitors given with hydralazine,minoxidil or sodium nitroprussideAcebutolol see Beta-blockersAceclofenac see NSAIDsAcemetacin see NSAIDsAcenocoumarol see CoumarinsAcetazolamide see DiureticsAciclovirNote Interactions do not apply to topical aciclovir preparationsNote Valaciclovir interactions as for aciclovirCiclosporin: increased risk of nephrotoxicity whenaciclovir given with ciclosporinMycophenolate: plasma concentration of aciclovirincreased by mycophenolate, also plasma concentrationof inactive metabolite of mycophenolateincreasedProbenecid: excretion of aciclovir reduced by probenecid(increased plasma concentration)Tacrolimus: possible increased risk of nephrotoxicitywhen aciclovir given with tacrolimusTheophylline: aciclovir possibly increases plasmaconcentration of theophyllineAcitretin see Retinoids

BNFC 2011–2012 Appendix 1: Interactions 657Acrivastine see AntihistaminesAdalimumabAbatacept: increased risk of side-effects when adalimumabgiven with abatacept. Anakinra: avoid concomitant use of adalimumab with.anakinra. Vaccines: avoid concomitant use of adalimumab withlive .vaccines (see p. 599)AdefovirAntivirals: avoidance of adefovir advised by manufacturerof tenofovirAdenosineNote Possibility of interaction with drugs tending to impairmyocardial conductionAnaesthetics, Local: increased myocardial depressionwhen anti-arrhythmics given with bupivacaine, levobupivacaine,prilocaine or ropivacaine. Anti-arrhythmics: increased myocardial depressionwhen anti-arrhythmics given with other .antiarrhythmics. Antipsychotics: increased risk of ventricular arrhythmiaswhen anti-arrhythmics that prolong the QTinterval given with .antipsychotics that prolong theQT interval. Beta-blockers: increased myocardial depression whenanti-arrhythmics given with .beta-blockers. Dipyridamole: effect of adenosine enhanced andextended by .dipyridamole (important risk of toxicity)Nicotine: effects of adenosine possibly enhanced bynicotineTheophylline: anti-arrhythmic effect of adenosineantagonised by theophyllineAdrenaline (epinephrine) see SympathomimeticsAdrenergic Neurone BlockersAlcohol: enhanced hypotensive effect when adrenergicneurone blockers given with alcoholAlpha-blockers: enhanced hypotensive effect whenadrenergic neurone blockers given with alpha-blockers. Anaesthetics, General: enhanced hypotensive effectwhen adrenergic neurone blockers given with.general anaestheticsAnalgesics: hypotensive effect of adrenergic neuroneblockers antagonised by NSAIDsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when adrenergic neurone blockersgiven with angiotensin-II receptor antagonistsAntidepressants: enhanced hypotensive effect whenadrenergic neurone blockers given with MAOIs;hypotensive effect of adrenergic neurone blockersantagonised by tricyclicsAntipsychotics: hypotensive effect of adrenergicneurone blockers antagonised by haloperidol; hypotensiveeffect of adrenergic neurone blockers antagonisedby higher doses of chlorpromazine; enhancedhypotensive effect when adrenergic neurone blockersgiven with phenothiazinesAnxiolytics and Hypnotics: enhanced hypotensiveeffect when adrenergic neurone blockers given withanxiolytics and hypnoticsBeta-blockers: enhanced hypotensive effect whenadrenergic neurone blockers given with beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when adrenergic neurone blockers given withcalcium-channel blockersClonidine: enhanced hypotensive effect when adrenergicneurone blockers given with clonidineCorticosteroids: hypotensive effect of adrenergicneurone blockers antagonised by corticosteroidsDiazoxide: enhanced hypotensive effect when adrenergicneurone blockers given with diazoxideDiuretics: enhanced hypotensive effect when adrenergicneurone blockers given with diureticsDopaminergics: enhanced hypotensive effect whenadrenergic neurone blockers given with levodopaMethyldopa: enhanced hypotensive effect when adrenergicneurone blockers given with methyldopaAdrenergic Neurone Blockers (continued)Moxisylyte: enhanced hypotensive effect when adrenergicneurone blockers given with moxisylyteMoxonidine: enhanced hypotensive effect when adrenergicneurone blockers given with moxonidineMuscle Relaxants: enhanced hypotensive effect whenadrenergic neurone blockers given with baclofen ortizanidineNitrates: enhanced hypotensive effect when adrenergicneurone blockers given with nitratesOestrogens: hypotensive effect of adrenergic neuroneblockers antagonised by oestrogensPizotifen: hypotensive effect of adrenergic neuroneblockers antagonised by pizotifenProstaglandins: enhanced hypotensive effect whenadrenergic neurone blockers given with alprostadil. Sympathomimetics: hypotensive effect of guanethidineantagonised by .dexamfetamine; hypotensiveeffect of adrenergic neurone blockers antagonised by.ephedrine, .isometheptene, .metaraminol,.methylphenidate, .noradrenaline (norepinephrine),.oxymetazoline, .phenylephrine,.pseudoephedrine and .xylometazolineVasodilator Antihypertensives: enhanced hypotensiveeffect when adrenergic neurone blockers given withhydralazine, minoxidil or sodium nitroprussideAdsorbents see KaolinAgalsidase Alfa and BetaAnti-arrhythmics: effects of agalsidase alfa and betapossibly inhibited by amiodarone (manufacturers ofagalsidase alfa and beta advise avoid concomitantuse)Antibacterials: effects of agalsidase alfa and betapossibly inhibited by gentamicin (manufacturers ofagalsidase alfa and beta advise avoid concomitantuse)Antimalarials: effects of agalsidase alfa and betapossibly inhibited by chloroquine and hydroxychloroquine(manufacturers of agalsidase alfa andbeta advise avoid concomitant use)Agomelatine. Antibacterials: manufacturer of agomelatine advisesavoid concomitant use with .ciprofloxacin. Antidepressants: metabolism of agomelatine inhibitedby .fluvoxamine (increased plasma concentration). Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrineAtomoxetine: possible increased risk of convulsionswhen antidepressants given with atomoxetineAlcoholACE Inhibitors: enhanced hypotensive effect whenalcohol given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when alcohol given with adrenergic neuroneblockersAlpha-blockers: increased sedative effect when alcoholgiven with indoramin; enhanced hypotensive effectwhen alcohol given with alpha-blockersAnalgesics: enhanced hypotensive and sedative effectswhen alcohol given with opioid analgesicsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when alcohol given with angiotensin-IIreceptor antagonists. Antibacterials: disulfiram-like reaction when alcoholgiven with metronidazole; possibility of disulfiramlikereaction when alcohol given with tinidazole;increased risk of convulsions when alcohol given with.cycloserine. Anticoagulants: major changes in consumption ofalcohol may affect anticoagulant control with.coumarins or .phenindione. Antidepressants: some beverages containing alcoholand some dealcoholised beverages contain tyraminewhich interacts with .MAOIs (hypertensive crisis)—ifno tyramine, enhanced hypotensive effect; sedativeeffects possibly increased when alcohol given withSSRIs; increased sedative effect when alcohol givenwith .mirtazapine, .tricyclic-relatedantidepressants or .tricyclicsAppendix 1: Interactions

658 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsAlcohol (continued)Antidiabetics: alcohol enhances hypoglycaemic effectof antidiabetics; increased risk of lactic acidosis whenalcohol given with metforminAntiepileptics: alcohol possibly increases CNS sideeffectsof carbamazepine; increased sedative effectwhen alcohol given with phenobarbital; chronicheavy consumption of alcohol possibly reducesplasma concentration of phenytoinAntifungals: effects of alcohol possibly enhanced bygriseofulvinAntihistamines: increased sedative effect whenalcohol given with antihistamines (possibly less effectwith non-sedating antihistamines)Antimuscarinics: increased sedative effect whenalcohol given with hyoscineAntipsychotics: increased sedative effect when alcoholgiven with antipsychoticsAnxiolytics and Hypnotics: increased sedative effectwhen alcohol given with anxiolytics and hypnoticsBeta-blockers: enhanced hypotensive effect whenalcohol given with beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when alcohol given with calcium-channelblockers; plasma concentration of alcohol possiblyincreased by verapamilClonidine: enhanced hypotensive effect when alcoholgiven with clonidineCytotoxics: disulfiram-like reaction when alcohol givenwith procarbazineDiazoxide: enhanced hypotensive effect when alcoholgiven with diazoxideDisulfiram: disulfiram reaction when alcohol given withdisulfiram (see BNF section 4.10.1)Diuretics: enhanced hypotensive effect when alcoholgiven with diureticsDopaminergics: alcohol reduces tolerance to bromocriptineLevamisole: possibility of disulfiram-like reaction whenalcohol given with levamisoleLofexidine: increased sedative effect when alcoholgiven with lofexidineMethyldopa: enhanced hypotensive effect whenalcohol given with methyldopaMetoclopramide: absorption of alcohol possiblyincreased by metoclopramideMoxonidine: enhanced hypotensive effect whenalcohol given with moxonidineMuscle Relaxants: increased sedative effect whenalcohol given with baclofen, methocarbamol ortizanidineNicorandil: alcohol possibly enhances hypotensiveeffect of nicorandilNitrates: enhanced hypotensive effect when alcoholgiven with nitrates. Paraldehyde: increased sedative effect when alcoholgiven with .paraldehyde. Retinoids: presence of alcohol causes etretinate to beformed from .acitretin (increased risk of teratogenecityin women of child-bearing potential)Sympathomimetics: alcohol possibly enhances effectsof methylphenidateVasodilator Antihypertensives: enhanced hypotensiveeffect when alcohol given with hydralazine,minoxidil or sodium nitroprussideAldesleukinACE Inhibitors: enhanced hypotensive effect whenaldesleukin given with ACE inhibitorsAlpha-blockers: enhanced hypotensive effect whenaldesleukin given with alpha-blockersAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when aldesleukin given withangiotensin-II receptor antagonistsAntivirals: aldesleukin possibly increases plasma concentrationof indinavirBeta-blockers: enhanced hypotensive effect whenaldesleukin given with beta-blockersAldesleukin (continued)Calcium-channel Blockers: enhanced hypotensiveeffect when aldesleukin given with calcium-channelblockersClonidine: enhanced hypotensive effect when aldesleukingiven with clonidine. Corticosteroids: manufacturer of aldesleukin advisesavoid concomitant use with .corticosteroids. Cytotoxics: manufacturer of aldesleukin advises avoidconcomitant use with .cisplatin, .dacarbazine and.vinblastineDiazoxide: enhanced hypotensive effect when aldesleukingiven with diazoxideDiuretics: enhanced hypotensive effect when aldesleukingiven with diureticsMethyldopa: enhanced hypotensive effect whenaldesleukin given with methyldopaMoxonidine: enhanced hypotensive effect whenaldesleukin given with moxonidineNitrates: enhanced hypotensive effect when aldesleukingiven with nitratesVasodilator Antihypertensives: enhanced hypotensiveeffect when aldesleukin given with hydralazine,minoxidil or sodium nitroprussideAlendronic Acid see BisphosphonatesAlfentanil see Opioid AnalgesicsAlfuzosin see Alpha-blockersAlimemazine see AntihistaminesAliskirenAnalgesics: hypotensive effect of aliskiren possiblyantagonised by NSAIDsAngiotensin-II Receptor Antagonists: plasma concentrationof aliskiren possibly reduced by irbesartanAnticoagulants: increased risk of hyperkalaemia whenaliskiren given with heparinsAntifungals: plasma concentration of aliskirenincreased by ketoconazoleCalcium-channel Blockers: manufacturer of aliskirenadvises avoid concomitant use with verapamil. Ciclosporin: plasma concentration of aliskirenincreased by .ciclosporin—avoid concomitant useDiuretics: aliskiren reduces plasma concentration offurosemide; increased risk of hyperkalaemia whenaliskiren given with potassium-sparing diuretics andaldosterone antagonistsPotassium Salts: increased risk of hyperkalaemiawhen aliskiren given with potassium saltsAlitretinoin see RetinoidsAlkylating Drugs see Bendamustine, Busulfan, Carmustine,Cyclophosphamide, Estramustine, Ifosfamide,Lomustine, Melphalan, and ThiotepaAllopurinolACE Inhibitors: increased risk of leucopenia andhypersensitivity reactions when allopurinol givenwith ACE inhibitors especially in renal impairmentAntibacterials: increased risk of rash when allopurinolgiven with amoxicillin or ampicillinAnticoagulants: allopurinol possibly enhances anticoagulanteffect of coumarins. Antivirals: allopurinol increases plasma concentrationof .didanosine (risk of toxicity)—avoid concomitantuse. Azathioprine: allopurinol enhances effects andincreases toxicity of .azathioprine (reduce dose ofazathioprine to one quarter of usual dose)Ciclosporin: allopurinol possibly increases plasmaconcentration of ciclosporin (risk of nephrotoxicity). Cytotoxics: allopurinol enhances effects and increasestoxicity of .mercaptopurine (reduce dose ofmercaptopurine to one quarter of usual dose);avoidance of allopurinol advised by manufacturer of.capecitabineDiuretics: increased risk of hypersensitivity whenallopurinol given with thiazides and related diureticsespecially in renal impairmentTheophylline: allopurinol possibly increases plasmaconcentration of theophyllineAlmotriptan see 5HT 1 Agonists

BNFC 2011–2012 Appendix 1: Interactions 659Alpha 2 -adrenoceptor Stimulants see Apraclonidine,Brimonidine, Clonidine and MethyldopaAlpha-blockersACE Inhibitors: enhanced hypotensive effect whenalpha-blockers given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when alpha-blockers given with adrenergicneurone blockersAlcohol: enhanced hypotensive effect when alphablockersgiven with alcohol; increased sedative effectwhen indoramin given with alcoholAldesleukin: enhanced hypotensive effect when alphablockersgiven with aldesleukin. Anaesthetics, General: enhanced hypotensive effectwhen alpha-blockers given with .general anaestheticsAnalgesics: hypotensive effect of alpha-blockersantagonised by NSAIDsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when alpha-blockers given withangiotensin-II receptor antagonists. Antidepressants: enhanced hypotensive effect whenalpha-blockers given with MAOIs; manufacturer ofindoramin advises avoid concomitant use with.MAOIsAntifungals: plasma concentration of alfuzosin possiblyincreased by ketoconazoleAntipsychotics: enhanced hypotensive effect whenalpha-blockers given with antipsychotics. Antivirals: plasma concentration of alfuzosin possiblyincreased by .ritonavir—avoid concomitant useAnxiolytics and Hypnotics: enhanced hypotensive andsedative effects when alpha-blockers given withanxiolytics and hypnotics. Beta-blockers: enhanced hypotensive effect whenalpha-blockers given with .beta-blockers, alsoincreased risk of first-dose hypotension with postsynapticalpha-blockers such as prazosin. Calcium-channel Blockers: enhanced hypotensiveeffect when alpha-blockers given with .calciumchannelblockers, also increased risk of first-dosehypotension with post-synaptic alpha-blockers suchas prazosinCardiac Glycosides: prazosin increases plasma concentrationof digoxinClonidine: enhanced hypotensive effect when alphablockersgiven with clonidineCorticosteroids: hypotensive effect of alpha-blockersantagonised by corticosteroidsDiazoxide: enhanced hypotensive effect when alphablockersgiven with diazoxide. Diuretics: enhanced hypotensive effect when alphablockersgiven with .diuretics, also increased risk offirst-dose hypotension with post-synaptic alphablockerssuch as prazosinDopaminergics: enhanced hypotensive effect whenalpha-blockers given with levodopaMethyldopa: enhanced hypotensive effect when alphablockersgiven with methyldopa. Moxisylyte: possible severe postural hypotension whenalpha-blockers given with .moxisylyteMoxonidine: enhanced hypotensive effect when alphablockersgiven with moxonidineMuscle Relaxants: enhanced hypotensive effect whenalpha-blockers given with baclofen or tizanidineNitrates: enhanced hypotensive effect when alphablockersgiven with nitratesOestrogens: hypotensive effect of alpha-blockersantagonised by oestrogensProstaglandins: enhanced hypotensive effect whenalpha-blockers given with alprostadil. Sildenafil: enhanced hypotensive effect when alphablockersgiven with .sildenafil (avoid alpha-blockersfor 4 hours after sildenafil)—see also under Phosphodiesterasetype-5 inhibitors, BNF section 7.4.5. Sympathomimetics: avoid concomitant use of tolazolinewith .adrenaline (epinephrine) or .dopamine. Tadalafil: enhanced hypotensive effect when alphablockersgiven with .tadalafil—see also under Phos-Alpha-blockers. Tadalafil (continued)phodiesterase type-5 inhibitors, BNF section7.4.5; enhanced hypotensive effect when doxazosingiven with .tadalafil—manufacturer oftadalafil advises avoid concomitant use. Ulcer-healing Drugs: effects of tolazoline antagonisedby .cimetidine and .ranitidine. Vardenafil: enhanced hypotensive effect when alphablockers(excludes tamsulosin) given with.vardenafil—separate doses by 6 hours—see alsounder Phosphodiesterase type-5 inhibitors, BNFsection 7.4.5Vasodilator Antihypertensives: enhanced hypotensiveeffect when alpha-blockers given with hydralazine,minoxidil or sodium nitroprussideAlpha-blockers (post-synaptic) see Alpha-blockersAlprazolam see Anxiolytics and HypnoticsAlprostadil see ProstaglandinsAluminium Hydroxide see AntacidsAmantadineAntimalarials: plasma concentration of amantadinepossibly increased by quinineAntipsychotics: increased risk of extrapyramidal sideeffectswhen amantadine given with antipsychoticsBupropion: increased risk of side-effects when amantadinegiven with bupropion. Memantine: increased risk of CNS toxicity whenamantadine given with .memantine (manufacturer ofmemantine advises avoid concomitant use); effects ofdopaminergics possibly enhanced by memantineMethyldopa: increased risk of extrapyramidal sideeffectswhen amantadine given with methyldopa;antiparkinsonian effect of dopaminergics antagonisedby methyldopaTetrabenazine: increased risk of extrapyramidal sideeffectswhen amantadine given with tetrabenazineAmikacin see AminoglycosidesAmiloride see DiureticsAminoglycosidesAgalsidase Alfa and Beta: gentamicin possibly inhibitseffects of agalsidase alfa and beta (manufacturers ofagalsidase alfa and beta advise avoid concomitantuse)Analgesics: plasma concentration of amikacin andgentamicin in neonates possibly increased by indometacin. Antibacterials: neomycin reduces absorption ofphenoxymethylpenicillin; increased risk of nephrotoxicitywhen aminoglycosides given with colistimethatesodium or polymyxins; increased risk ofnephrotoxicity and ototoxicity when aminoglycosidesgiven with capreomycin or .vancomycin; possibleincreased risk of nephrotoxicity when aminoglycosidesgiven with cephalosporins. Anticoagulants: experience in anticoagulant clinicssuggests that INR possibly altered when neomycin(given for local action on gut) is given with.coumarins or .phenindioneAntidiabetics: neomycin possibly enhances hypoglycaemiceffect of acarbose, also severity of gastrointestinaleffects increasedAntifungals: increased risk of nephrotoxicity whenaminoglycosides given with amphotericinBisphosphonates: increased risk of hypocalcaemiawhen aminoglycosides given with bisphosphonatesCardiac Glycosides: neomycin reduces absorption ofdigoxin; gentamicin possibly increases plasma concentrationof digoxin. Ciclosporin: increased risk of nephrotoxicity whenaminoglycosides given with .ciclosporin. Cytotoxics: neomycin possibly reduces absorption ofmethotrexate; neomycin reduces bioavailability ofsorafenib; increased risk of nephrotoxicity andpossibly of ototoxicity when aminoglycosides givenwith .platinum compounds. Diuretics: increased risk of otoxicity when aminoglycosidesgiven with .loop diureticsAppendix 1: Interactions

660 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsAminoglycosides (continued). Muscle Relaxants: aminoglycosides enhance effects of.non-depolarising muscle relaxants and.suxamethonium. Parasympathomimetics: aminoglycosides antagoniseeffects of .neostigmine and .pyridostigmine. Tacrolimus: increased risk of nephrotoxicity whenaminoglycosides given with .tacrolimusVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Vitamins: neomycin possibly reduces absorption ofvitamin AAminophylline see TheophyllineAminosalicylatesAzathioprine: possible increased risk of leucopeniawhen aminosalicylates given with azathioprineCardiac Glycosides: sulfasalazine possibly reducesabsorption of digoxinCytotoxics: possible increased risk of leucopenia whenaminosalicylates given with mercaptopurineFolates: sulfasalazine possibly reduces absorption offolic acidAmiodaroneNote Amiodarone has a long half-life; there is a potential fordrug interactions to occur for several weeks (or evenmonths) after treatment with it has been stoppedAgalsidase Alfa and Beta: amiodarone possiblyinhibits effects of agalsidase alfa and beta (manufacturersof agalsidase alfa and beta advise avoidconcomitant use)Anaesthetics, Local: increased myocardial depressionwhen anti-arrhythmics given with bupivacaine, levobupivacaine,prilocaine or ropivacaine. Anti-arrhythmics: increased myocardial depressionwhen anti-arrhythmics given with other .antiarrhythmics;increased risk of ventricular arrhythmiaswhen amiodarone given with .disopyramide or.dronedarone—avoid concomitant use; amiodaroneincreases plasma concentration of .flecainide (halvedose of flecainide). Antibacterials: increased risk of ventricular arrhythmiaswhen amiodarone given with parenteral.erythromycin—avoid concomitant use; increasedrisk of ventricular arrhythmias when amiodaronegiven with .levofloxacin or .moxifloxacin—avoidconcomitant use; possible increased risk of ventriculararrhythmias when amiodarone given withsulfamethoxazole and trimethoprim (as co-trimoxazole)—manufacturerof amiodarone advises avoidconcomitant use of co-trimoxazole. Anticoagulants: amiodarone inhibits metabolism of.coumarins and .phenindione (enhanced anticoagulanteffect); amiodarone increases plasmaconcentration of .dabigatran etexilate (reduce doseof dabigatran etexilate). Antidepressants: increased risk of ventricular arrhythmiaswhen amiodarone given with .tricyclics—avoid concomitant use. Antiepileptics: amiodarone inhibits metabolism of.phenytoin (increased plasma concentration). Antihistamines: increased risk of ventricular arrhythmiaswhen amiodarone given with .mizolastine—avoid concomitant use. Antimalarials: avoidance of amiodarone advised bymanufacturer of .artemether/lumefantrine (risk ofventricular arrhythmias); increased risk of ventriculararrhythmias when amiodarone given with .chloroquineand hydroxychloroquine, .mefloquine or.quinine—avoid concomitant use. Antimuscarinics: increased risk of ventricular arrhythmiaswhen amiodarone given with .tolterodine. Antipsychotics: increased risk of ventricular arrhythmiaswhen anti-arrhythmics that prolong the QTinterval given with .antipsychotics that prolong theQT interval; increased risk of ventricular arrhythmiaswhen amiodarone given with .benperidol—manufacturerof benperidol advises avoid concomitant use;increased risk of ventricular arrhythmias whenamiodarone given with .amisulpride, .droperidol,Amiodarone. Antipsychotics (continued).haloperidol, .phenothiazines, .pimozide or.zuclopenthixol—avoid concomitant use; increasedrisk of ventricular arrhythmias when amiodaronegiven with .sulpiride. Antivirals: plasma concentration of amiodarone possiblyincreased by .atazanavir; plasma concentrationof amiodarone possibly increased by .fosamprenavir(increased risk of ventricular arrhythmias—avoidconcomitant use); plasma concentration of amiodaronepossibly increased by .indinavir—avoid concomitantuse; increased risk of ventriculararrhythmias when amiodarone given with.nelfinavir or .saquinavir—avoid concomitant use;plasma concentration of amiodarone increased by.ritonavir (increased risk of ventricular arrhythmias—avoidconcomitant use). Atomoxetine: increased risk of ventricular arrhythmiaswhen amiodarone given with .atomoxetine. Beta-blockers: increased risk of bradycardia, AV blockand myocardial depression when amiodarone givenwith .beta-blockers; increased myocardial depressionwhen anti-arrhythmics given with .beta-blockers;increased risk of ventricular arrhythmias whenamiodarone given with .sotalol—avoid concomitantuse. Calcium-channel Blockers: increased risk of bradycardia,AV block and myocardial depression whenamiodarone given with .diltiazem or .verapamil. Cardiac Glycosides: amiodarone increases plasmaconcentration of .digoxin (halve dose of digoxin)Ciclosporin: amiodarone possibly increases plasmaconcentration of ciclosporin. Colchicine: amiodarone possibly increases risk of.colchicine toxicity. Cytotoxics: increased risk of ventricular arrhythmiaswhen amiodarone given with .arsenic trioxideDiuretics: increased cardiac toxicity with amiodarone ifhypokalaemia occurs with acetazolamide, loopdiuretics or thiazides and related diuretics; amiodaroneincreases plasma concentration of eplerenone(reduce dose of eplerenone)Grapefruit Juice: plasma concentration of amiodaroneincreased by grapefruit juice. Ivabradine: increased risk of ventricular arrhythmiaswhen amiodarone given with .ivabradine. Lipid-regulating Drugs: increased risk of myopathywhen amiodarone given with .simvastatin. Lithium: manufacturer of amiodarone advises avoidconcomitant use with .lithium (risk of ventriculararrhythmias)Orlistat: plasma concentration of amiodarone possiblyreduced by orlistat. Pentamidine Isetionate: increased risk of ventriculararrhythmias when amiodarone given with .pentamidineisetionate—avoid concomitant useThyroid Hormones: for concomitant use of amiodaroneand thyroid hormones see p. 83Ulcer-healing Drugs: plasma concentration of amiodaroneincreased by cimetidineAmisulpride see AntipsychoticsAmitriptyline see Antidepressants, TricyclicAmlodipine see Calcium-channel BlockersAmoxicillin see PenicillinsAmphotericinNote Close monitoring required with concomitant administrationof nephrotoxic drugs or cytotoxicsAntibacterials: increased risk of nephrotoxicity whenamphotericin given with aminoglycosides or polymyxins;possible increased risk of nephrotoxicitywhen amphotericin given with vancomycinAntifungals: amphotericin reduces renal excretion andincreases cellular uptake of flucytosine (toxicitypossibly increased); effects of amphotericin possiblyantagonised by imidazoles and triazoles; plasmaconcentration of amphotericin possibly increased bymicafungin

BNFC 2011–2012 Appendix 1: Interactions 661Amphotericin (continued). Cardiac Glycosides: hypokalaemia caused byamphotericin increases cardiac toxicity with .cardiacglycosides. Ciclosporin: increased risk of nephrotoxicity whenamphotericin given with .ciclosporin. Corticosteroids: increased risk of hypokalaemia whenamphotericin given with .corticosteroids—avoidconcomitant use unless corticosteroids needed tocontrol reactions. Cytotoxics: increased risk of ventricular arrhythmiaswhen amphotericin given with .arsenic trioxideDiuretics: increased risk of hypokalaemia whenamphotericin given with loop diuretics or thiazidesand related diureticsPentamidine Isetionate: possible increased risk ofnephrotoxicity when amphotericin given with pentamidineisetionate. Tacrolimus: increased risk of nephrotoxicity whenamphotericin given with .tacrolimusAmpicillin see PenicillinsAnabolic Steroids. Anticoagulants: anabolic steroids enhance anticoagulanteffect of .coumarins and .phenindioneAntidiabetics: anabolic steroids possibly enhancehypoglycaemic effect of antidiabeticsAnaesthetics, GeneralNote See also Surgery and Long-term Medication, p. 628ACE Inhibitors: enhanced hypotensive effect whengeneral anaesthetics given with ACE inhibitors. Adrenergic Neurone Blockers: enhanced hypotensiveeffect when general anaesthetics given with .adrenergicneurone blockers. Alpha-blockers: enhanced hypotensive effect whengeneral anaesthetics given with .alpha-blockersAnalgesics: metabolism of etomidate inhibited byfentanyl (consider reducing dose of etomidate);effects of thiopental possibly enhanced by aspirin;effects of intravenous general anaesthetics and volatileliquid general anaesthetics possibly enhanced byopioid analgesicsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when general anaesthetics givenwith angiotensin-II receptor antagonistsAntibacterials: effects of thiopental enhanced bysulfonamides; hypersensitivity-like reactions canoccur when general anaesthetics given with intravenousvancomycinAntidepressants: increased risk of arrhythmias andhypotension when general anaesthetics given withtricyclics. Antipsychotics: enhanced hypotensive effect whengeneral anaesthetics given with .antipsychotics;effects of thiopental enhanced by droperidolAnxiolytics and Hypnotics: increased sedative effectwhen general anaesthetics given with anxiolytics andhypnoticsBeta-blockers: enhanced hypotensive effect whengeneral anaesthetics given with beta-blockers. Calcium-channel Blockers: enhanced hypotensiveeffect when general anaesthetics or isoflurane givenwith calcium-channel blockers; general anaestheticsenhance hypotensive effect of .verapamil (also AVdelay)Clonidine: enhanced hypotensive effect when generalanaesthetics given with clonidine. Cytotoxics: nitrous oxide increases antifolate effect of.methotrexate—avoid concomitant useDiazoxide: enhanced hypotensive effect when generalanaesthetics given with diazoxideDiuretics: enhanced hypotensive effect when generalanaesthetics given with diuretics. Dopaminergics: increased risk of arrhythmias whenvolatile liquid general anaesthetics given with.levodopa. Doxapram: increased risk of arrhythmias when volatileliquid general anaesthetics given with .doxapram(avoid doxapram for at least 10 minutes after volatileliquid general anaesthetics)Anaesthetics, General (continued)Ergot Alkaloids: halothane reduces effects of ergometrineon the parturient uterus. Memantine: increased risk of CNS toxicity whenketamine given with .memantine (manufacturer ofmemantine advises avoid concomitant use)Methyldopa: enhanced hypotensive effect whengeneral anaesthetics given with methyldopaMetoclopramide: effects of thiopental enhanced bymetoclopramideMoxonidine: enhanced hypotensive effect whengeneral anaesthetics given with moxonidine. Muscle Relaxants: increased risk of myocardialdepression and bradycardia when propofol given with.suxamethonium; volatile liquid general anaestheticsenhance effects of non-depolarising musclerelaxants and suxamethonium; ketamine enhanceseffects of atracuriumNitrates: enhanced hypotensive effect when generalanaesthetics given with nitratesOxytocin: oxytocic effect possibly reduced, alsoenhanced hypotensive effect and risk of arrhythmiaswhen volatile liquid general anaesthetics given withoxytocinProbenecid: effects of thiopental possibly enhanced byprobenecid. Sympathomimetics: increased risk of arrhythmiaswhen volatile liquid general anaesthetics given with.adrenaline (epinephrine); increased risk of hypertensionwhen volatile liquid general anaestheticsgiven with .methylphenidateTheophylline: increased risk of convulsions whenketamine given with theophylline; increased risk ofarrhythmias when halothane given with theophyllineVasodilator Antihypertensives: enhanced hypotensiveeffect when general anaesthetics given with hydralazine,minoxidil or sodium nitroprussideAnaesthetics, General (intravenous) see Anaesthetics,GeneralAnaesthetics, General (volatile liquids) see Anaesthetics,GeneralAnaesthetics, Local see Bupivacaine, Levobupivacaine,Lidocaine, Prilocaine, and RopivacaineAnagrelide. Cilostazol: manufacturer of anagrelide advises avoidconcomitant use with .cilostazol. Phosphodiesterase Type-3 Inhibitors: manufacturerof anagrelide advises avoid concomitant use with.enoximone and .milrinoneAnakinra. Adalimumab: avoid concomitant use of anakinra with.adalimumab. Certolizumab pegol: avoid concomitant use of anakinrawith .certolizumab pegol. Etanercept: avoid concomitant use of anakinra with.etanercept. Golimumab: avoid concomitant use of anakinra with.golimumab. Infliximab: avoid concomitant use of anakinra with.infliximab. Vaccines: avoid concomitant use of anakinra with live.vaccines (see p. 599)Analgesics see Aspirin, Nefopam, NSAIDs, OpioidAnalgesics, and ParacetamolAngiotensin-II Receptor AntagonistsACE Inhibitors: increased risk of hyperkalaemia whenangiotensin-II receptor antagonists given with ACEinhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when angiotensin-II receptor antagonists givenwith adrenergic neurone blockersAlcohol: enhanced hypotensive effect when angiotensin-IIreceptor antagonists given with alcoholAldesleukin: enhanced hypotensive effect whenangiotensin-II receptor antagonists given with aldesleukinAliskiren: irbesartan possibly reduces plasma concentrationof aliskirenAppendix 1: Interactions

662 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsAngiotensin-II Receptor Antagonists (continued)Alpha-blockers: enhanced hypotensive effect whenangiotensin-II receptor antagonists given with alphablockersAnaesthetics, General: enhanced hypotensive effectwhen angiotensin-II receptor antagonists given withgeneral anaestheticsAnalgesics: increased risk of renal impairment whenangiotensin-II receptor antagonists given withNSAIDs, also hypotensive effect antagonisedAntibacterials: plasma concentration of losartan andits active metabolite reduced by rifampicin; possibleincreased risk of hyperkalaemia when angiotensin-IIreceptor antagonists given with trimethoprimAnticoagulants: increased risk of hyperkalaemia whenangiotensin-II receptor antagonists given withheparinsAntidepressants: hypotensive effect of angiotensin-IIreceptor antagonists possibly enhanced by MAOIsAntipsychotics: enhanced hypotensive effect whenangiotensin-II receptor antagonists given with antipsychoticsAnxiolytics and Hypnotics: enhanced hypotensiveeffect when angiotensin-II receptor antagonists givenwith anxiolytics and hypnoticsBeta-blockers: enhanced hypotensive effect whenangiotensin-II receptor antagonists given with betablockersCalcium-channel Blockers: enhanced hypotensiveeffect when angiotensin-II receptor antagonists givenwith calcium-channel blockers. Ciclosporin: increased risk of hyperkalaemia whenangiotensin-II receptor antagonists given with.ciclosporinClonidine: enhanced hypotensive effect when angiotensin-IIreceptor antagonists given with clonidineCorticosteroids: hypotensive effect of angiotensin-IIreceptor antagonists antagonised by corticosteroidsDiazoxide: enhanced hypotensive effect when angiotensin-IIreceptor antagonists given with diazoxide. Diuretics: enhanced hypotensive effect when angiotensin-IIreceptor antagonists given with .diuretics;increased risk of hyperkalaemia when angiotensin-IIreceptor antagonists given with .potassium-sparingdiuretics and aldosterone antagonistsDopaminergics: enhanced hypotensive effect whenangiotensin-II receptor antagonists given with levodopa. Lithium: angiotensin-II receptor antagonists reduceexcretion of .lithium (increased plasma concentration)Methyldopa: enhanced hypotensive effect whenangiotensin-II receptor antagonists given withmethyldopaMoxisylyte: enhanced hypotensive effect when angiotensin-IIreceptor antagonists given with moxisylyteMoxonidine: enhanced hypotensive effect whenangiotensin-II receptor antagonists given with moxonidineMuscle Relaxants: enhanced hypotensive effect whenangiotensin-II receptor antagonists given withbaclofen or tizanidineNitrates: enhanced hypotensive effect when angiotensin-IIreceptor antagonists given with nitratesOestrogens: hypotensive effect of angiotensin-IIreceptor antagonists antagonised by oestrogens. Potassium Salts: increased risk of hyperkalaemiawhen angiotensin-II receptor antagonists given with.potassium saltsProstaglandins: enhanced hypotensive effect whenangiotensin-II receptor antagonists given with alprostadilTacrolimus: increased risk of hyperkalaemia whenangiotensin-II receptor antagonists given with tacrolimusVasodilator Antihypertensives: enhanced hypotensiveeffect when angiotensin-II receptor antagonists givenwith hydralazine, minoxidil or sodium nitroprussideAntacidsNote Antacids should preferably not be taken at the sametime as other drugs since they may impair absorptionACE Inhibitors: antacids possibly reduce absorption ofACE inhibitors; antacids reduce absorption ofcaptopril, enalapril and fosinoprilAnalgesics: alkaline urine due to some antacidsincreases excretion of aspirinAntibacterials: antacids reduce absorption of azithromycin,cefaclor, cefpodoxime, ciprofloxacin, isoniazid,levofloxacin, moxifloxacin, norfloxacin,ofloxacin, rifampicin and tetracyclines; avoid concomitantuse of antacids with methenamine; oralmagnesium salts (as magnesium trisilicate) reduceabsorption of nitrofurantoinAntiepileptics: antacids reduce absorption ofgabapentin and phenytoinAntifungals: antacids reduce absorption ofitraconazole and ketoconazoleAntihistamines: antacids reduce absorption of fexofenadineAntimalarials: antacids reduce absorption of chloroquineand hydroxychloroquine; oral magnesium salts(as magnesium trisilicate) reduce absorption of proguanilAntipsychotics: antacids reduce absorption ofphenothiazines and sulpirideAntivirals: antacids possibly reduce plasma concentrationof atazanavir; antacids reduce absorption oftipranavirBile Acids: antacids possibly reduce absorption of bileacidsBisphosphonates: antacids reduce absorption of bisphosphonatesCardiac Glycosides: antacids possibly reduce absorptionof digoxinCorticosteroids: antacids reduce absorption of deflazacort. Cytotoxics: antacids possibly reduce plasma concentrationof .erlotinib—give antacids at least 4 hoursbefore or 2 hours after erlotinibDeferasirox: antacids containing aluminium possiblyreduce absorption of deferasirox (manufacturer ofdeferasirox advises avoid concomitant use)Dipyridamole: antacids possibly reduce absorption ofdipyridamoleEltrombopag: antacids reduce absorption of eltrombopag(give at least 4 hours apart)Iron: oral magnesium salts (as magnesium trisilicate)reduce absorption of oral ironLipid-regulating Drugs: antacids reduce absorption ofrosuvastatinLithium: sodium bicarbonate increases excretion oflithium (reduced plasma concentration)Mycophenolate: antacids reduce absorption of mycophenolatePenicillamine: antacids reduce absorption of penicillaminePolystyrene Sulphonate Resins: risk of intestinalobstruction when aluminium hydroxide given withpolystyrene sulphonate resins; risk of metabolicalkalosis when oral magnesium salts given withpolystyrene sulphonate resinsThyroid Hormones: antacids possibly reduce absorptionof levothyroxineUlcer-healing Drugs: antacids possibly reduceabsorption of lansoprazole. Ulipristal: avoidance of antacids advised by manufacturerof .ulipristal (plasma concentration of ulipristalpossibly reduced)Antazoline see AntihistaminesAnti-arrhythmics see Adenosine, Amiodarone, Disopyramide,Dronedarone, Flecainide, Lidocaine, andPropafenoneAntibacterials see individual drugsAntibiotics (cytotoxic) see Bleomycin, Doxorubicin,Epirubicin, Idarubicin, Mitomycin, and Mitoxantrone

BNFC 2011–2012 Appendix 1: Interactions 663Anticoagulants see Coumarins, Dabigatran etexilate,Heparins, Phenindione, and RivaroxabanAntidepressants see Agomelatine; Antidepressants,SSRI; Antidepressants, Tricyclic; Antidepressants,Tricyclic (related); MAOIs; Mirtazapine; Moclobemide;Reboxetine; St John’s Wort; Tryptophan;VenlafaxineAntidepressants, Noradrenaline Re-uptake Inhibitorssee ReboxetineAntidepressants, SSRIAlcohol: sedative effects possibly increased whenSSRIs given with alcoholAnaesthetics, Local: fluvoxamine inhibits metabolismof ropivacaine—avoid prolonged administration ofropivacaine. Analgesics: increased risk of bleeding when SSRIsgiven with .NSAIDs or .aspirin; fluoxetine, fluvoxamine,paroxetine and sertraline possibly increaseplasma concentration of methadone; increased risk ofCNS toxicity when SSRIs given with .tramadolAnti-arrhythmics: fluoxetine increases plasma concentrationof flecainide; paroxetine possibly inhibitsmetabolism of propafenone (increased risk of toxicity). Anticoagulants: SSRIs possibly enhance anticoagulanteffect of .coumarins. Antidepressants: avoidance of fluvoxamine advised bymanufacturer of .reboxetine; possible increasedserotonergic effects when SSRIs given with duloxetine;fluvoxamine inhibits metabolism of.duloxetine—avoid concomitant use; CNS effects ofSSRIs increased by .MAOIs (risk of serious toxicity);citalopram, escitalopram, fluvoxamine, paroxetine orsertraline should not be started until 2 weeks afterstopping .MAOIs, also MAOIs should not be starteduntil at least 1 week after stopping citalopram,escitalopram, fluvoxamine, paroxetine or sertraline;fluoxetine should not be started until 2 weeks afterstopping .MAOIs, also MAOIs should not be starteduntil at least 5 weeks after stopping fluoxetine;increased risk of CNS toxicity when escitalopramgiven with .moclobemide, preferably avoid concomitantuse; after stopping citalopram, fluvoxamine,paroxetine or sertraline do not start .moclobemidefor at least 1 week; after stopping fluoxetine do notstart .moclobemide for 5 weeks; increased serotonergiceffects when SSRIs given with .St John’swort—avoid concomitant use; fluvoxamine inhibitsmetabolism of .agomelatine (increased plasma concentration);possible increased serotonergic effectswhen fluoxetine or fluvoxamine given with mirtazapine;SSRIs increase plasma concentration of some.tricyclics; CNS toxicity reported when fluoxetinegiven with tryptophan; agitation and nausea mayoccur when SSRIs given with .tryptophan. Antiepileptics: SSRIs antagonise anticonvulsant effectof .antiepileptics (convulsive threshold lowered);fluoxetine and fluvoxamine increase plasma concentrationof .carbamazepine; plasma concentrationof paroxetine reduced by phenobarbital and phenytoin;plasma concentration of sertraline possiblyreduced by phenytoin, also plasma concentration ofphenytoin possibly increased; fluoxetine and fluvoxamineincrease plasma concentration of .phenytoinAntihistamines: antidepressant effect of SSRIs possiblyantagonised by cyproheptadine. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrineAntimuscarinics: paroxetine increases plasma concentrationof darifenacin and procyclidine. Antipsychotics: avoidance of fluoxetine,fluvoxamine or sertraline advised by manufacturer of.droperidol (risk of ventricular arrhythmias); fluoxetineincreases plasma concentration of .clozapine,.haloperidol and risperidone; fluvoxamine possiblyincreases plasma concentration of haloperidol; paroxetineinhibits metabolism of perphenazine (reducedose of perphenazine); fluoxetine and paroxetineAntidepressants, SSRI. Antipsychotics (continued)possibly inhibit metabolism of .aripiprazole(reduce dose of aripiprazole); citalopram possiblyincreases plasma concentration of clozapine(increased risk of toxicity); fluvoxamine,paroxetine and sertraline increase plasma concentrationof .clozapine; fluvoxamine increasesplasma concentration of olanzapine; SSRIs possiblyincrease plasma concentration of .pimozide(increased risk of ventricular arrhythmias—avoidconcomitant use); paroxetine possibly increasesplasma concentration of risperidone (increasedrisk of toxicity). Antivirals: plasma concentration of paroxetine andsertraline possibly reduced by darunavir; plasmaconcentration of SSRIs possibly increased by.ritonavir; plasma concentration of paroxetine possiblyreduced by ritonavir. Anxiolytics and Hypnotics: fluoxetine increasesplasma concentration of alprazolam; fluvoxamineincreases plasma concentration of some benzodiazepines;fluvoxamine increases plasma concentrationof .melatonin—avoid concomitant use; sedativeeffects possibly increased when sertraline given withzolpidemAtomoxetine: possible increased risk of convulsionswhen antidepressants given with atomoxetine;fluoxetine and paroxetine possibly inhibit metabolismof atomoxetineBeta-blockers: citalopram and escitalopram increaseplasma concentration of metoprolol; paroxetinepossibly increases plasma concentration ofmetoprolol (enhanced effect); fluvoxamine increasesplasma concentration of propranololBupropion: plasma concentration of citalopram possiblyincreased by bupropionCalcium-channel Blockers: fluoxetine possibly inhibitsmetabolism of nifedipine (increased plasma concentration). Clopidogrel: fluoxetine and fluvoxamine possiblyreduce antiplatelet effect of .clopidogrel. Dopaminergics: caution with paroxetine advised bymanufacturer of entacapone; fluoxetine should not bestarted until 2 weeks after stopping .rasagiline, alsorasagiline should not be started until at least 5 weeksafter stopping fluoxetine; increased risk of CNStoxicity when SSRIs given with .rasagiline; fluvoxamineshould not be started until 2 weeks afterstopping .rasagiline; increased risk of hypertensionand CNS excitation when fluvoxamine or sertralinegiven with .selegiline (selegiline should not bestarted until 1 week after stopping fluvoxamine orsertraline, avoid fluvoxamine or sertraline for 2 weeksafter stopping selegiline); increased risk of hypertensionand CNS excitation when paroxetine givenwith .selegiline (selegiline should not be started until2 weeks after stopping paroxetine, avoid paroxetinefor 2 weeks after stopping selegiline); increased riskof hypertension and CNS excitation when fluoxetinegiven with .selegiline (selegiline should not bestarted until 5 weeks after stopping fluoxetine, avoidfluoxetine for 2 weeks after stopping selegiline);avoidance of citalopram and escitalopram advised bymanufacturer of selegiline. Hormone Antagonists: fluoxetine and paroxetinepossibly inhibit metabolism of .tamoxifen to activemetabolite (avoid concomitant use). 5HT 1 Agonists: fluvoxamine inhibits the metabolism offrovatriptan; CNS toxicity reported when sertralinegiven with sumatriptan; increased risk of CNS toxicitywhen citalopram, escitalopram, fluoxetine,fluvoxamine or paroxetine given with .sumatriptan;fluvoxamine possibly inhibits metabolism of zolmitriptan(reduce dose of zolmitriptan). Lithium: Increased risk of CNS effects when SSRIsgiven with .lithium (lithium toxicity reported)Appendix 1: Interactions

664 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsAntidepressants, SSRI (continued)Metoclopramide: CNS toxicity reported when SSRIsgiven with metoclopramide. Muscle Relaxants: fluvoxamine increases plasmaconcentration of .tizanidine (increased risk of toxicity)—avoidconcomitant useParasympathomimetics: paroxetine increases plasmaconcentration of galantamineRanolazine: paroxetine increases plasma concentrationof ranolazineRoflumilast: fluvoxamine inhibits the metabolism ofroflumilastSympathomimetics: metabolism of SSRIs possiblyinhibited by methylphenidate. Theophylline: fluvoxamine increases plasma concentrationof .theophylline (concomitant use shouldusually be avoided, but where not possible halvetheophylline dose and monitor plasma-theophyllineconcentration)Ulcer-healing Drugs: plasma concentration of citalopram,escitalopram and sertraline increased bycimetidine; fluvoxamine possibly increases plasmaconcentration of lansoprazole; plasma concentrationof escitalopram increased by omeprazoleAntidepressants, SSRI (related) see Duloxetine andVenlafaxineAntidepressants, TricyclicAdrenergic Neurone Blockers: tricyclics antagonisehypotensive effect of adrenergic neurone blockers. Alcohol: increased sedative effect when tricyclics givenwith .alcoholAlpha 2 -adrenoceptor Stimulants: avoidance of tricyclicsadvised by manufacturer of apraclonidine andbrimonidineAnaesthetics, General: increased risk of arrhythmiasand hypotension when tricyclics given with generalanaesthetics. Analgesics: increased risk of CNS toxicity whentricyclics given with .tramadol; side-effects possiblyincreased when tricyclics given with nefopam;sedative effects possibly increased when tricyclicsgiven with opioid analgesics. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen tricyclics given with .amiodarone—avoid concomitant use; increased risk of ventriculararrhythmias when tricyclics given with.disopyramide or .flecainide; avoidance of tricyclicsadvised by manufacturer of .dronedarone (risk ofventricular arrhythmias); increased risk of arrhythmiaswhen tricyclics given with .propafenone. Antibacterials: increased risk of ventricular arrhythmiaswhen tricyclics given with .moxifloxacin—avoid concomitant use. Anticoagulants: tricyclics may enhance or reduceanticoagulant effect of .coumarins. Antidepressants: possible increased serotonergiceffects when amitriptyline or clomipramine givenwith duloxetine; increased risk of hypertension andCNS excitation when tricyclics given with .MAOIs,tricyclics should not be started until 2 weeks afterstopping MAOIs (3 weeks if starting clomipramine orimipramine), also MAOIs should not be started for atleast 1–2 weeks after stopping tricyclics (3 weeks inthe case of clomipramine or imipramine); afterstopping tricyclics do not start .moclobemide for atleast 1 week; plasma concentration of some tricyclicsincreased by .SSRIs; plasma concentration of amitriptylinereduced by St John’s wort. Antiepileptics: tricyclics antagonise anticonvulsanteffect of .antiepileptics (convulsive thresholdlowered); metabolism of tricyclics accelerated by.carbamazepine (reduced plasma concentration andreduced effect); metabolism of tricyclics possiblyaccelerated by .phenobarbital (reduced plasma concentration);plasma concentration of tricyclics possiblyreduced by .phenytoinAntifungals: plasma concentration of tricyclics possiblyincreased by terbinafineAntidepressants, Tricyclic (continued)Antihistamines: increased antimuscarinic and sedativeeffects when tricyclics given with antihistamines. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrineAntimuscarinics: increased risk of antimuscarinic sideeffectswhen tricyclics given with antimuscarinics. Antipsychotics: plasma concentration of tricyclicsincreased by .antipsychotics—possibly increasedrisk of ventricular arrhythmias; avoidance of tricyclicsadvised by manufacturer of .droperidol (risk ofventricular arrhythmias); possible increased antimuscarinicside-effects when tricyclics given withclozapine; increased risk of antimuscarinic sideeffectswhen tricyclics given with phenothiazines;increased risk of ventricular arrhythmias whentricyclics given with .pimozide—avoid concomitantuse. Antivirals: plasma concentration of tricyclics possiblyincreased by .ritonavir; increased risk of ventriculararrhythmias when tricyclics given with .saquinavir—avoid concomitant useAnxiolytics and Hypnotics: increased sedative effectwhen tricyclics given with anxiolytics and hypnotics. Atomoxetine: increased risk of ventricular arrhythmiaswhen tricyclics given with .atomoxetine; possibleincreased risk of convulsions when antidepressantsgiven with atomoxetine. Beta-blockers: plasma concentration of imipramineincreased by labetalol and propranolol; increased riskof ventricular arrhythmias when tricyclics given with.sotalolBupropion: plasma concentration of tricyclics possiblyincreased by bupropion (possible increased risk ofconvulsions)Calcium-channel Blockers: plasma concentration ofimipramine increased by diltiazem and verapamil;plasma concentration of tricyclics possibly increasedby diltiazem and verapamilCannabis Extract: possible increased risk of hypertensionand tachycardia when tricyclics given withcannabis extract. Clonidine: tricyclics antagonise hypotensive effect of.clonidine, also increased risk of hypertension onclonidine withdrawal. Cytotoxics: increased risk of ventricular arrhythmiaswhen amitriptyline or clomipramine given with.arsenic trioxideDisulfiram: metabolism of tricyclics inhibited bydisulfiram (increased plasma concentration); concomitantamitriptyline reported to increase disulfiramreaction with alcoholDiuretics: increased risk of postural hypotension whentricyclics given with diuretics. Dopaminergics: caution with tricyclics advised bymanufacturer of entacapone; increased risk of CNStoxicity when tricyclics given with .rasagiline; CNStoxicity reported when tricyclics given with.selegilineHistamine: tricyclics theoretically antagonise effects ofhistamine—manufacturer of histamine advises avoidconcomitant useLithium: risk of toxicity when tricyclics given withlithiumMoxonidine: tricyclics possibly antagonise hypotensiveeffect of moxonidine (manufacturer of moxonidineadvises avoid concomitant use)Muscle Relaxants: tricyclics enhance muscle relaxanteffect of baclofenNicorandil: tricyclics possibly enhance hypotensiveeffect of nicorandilNitrates: tricyclics reduce effects of sublingual tabletsof nitrates (failure to dissolve under tongue owing todry mouth)Oestrogens: antidepressant effect of tricyclics antagonisedby oestrogens (but side-effects of tricyclicspossibly increased due to increased plasma concentration)

BNFC 2011–2012 Appendix 1: Interactions 665Antidepressants, Tricyclic (continued). Pentamidine Isetionate: increased risk of ventriculararrhythmias when tricyclics given with .pentamidineisetionateSodium Oxybate: increased risk of side-effects whentricyclics given with sodium oxybate. Sympathomimetics: increased risk of hypertensionand arrhythmias when tricyclics given with .adrenaline(epinephrine) (but local anaesthetics with adrenalineappear to be safe); metabolism of tricyclicspossibly inhibited by methylphenidate; increased riskof hypertension and arrhythmias when tricyclicsgiven with .noradrenaline (norepinephrine)Thyroid Hormones: effects of tricyclics possiblyenhanced by thyroid hormones; effects ofamitriptyline and imipramine enhanced by thyroidhormonesUlcer-healing Drugs: plasma concentration of tricyclicspossibly increased by cimetidine; metabolism ofamitriptyline, doxepin, imipramine and nortriptylineinhibited by cimetidine (increased plasma concentration)Antidepressants, Tricyclic (related). Alcohol: increased sedative effect when tricyclicrelatedantidepressants given with .alcoholAlpha 2 -adrenoceptor Stimulants: avoidance of tricyclic-relatedantidepressants advised by manufacturerof apraclonidine and brimonidineAnticoagulants: trazodone may enhance or reduceanticoagulant effect of warfarin. Antidepressants: tricyclic-related antidepressantsshould not be started until 2 weeks after stopping.MAOIs, also MAOIs should not be started until atleast 1–2 weeks after stopping tricyclic-related antidepressants;after stopping tricyclic-related antidepressantsdo not start .moclobemide for at least 1week. Antiepileptics: tricyclic-related antidepressants possiblyantagonise anticonvulsant effect of .antiepileptics(convulsive threshold lowered); plasma concentrationof mianserin reduced by .carbamazepine and.phenytoin; metabolism of mianserin accelerated by.phenobarbital (reduced plasma concentration)Antihistamines: possible increased antimuscarinic andsedative effects when tricyclic-related antidepressantsgiven with antihistamines. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrineAntimuscarinics: possible increased antimuscarinicside-effects when tricyclic-related antidepressantsgiven with antimuscarinics. Antivirals: plasma concentration of trazodoneincreased by .ritonavir (increased risk of toxicity);increased risk of ventricular arrhythmias whentrazodone given with .saquinavir—avoid concomitantuseAnxiolytics and Hypnotics: increased sedative effectwhen tricyclic-related antidepressants given withanxiolytics and hypnoticsAtomoxetine: possible increased risk of convulsionswhen antidepressants given with atomoxetineDiazoxide: enhanced hypotensive effect when tricyclicrelatedantidepressants given with diazoxideNitrates: tricyclic-related antidepressants possiblyreduce effects of sublingual tablets of nitrates (failureto dissolve under tongue owing to dry mouth)Vasodilator Antihypertensives: enhanced hypotensiveeffect when tricyclic-related antidepressants givenwith hydralazine or sodium nitroprussideAntidiabeticsNote Other oral drugs may be taken at least 1 hour before or4 hours after exenatide injection, or taken with a meal whenexenatide is not administered, to minimise possible interferencewith absorptionACE Inhibitors: hypoglycaemic effect of insulin,metformin and sulfonylureas possibly enhanced byACE inhibitorsAntidiabetics (continued)Alcohol: hypoglycaemic effect of antidiabeticsenhanced by alcohol; increased risk of lactic acidosiswhen metformin given with alcoholAnabolic Steroids: hypoglycaemic effect of antidiabeticspossibly enhanced by anabolic steroids. Analgesics: effects of sulfonylureas possibly enhancedby .NSAIDsAnti-arrhythmics: hypoglycaemic effect of gliclazide,insulin and metformin possibly enhanced by disopyramide. Antibacterials: hypoglycaemic effect of acarbose possiblyenhanced by neomycin, also severity of gastrointestinaleffects increased; effects of repaglinideenhanced by clarithromycin; effects of glibenclamidepossibly enhanced by norfloxacin; plasma concentrationof nateglinide reduced by rifampicin; hypoglycaemiceffect of repaglinide possibly antagonisedby rifampicin; effects of sulfonylureas enhanced by.chloramphenicol; metabolism of tolbutamide acceleratedby .rifamycins (reduced effect); metabolism ofsulfonylureas possibly accelerated by .rifamycins(reduced effect); effects of sulfonylureas rarelyenhanced by sulfonamides and trimethoprim; hypoglycaemiceffect of sulfonylureas possibly enhancedby tetracyclines; hypoglycaemic effect of repaglinidepossibly enhanced by trimethoprim—manufactureradvises avoid concomitant use. Anticoagulants: exenatide possibly enhances anticoagulanteffect of warfarin; hypoglycaemic effect ofsulfonylureas possibly enhanced by .coumarins, alsopossible changes to anticoagulant effectAntidepressants: hypoglycaemic effect of antidiabeticspossibly enhanced by MAOIs; hypoglycaemic effectof insulin, metformin and sulfonylureas enhanced byMAOIsAntiepileptics: tolbutamide transiently increasesplasma concentration of phenytoin (possibility oftoxicity); plasma concentration of glibenclamidepossibly reduced by topiramate; plasma concentrationof metformin possibly increased by topiramate. Antifungals: plasma concentration of sulfonylureasincreased by .fluconazole and .miconazole; hypoglycaemiceffect of gliclazide and glipizide enhancedby .miconazole—avoid concomitant use; hypoglycaemiceffect of nateglinide possibly enhanced byfluconazole; hypoglycaemic effect of repaglinidepossibly enhanced by itraconazole; hypoglycaemiceffect of glipizide possibly enhanced by posaconazole;plasma concentration of sulfonylureas possiblyincreased by voriconazoleAntihistamines: thrombocyte count depressed whenmetformin given with ketotifen (manufacturer ofketotifen advises avoid concomitant use)Antipsychotics: hypoglycaemic effect of sulfonylureaspossibly antagonised by phenothiazinesAntivirals: plasma concentration of tolbutamide possiblyincreased by ritonavirAprepitant: plasma concentration of tolbutamidereduced by aprepitantBeta-blockers: warning signs of hypoglycaemia (suchas tremor) with antidiabetics may be masked whengiven with beta-blockers; hypoglycaemic effect ofinsulin enhanced by beta-blockers. Bosentan: increased risk of hepatotoxicity whenglibenclamide given with .bosentan—avoid concomitantuseCalcium-channel Blockers: glucose tolerance occasionallyimpaired when insulin given with nifedipineCardiac Glycosides: acarbose possibly reduces plasmaconcentration of digoxin; sitagliptin increases plasmaconcentration of digoxinCiclosporin: hypoglycaemic effect of repaglinide possiblyenhanced by ciclosporinCorticosteroids: hypoglycaemic effect of antidiabeticsantagonised by corticosteroids. Cytotoxics: avoidance of repaglinide advised by manufacturerof .lapatinibAppendix 1: Interactions

666 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsAntidiabetics (continued)Deferasirox: plasma concentration of repaglinideincreased by deferasiroxDiazoxide: hypoglycaemic effect of antidiabeticsantagonised by diazoxideDiuretics: hypoglycaemic effect of antidiabetics antagonisedby loop diuretics and thiazides and relateddiureticsHormone Antagonists: requirements for insulin, metformin,repaglinide and sulfonylureas possiblyreduced by lanreotide; requirements for insulin,metformin, repaglinide and sulfonylureas possiblyreduced by octreotideLeflunomide: hypoglycaemic effect of tolbutamidepossibly enhanced by leflunomide. Lipid-regulating Drugs: absorption of glibenclamidereduced by colesevelam; hypoglycaemic effect ofacarbose possibly enhanced by colestyramine;hypoglycaemic effect of nateglinide possiblyenhanced by gemfibrozil; increased risk of severehypoglycaemia when repaglinide given with.gemfibrozil—avoid concomitant use; plasma concentrationof glibenclamide possibly increased byfluvastatin; may be improved glucose tolerance andan additive effect when insulin or sulfonylureas givenwith fibratesOestrogens: hypoglycaemic effect of antidiabeticsantagonised by oestrogensOrlistat: avoidance of acarbose advised by manufacturerof orlistatPancreatin: hypoglycaemic effect of acarbose antagonisedby pancreatinProgestogens: hypoglycaemic effect of antidiabeticsantagonised by progestogens. Sulfinpyrazone: effects of sulfonylureas enhanced by.sulfinpyrazoneTestosterone: hypoglycaemic effect of antidiabeticspossibly enhanced by testosteroneUlcer-healing Drugs: excretion of metformin reducedby cimetidine (increased plasma concentration);hypoglycaemic effect of sulfonylureas enhanced bycimetidineAntiepileptics see Carbamazepine, Eslicarbazepine,Ethosuximide, Gabapentin, Lacosamide, Lamotrigine,Levetiracetam, Oxcarbazepine, Phenobarbital,Phenytoin, Rufinamide, Stiripentol, Tiagabine,Topiramate, Valproate, Vigabatrin, and ZonisamideAntifungals see Amphotericin; Antifungals, Imidazole;Antifungals, Triazole; Caspofungin; Flucytosine;Griseofulvin; Micafungin; TerbinafineAntifungals, ImidazoleAliskiren: ketoconazole increases plasma concentrationof aliskirenAlpha-blockers: ketoconazole possibly increasesplasma concentration of alfuzosin. Analgesics: ketoconazole inhibits metabolism of.buprenorphine (reduce dose of buprenorphine)Antacids: absorption of ketoconazole reduced byantacids. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen ketoconazole given with.disopyramide—avoid concomitant use; ketoconazoleincreases plasma concentration of.dronedarone—avoid concomitant use. Antibacterials: metabolism of ketoconazole acceleratedby .rifampicin (reduced plasma concentration),also plasma concentration of rifampicin may bereduced by ketoconazole; plasma concentration ofketoconazole possibly reduced by isoniazid; avoidanceof concomitant ketoconazole in severe renaland hepatic impairment advised by manufacturer of.telithromycin. Anticoagulants: ketoconazole enhances anticoagulanteffect of .coumarins; miconazole enhances anticoagulanteffect of .coumarins (miconazole oral geland possibly vaginal formulations absorbed); ketoconazoleincreases plasma concentration of.rivaroxaban—avoid concomitant useAntifungals, Imidazole (continued). Antidepressants: avoidance of imidazoles advised bymanufacturer of .reboxetine; ketoconazole increasesplasma concentration of mirtazapine. Antidiabetics: miconazole enhances hypoglycaemiceffect of .gliclazide and .glipizide—avoid concomitantuse; miconazole increases plasma concentrationof .sulfonylureas. Antiepileptics: ketoconazole and miconazole possiblyincrease plasma concentration of carbamazepine;plasma concentration of ketoconazole reduced by.phenytoin; miconazole enhances anticonvulsanteffect of .phenytoin (plasma concentration ofphenytoin increased)Antifungals: imidazoles possibly antagonise effects ofamphotericin. Antihistamines: manufacturer of loratadine advisesketoconazole possibly increases plasma concentrationof loratadine; imidazoles possibly inhibit metabolismof .mizolastine (avoid concomitant use);ketoconazole inhibits metabolism of .mizolastine—avoid concomitant use; ketoconazole increasesplasma concentration of rupatadine. Antimalarials: avoidance of imidazoles advised bymanufacturer of .artemether/lumefantrine; ketoconazoleincreases plasma concentration of mefloquineAntimuscarinics: absorption of ketoconazole reducedby antimuscarinics; ketoconazole increases plasmaconcentration of darifenacin—avoid concomitantuse; manufacturer of fesoterodine advises dosereduction when ketoconazole given with fesoterodine—consultfesoterodine product literature; ketoconazoleincreases plasma concentration ofsolifenacin; avoidance of ketoconazole advised bymanufacturer of tolterodine. Antipsychotics: ketoconazole inhibits metabolism of.aripiprazole (reduce dose of aripiprazole); increasedrisk of ventricular arrhythmias when imidazoles givenwith .pimozide—avoid concomitant use; imidazolespossibly increase plasma concentration of quetiapine(reduce dose of quetiapine). Antivirals: plasma concentration of both drugsincreased when ketoconazole given with darunavir;plasma concentration of ketoconazole increased byfosamprenavir (also plasma concentration of fosamprenavirpossibly increased); ketoconazole increasesplasma concentration of .indinavir and .maraviroc(consider reducing dose of indinavir and maraviroc);plasma concentration of ketoconazole reduced by.nevirapine—avoid concomitant use; combination ofketoconazole with .ritonavir may increase plasmaconcentration of either drug (or both); imidazolespossibly increase plasma concentration of saquinavir;ketoconazole increases plasma concentration ofsaquinavir. Anxiolytics and Hypnotics: ketoconazole increasesplasma concentration of alprazolam; ketoconazoleincreases plasma concentration of .midazolam (riskof prolonged sedation)Aprepitant: ketoconazole increases plasma concentrationof aprepitantBosentan: ketoconazole increases plasma concentrationof bosentan. Calcium-channel Blockers: ketoconazole inhibitsmetabolism of .felodipine (increased plasma concentration);avoidance of ketoconazole advised bymanufacturer of lercanidipine; ketoconazole possiblyinhibits metabolism of dihydropyridines (increasedplasma concentration). Ciclosporin: ketoconazole inhibits metabolism of.ciclosporin (increased plasma concentration);miconazole possibly inhibits metabolism of.ciclosporin (increased plasma concentration)Cilostazol: ketoconazole increases plasma concentrationof cilostazol (consider reducing dose of cilostazol)Cinacalcet: ketoconazole inhibits metabolism of cinacalcet(increased plasma concentration)

BNFC 2011–2012 Appendix 1: Interactions 667Antifungals, Imidazole (continued). Clopidogrel: ketoconazole possibly reduces antiplateleteffect of .clopidogrel. Colchicine: ketoconazole possibly increases risk of.colchicine toxicity—suspend or reduce dose ofcolchicine (avoid concomitant use in hepatic or renalimpairment)Corticosteroids: ketoconazole possibly inhibits metabolismof corticosteroids; ketoconazole increasesplasma concentration of inhaled and oral budesonide;ketoconazole increases plasma concentration ofactive metabolite of ciclesonide; ketoconazole inhibitsthe metabolism of methylprednisolone; ketoconazoleincreases plasma concentration of inhaledmometasone. Cytotoxics: ketoconazole possibly increases plasmaconcentration of dasatinib; ketoconazole inhibitsmetabolism of erlotinib and sunitinib (increasedplasma concentration); ketoconazole increasesplasma concentration of .everolimus, .lapatinib and.nilotinib—avoid concomitant use; ketoconazoleincreases plasma concentration of bortezomib andimatinib; avoidance of ketoconazole advised bymanufacturer of .pazopanib; ketoconazole increasesplasma concentration of active metabolite of.temsirolimus—avoid concomitant use; in vitrostudies suggest a possible interaction between ketoconazoleand docetaxel (consult docetaxel productliterature); ketoconazole reduces plasma concentrationof .irinotecan (but concentration of activemetabolite of irinotecan increased)—avoid concomitantuse; ketoconazole increases plasma concentrationof .vinflunine—manufacturer of vinflunineadvises avoid concomitant use. Diuretics: ketoconazole increases plasma concentrationof .eplerenone—avoid concomitant use. Domperidone: ketoconazole possibly increases risk ofarrhythmias with .domperidone. Ergot Alkaloids: increased risk of ergotism whenimidazoles given with .ergotamine and methysergide—avoidconcomitant use. 5HT 1 Agonists: ketoconazole increases plasma concentrationof almotriptan (increased risk of toxicity);ketoconazole increases plasma concentration of.eletriptan (risk of toxicity)—avoid concomitant use. Ivabradine: ketoconazole increases plasma concentrationof .ivabradine—avoid concomitant useLanthanum: absorption of ketoconazole possiblyreduced by lanthanum (give at least 2 hours apart). Lipid-regulating Drugs: possible increased risk ofmyopathy when imidazoles given with atorvastatin;increased risk of myopathy when ketoconazole givenwith .simvastatin (avoid concomitant use); possibleincreased risk of myopathy when miconazole givenwith .simvastatin—avoid concomitant useOestrogens: anecdotal reports of contraceptive failurewhen imidazoles given with oestrogensParasympathomimetics: ketoconazole increasesplasma concentration of galantamine. Ranolazine: ketoconazole increases plasma concentrationof .ranolazine—avoid concomitant useRetinoids: ketoconazole increases plasma concentrationof alitretinoinSildenafil: ketoconazole increases plasma concentrationof sildenafil—reduce initial dose of sildenafil. Sirolimus: ketoconazole increases plasma concentrationof .sirolimus—avoid concomitant use; miconazoleincreases plasma concentration of .sirolimusSympathomimetics, Beta 2 : ketoconazole inhibitsmetabolism of salmeterol (increased plasma concentration). Tacrolimus: imidazoles possibly increase plasma concentrationof .tacrolimus; ketoconazole increasesplasma concentration of .tacrolimus (consider reducingdose of tacrolimus). Tadalafil: ketoconazole increases plasma concentrationof .tadalafil—manufacturer of tadalafil advises avoidconcomitant useAntifungals, Imidazole (continued). Theophylline: ketoconazole possibly increases plasmaconcentration of .theophyllineTolvaptan: ketoconazole increases plasma concentrationof tolvaptanUlcer-healing Drugs: absorption of ketoconazolereduced by histamine H 2 -antagonists, proton pumpinhibitors and sucralfate. Vardenafil: ketoconazole increases plasma concentrationof .vardenafil—avoid concomitant useVitamins: ketoconazole possibly increases plasmaconcentration of paricalcitolAntifungals, Polyene see AmphotericinAntifungals, TriazoleNote In general, fluconazole interactions relate to multipledosetreatment. Analgesics: fluconazole increases plasma concentrationof celecoxib (halve dose of celecoxib); voriconazoleincreases plasma concentration of diclofenac,ibuprofen and .oxycodone; fluconazole increasesplasma concentration of flurbiprofen and ibuprofen;fluconazole increases plasma concentration of parecoxib(reduce dose of parecoxib); voriconazoleincreases plasma concentration of .alfentanil and.methadone (consider reducing dose ofalfentanil and methadone); fluconazole inhibitsmetabolism of alfentanil (risk of prolonged or delayedrespiratory depression); itraconazole possibly inhibitsmetabolism of alfentanil; triazoles possibly increaseplasma concentration of .fentanylAntacids: absorption of itraconazole reduced byantacids. Anti-arrhythmics: manufacturer of itraconazole advisesavoid concomitant use with .disopyramide; avoidanceof itraconazole, posaconazole and voriconazoleadvised by manufacturer of .dronedarone. Antibacterials: plasma concentration of itraconazoleincreased by clarithromycin; triazoles possiblyincrease plasma concentration of .rifabutin(increased risk of uveitis—reduce rifabutin dose);posaconazole increases plasma concentration of.rifabutin (also plasma concentration of posaconazolereduced); voriconazole increases plasma concentrationof .rifabutin, also rifabutin reduces plasmaconcentration of voriconazole (increase dose ofvoriconazole and also monitor for rifabutin toxicity);fluconazole increases plasma concentration of.rifabutin (increased risk of uveitis—reduce rifabutindose); plasma concentration of itraconazole reducedby .rifabutin and .rifampicin—manufacturer of itraconazoleadvises avoid concomitant use; plasmaconcentration of posaconazole reduced by.rifampicin; plasma concentration of voriconazolereduced by .rifampicin—avoid concomitant use;metabolism of fluconazole accelerated by .rifampicin(reduced plasma concentration). Anticoagulants: fluconazole, itraconazole and voriconazoleenhance anticoagulant effect of .coumarins;avoidance of itraconazole, posaconazole and voriconazoleadvised by manufacturer of rivaroxaban. Antidepressants: avoidance of triazoles advised bymanufacturer of .reboxetine; plasma concentrationof voriconazole reduced by .St John’s wort—avoidconcomitant use. Antidiabetics: posaconazole possibly enhances hypoglycaemiceffect of glipizide; fluconazole possiblyenhances hypoglycaemic effect of nateglinide; itraconazolepossibly enhances hypoglycaemic effect ofrepaglinide; fluconazole increases plasma concentrationof .sulfonylureas; voriconazole possiblyincreases plasma concentration of sulfonylureas. Antiepileptics: fluconazole possibly increases plasmaconcentration of carbamazepine; plasma concentrationof voriconazole possibly reduced by.carbamazepine and .phenobarbital—avoid concomitantuse; plasma concentration of itraconazole andposaconazole possibly reduced by .carbamazepine;plasma concentration of itraconazole and posaconazolepossibly reduced by .phenobarbital; fluconazoleAppendix 1: Interactions

668 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsAntifungals, Triazole. Antiepileptics (continued)increases plasma concentration of .phenytoin(consider reducing dose of phenytoin); voriconazoleincreases plasma concentration of.phenytoin, also phenytoin reduces plasma concentrationof voriconazole (increase dose ofvoriconazole and also monitor for phenytointoxicity); plasma concentration of posaconazolereduced by .phenytoin; plasma concentration ofitraconazole reduced by .phenytoin—avoid concomitantuseAntifungals: triazoles possibly antagonise effects ofamphotericin; plasma concentration of itraconazoleincreased by micafungin (consider reducing dose ofitraconazole). Antihistamines: itraconazole inhibits metabolism of.mizolastine—avoid concomitant use. Antimalarials: avoidance of triazoles advised bymanufacturer of .artemether/lumefantrineAntimuscarinics: avoidance of itraconazole advised bymanufacturer of darifenacin and tolterodine; manufacturerof fesoterodine advises dose reduction whenitraconazole given with fesoterodine—consult fesoterodineproduct literature; itraconazole increasesplasma concentration of solifenacin. Antipsychotics: itraconazole possibly increases plasmaconcentration of haloperidol; itraconazole possiblyinhibits metabolism of .aripiprazole (reduce dose ofaripiprazole); increased risk of ventricular arrhythmiaswhen triazoles given with .pimozide—avoidconcomitant use; triazoles possibly increase plasmaconcentration of quetiapine (reduce dose of quetiapine). Antivirals: posaconazole increases plasma concentrationof .atazanavir; plasma concentration ofitraconazole and posaconazole reduced by.efavirenz; plasma concentration of voriconazolereduced by .efavirenz, also plasma concentration ofefavirenz increased (increase voriconazole dose andreduce efavirenz dose); plasma concentration of bothdrugs may increase when itraconazole given withfosamprenavir; itraconazole increases plasma concentrationof .indinavir (consider reducing dose ofindinavir); plasma concentration of itraconazolepossibly reduced by nevirapine—consider increasingdose of itraconazole; fluconazole increases plasmaconcentration of .nevirapine, ritonavir and tipranavir;combination of itraconazole with .ritonavir mayincrease plasma concentration of either drug (orboth); plasma concentration of voriconazole reducedby .ritonavir—avoid concomitant use; triazolespossibly increase plasma concentration of saquinavir;fluconazole increases plasma concentration of.zidovudine (increased risk of toxicity). Anxiolytics and Hypnotics: itraconazole increasesplasma concentration of alprazolam; posaconazoleincreases plasma concentration of .midazolam;fluconazole and itraconazole increase plasma concentrationof .midazolam (risk of prolonged sedation);itraconazole increases plasma concentration ofbuspirone (reduce dose of buspirone). Bosentan: fluconazole possibly increases plasma concentrationof .bosentan—avoid concomitant use;itraconazole possibly increases plasma concentrationof bosentan. Calcium-channel Blockers: negative inotropic effectpossibly increased when itraconazole given withcalcium-channel blockers; itraconazole inhibitsmetabolism of .felodipine (increased plasma concentration);avoidance of itraconazole advised bymanufacturer of lercanidipine; itraconazole possiblyinhibits metabolism of dihydropyridines (increasedplasma concentration). Cardiac Glycosides: itraconazole increases plasmaconcentration of .digoxinAntifungals, Triazole (continued). Ciclosporin: fluconazole, itraconazole,posaconazole and voriconazole inhibit metabolism of.ciclosporin (increased plasma concentration). Clopidogrel: fluconazole, itraconazole and voriconazolepossibly reduce antiplatelet effect of.clopidogrel. Colchicine: itraconazole possibly increases risk of.colchicine toxicity—suspend or reduce dose ofcolchicine (avoid concomitant use in hepatic or renalimpairment)Corticosteroids: itraconazole possibly inhibits metabolismof corticosteroids and methylprednisolone;itraconazole increases plasma concentration ofinhaled budesonide. Cytotoxics: itraconazole inhibits metabolism of busulfan(increased risk of toxicity); itraconazole possiblyincreases side-effects of cyclophosphamide; itraconazole,posaconazole and voriconazole possiblyincrease plasma concentration of .everolimus—manufacturer of everolimus advises avoid concomitantuse; itraconazole increases plasma concentrationof gefitinib; avoidance of itraconazole,posaconazole and voriconazole advised by manufacturerof .lapatinib; avoidance of itraconazole andvoriconazole advised by manufacturer of .nilotinib;avoidance of itraconazole and voriconazole advisedby manufacturer of .pazopanib; posaconazole possiblyinhibits metabolism of .vinblastine and.vincristine (increased risk of neurotoxicity); itraconazolepossibly inhibits metabolism of.vincristine and .vinorelbine (increased risk ofneurotoxicity); itraconazole possibly increasesplasma concentration of .vinflunine—manufacturerof vinflunine advises avoid concomitant use. Diuretics: fluconazole increases plasma concentrationof eplerenone (reduce dose of eplerenone); itraconazoleincreases plasma concentration of.eplerenone—avoid concomitant use; plasma concentrationof fluconazole increased by hydrochlorothiazide. Ergot Alkaloids: increased risk of ergotism whentriazoles given with .ergotamine and methysergide—avoid concomitant use. 5HT 1 Agonists: itraconazole increases plasma concentrationof .eletriptan (risk of toxicity)—avoid concomitantuse. Ivabradine: fluconazole increases plasma concentrationof ivabradine—reduce initial dose of ivabradine;itraconazole possibly increases plasma concentrationof .ivabradine—avoid concomitant use. Lipid-regulating Drugs: possible increased risk ofmyopathy when triazoles given with atorvastatin;increased risk of myopathy when itraconazole orposaconazole given with .atorvastatin (avoid concomitantuse); fluconazole increases plasma concentrationof fluvastatin; increased risk of myopathywhen itraconazole or posaconazole given with.simvastatin (avoid concomitant use); possibleincreased risk of myopathy when voriconazole givenwith simvastatin; possible increased risk of myopathywhen fluconazole given with .simvastatin—avoidconcomitant useOestrogens: plasma concentration of voriconazoleincreased by oestrogensProgestogens: plasma concentration of voriconazolepossibly increased by progestogens. Ranolazine: itraconazole, posaconazole and voriconazolepossibly increase plasma concentration of.ranolazine—manufacturer of ranolazine advisesavoid concomitant useSildenafil: itraconazole increases plasma concentrationof sildenafil—reduce initial dose of sildenafil. Sirolimus: posaconazole possibly increases plasmaconcentration of sirolimus; itraconazole and voriconazoleincrease plasma concentration of .sirolimus—avoid concomitant use. Tacrolimus: fluconazole, itraconazole,posaconazole and voriconazole increase plasma

BNFC 2011–2012 Appendix 1: Interactions 669Antifungals, Triazole. Tacrolimus (continued)concentration of .tacrolimus (consider reducingdose of tacrolimus)Tadalafil: itraconazole possibly increases plasma concentrationof tadalafil. Theophylline: fluconazole possibly increases plasmaconcentration of .theophylline. Ulcer-healing Drugs: plasma concentration of posaconazolereduced by .cimetidine; voriconazole possiblyincreases plasma concentration of esomeprazole;voriconazole increases plasma concentration ofomeprazole (consider reducing dose of omeprazole);absorption of itraconazole reduced by histamine H 2 -antagonists and proton pump inhibitors; manufacturerof posaconazole advises avoid concomitant usewith histamine H 2 -antagonists and proton pumpinhibitors (plasma concentration of posaconazolepossibly reduced). Vardenafil: itraconazole possibly increases plasmaconcentration of .vardenafil—avoid concomitant useAntihistaminesNote Sedative interactions apply to a lesser extent to thenon-sedating antihistamines. Interactions do not generallyapply to antihistamines used for topical action (includinginhalation)Alcohol: increased sedative effect when antihistaminesgiven with alcohol (possibly less effect with nonsedatingantihistamines). Analgesics: sedative effects possibly increased whensedating antihistamines given with .opioid analgesicsAntacids: absorption of fexofenadine reduced byantacids. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen mizolastine given with .amiodarone,.disopyramide, .flecainide or .propafenone—avoidconcomitant use. Antibacterials: plasma concentration of rupatadineincreased by erythromycin; manufacturer of loratadineadvises plasma concentration possiblyincreased by erythromycin; metabolism of mizolastineinhibited by .erythromycin—avoid concomitantuse; increased risk of ventricular arrhythmias whenmizolastine given with .moxifloxacin—avoid concomitantuse; effects of fexofenadine possibly reducedby rifampicin; metabolism of mizolastine possiblyinhibited by .macrolides (avoid concomitant use)Antidepressants: increased antimuscarinic and sedativeeffects when antihistamines given with MAOIs ortricyclics; manufacturer of promethazine advisesavoid for 2 weeks after stopping MAOIs; cyproheptadinepossibly antagonises antidepressant effectof SSRIs; possible increased antimuscarinic andsedative effects when antihistamines given withtricyclic-related antidepressantsAntidiabetics: thrombocyte count depressed whenketotifen given with metformin (manufacturer ofketotifen advises avoid concomitant use). Antifungals: plasma concentration of rupatadineincreased by ketoconazole; manufacturer of loratadineadvises plasma concentration possiblyincreased by ketoconazole; metabolism of mizolastineinhibited by .itraconazole or .ketoconazole—avoid concomitant use; metabolism of mizolastinepossibly inhibited by .imidazoles (avoid concomitantuse)Antimuscarinics: increased risk of antimuscarinic sideeffectswhen antihistamines given with antimuscarinics. Antivirals: plasma concentration of chlorphenaminepossibly increased by lopinavir; plasma concentrationof non-sedating antihistamines possibly increased byritonavir; increased risk of ventricular arrhythmiaswhen mizolastine given with .saquinavir—avoidconcomitant useAnxiolytics and Hypnotics: increased sedative effectwhen antihistamines given with anxiolytics andhypnoticsAntihistamines (continued). Beta-blockers: increased risk of ventricular arrhythmiaswhen mizolastine given with .sotalol—avoidconcomitant useBetahistine: antihistamines theoretically antagoniseeffect of betahistine. Grapefruit Juice: plasma concentration of rupatadineincreased by .grapefruit juice—avoid concomitantuseHistamine: antihistamines theoretically antagoniseeffects of histamine—manufacturer of histamineadvises avoid concomitant useUlcer-healing Drugs: manufacturer of loratadineadvises plasma concentration possibly increased bycimetidineAntihistamines, Non-sedating see AntihistaminesAntihistamines, Sedating see AntihistaminesAntimalarials see Artemether with Lumefantrine,Chloroquine and Hydroxychloroquine, Mefloquine,Primaquine, Proguanil, Pyrimethamine, and QuinineAntimetabolites see Cytarabine, Fludarabine, Fluorouracil,Gemcitabine, Mercaptopurine, Methotrexate,Pemetrexed, Raltitrexed, and TioguanineAntimuscarinicsNote Many drugs have antimuscarinic effects; concomitantuse of two or more such drugs can increase side-effects suchas dry mouth, urine retention, and constipation; concomitantuse can also lead to confusion in the elderly. Interactions donot generally apply to antimuscarinics used by inhalationAlcohol: increased sedative effect when hyoscine givenwith alcoholAnalgesics: possible increased risk of antimuscarinicside-effects when antimuscarinics given withcodeine; increased risk of antimuscarinic side-effectswhen antimuscarinics given with nefopam. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen tolterodine given with .amiodarone,.disopyramide or .flecainide; increased risk of antimuscarinicside-effects when antimuscarinics givenwith disopyramideAntibacterials: manufacturer of fesoterodine advisesdose reduction when fesoterodine given withclarithromycin and telithromycin—consult fesoterodineproduct literature; manufacturer of tolterodineadvises avoid concomitant use withclarithromycin and erythromycin; plasma concentrationof darifenacin possibly increased by erythromycin;plasma concentration of active metabolite offesoterodine reduced by rifampicinAntidepressants: plasma concentration ofdarifenacin and procyclidine increased by paroxetine;increased risk of antimuscarinic side-effects whenantimuscarinics given with MAOIs or tricyclics;possible increased antimuscarinic side-effects whenantimuscarinics given with tricyclic-related antidepressantsAntifungals: antimuscarinics reduce absorption ofketoconazole; manufacturer of fesoterodine advisesdose reduction when fesoterodine given withitraconazole and ketoconazole—consult fesoterodineproduct literature; plasma concentration of darifenacinincreased by ketoconazole—avoid concomitantuse; plasma concentration of solifenacin increased byitraconazole and ketoconazole; manufacturer oftolterodine advises avoid concomitant use withitraconazole and ketoconazole; manufacturer ofdarifenacin advises avoid concomitant use withitraconazoleAntihistamines: increased risk of antimuscarinic sideeffectswhen antimuscarinics given with antihistaminesAntipsychotics: antimuscarinics possibly reduceeffects of haloperidol; increased risk of antimuscarinicside-effects when antimuscarinics givenwith clozapine; antimuscarinics reduce plasma concentrationof phenothiazines, but risk of antimuscarinicside-effects increasedAntivirals: manufacturer of darifenacin advises avoidconcomitant use with atazanavir, fosamprenavir,Appendix 1: Interactions

670 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsAntimuscarinicsAntivirals (continued)indinavir, lopinavir, nelfinavir, ritonavir,saquinavir and tipranavir; manufacturer of fesoterodineadvises dose reduction when fesoterodinegiven with atazanavir, indinavir, nelfinavir,ritonavir and saquinavir—consult fesoterodineproduct literature; manufacturer of tolterodineadvises avoid concomitant use with fosamprenavir,indinavir, lopinavir, nelfinavir, ritonavir andsaquinavir; plasma concentration of solifenacinincreased by nelfinavir and ritonavir. Beta-blockers: increased risk of ventricular arrhythmiaswhen tolterodine given with .sotalolCalcium-channel Blockers: manufacturer of darifenacinadvises avoid concomitant use with verapamilCardiac Glycosides: darifenacin possibly increasesplasma concentration of digoxinCiclosporin: manufacturer of darifenacin advises avoidconcomitant use with ciclosporinDomperidone: antimuscarinics antagonise effects ofdomperidone on gastro-intestinal activityDopaminergics: antimuscarinics possibly reduceabsorption of levodopaMemantine: effects of antimuscarinics possiblyenhanced by memantineMetoclopramide: antimuscarinics antagonise effects ofmetoclopramide on gastro-intestinal activityNitrates: antimuscarinics possibly reduce effects ofsublingual tablets of nitrates (failure to dissolve undertongue owing to dry mouth)Parasympathomimetics: antimuscarinics antagoniseeffects of parasympathomimeticsAntipsychoticsNote Increased risk of toxicity with myelosuppressive drugsNote Avoid concomitant use of clozapine with drugs thathave a substantial potential for causing agranulocytosisACE Inhibitors: enhanced hypotensive effect whenantipsychotics given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when phenothiazines given with adrenergicneurone blockers; higher doses of chlorpromazineantagonise hypotensive effect of adrenergic neuroneblockers; haloperidol antagonises hypotensive effectof adrenergic neurone blockersAdsorbents: absorption of phenothiazines possiblyreduced by kaolinAlcohol: increased sedative effect when antipsychoticsgiven with alcoholAlpha-blockers: enhanced hypotensive effect whenantipsychotics given with alpha-blockers. Anaesthetics, General: droperidol enhances effects ofthiopental; enhanced hypotensive effect when antipsychoticsgiven with .general anaesthetics. Analgesics: possible severe drowsiness when haloperidolgiven with indometacin; increased risk ofventricular arrhythmias when antipsychotics thatprolong the QT interval given with .methadone;increased risk of ventricular arrhythmias whenamisulpride given with .methadone—avoid concomitantuse; increased risk of convulsions whenantipsychotics given with tramadol; enhanced hypotensiveand sedative effects when antipsychoticsgiven with opioid analgesicsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when antipsychotics given withangiotensin-II receptor antagonistsAntacids: absorption of phenothiazines and sulpiridereduced by antacids. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen antipsychotics that prolong the QTinterval given with .anti-arrhythmics that prolong theQT interval; increased risk of ventricular arrhythmiaswhen amisulpride, droperidol, haloperidol, phenothiazines,pimozide or zuclopenthixol given with.amiodarone—avoid concomitant use; increased riskof ventricular arrhythmias when benperidol givenwith .amiodarone—manufacturer of benperidolAntipsychotics. Anti-arrhythmics (continued)advises avoid concomitant use; increased risk ofventricular arrhythmias when sulpiride given with.amiodarone or .disopyramide; increased risk ofventricular arrhythmias when amisulpride, droperidol,pimozide or zuclopenthixol given with.disopyramide—avoid concomitant use; possibleincreased risk of ventricular arrhythmias whenhaloperidol given with .disopyramide—avoidconcomitant use; increased risk of ventriculararrhythmias when phenothiazines given with.disopyramide; avoidance of phenothiazinesadvised by manufacturer of .dronedarone (risk ofventricular arrhythmias); increased risk of arrhythmiaswhen clozapine given with .flecainide. Antibacterials: increased risk of ventricular arrhythmiaswhen pimozide given with .clarithromycin,.moxifloxacin or .telithromycin—avoid concomitantuse; increased risk of ventricular arrhythmias whenamisulpride given with .erythromycin—avoid concomitantuse; plasma concentration of clozapinepossibly increased by .erythromycin (possibleincreased risk of convulsions); possible increased riskof ventricular arrhythmias when pimozide given with.erythromycin—avoid concomitant use; increasedrisk of ventricular arrhythmias when sulpiride givenwith parenteral .erythromycin; increased risk ofventricular arrhythmias when zuclopenthixol givenwith parenteral .erythromycin—avoid concomitantuse; plasma concentration of clozapine increased byciprofloxacin; plasma concentration of olanzapinepossibly increased by ciprofloxacin; increased risk ofventricular arrhythmias when droperidol, haloperidol,phenothiazines or zuclopenthixol given with.moxifloxacin—avoid concomitant use; increasedrisk of ventricular arrhythmias when benperidol givenwith .moxifloxacin—manufacturer of benperidoladvises avoid concomitant use; plasma concentrationof aripiprazole possibly reduced by .rifabutin and.rifampicin—increase dose of aripiprazole; plasmaconcentration of clozapine possibly reduced byrifampicin; metabolism of haloperidol accelerated by.rifampicin (reduced plasma concentration); avoidconcomitant use of clozapine with.chloramphenicol or .sulfonamides (increased risk ofagranulocytosis); plasma concentration of quetiapinepossibly increased by macrolides (reduce dose ofquetiapine); manufacturer of droperidol advises avoidconcomitant use with .macrolides (risk of ventriculararrhythmias). Antidepressants: plasma concentration of clozapinepossibly increased by citalopram (increased risk oftoxicity); metabolism of aripiprazole possibly inhibitedby .fluoxetine and .paroxetine (reduce dose ofaripiprazole); plasma concentration of clozapine,haloperidol and risperidone increased by .fluoxetine;manufacturer of droperidol advises avoid concomitantuse with .fluoxetine, .fluvoxamine,.sertraline or .tricyclics (risk of ventricular arrhythmias);plasma concentration of clozapine and olanzapineincreased by .fluvoxamine; plasmaconcentration of haloperidol possibly increased byfluvoxamine; plasma concentration of clozapineincreased by .paroxetine, .sertraline and.venlafaxine; plasma concentration of risperidonepossibly increased by paroxetine (increased risk oftoxicity); metabolism of perphenazine inhibited byparoxetine (reduce dose of perphenazine); plasmaconcentration of haloperidol increased by venlafaxine;clozapine possibly increases CNS effects of.MAOIs; plasma concentration of pimozide possiblyincreased by .SSRIs (increased risk of ventriculararrhythmias—avoid concomitant use); plasma concentrationof aripiprazole possibly reduced by .StJohn’s wort—increase dose of aripiprazole; antipsychoticsincrease plasma concentration of.tricyclics—possibly increased risk of ventricular

BNFC 2011–2012 Appendix 1: Interactions 671Antipsychotics. Antidepressants (continued)arrhythmias; increased risk of antimuscarinicside-effects when phenothiazines given withtricyclics; increased risk of ventricular arrhythmiaswhen pimozide given with .tricyclics—avoid concomitant use; possible increased antimuscarinicside-effects when clozapine givenwith tricyclicsAntidiabetics: phenothiazines possibly antagonisehypoglycaemic effect of sulfonylureas. Antiepileptics: antipsychotics antagonise anticonvulsanteffect of .antiepileptics (convulsivethreshold lowered); metabolism of clozapine acceleratedby .carbamazepine (reduced plasma concentration),also avoid concomitant use of drugs withsubstantial potential for causing agranulocytosis;plasma concentration of aripiprazole reduced by.carbamazepine—increase dose of aripiprazole;plasma concentration of paliperidone reduced bycarbamazepine; metabolism of haloperidol, olanzapine,quetiapine and risperidone accelerated bycarbamazepine (reduced plasma concentration);metabolism of haloperidol accelerated by phenobarbital(reduced plasma concentration); plasma concentrationof both drugs reduced whenchlorpromazine given with phenobarbital; plasmaconcentration of clozapine possibly reduced byphenobarbital; plasma concentration of aripiprazolepossibly reduced by .phenobarbital and.phenytoin—increase dose of aripiprazole; plasmaconcentration of haloperidol reduced by phenytoin;chlorpromazine possibly increases or decreasesplasma concentration of phenytoin; metabolism ofclozapine and quetiapine accelerated by phenytoin(reduced plasma concentration); increased risk ofside-effects including neutropenia when olanzapinegiven with .valproate; plasma concentration ofclozapine possibly increased or decreased by valproate;plasma concentration of quetiapine possiblyincreased by valproate. Antifungals: metabolism of aripiprazole inhibited by.ketoconazole (reduce dose of aripiprazole); metabolismof aripiprazole possibly inhibited by.itraconazole (reduce dose of aripiprazole); plasmaconcentration of haloperidol possibly increased byitraconazole; increased risk of ventricular arrhythmiaswhen pimozide given with .imidazoles or.triazoles—avoid concomitant use; plasma concentrationof quetiapine possibly increased byimidazoles and triazoles (reduce dose of quetiapine). Antimalarials: avoidance of antipsychotics advised bymanufacturer of .artemether/lumefantrine;increased risk of ventricular arrhythmias when droperidolgiven with .chloroquine andhydroxychloroquine or .quinine—avoid concomitantuse; increased risk of ventricular arrhythmias whenpimozide given with .mefloquine or .quinine—avoidconcomitant use; possible increased risk of ventriculararrhythmias when haloperidol given with.mefloquine or .quinine—avoid concomitant useAntimuscarinics: increased risk of antimuscarinic sideeffectswhen clozapine given with antimuscarinics;plasma concentration of phenothiazines reduced byantimuscarinics, but risk of antimuscarinic sideeffectsincreased; effects of haloperidol possiblyreduced by antimuscarinics. Antipsychotics: increased risk of ventricular arrhythmiaswhen amisulpride, pimozide or sulpiride givenwith .droperidol—avoid concomitant use; increasedrisk of ventricular arrhythmias when phenothiazinesthat prolong the QT interval given with .droperidol—avoid concomitant use; avoid concomitant use ofclozapine with depot formulation of .flupentixol,.fluphenazine, .haloperidol, .pipotiazine,.risperidone or .zuclopenthixol as cannot be withdrawnquickly if neutropenia occurs; increased risk ofventricular arrhythmias when sulpiride given withAntipsychotics. Antipsychotics (continued).haloperidol; chlorpromazine possibly increasesplasma concentration of haloperidol; increased risk ofventricular arrhythmias when droperidol given with.haloperidol—avoid concomitant use; increased riskof ventricular arrhythmias when pimozide given with.phenothiazines—avoid concomitant use; increasedrisk of ventricular arrhythmias when pimozide givenwith .sulpiride. Antivirals: metabolism of aripiprazole possibly inhibitedby .atazanavir, .fosamprenavir, .indinavir,.lopinavir, .nelfinavir, .ritonavir and .saquinavir(reduce dose of aripiprazole); plasma concentrationof pimozide possibly increased by .atazanavir—avoidconcomitant use; plasma concentration of aripiprazolepossibly reduced by .efavirenz and.nevirapine—increase dose of aripiprazole; plasmaconcentration of pimozide possibly increased by.efavirenz, .indinavir, .nelfinavir and .saquinavir(increased risk of ventricular arrhythmias—avoidconcomitant use); plasma concentration of pimozideincreased by .fosamprenavir and .ritonavir(increased risk of ventricular arrhythmias—avoidconcomitant use); plasma concentration of olanzapinereduced by ritonavir—consider increasing doseof olanzapine; plasma concentration of clozapineincreased by .ritonavir (increased risk of toxicity)—avoid concomitant use; plasma concentration ofantipsychotics possibly increased by .ritonavir;increased risk of ventricular arrhythmias when clozapine,haloperidol or phenothiazines given with.saquinavir—avoid concomitant use. Anxiolytics and Hypnotics: increased sedative effectwhen antipsychotics given with anxiolytics andhypnotics; serious adverse events reported withconcomitant use of clozapine and .lorazepam(causality not established); increased risk of hypotension,bradycardia and respiratory depressionwhen intramuscular olanzapine given with parenteral.benzodiazepines; plasma concentration ofhaloperidol increased by buspirone. Aprepitant: avoidance of pimozide advised by manufacturerof .aprepitant. Atomoxetine: increased risk of ventricular arrhythmiaswhen antipsychotics that prolong the QT intervalgiven with .atomoxetine. Beta-blockers: enhanced hypotensive effect whenphenothiazines given with beta-blockers; plasmaconcentration of both drugs may increase whenchlorpromazine given with .propranolol; increasedrisk of ventricular arrhythmias when amisulpride,phenothiazines, pimozide or sulpiride given with.sotalol; increased risk of ventricular arrhythmiaswhen droperidol or zuclopenthixol given with.sotalol—avoid concomitant use; possible increasedrisk of ventricular arrhythmias when haloperidolgiven with .sotalol—avoid concomitant useCalcium-channel Blockers: enhanced hypotensiveeffect when antipsychotics given with calciumchannelblockersClonidine: enhanced hypotensive effect when phenothiazinesgiven with clonidine. Cytotoxics: avoid concomitant use of clozapine with.cytotoxics (increased risk of agranulocytosis);avoidance of pimozide advised by manufacturer of.lapatinib; increased risk of ventricular arrhythmiaswhen haloperidol given with .arsenic trioxide;increased risk of ventricular arrhythmias when antipsychoticsthat prolong the QT interval given with.arsenic trioxideDesferrioxamine: manufacturer of levomepromazineadvises avoid concomitant use with desferrioxamine;avoidance of prochlorperazine advised by manufacturerof desferrioxamineDiazoxide: enhanced hypotensive effect when phenothiazinesgiven with diazoxide. Diuretics: risk of ventricular arrhythmias with amisulprideincreased by hypokalaemia caused byAppendix 1: Interactions

672 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsAntipsychotics. Diuretics (continued).diuretics; risk of ventricular arrhythmias withpimozide increased by hypokalaemia caused by.diuretics (avoid concomitant use); enhanced hypotensiveeffect when phenothiazines given with diureticsDopaminergics: increased risk of extrapyramidal sideeffectswhen antipsychotics given with amantadine;antipsychotics antagonise effects of apomorphine,levodopa and pergolide; antipsychotics antagonisehypoprolactinaemic and antiparkinsonian effects ofbromocriptine and cabergoline; manufacturer ofamisulpride advises avoid concomitant use of levodopa(antagonism of effect); avoidance of antipsychoticsadvised by manufacturer of pramipexole,ropinirole and rotigotine (antagonism of effect)Histamine: antipsychotics theoretically antagoniseeffects of histamine—manufacturer of histamineadvises avoid concomitant use. Hormone Antagonists: manufacturer of droperidoladvises avoid concomitant use with .tamoxifen (riskof ventricular arrhythmias). Ivabradine: increased risk of ventricular arrhythmiaswhen pimozide given with .ivabradineLithium: increased risk of extrapyramidal side-effectsand possibly neurotoxicity when clozapine, flupentixol,haloperidol, phenothiazines or zuclopenthixolgiven with lithium; possible risk of toxicity whenolanzapine given with lithium; increased risk ofextrapyramidal side-effects when sulpiride given withlithiumMemantine: effects of antipsychotics possibly reducedby memantineMethyldopa: enhanced hypotensive effect when antipsychoticsgiven with methyldopa (also increasedrisk of extrapyramidal effects)Metoclopramide: increased risk of extrapyramidalside-effects when antipsychotics given with metoclopramideMoxonidine: enhanced hypotensive effect whenphenothiazines given with moxonidineMuscle Relaxants: promazine possibly enhanceseffects of suxamethoniumNitrates: enhanced hypotensive effect when phenothiazinesgiven with nitrates. Penicillamine: avoid concomitant use of clozapine with.penicillamine (increased risk of agranulocytosis). Pentamidine Isetionate: increased risk of ventriculararrhythmias when amisulpride or droperidol givenwith .pentamidine isetionate—avoid concomitantuse; increased risk of ventricular arrhythmias whenphenothiazines given with .pentamidine isetionateSodium Benzoate: haloperidol possibly reduces effectsof sodium benzoateSodium Oxybate: antipsychotics possibly enhanceeffects of sodium oxybateSodium Phenylbutyrate: haloperidol possibly reduceseffects of sodium phenylbutyrateSympathomimetics: antipsychotics antagonise hypertensiveeffect of sympathomimetics; antipsychoticeffects of chlorpromazine possibly antagonised bydexamfetamine; side-effects of risperidone possiblyincreased by methylphenidate. Tacrolimus: manufacturer of droperidol advises avoidconcomitant use with .tacrolimus (risk of ventriculararrhythmias)Tetrabenazine: increased risk of extrapyramidal sideeffectswhen antipsychotics given with tetrabenazineUlcer-healing Drugs: effects of antipsychotics,chlorpromazine and clozapine possibly enhanced bycimetidine; plasma concentration of clozapine possiblyreduced by omeprazole; absorption of sulpiridereduced by sucralfateVasodilator Antihypertensives: enhanced hypotensiveeffect when phenothiazines given with hydralazine,minoxidil or sodium nitroprussideAntivirals see Abacavir, Aciclovir, Adefovir, Atazanavir,Cidofovir, Darunavir, Didanosine, Efavirenz, Emtricitabine,Etravirine, Famciclovir, Fosamprenavir,Foscarnet, Ganciclovir, Indinavir, Lamivudine, Lopinavir,Maraviroc, Nelfinavir, Nevirapine, Raltegravir,Ribavirin, Ritonavir, Saquinavir, Stavudine, Telbivudine,Tenofovir, Tipranavir, Valaciclovir, and ZidovudineAnxiolytics and HypnoticsACE Inhibitors: enhanced hypotensive effect whenanxiolytics and hypnotics given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when anxiolytics and hypnotics given withadrenergic neurone blockersAlcohol: increased sedative effect when anxiolytics andhypnotics given with alcoholAlpha-blockers: enhanced hypotensive and sedativeeffects when anxiolytics and hypnotics given withalpha-blockersAnaesthetics, General: increased sedative effect whenanxiolytics and hypnotics given with general anaestheticsAnalgesics: metabolism of midazolam possibly inhibitedby fentanyl; increased sedative effect whenanxiolytics and hypnotics given with opioid analgesicsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when anxiolytics and hypnoticsgiven with angiotensin-II receptor antagonists. Antibacterials: metabolism of midazolam inhibited by.clarithromycin, .erythromycin and .telithromycin(increased plasma concentration with increasedsedation); plasma concentration of buspironeincreased by erythromycin (reduce dose of buspirone);metabolism of zopiclone inhibited by erythromycin;metabolism of benzodiazepines possiblyaccelerated by rifampicin (reduced plasma concentration);metabolism of diazepam accelerated byrifampicin (reduced plasma concentration); metabolismof buspirone and zaleplon possibly acceleratedby rifampicin; metabolism of zolpidem accelerated byrifampicin (reduced plasma concentration andreduced effect); plasma concentration of zopiclonesignificantly reduced by rifampicin; metabolism ofdiazepam inhibited by isoniazidAnticoagulants: chloral may transiently enhance anticoagulanteffect of coumarins. Antidepressants: plasma concentration of alprazolamincreased by fluoxetine; plasma concentration ofmelatonin increased by .fluvoxamine—avoid concomitantuse; plasma concentration of some benzodiazepinesincreased by fluvoxamine; sedative effectspossibly increased when zolpidem given with sertraline;manufacturer of buspirone advises avoid concomitantuse with MAOIs; avoidance of buspirone for10 days after stopping tranylcypromine advised bymanufacturer of tranylcypromine; plasma concentrationof oral midazolam possibly reduced by StJohn’s wort; increased sedative effect when anxiolyticsand hypnotics given with mirtazapine, tricyclicrelatedantidepressants or tricyclicsAntiepileptics: plasma concentration of midazolamreduced by carbamazepine; plasma concentration ofclonazepam often reduced by carbamazepine,phenobarbital and phenytoin; benzodiazepines possiblyincrease or decrease plasma concentration ofphenytoin; diazepam increases or decreases plasmaconcentration of phenytoin; plasma concentration ofclobazam increased by stiripentol; clobazam possiblyincreases plasma concentration of valproate; plasmaconcentration of diazepam and lorazepam possiblyincreased by valproate; increased risk of side-effectswhen clonazepam given with valproate. Antifungals: plasma concentration of alprazolamincreased by itraconazole and ketoconazole; plasmaconcentration of midazolam increased by.fluconazole, .itraconazole and .ketoconazole (riskof prolonged sedation); plasma concentration ofbuspirone increased by itraconazole (reduce dose ofbuspirone); plasma concentration of midazolamincreased by .posaconazole

BNFC 2011–2012 Appendix 1: Interactions 673Anxiolytics and Hypnotics (continued)Antihistamines: increased sedative effect whenanxiolytics and hypnotics given with antihistamines. Antipsychotics: increased sedative effect when anxiolyticsand hypnotics given with antipsychotics;buspirone increases plasma concentration of haloperidol;serious adverse events reported with concomitantuse of lorazepam and .clozapine (causalitynot established); increased risk of hypotension,bradycardia and respiratory depression when parenteralbenzodiazepines given with intramuscular.olanzapine. Antivirals: plasma concentration of midazolam possiblyincreased by .atazanavir—avoid concomitant use oforal midazolam; increased risk of prolonged sedationwhen midazolam given with .efavirenz—avoid concomitantuse; plasma concentration of midazolampossibly increased by .fosamprenavir, .indinavir,.nelfinavir and .ritonavir (risk of prolonged sedation—avoidconcomitant use of oral midazolam);increased risk of prolonged sedation when alprazolamgiven with .indinavir—avoid concomitant use;plasma concentration of alprazolam, diazepam,flurazepam and zolpidem possibly increased by.ritonavir (risk of extreme sedation and respiratorydepression—avoid concomitant use); plasma concentrationof anxiolytics and hypnotics possiblyincreased by .ritonavir; plasma concentration ofbuspirone increased by ritonavir (increased risk oftoxicity); plasma concentration of midazolamincreased by .saquinavir (risk of prolonged sedation—avoidconcomitant use of oral midazolam)Aprepitant: plasma concentration of midazolamincreased by aprepitant (risk of prolonged sedation)Beta-blockers: enhanced hypotensive effect whenanxiolytics and hypnotics given with beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when anxiolytics and hypnotics given withcalcium-channel blockers; midazolam increasesabsorption of lercanidipine; metabolism of midazolaminhibited by diltiazem and verapamil(increased plasma concentration with increasedsedation); plasma concentration of buspironeincreased by diltiazem and verapamil (reduce dose ofbuspirone)Cardiac Glycosides: alprazolam increases plasmaconcentration of digoxin (increased risk of toxicity)Clonidine: enhanced hypotensive effect when anxiolyticsand hypnotics given with clonidineCytotoxics: plasma concentration of midazolamincreased by nilotinibDeferasirox: plasma concentration of midazolam possiblyreduced by deferasiroxDiazoxide: enhanced hypotensive effect when anxiolyticsand hypnotics given with diazoxideDisulfiram: metabolism of benzodiazepines inhibitedby disulfiram (increased sedative effects); increasedrisk of temazepam toxicity when given with disulfiramDiuretics: enhanced hypotensive effect when anxiolyticsand hypnotics given with diuretics; administrationof chloral with parenteral furosemide maydisplace thyroid hormone from binding sitesDopaminergics: benzodiazepines possibly antagoniseeffects of levodopaGrapefruit Juice: plasma concentration of buspironeincreased by grapefruit juiceLithium: increased risk of neurotoxicity when clonazepamgiven with lithiumLofexidine: increased sedative effect when anxiolyticsand hypnotics given with lofexidineMethyldopa: enhanced hypotensive effect whenanxiolytics and hypnotics given with methyldopaMoxonidine: enhanced hypotensive effect whenanxiolytics and hypnotics given with moxonidine;sedative effects possibly increased when benzodiazepinesgiven with moxonidineAnxiolytics and Hypnotics (continued)Muscle Relaxants: increased sedative effect whenanxiolytics and hypnotics given with baclofen ortizanidineNitrates: enhanced hypotensive effect when anxiolyticsand hypnotics given with nitratesOestrogens: plasma concentration of melatoninincreased by oestrogensProbenecid: excretion of lorazepam reduced by probenecid(increased plasma concentration); excretionof nitrazepam possibly reduced by probenecid(increased plasma concentration). Sodium Oxybate: benzodiazepines enhance effects of.sodium oxybate (avoid concomitant use)Theophylline: effects of benzodiazepines possiblyreduced by theophyllineUlcer-healing Drugs: plasma concentration of melatoninincreased by cimetidine; metabolism of benzodiazepines,clomethiazole and zaleplon inhibited bycimetidine (increased plasma concentration); metabolismof diazepam possibly inhibited byesomeprazole and omeprazole (increased plasmaconcentration)Vasodilator Antihypertensives: enhanced hypotensiveeffect when anxiolytics and hypnotics given withhydralazine, minoxidil or sodium nitroprussideApomorphineAntipsychotics: effects of apomorphine antagonised byantipsychoticsDopaminergics: effects of apomorphine possiblyenhanced by entacaponeMemantine: effects of dopaminergics possiblyenhanced by memantineMethyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopaApraclonidineAntidepressants: manufacturer of apraclonidineadvises avoid concomitant use with MAOIs, tricyclicrelatedantidepressants and tricyclicsAprepitantNote Fosaprepitant is a prodrug of aprepitantAntibacterials: plasma concentration of aprepitantpossibly increased by clarithromycin and telithromycin;plasma concentration of aprepitant reduced byrifampicinAnticoagulants: aprepitant possibly reduces anticoagulanteffect of warfarin. Antidepressants: manufacturer of aprepitant advisesavoid concomitant use with .St John’s wortAntidiabetics: aprepitant reduces plasma concentrationof tolbutamideAntiepileptics: plasma concentration of aprepitantpossibly reduced by carbamazepine,phenobarbital and phenytoinAntifungals: plasma concentration of aprepitantincreased by ketoconazole. Antipsychotics: manufacturer of aprepitant advisesavoid concomitant use with .pimozideAntivirals: plasma concentration of aprepitant possiblyincreased by ritonavirAnxiolytics and Hypnotics: aprepitant increasesplasma concentration of midazolam (risk of prolongedsedation)Calcium-channel Blockers: plasma concentration ofboth drugs may increase when aprepitant given withdiltiazemCorticosteroids: aprepitant inhibits metabolism ofdexamethasone and methylprednisolone (reducedose of dexamethasone and methylprednisolone). Oestrogens: aprepitant possibly causes contraceptivefailure of hormonal contraceptives containing.oestrogens (alternative contraception recommended). Progestogens: aprepitant possibly causes contraceptivefailure of hormonal contraceptives containing.progestogens (alternative contraception recommended)Aripiprazole see AntipsychoticsAppendix 1: Interactions

674 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsArsenic Trioxide. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen arsenic trioxide given with.amiodarone or .disopyramide. Antibacterials: increased risk of ventricular arrhythmiaswhen arsenic trioxide given with .erythromycin,.levofloxacin or .moxifloxacin. Antidepressants: increased risk of ventricular arrhythmiaswhen arsenic trioxide given with.amitriptyline or .clomipramine. Antifungals: increased risk of ventricular arrhythmiaswhen arsenic trioxide given with .amphotericin. Antipsychotics: increased risk of ventricular arrhythmiaswhen arsenic trioxide given with.antipsychotics that prolong the QT interval;increased risk of ventricular arrhythmias whenarsenic trioxide given with .haloperidol; avoid concomitantuse of cytotoxics with .clozapine (increasedrisk of agranulocytosis). Beta-blockers: increased risk of ventricular arrhythmiaswhen arsenic trioxide given with .sotalol. Diuretics: risk of ventricular arrhythmias with arsenictrioxide increased by hypokalaemia caused by.acetazolamide, .loop diuretics or .thiazides andrelated diuretics. Lithium: increased risk of ventricular arrhythmias whenarsenic trioxide given with .lithiumArtemether with Lumefantrine. Anti-arrhythmics: manufacturer of artemether/lumefantrineadvises avoid concomitant use with.amiodarone, .disopyramide or .flecainide (risk ofventricular arrhythmias). Antibacterials: manufacturer of artemether/lumefantrineadvises avoid concomitant use with.macrolides and .quinolones. Antidepressants: manufacturer of artemether/lumefantrineadvises avoid concomitant use with.antidepressants. Antifungals: manufacturer of artemether/lumefantrineadvises avoid concomitant use with .imidazoles and.triazoles. Antimalarials: manufacturer of artemether/lumefantrineadvises avoid concomitant use with.antimalarials; increased risk of ventricular arrhythmiaswhen artemether/lumefantrine given with.quinine. Antipsychotics: manufacturer of artemether/lumefantrineadvises avoid concomitant use with.antipsychoticsAntivirals: manufacturer of artemether/lumefantrineadvises caution with atazanavir, darunavir, fosamprenavir,indinavir, lopinavir, nelfinavir, ritonavir,saquinavir and tipranavir. Beta-blockers: manufacturer of artemether/lumefantrineadvises avoid concomitant use with.metoprolol and .sotalolGrapefruit Juice: plasma concentration of artemether/lumefantrine possibly increased by grapefruit juiceHistamine: avoidance of antimalarials advised bymanufacturer of histamine. Ulcer-healing Drugs: manufacturer of artemether/lumefantrine advises avoid concomitant use with.cimetidineVaccines: antimalarials inactivate oral typhoidvaccine—see p. 620Ascorbic acid see VitaminsAspirinAdsorbents: absorption of aspirin possibly reduced bykaolinAnaesthetics, General: aspirin possibly enhanceseffects of thiopental. Analgesics: avoid concomitant use of aspirin with.NSAIDs (increased side-effects); antiplatelet effectof aspirin possibly reduced by ibuprofenAntacids: excretion of aspirin increased by alkalineurine due to some antacids. Anticoagulants: increased risk of bleeding whenaspirin given with .coumarins or .phenindione (dueAspirin. Anticoagulants (continued)to antiplatelet effect); aspirin enhances anticoagulanteffect of .heparins. Antidepressants: increased risk of bleeding whenaspirin given with .SSRIs or .venlafaxineAntiepileptics: aspirin enhances effects ofphenytoin and valproateClopidogrel: increased risk of bleeding when aspiringiven with clopidogrelCorticosteroids: increased risk of gastro-intestinalbleeding and ulceration when aspirin given withcorticosteroids, also corticosteroids reduce plasmaconcentration of salicylate. Cytotoxics: aspirin reduces excretion of .methotrexate(increased risk of toxicity)Diuretics: aspirin antagonises diuretic effect ofspironolactone; increased risk of toxicity when highdoseaspirin given with carbonic anhydrase inhibitorsIloprost: increased risk of bleeding when aspirin givenwith iloprostLeukotriene Receptor Antagonists: aspirin increasesplasma concentration of zafirlukastMetoclopramide: rate of absorption of aspirinincreased by metoclopramide (enhanced effect)Probenecid: aspirin antagonises effects of probenecidSulfinpyrazone: aspirin antagonises effects of sulfinpyrazoneAtazanavirAntacids: plasma concentration of atazanavir possiblyreduced by antacids. Anti-arrhythmics: atazanavir possibly increases plasmaconcentration of .amiodarone and .lidocaine. Antibacterials: plasma concentration of both drugsincreased when atazanavir given with clarithromycin;atazanavir increases plasma concentration of.rifabutin (reduce dose of rifabutin); plasma concentrationof atazanavir reduced by .rifampicin—avoidconcomitant use; avoidance of concomitant atazanavirin severe renal and hepatic impairment advisedby manufacturer of .telithromycinAnticoagulants: atazanavir may enhance or reduceanticoagulant effect of warfarin; avoidance of atazanaviradvised by manufacturer of rivaroxaban. Antidepressants: plasma concentration of atazanavirreduced by .St John’s wort—avoid concomitant use. Antifungals: plasma concentration of atazanavirincreased by .posaconazole. Antimalarials: caution with atazanavir advised bymanufacturer of artemether/lumefantrine; atazanavirpossibly increases plasma concentration of .quinine(increased risk of toxicity)Antimuscarinics: avoidance of atazanavir advised bymanufacturer of darifenacin; manufacturer of fesoterodineadvises dose reduction when atazanavirgiven with fesoterodine—consult fesoterodineproduct literature. Antipsychotics: atazanavir possibly inhibits metabolismof .aripiprazole (reduce dose of aripiprazole);atazanavir possibly increases plasma concentrationof .pimozide—avoid concomitant use. Antivirals: manufacturer of atazanavir advises avoidconcomitant use with .efavirenz (plasma concentrationof atazanavir reduced); avoid concomitant use ofatazanavir with .indinavir; atazanavir increasesplasma concentration of .maraviroc (consider reducingdose of maraviroc); plasma concentration ofatazanavir possibly reduced by .nevirapine—avoidconcomitant use; increased risk of ventricular arrhythmiaswhen atazanavir given with .saquinavir—avoid concomitant use; plasma concentration ofatazanavir reduced by tenofovir, also plasma concentrationof tenofovir possibly increased; atazanavirincreases plasma concentration of tipranavir (alsoplasma concentration of atazanavir reduced). Anxiolytics and Hypnotics: atazanavir possiblyincreases plasma concentration of .midazolam—avoid concomitant use of oral midazolam

BNFC 2011–2012 Appendix 1: Interactions 675Atazanavir (continued). Calcium-channel Blockers: atazanavir increasesplasma concentration of .diltiazem (reduce dose ofdiltiazem); atazanavir possibly increases plasmaconcentration of verapamil. Ciclosporin: atazanavir possibly increases plasmaconcentration of .ciclosporin. Colchicine: atazanavir possibly increases risk of.colchicine toxicity—suspend or reduce dose ofcolchicine (avoid concomitant use in hepatic or renalimpairment). Cytotoxics: atazanavir possibly increases plasma concentrationof .everolimus—manufacturer of everolimusadvises avoid concomitant use; avoidance ofatazanavir advised by manufacturer of .pazopanib;atazanavir possibly inhibits metabolism of.irinotecan (increased risk of toxicity). Ergot Alkaloids: atazanavir possibly increases plasmaconcentration of .ergot alkaloids—avoid concomitantuse. Lipid-regulating Drugs: possible increased risk ofmyopathy when atazanavir given with atorvastatin;possible increased risk of myopathy when atazanavirgiven with .rosuvastatin—manufacturer of rosuvastatinadvises avoid concomitant use; increased risk ofmyopathy when atazanavir given with .simvastatin(avoid concomitant use)Oestrogens: atazanavir increases plasma concentrationof ethinylestradiolProgestogens: atazanavir increases plasma concentrationof norethisterone. Ranolazine: atazanavir possibly increases plasmaconcentration of .ranolazine—manufacturer ofranolazine advises avoid concomitant use. Sildenafil: atazanavir possibly increases side-effects of.sildenafil. Sirolimus: atazanavir possibly increases plasma concentrationof .sirolimus. Tacrolimus: atazanavir possibly increases plasma concentrationof .tacrolimus. Ulcer-healing Drugs: plasma concentration of atazanavirreduced by .histamine H 2 -antagonists; plasmaconcentration of atazanavir reduced by .protonpump inhibitors—avoid or adjust dose of both drugs(consult product literature)Atenolol see Beta-blockersAtomoxetine. Analgesics: increased risk of ventricular arrhythmiaswhen atomoxetine given with .methadone; possibleincreased risk of convulsions when atomoxetinegiven with tramadol. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen atomoxetine given with .amiodarone or.disopyramide. Antibacterials: increased risk of ventricular arrhythmiaswhen atomoxetine given with parenteral.erythromycin; increased risk of ventricular arrhythmiaswhen atomoxetine given with .moxifloxacin. Antidepressants: metabolism of atomoxetine possiblyinhibited by fluoxetine and paroxetine; possibleincreased risk of convulsions when atomoxetinegiven with antidepressants; atomoxetine should notbe started until 2 weeks after stopping .MAOIs, alsoMAOIs should not be started until at least 2 weeksafter stopping atomoxetine; increased risk of ventriculararrhythmias when atomoxetine given with.tricyclics. Antimalarials: increased risk of ventricular arrhythmiaswhen atomoxetine given with .mefloquine. Antipsychotics: increased risk of ventricular arrhythmiaswhen atomoxetine given with .antipsychoticsthat prolong the QT interval. Beta-blockers: increased risk of ventricular arrhythmiaswhen atomoxetine given with .sotalolBupropion: possible increased risk of convulsionswhen atomoxetine given with bupropion. Diuretics: risk of ventricular arrhythmias with atomoxetineincreased by hypokalaemia caused by.diureticsAtomoxetine (continued)Sympathomimetics, Beta 2 : Increased risk of cardiovascularside-effects when atomoxetine given withparenteral salbutamolAtorvastatin see StatinsAtovaquone. Antibacterials: plasma concentration of atovaquonereduced by .rifabutin and .rifampicin (possibletherapeutic failure of atovaquone); plasma concentrationof atovaquone reduced by tetracyclineAntivirals: atovaquone possibly reduces plasma concentrationof indinavir; atovaquone possibly inhibitsmetabolism of zidovudine (increased plasma concentration)Histamine: avoidance of atovaquone advised bymanufacturer of histamineMetoclopramide: plasma concentration of atovaquonereduced by metoclopramideAtracurium see Muscle RelaxantsAtropine see AntimuscarinicsAzathioprineACE Inhibitors: increased risk of anaemia or leucopeniawhen azathioprine given with captopril especially inrenal impairment; increased risk of anaemia whenazathioprine given with enalapril especially in renalimpairment. Allopurinol: enhanced effects and increased toxicity ofazathioprine when given with .allopurinol (reducedose of azathioprine to one quarter of usual dose)Aminosalicylates: possible increased risk of leucopeniawhen azathioprine given with aminosalicylates. Antibacterials: increased risk of haematological toxicitywhen azathioprine given with .sulfamethoxazole(as co-trimoxazole); increased risk of haematologicaltoxicity when azathioprine given with .trimethoprim(also with co-trimoxazole). Anticoagulants: azathioprine possibly reduces anticoagulanteffect of .coumarins. Antivirals: myelosuppressive effects of azathioprinepossibly enhanced by .ribavirin. Febuxostat: avoidance of azathioprine advised bymanufacturer of .febuxostatAzithromycin see MacrolidesAztreonam. Anticoagulants: aztreonam possibly enhances anticoagulanteffect of .coumarinsVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Baclofen see Muscle RelaxantsBalsalazide see AminosalicylatesBambuterol see Sympathomimetics, Beta 2Beclometasone see CorticosteroidsBemiparin see HeparinsBendamustine. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Bendroflumethiazide see DiureticsBenperidol see AntipsychoticsBenzodiazepines see Anxiolytics and HypnoticsBenzthiazide see DiureticsBenzylpenicillin see PenicillinsBeta-blockersNote Since systemic absorption may follow topical applicationof beta-blockers to the eye the possibility of interactions,in particular, with drugs such as verapamil should beborne in mindACE Inhibitors: enhanced hypotensive effect whenbeta-blockers given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when beta-blockers given with adrenergicneurone blockersAlcohol: enhanced hypotensive effect when betablockersgiven with alcoholAldesleukin: enhanced hypotensive effect when betablockersgiven with aldesleukin. Alpha-blockers: enhanced hypotensive effect whenbeta-blockers given with .alpha-blockers, alsoAppendix 1: Interactions

676 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsBeta-blockers. Alpha-blockers (continued)increased risk of first-dose hypotension with postsynapticalpha-blockers such as prazosinAnaesthetics, General: enhanced hypotensive effectwhen beta-blockers given with general anaesthetics. Anaesthetics, Local: propranolol increases risk of.bupivacaine toxicityAnalgesics: hypotensive effect of beta-blockers antagonisedby NSAIDs; plasma concentration of esmololpossibly increased by morphineAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when beta-blockers given withangiotensin-II receptor antagonists. Anti-arrhythmics: increased myocardial depressionwhen beta-blockers given with .anti-arrhythmics;increased risk of ventricular arrhythmias when sotalolgiven with .amiodarone, .disopyramide or.dronedarone—avoid concomitant use; increasedrisk of bradycardia, AV block and myocardialdepression when beta-blockers given with.amiodarone; plasma concentration ofmetoprolol and propranolol possibly increased bydronedarone; increased risk of myocardial depressionand bradycardia when beta-blockers given with.flecainide; propranolol increases risk of .lidocainetoxicity; plasma concentration of metoprolol andpropranolol increased by propafenone. Antibacterials: increased risk of ventricular arrhythmiaswhen sotalol given with .moxifloxacin—avoidconcomitant use; metabolism of bisoprolol andpropranolol accelerated by rifampicin (plasma concentrationsignificantly reduced); plasma concentrationof carvedilol, celiprolol and metoprolol reducedby rifampicin. Antidepressants: plasma concentration of metoprololincreased by citalopram and escitalopram; plasmaconcentration of propranolol increased by fluvoxamine;plasma concentration of metoprolol possiblyincreased by paroxetine (enhanced effect);labetalol and propranolol increase plasma concentrationof imipramine; enhanced hypotensive effectwhen beta-blockers given with MAOIs; increased riskof ventricular arrhythmias when sotalol given with.tricyclicsAntidiabetics: beta-blockers may mask warning signsof hypoglycaemia (such as tremor) with antidiabetics;beta-blockers enhance hypoglycaemic effect ofinsulinAntiepileptics: plasma concentration of propranololpossibly reduced by phenobarbital. Antihistamines: increased risk of ventricular arrhythmiaswhen sotalol given with .mizolastine—avoidconcomitant use. Antimalarials: avoidance of metoprolol and sotaloladvised by manufacturer of .artemether/lumefantrine;increased risk of bradycardia when betablockersgiven with mefloquine. Antimuscarinics: increased risk of ventricular arrhythmiaswhen sotalol given with .tolterodine. Antipsychotics: increased risk of ventricular arrhythmiaswhen sotalol given with .droperidol or.zuclopenthixol—avoid concomitant use; possibleincreased risk of ventricular arrhythmias when sotalolgiven with .haloperidol—avoid concomitant use;plasma concentration of both drugs may increasewhen propranolol given with .chlorpromazine;increased risk of ventricular arrhythmias when sotalolgiven with .amisulpride, .phenothiazines,.pimozide or .sulpiride; enhanced hypotensive effectwhen beta-blockers given with phenothiazines. Antivirals: increased risk of ventricular arrhythmiaswhen sotalol given with .saquinavir—avoid concomitantuse; avoidance of metoprolol for heart failureadvised by manufacturer of .tipranavirAnxiolytics and Hypnotics: enhanced hypotensiveeffect when beta-blockers given with anxiolytics andhypnoticsBeta-blockers (continued). Atomoxetine: increased risk of ventricular arrhythmiaswhen sotalol given with .atomoxetine. Calcium-channel Blockers: enhanced hypotensiveeffect when beta-blockers given with calciumchannelblockers; possible severe hypotension andheart failure when beta-blockers given with.nifedipine; increased risk of AV block and bradycardiawhen beta-blockers given with .diltiazem;asystole, severe hypotension and heart failure whenbeta-blockers given with .verapamil (see p. 109)Cardiac Glycosides: increased risk of AV block andbradycardia when beta-blockers given with cardiacglycosides. Ciclosporin: carvedilol increases plasma concentrationof .ciclosporin. Clonidine: increased risk of withdrawal hypertensionwhen beta-blockers given with .clonidine (withdrawbeta-blockers several days before slowly withdrawingclonidine)Corticosteroids: hypotensive effect of beta-blockersantagonised by corticosteroids. Cytotoxics: increased risk of ventricular arrhythmiaswhen sotalol given with .arsenic trioxideDiazoxide: enhanced hypotensive effect when betablockersgiven with diazoxide. Diuretics: enhanced hypotensive effect when betablockersgiven with diuretics; risk of ventriculararrhythmias with sotalol increased by hypokalaemiacaused by .loop diuretics or .thiazides and relateddiureticsDopaminergics: enhanced hypotensive effect whenbeta-blockers given with levodopaErgot Alkaloids: increased peripheral vasoconstrictionwhen beta-blockers given with ergotamine andmethysergide5HT 1 Agonists: propranolol increases plasma concentrationof rizatriptan (manufacturer of rizatriptanadvises halve dose and avoid within 2 hours ofpropranolol). Ivabradine: increased risk of ventricular arrhythmiaswhen sotalol given with .ivabradineMethyldopa: enhanced hypotensive effect when betablockersgiven with methyldopa. Moxisylyte: possible severe postural hypotension whenbeta-blockers given with .moxisylyteMoxonidine: enhanced hypotensive effect when betablockersgiven with moxonidineMuscle Relaxants: propranolol enhances effects ofmuscle relaxants; enhanced hypotensive effect whenbeta-blockers given with baclofen; possible enhancedhypotensive effect and bradycardia when betablockersgiven with tizanidineNitrates: enhanced hypotensive effect when betablockersgiven with nitratesOestrogens: hypotensive effect of beta-blockersantagonised by oestrogensParasympathomimetics: propranolol antagoniseseffects of neostigmine and pyridostigmine; increasedrisk of arrhythmias when beta-blockers given withpilocarpineProstaglandins: enhanced hypotensive effect whenbeta-blockers given with alprostadil. Ranolazine: avoidance of sotalol advised by manufacturerof .ranolazine. Sympathomimetics: increased risk of severe hypertensionand bradycardia when non-cardioselectivebeta-blockers given with .adrenaline (epinephrine),also reponse to adrenaline (epinephrine) may bereduced; increased risk of severe hypertension andbradycardia when non-cardioselective beta-blockersgiven with .dobutamine; possible increased risk ofsevere hypertension and bradycardia when noncardioselectivebeta-blockers given with .noradrenaline(norepinephrine)Thyroid Hormones: metabolism of propranolol acceleratedby levothyroxine

BNFC 2011–2012 Appendix 1: Interactions 677Beta-blockers (continued)Ulcer-healing Drugs: plasma concentration of labetalol,metoprolol and propranolol increased by cimetidineVasodilator Antihypertensives: enhanced hypotensiveeffect when beta-blockers given with hydralazine,minoxidil or sodium nitroprussideBetahistineAntihistamines: effect of betahistine theoreticallyantagonised by antihistaminesBetamethasone see CorticosteroidsBetaxolol see Beta-blockersBethanechol see ParasympathomimeticsBexarotene. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Lipid-regulating Drugs: plasma concentration of bexaroteneincreased by .gemfibrozil—avoid concomitantuseBezafibrate see FibratesBicalutamideAnticoagulants: bicalutamide possibly enhances anticoagulanteffect of coumarinsBiguanides see AntidiabeticsBile Acid Sequestrants see Colesevelam, Colestipol,and ColestyramineBile AcidsAntacids: absorption of bile acids possibly reduced byantacids. Ciclosporin: ursodeoxycholic acid increases absorptionof .ciclosporinLipid-regulating Drugs: absorption of bile acids possiblyreduced by colestipol and colestyramineBisoprolol see Beta-blockersBisphosphonatesAnalgesics: bioavailability of tiludronic acid increasedby indometacinAntacids: absorption of bisphosphonates reduced byantacidsAntibacterials: increased risk of hypocalcaemia whenbisphosphonates given with aminoglycosidesCalcium Salts: absorption of bisphosphonates reducedby calcium salts. Cytotoxics: sodium clodronate increases plasma concentrationof .estramustineIron: absorption of bisphosphonates reduced by oralironBleomycin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cardiac Glycosides: bleomycin possibly reducesabsorption of digoxin tablets. Cytotoxics: increased pulmonary toxicity when bleomycingiven with .cisplatinBortezomibAntifungals: plasma concentration of bortezomibincreased by ketoconazole. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Bosentan. Antibacterials: plasma concentration of bosentanreduced by .rifampicin—avoid concomitant useAnticoagulants: manufacturer of bosentan recommendsmonitoring anticoagulant effect of coumarins. Antidiabetics: increased risk of hepatotoxicity whenbosentan given with .glibenclamide—avoid concomitantuse. Antifungals: plasma concentration of bosentanincreased by ketoconazole; plasma concentration ofbosentan possibly increased by .fluconazole—avoidconcomitant use; plasma concentration of bosentanpossibly increased by itraconazoleAntivirals: plasma concentration of bosentan possiblyincreased by ritonavir. Ciclosporin: plasma concentration of bosentanincreased by .ciclosporin (also plasma concentrationof ciclosporin reduced—avoid concomitant use)Bosentan (continued)Lipid-regulating Drugs: bosentan reduces plasmaconcentration of simvastatin. Oestrogens: bosentan possibly causes contraceptivefailure of hormonal contraceptives containing.oestrogens (alternative contraception recommended). Progestogens: bosentan possibly causes contraceptivefailure of hormonal contraceptives containing.progestogens (alternative contraception recommended)Sildenafil: bosentan reduces plasma concentration ofsildenafilTadalafil: bosentan reduces plasma concentration oftadalafilBrimonidineAntidepressants: manufacturer of brimonidine advisesavoid concomitant use with MAOIs, tricyclic-relatedantidepressants and tricyclicsBrinzolamide see DiureticsBromocriptineAlcohol: tolerance of bromocriptine reduced by alcoholAntibacterials: plasma concentration of bromocriptineincreased by erythromycin (increased risk of toxicity);plasma concentration of bromocriptine possiblyincreased by macrolides (increased risk of toxicity)Antipsychotics: hypoprolactinaemic and antiparkinsonianeffects of bromocriptine antagonised byantipsychoticsDomperidone: hypoprolactinaemic effect of bromocriptinepossibly antagonised by domperidoneHormone Antagonists: plasma concentration ofbromocriptine increased by octreotideMemantine: effects of dopaminergics possiblyenhanced by memantineMethyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopaMetoclopramide: hypoprolactinaemic effect ofbromocriptine antagonised by metoclopramide. Sympathomimetics: risk of toxicity when bromocriptinegiven with .isomethepteneBuclizine see AntihistaminesBudesonide see CorticosteroidsBumetanide see DiureticsBupivacaineAnti-arrhythmics: increased myocardial depressionwhen bupivacaine given with anti-arrhythmics. Beta-blockers: increased risk of bupivacaine toxicitywhen given with .propranololBuprenorphine see Opioid AnalgesicsBupropion. Antidepressants: bupropion possibly increases plasmaconcentration of citalopram; manufacturer of bupropionadvises avoid for 2 weeks after stopping.MAOIs; manufacturer of bupropion advises avoidconcomitant use with .moclobemide; bupropionpossibly increases plasma concentration of tricyclics(possible increased risk of convulsions)Antiepileptics: plasma concentration of bupropionreduced by carbamazepine and phenytoin; metabolismof bupropion inhibited by valproateAntivirals: plasma concentration of bupropion reducedby ritonavirAtomoxetine: possible increased risk of convulsionswhen bupropion given with atomoxetineDopaminergics: increased risk of side-effects whenbupropion given with amantadine or levodopa. Hormone Antagonists: bupropion possibly inhibitsmetabolism of .tamoxifen to active metabolite (avoidconcomitant use)Buspirone see Anxiolytics and HypnoticsBusulfanAnalgesics: metabolism of intravenous busulfan possiblyinhibited by paracetamol (manufacturer ofintravenous busulfan advises caution within 72 hoursof paracetamol)Appendix 1: Interactions

678 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsBusulfan (continued). Antibacterials: plasma concentration of busulfanincreased by .metronidazole (increased risk oftoxicity)Antiepileptics: plasma concentration of busulfan possiblyreduced by phenytoinAntifungals: metabolism of busulfan inhibited by itraconazole(increased risk of toxicity). Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cytotoxics: increased risk of hepatotoxicity whenbusulfan given with tioguanineButyrophenones see AntipsychoticsCabergolineAntibacterials: plasma concentration of cabergolineincreased by erythromycin (increased risk of toxicity);plasma concentration of cabergoline possiblyincreased by macrolides (increased risk of toxicity)Antipsychotics: hypoprolactinaemic and antiparkinsonianeffects of cabergoline antagonised byantipsychoticsDomperidone: hypoprolactinaemic effect of cabergolinepossibly antagonised by domperidoneMemantine: effects of dopaminergics possiblyenhanced by memantineMethyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopaMetoclopramide: hypoprolactinaemic effect of cabergolineantagonised by metoclopramideCalcium SaltsNote see also AntacidsAntibacterials: calcium salts reduce absorption ofciprofloxacin and tetracyclineBisphosphonates: calcium salts reduce absorption ofbisphosphonatesCardiac Glycosides: large intravenous doses ofcalcium salts can precipitate arrhythmias when givenwith cardiac glycosidesCorticosteroids: absorption of calcium salts reduced bycorticosteroidsDiuretics: increased risk of hypercalcaemia whencalcium salts given with thiazides and related diureticsEltrombopag: calcium salts possibly reduce absorptionof eltrombopag (give at least 4 hours apart)Fluorides: calcium salts reduce absorption of fluoridesIron: calcium salts reduce absorption of oral ironThyroid Hormones: calcium salts reduce absorption oflevothyroxineZinc: calcium salts reduce absorption of zincCalcium-channel BlockersNote Dihydropyridine calcium-channel blockers includeamlodipine, felodipine, isradipine, lacidipine, lercanidipine,nicardipine, nifedipine, and nimodipineACE Inhibitors: enhanced hypotensive effect whencalcium-channel blockers given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when calcium-channel blockers given withadrenergic neurone blockersAlcohol: enhanced hypotensive effect when calciumchannelblockers given with alcohol; verapamilpossibly increases plasma concentration of alcoholAldesleukin: enhanced hypotensive effect whencalcium-channel blockers given with aldesleukinAliskiren: avoidance of verapamil advised by manufacturerof aliskiren. Alpha-blockers: enhanced hypotensive effect whencalcium-channel blockers given with .alpha-blockers,also increased risk of first-dose hypotension withpost-synaptic alpha-blockers such as prazosin. Anaesthetics, General: enhanced hypotensive effectwhen calcium-channel blockers given with generalanaesthetics or isoflurane; hypotensive effect ofverapamil enhanced by .general anaesthetics (alsoAV delay)Analgesics: hypotensive effect of calcium-channelblockers antagonised by NSAIDs; diltiazem inhibitsmetabolism of alfentanil (risk of prolonged or delayedrespiratory depression)Calcium-channel Blockers (continued)Angiotensin-II Receptor Antagonists: enhancedhypotensive effect when calcium-channel blockersgiven with angiotensin-II receptor antagonists. Anti-arrhythmics: increased risk of bradycardia, AVblock and myocardial depression when diltiazem orverapamil given with .amiodarone; increased risk ofmyocardial depression and asystole when verapamilgiven with .disopyramide or .flecainide; increasedrisk of bradycardia and myocardial depression whendiltiazem and verapamil given with .dronedarone;nifedipine increases plasma concentration of.dronedarone. Antibacterials: metabolism of verapamil possiblyinhibited by .clarithromycin and .erythromycin(increased risk of toxicity); metabolism of felodipinepossibly inhibited by erythromycin (increased plasmaconcentration); manufacturer of lercanidipine advisesavoid concomitant use with erythromycin; metabolismof diltiazem, nifedipine, nimodipine andverapamil accelerated by .rifampicin (plasma concentrationsignificantly reduced); metabolism ofisradipine and nicardipine possibly accelerated by.rifampicin (possible significantly reduced plasmaconcentration). Anticoagulants: verapamil possibly increases plasmaconcentration of .dabigatran etexilate (reduce doseof dabigatran etexilate). Antidepressants: metabolism of nifedipine possiblyinhibited by fluoxetine (increased plasma concentration);diltiazem and verapamil increase plasmaconcentration of imipramine; enhanced hypotensiveeffect when calcium-channel blockers given withMAOIs; plasma concentration of verapamil significantlyreduced by .St John’s wort; plasma concentrationof nifedipine reduced by St John’s wort;plasma concentration of amlodipine possibly reducedby St John’s wort; diltiazem and verapamil possiblyincrease plasma concentration of tricyclicsAntidiabetics: glucose tolerance occasionally impairedwhen nifedipine given with insulin. Antiepileptics: effects of dihydropyridines,nicardipine and nifedipine probably reduced bycarbamazepine; effects of felodipine and isradipinereduced by carbamazepine; diltiazem and verapamilenhance effects of .carbamazepine; manufacturer ofnimodipine advises avoid concomitant use withcarbamazepine and phenytoin (plasma concentrationof nimodipine possibly reduced); manufacturer ofnimodipine advises avoid concomitant use with.phenobarbital (plasma concentration of nimodipinereduced); manufacturer of isradipine advises avoidconcomitant use with phenobarbital and phenytoin;effects of calcium-channel blockers probably reducedby .phenobarbital; effects of felodipine and verapamilreduced by phenytoin; diltiazem increasesplasma concentration of .phenytoin but also effect ofdiltiazem reduced. Antifungals: metabolism of dihydropyridines possiblyinhibited by itraconazole and ketoconazole(increased plasma concentration); metabolism offelodipine inhibited by .itraconazole and.ketoconazole (increased plasma concentration);manufacturer of lercanidipine advises avoid concomitantuse with itraconazole and ketoconazole;negative inotropic effect possibly increased whencalcium-channel blockers given with itraconazole;plasma concentration of nifedipine increased bymicafunginAntimalarials: possible increased risk of bradycardiawhen calcium-channel blockers given with mefloquineAntimuscarinics: avoidance of verapamil advised bymanufacturer of darifenacinAntipsychotics: enhanced hypotensive effect whencalcium-channel blockers given with antipsychotics. Antivirals: plasma concentration of verapamil possiblyincreased by atazanavir; plasma concentration ofdiltiazem increased by .atazanavir (reduce dose of

BNFC 2011–2012 Appendix 1: Interactions 679Calcium-channel Blockers. Antivirals (continued)diltiazem); plasma concentration of diltiazemreduced by efavirenz; plasma concentration ofcalcium-channel blockers possibly increased by.ritonavir; manufacturer of lercanidipine advisesavoid concomitant use with ritonavirAnxiolytics and Hypnotics: enhanced hypotensiveeffect when calcium-channel blockers given withanxiolytics and hypnotics; diltiazem and verapamilinhibit metabolism of midazolam (increased plasmaconcentration with increased sedation); absorption oflercanidipine increased by midazolam; diltiazem andverapamil increase plasma concentration of buspirone(reduce dose of buspirone)Aprepitant: plasma concentration of both drugs mayincrease when diltiazem given with aprepitant. Beta-blockers: enhanced hypotensive effect whencalcium-channel blockers given with beta-blockers;increased risk of AV block and bradycardia whendiltiazem given with .beta-blockers; asystole, severehypotension and heart failure when verapamil givenwith .beta-blockers (see p. 109); possible severehypotension and heart failure when nifedipine givenwith .beta-blockersCalcium-channel Blockers: plasma concentration ofboth drugs may increase when diltiazem given withnifedipine. Cardiac Glycosides: nifedipine possibly increasesplasma concentration of .digoxin; diltiazem,lercanidipine and nicardipine increase plasma concentrationof .digoxin; verapamil increases plasmaconcentration of .digoxin, also increased risk of AVblock and bradycardia. Ciclosporin: diltiazem, nicardipine and verapamilincrease plasma concentration of .ciclosporin; combinationof lercanidipine with .ciclosporin mayincrease plasma concentration of either drug (orboth)—avoid concomitant use; plasma concentrationof nifedipine possibly increased by ciclosporin(increased risk of toxicity including gingival hyperplasia)Cilostazol: diltiazem increases plasma concentration ofcilostazol (consider reducing dose of cilostazol)Clonidine: enhanced hypotensive effect when calciumchannelblockers given with clonidine. Colchicine: diltiazem and verapamil possibly increaserisk of .colchicine toxicity—suspend or reduce doseof colchicine (avoid concomitant use in hepatic orrenal impairment)Corticosteroids: hypotensive effect of calcium-channelblockers antagonised by corticosteroids; diltiazemincreases plasma concentration of methylprednisolone. Cytotoxics: verapamil possibly increases plasma concentrationof doxorubicin; plasma concentration ofboth drugs may increase when verapamil given with.everolimus; nifedipine possibly inhibits metabolismof vincristineDiazoxide: enhanced hypotensive effect when calciumchannelblockers given with diazoxideDiuretics: enhanced hypotensive effect when calciumchannelblockers given with diuretics; diltiazem andverapamil increase plasma concentration of eplerenone(reduce dose of eplerenone)Dopaminergics: enhanced hypotensive effect whencalcium-channel blockers given with levodopaGrapefruit Juice: plasma concentration of felodipine,isradipine, lacidipine, lercanidipine, nicardipine, nifedipine,nimodipine and verapamil increased bygrapefruit juice; plasma concentration of amlodipinepossibly increased by grapefruit juiceHormone Antagonists: diltiazem and verapamilincrease plasma concentration of dutasteride. Ivabradine: diltiazem and verapamil increase plasmaconcentration of .ivabradine—avoid concomitantuseCalcium-channel Blockers (continued). Lipid-regulating Drugs: diltiazem increases plasmaconcentration of atorvastatin and simvastatin—possibleincreased risk of myopathy; increased risk ofmyopathy when verapamil given with .simvastatin;possible increased risk of myopathy when amlodipinegiven with simvastatinLithium: neurotoxicity may occur when diltiazem orverapamil given with lithium without increasedplasma concentration of lithium. Magnesium (parenteral): profound hypotensionreported with concomitant use of nifedipine and.parenteral magnesium in pre-eclampsiaMethyldopa: enhanced hypotensive effect whencalcium-channel blockers given with methyldopaMoxisylyte: enhanced hypotensive effect whencalcium-channel blockers given with moxisylyteMoxonidine: enhanced hypotensive effect whencalcium-channel blockers given with moxonidineMuscle Relaxants: verapamil enhances effects of nondepolarisingmuscle relaxants and suxamethonium;enhanced hypotensive effect when calcium-channelblockers given with baclofen or tizanidine; manufacturerof verapamil advises avoid concomitant use ofintravenous dantrolene; possible increased risk ofventricular arrhythmias when diltiazem given withintravenous dantrolene—manufacturer of diltiazemadvises avoid concomitant use; calcium-channelblockers possibly enhance effects of non-depolarisingmuscle relaxantsNitrates: enhanced hypotensive effect when calciumchannelblockers given with nitratesOestrogens: hypotensive effect of calcium-channelblockers antagonised by oestrogensProstaglandins: enhanced hypotensive effect whencalcium-channel blockers given with alprostadilRanolazine: diltiazem and verapamil increase plasmaconcentration of ranolazine (consider reducing doseof ranolazine)Sildenafil: enhanced hypotensive effect when amlodipinegiven with sildenafil. Sirolimus: diltiazem increases plasma concentration of.sirolimus; plasma concentration of both drugsincreased when verapamil given with .sirolimusSulfinpyrazone: plasma concentration of verapamilreduced by sulfinpyrazone. Tacrolimus: diltiazem and nifedipine increase plasmaconcentration of .tacrolimus; felodipine,nicardipine and verapamil possibly increase plasmaconcentration of tacrolimus. Theophylline: calcium-channel blockers possiblyincrease plasma concentration of .theophylline(enhanced effect); diltiazem increases plasma concentrationof theophylline; verapamil increasesplasma concentration of .theophylline (enhancedeffect)Ulcer-healing Drugs: metabolism of calcium-channelblockers possibly inhibited by cimetidine (increasedplasma concentration); plasma concentration ofisradipine increased by cimetidine (halve dose ofisradipine)Vardenafil: enhanced hypotensive effect when nifedipinegiven with vardenafilVasodilator Antihypertensives: enhanced hypotensiveeffect when calcium-channel blockers given withhydralazine, minoxidil or sodium nitroprussideCalcium-channel Blockers (dihydropyridines) seeCalcium-channel BlockersCandesartan see Angiotensin-II Receptor AntagonistsCannabis ExtractAntidepressants: possible increased risk of hypertensionand tachycardia when cannabis extract givenwith tricyclicsCapecitabine see FluorouracilCapreomycinAntibacterials: increased risk of nephrotoxicity whencapreomycin given with colistimethate sodium orpolymyxins; increased risk of nephrotoxicity andAppendix 1: Interactions

680 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsCapreomycinAntibacterials (continued)ototoxicity when capreomycin given withaminoglycosides or vancomycinCytotoxics: increased risk of nephrotoxicity and ototoxicitywhen capreomycin given with platinumcompoundsVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Captopril see ACE InhibitorsCarbamazepineAlcohol: CNS side-effects of carbamazepine possiblyincreased by alcohol. Analgesics: effects of carbamazepine enhanced by.dextropropoxyphene; carbamazepine reducesplasma concentration of methadone; carbamazepinereduces effects of tramadol; carbamazepine possiblyaccelerates metabolism of paracetamol. Anti-arrhythmics: carbamazepine possibly reducesplasma concentration of .dronedarone—avoid concomitantuse. Antibacterials: plasma concentration of carbamazepineincreased by .clarithromycin and.erythromycin; plasma concentration of carbamazepinereduced by .rifabutin; carbamazepine acceleratesmetabolism of doxycycline (reduced effect);plasma concentration of carbamazepine increased by.isoniazid (also possibly increased isoniazid hepatotoxicity);carbamazepine reduces plasma concentrationof .telithromycin (avoid during and for 2 weeksafter carbamazepine). Anticoagulants: carbamazepine accelerates metabolismof .coumarins (reduced anticoagulant effect). Antidepressants: plasma concentration of carbamazepineincreased by .fluoxetine and .fluvoxamine;carbamazepine reduces plasma concentration of.mianserin and mirtazapine; anticonvulsant effect ofantiepileptics possibly antagonised by MAOIs and.tricyclic-related antidepressants (convulsive thresholdlowered); manufacturer of carbamazepine advisesavoid for 2 weeks after stopping .MAOIs, alsoantagonism of anticonvulsant effect; anticonvulsanteffect of antiepileptics antagonised by .SSRIs and.tricyclics (convulsive threshold lowered); avoidconcomitant use of antiepileptics with .St John’swort; carbamazepine accelerates metabolism of.tricyclics (reduced plasma concentration andreduced effect). Antiepileptics: plasma concentration of both drugsreduced when carbamazepine given with eslicarbazepine;carbamazepine possibly reduces plasmaconcentration of ethosuximide; carbamazepine oftenreduces plasma concentration of lamotrigine, alsoplasma concentration of an active metabolite ofcarbamazepine sometimes raised (but evidence isconflicting); possible increased risk of carbamazepinetoxicity when given with levetiracetam; plasmaconcentration of carbamazepine sometimes reducedby oxcarbazepine (but concentration of an activemetabolite of carbamazepine may be increased), alsoplasma concentration of an active metabolite ofoxcarbazepine often reduced; carbamazepine possiblyincreases plasma concentration of phenobarbital;plasma concentration of both drugs often reducedwhen carbamazepine given with phenytoin, alsoplasma concentration of phenytoin may be increased;plasma concentration of both drugs possibly reducedwhen carbamazepine given with rufinamide; plasmaconcentration of carbamazepine increased by.stiripentol; carbamazepine reduces plasma concentrationof tiagabine and zonisamide; carbamazepineoften reduces plasma concentration of topiramate;carbamazepine reduces plasma concentration ofvalproate, also plasma concentration of activemetabolite of carbamazepine increased. Antifungals: plasma concentration of carbamazepinepossibly increased by fluconazole, ketoconazole andmiconazole; carbamazepine possibly reduces plasmaCarbamazepine. Antifungals (continued)concentration of itraconazole and .posaconazole;carbamazepine possibly reduces plasma concentrationof .voriconazole—avoid concomitant use;carbamazepine possibly reduces plasma concentrationof caspofungin—consider increasing doseof caspofungin. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered); carbamazepine accelerates metabolism ofhaloperidol, olanzapine, quetiapine and risperidone(reduced plasma concentration); carbamazepinereduces plasma concentration of .aripiprazole—increase dose of aripiprazole; carbamazepine acceleratesmetabolism of .clozapine (reduced plasmaconcentration), also avoid concomitant use of drugswith substantial potential for causing agranulocytosis;carbamazepine reduces plasma concentration ofpaliperidone. Antivirals: carbamazepine possibly reduces plasmaconcentration of darunavir, fosamprenavir, lopinavir,nelfinavir, saquinavir and tipranavir; plasma concentrationof both drugs reduced when carbamazepinegiven with efavirenz; avoidance of carbamazepineadvised by manufacturer of etravirine; carbamazepinepossibly reduces plasma concentration of.indinavir, also plasma concentration of carbamazepinepossibly increased; carbamazepine reducesplasma concentration of nevirapine; plasma concentrationof carbamazepine possibly increased by.ritonavirAnxiolytics and Hypnotics: carbamazepine oftenreduces plasma concentration of clonazepam;carbamazepine reduces plasma concentration ofmidazolamAprepitant: carbamazepine possibly reduces plasmaconcentration of aprepitantBupropion: carbamazepine reduces plasma concentrationof bupropion. Calcium-channel Blockers: carbamazepine reduceseffects of felodipine and isradipine; carbamazepineprobably reduces effects of dihydropyridines,nicardipine and nifedipine; avoidance of carbamazepineadvised by manufacturer of nimodipine (plasmaconcentration of nimodipine possibly reduced);effects of carbamazepine enhanced by .diltiazem and.verapamil. Ciclosporin: carbamazepine accelerates metabolism of.ciclosporin (reduced plasma concentration). Clopidogrel: carbamazepine possibly reduces antiplateleteffect of .clopidogrel. Corticosteroids: carbamazepine accelerates metabolismof .corticosteroids (reduced effect). Cytotoxics: avoidance of carbamazepine advised bymanufacturer of gefitinib; carbamazepine reducesplasma concentration of .imatinib and .lapatinib—avoid concomitant use; carbamazepine reducesplasma concentration of irinotecan and its activemetabolite. Diuretics: increased risk of hyponatraemia whencarbamazepine given with diuretics; plasma concentrationof carbamazepine increased by.acetazolamide; carbamazepine reduces plasmaconcentration of .eplerenone—avoid concomitantuse. Hormone Antagonists: metabolism of carbamazepineinhibited by .danazol (increased risk of toxicity);carbamazepine possibly accelerates metabolism oftoremifene (reduced plasma concentration)5HT 3 Antagonists: carbamazepine accelerates metabolismof ondansetron (reduced effect)

BNFC 2011–2012 Appendix 1: Interactions 681Carbamazepine (continued). Lipid-regulating Drugs: carbamazepine reducesplasma concentration of .simvastatin—considerincreasing dose of simvastatinLithium: neurotoxicity may occur when carbamazepinegiven with lithium without increased plasma concentrationof lithiumMuscle Relaxants: carbamazepine antagonises musclerelaxant effect of non-depolarising muscle relaxants(accelerated recovery from neuromuscular blockade). Oestrogens: carbamazepine accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistat. Progestogens: carbamazepine accelerates metabolismof .progestogens (reduced contraceptive effect—seep. 398)Retinoids: plasma concentration of carbamazepinepossibly reduced by isotretinoinTheophylline: carbamazepine accelerates metabolismof theophylline (reduced effect)Thyroid Hormones: carbamazepine acceleratesmetabolism of thyroid hormones (may increaserequirements for thyroid hormones in hypothyroidism)Tibolone: carbamazepine accelerates metabolism oftibolone (reduced plasma concentration). Ulcer-healing Drugs: metabolism of carbamazepineinhibited by .cimetidine (increased plasma concentration). Ulipristal: avoidance of carbamazepine advised bymanufacturer of .ulipristal (contraceptive effect ofulipristal possibly reduced)Vitamins: carbamazepine possibly increases requirementsfor vitamin DCarbapenems see Doripenem, Ertapenem, Imipenemwith Cilastatin, and MeropenemCarbonic Anhydrase Inhibitors see DiureticsCarboplatin see Platinum CompoundsCarboprost see ProstaglandinsCardiac GlycosidesACE Inhibitors: plasma concentration of digoxinpossibly increased by captoprilAlpha-blockers: plasma concentration of digoxinincreased by prazosinAminosalicylates: absorption of digoxin possiblyreduced by sulfasalazineAnalgesics: plasma concentration of cardiac glycosidespossibly increased by NSAIDs, also possible exacerbationof heart failure and reduction of renal functionAntacids: absorption of digoxin possibly reduced byantacids. Anti-arrhythmics: plasma concentration of digoxinincreased by .amiodarone, .dronedarone and.propafenone (halve dose of digoxin)Antibacterials: plasma concentration of digoxin possiblyincreased by gentamicin, telithromycin andtrimethoprim; absorption of digoxin reduced byneomycin; plasma concentration of digoxin possiblyreduced by rifampicin; plasma concentration ofdigoxin increased by macrolides (increased risk oftoxicity). Antidepressants: plasma concentration of digoxinreduced by .St John’s wort—avoid concomitant useAntidiabetics: plasma concentration of digoxin possiblyreduced by acarbose; plasma concentration ofdigoxin increased by sitagliptinAntiepileptics: plasma concentration of digoxin possiblyreduced by phenytoin. Antifungals: increased cardiac toxicity with cardiacglycosides if hypokalaemia occurs with.amphotericin; plasma concentration of digoxinincreased by .itraconazole. Antimalarials: plasma concentration of digoxin possiblyincreased by .chloroquine and hydroxychloroquine;possible increased risk of bradycardia whendigoxin given with mefloquine; plasma concentrationof digoxin increased by .quinineCardiac Glycosides (continued)Antimuscarinics: plasma concentration of digoxinpossibly increased by darifenacinAntivirals: plasma concentration of digoxin increasedby etravirine; plasma concentration of digoxinpossibly increased by ritonavirAnxiolytics and Hypnotics: plasma concentration ofdigoxin increased by alprazolam (increased risk oftoxicity)Beta-blockers: increased risk of AV block and bradycardiawhen cardiac glycosides given with betablockersCalcium Salts: arrhythmias can be precipitated whencardiac glycosides given with large intravenous dosesof calcium salts. Calcium-channel Blockers: plasma concentration ofdigoxin increased by .diltiazem, .lercanidipine and.nicardipine; plasma concentration of digoxin possiblyincreased by .nifedipine; plasma concentration ofdigoxin increased by .verapamil, also increased riskof AV block and bradycardia. Ciclosporin: plasma concentration of digoxin increasedby .ciclosporin (increased risk of toxicity). Colchicine: possible increased risk of myopathy whendigoxin given with .colchicineCorticosteroids: increased risk of hypokalaemia whencardiac glycosides given with corticosteroidsCytotoxics: absorption of digoxin tablets possiblyreduced by bleomycin, carmustine, cyclophosphamide,cytarabine, doxorubicin, melphalan, methotrexate,procarbazine and vincristine. Diuretics: increased cardiac toxicity with cardiacglycosides if hypokalaemia occurs with.acetazolamide, .loop diuretics or .thiazides andrelated diuretics; plasma concentration of digoxinpossibly increased by potassium canrenoate; plasmaconcentration of digoxin increased by.spironolactoneLenalidomide: plasma concentration of digoxin possiblyincreased by lenalidomideLipid-regulating Drugs: absorption of cardiac glycosidespossibly reduced by colestipol and colestyramine;plasma concentration of digoxin possiblyincreased by atorvastatinMuscle Relaxants: risk of ventricular arrhythmiaswhen cardiac glycosides given with suxamethonium;possible increased risk of bradycardia when cardiacglycosides given with tizanidinePenicillamine: plasma concentration of digoxin possiblyreduced by penicillamineRanolazine: plasma concentration of digoxin increasedby ranolazineSympathomimetics, Beta 2 : plasma concentration ofdigoxin possibly reduced by salbutamolTolvaptan: plasma concentration of digoxin increasedby tolvaptan (increased risk of toxicity)Ulcer-healing Drugs: plasma concentration of digoxinpossibly slightly increased by proton pump inhibitors;absorption of cardiac glycosides possibly reduced bysucralfateCarmustine. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cardiac Glycosides: carmustine possibly reducesabsorption of digoxin tabletsUlcer-healing Drugs: myelosuppressive effects ofcarmustine possibly enhanced by cimetidineCarteolol see Beta-blockersCarvedilol see Beta-blockersCaspofunginAntibacterials: plasma concentration of caspofungininitially increased and then reduced by rifampicin(consider increasing dose of caspofungin)Antiepileptics: plasma concentration of caspofunginpossibly reduced by carbamazepine and phenytoin—consider increasing dose of caspofunginAntivirals: plasma concentration of caspofungin possiblyreduced by efavirenz and nevirapine—considerincreasing dose of caspofunginAppendix 1: Interactions

682 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsCaspofungin (continued). Ciclosporin: plasma concentration of caspofunginincreased by .ciclosporin (manufacturer of caspofunginrecommends monitoring liver enzymes)Corticosteroids: plasma concentration of caspofunginpossibly reduced by dexamethasone—considerincreasing dose of caspofungin. Tacrolimus: caspofungin reduces plasma concentrationof .tacrolimusCefaclor see CephalosporinsCefadroxil see CephalosporinsCefalexin see CephalosporinsCefixime see CephalosporinsCefotaxime see CephalosporinsCefpodoxime see CephalosporinsCefradine see CephalosporinsCeftazidime see CephalosporinsCeftriaxone see CephalosporinsCefuroxime see CephalosporinsCelecoxib see NSAIDsCeliprolol see Beta-blockersCephalosporinsAntacids: absorption of cefaclor and cefpodoximereduced by antacidsAntibacterials: possible increased risk of nephrotoxicitywhen cephalosporins given with aminoglycosides. Anticoagulants: cephalosporins possibly enhanceanticoagulant effect of .coumarinsProbenecid: excretion of cephalosporins reduced byprobenecid (increased plasma concentration)Ulcer-healing Drugs: absorption of cefpodoximereduced by histamine H 2 -antagonistsVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Certolizumab pegol. Abatacept: avoid concomitant use of certolizumabpegol with .abatacept. Anakinra: avoid concomitant use of certolizumab pegolwith .anakinra. Vaccines: avoid concomitant use of certolizumab pegolwith live .vaccines (see p. 599)Cetirizine see AntihistaminesChenodeoxycholic Acid see Bile AcidsChloral see Anxiolytics and HypnoticsChloramphenicolAntibacterials: metabolism of chloramphenicol acceleratedby rifampicin (reduced plasma concentration). Anticoagulants: chloramphenicol enhances anticoagulanteffect of .coumarins. Antidiabetics: chloramphenicol enhances effects of.sulfonylureas. Antiepileptics: metabolism of chloramphenicol possiblyaccelerated by .phenobarbital (reduced plasmaconcentration); chloramphenicol increases plasmaconcentration of .phenytoin (increased risk oftoxicity). Antipsychotics: avoid concomitant use of chloramphenicolwith .clozapine (increased risk ofagranulocytosis). Ciclosporin: chloramphenicol possibly increasesplasma concentration of .ciclosporin. Clopidogrel: chloramphenicol possibly reduces antiplateleteffect of .clopidogrelHydroxocobalamin: chloramphenicol reducesresponse to hydroxocobalamin. Tacrolimus: chloramphenicol possibly increasesplasma concentration of .tacrolimusVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Chlordiazepoxide see Anxiolytics and HypnoticsChloroquine and HydroxychloroquineAdsorbents: absorption of chloroquine and hydroxychloroquinereduced by kaolinAgalsidase Alfa and Beta: chloroquine and hydroxychloroquinepossibly inhibit effects of agalsidase alfaand beta (manufacturers of agalsidase alfa and betaadvise avoid concomitant use)Chloroquine and Hydroxychloroquine (continued)Antacids: absorption of chloroquine and hydroxychloroquinereduced by antacids. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen chloroquine and hydroxychloroquinegiven with .amiodarone—avoid concomitant use. Antibacterials: increased risk of ventricular arrhythmiaswhen chloroquine and hydroxychloroquinegiven with .moxifloxacin—avoid concomitant useAntiepileptics: possible increased risk of convulsionswhen chloroquine and hydroxychloroquine givenwith antiepileptics. Antimalarials: avoidance of antimalarials advised bymanufacturer of .artemether/lumefantrine;increased risk of convulsions when chloroquine andhydroxychloroquine given with .mefloquine. Antipsychotics: increased risk of ventricular arrhythmiaswhen chloroquine and hydroxychloroquinegiven with .droperidol—avoid concomitant use. Cardiac Glycosides: chloroquine and hydroxychloroquinepossibly increase plasma concentration of.digoxin. Ciclosporin: chloroquine and hydroxychloroquineincrease plasma concentration of .ciclosporin(increased risk of toxicity)Histamine: avoidance of antimalarials advised bymanufacturer of histamineLanthanum: absorption of chloroquine and hydroxychloroquinepossibly reduced by lanthanum (give atleast 2 hours apart)Laronidase: chloroquine and hydroxychloroquine possiblyinhibit effects of laronidase (manufacturer oflaronidase advises avoid concomitant use)Parasympathomimetics: chloroquine and hydroxychloroquinehave potential to increase symptoms ofmyasthenia gravis and thus diminish effect ofneostigmine and pyridostigmineUlcer-healing Drugs: metabolism of chloroquine andhydroxychloroquine inhibited by cimetidine(increased plasma concentration)Vaccines: antimalarials inactivate oral typhoidvaccine—see p. 620Chlorothiazide see DiureticsChlorphenamine see AntihistaminesChlorpromazine see AntipsychoticsChlortalidone see DiureticsCiclesonide see CorticosteroidsCiclosporin. ACE Inhibitors: increased risk of hyperkalaemia whenciclosporin given with .ACE inhibitors. Aliskiren: ciclosporin increases plasma concentrationof .aliskiren—avoid concomitant useAllopurinol: plasma concentration of ciclosporin possiblyincreased by allopurinol (risk of nephrotoxicity). Analgesics: increased risk of nephrotoxicity whenciclosporin given with .NSAIDs; ciclosporinincreases plasma concentration of .diclofenac (halvedose of diclofenac). Angiotensin-II Receptor Antagonists: increased risk ofhyperkalaemia when ciclosporin given with .angiotensin-IIreceptor antagonistsAnti-arrhythmics: plasma concentration of ciclosporinpossibly increased by amiodarone and propafenone. Antibacterials: metabolism of ciclosporin inhibited by.clarithromycin and .erythromycin (increasedplasma concentration); metabolism of ciclosporinaccelerated by .rifampicin (reduced plasma concentration);plasma concentration of ciclosporin possiblyreduced by .sulfadiazine; increased risk of nephrotoxicitywhen ciclosporin given with.aminoglycosides, .polymyxins, .quinolones,.sulfonamides or .vancomycin; plasma concentrationof ciclosporin possibly increased by.chloramphenicol and .telithromycin; increased riskof myopathy when ciclosporin given with.daptomycin (preferably avoid concomitant use);metabolism of ciclosporin possibly inhibited by.macrolides (increased plasma concentration);increased risk of nephrotoxicity when ciclosporin

BNFC 2011–2012 Appendix 1: Interactions 683Ciclosporin. Antibacterials (continued)given with .trimethoprim, also plasma concentrationof ciclosporin reduced by intravenoustrimethoprim. Antidepressants: plasma concentration of ciclosporinreduced by .St John’s wort—avoid concomitant useAntidiabetics: ciclosporin possibly enhances hypoglycaemiceffect of repaglinide. Antiepileptics: metabolism of ciclosporin acceleratedby .carbamazepine, .phenobarbital and .phenytoin(reduced plasma concentration); plasma concentrationof ciclosporin possibly reduced by oxcarbazepine. Antifungals: metabolism of ciclosporin inhibited by.fluconazole, .itraconazole, .ketoconazole,.posaconazole and .voriconazole (increased plasmaconcentration); metabolism of ciclosporin possiblyinhibited by .miconazole (increased plasma concentration);increased risk of nephrotoxicity whenciclosporin given with .amphotericin; ciclosporinincreases plasma concentration of .caspofungin(manufacturer of caspofungin recommends monitoringliver enzymes); plasma concentration of ciclosporinpossibly reduced by griseofulvin andterbinafine; plasma concentration of ciclosporinpossibly increased by micafungin. Antimalarials: plasma concentration of ciclosporinincreased by .chloroquine and hydroxychloroquine(increased risk of toxicity)Antimuscarinics: avoidance of ciclosporin advised bymanufacturer of darifenacin. Antivirals: increased risk of nephrotoxicity whenciclosporin given with aciclovir; plasma concentrationof ciclosporin possibly increased by .atazanavir,.nelfinavir and .ritonavir; plasma concentration ofciclosporin possibly reduced by .efavirenz; plasmaconcentration of ciclosporin increased by.fosamprenavir and .indinavir; plasma concentrationof both drugs increased when ciclosporin given with.saquinavir. Beta-blockers: plasma concentration of ciclosporinincreased by .carvedilol. Bile Acids: absorption of ciclosporin increased by.ursodeoxycholic acid. Bosentan: ciclosporin increases plasma concentrationof .bosentan (also plasma concentration of ciclosporinreduced—avoid concomitant use). Calcium-channel Blockers: combination of ciclosporinwith .lercanidipine may increase plasma concentrationof either drug (or both)—avoid concomitant use;plasma concentration of ciclosporin increased by.diltiazem, .nicardipine and .verapamil; ciclosporinpossibly increases plasma concentration of nifedipine(increased risk of toxicity including gingival hyperplasia). Cardiac Glycosides: ciclosporin increases plasmaconcentration of .digoxin (increased risk of toxicity). Colchicine: possible increased risk of nephrotoxicityand myotoxicity when ciclosporin given with.colchicine—suspend or reduce dose of colchicine(avoid concomitant use in hepatic or renal impairment). Corticosteroids: plasma concentration of ciclosporinincreased by high-dose .methylprednisolone (risk ofconvulsions); ciclosporin increases plasma concentrationof prednisolone. Cytotoxics: increased risk of nephrotoxicity whenciclosporin given with .melphalan; increased risk ofneurotoxicity when ciclosporin given with.doxorubicin; ciclosporin increases plasma concentrationof .epirubicin, .everolimus and .idarubicin;ciclosporin reduces excretion of mitoxantrone(increased plasma concentration); risk of toxicitywhen ciclosporin given with .methotrexate; plasmaconcentration of ciclosporin possibly increased byimatinib; in vitro studies suggest a possible interactionbetween ciclosporin and docetaxel (consultdocetaxel product literature); ciclosporin possiblyCiclosporin. Cytotoxics (continued)increases plasma concentration of etoposide(increased risk of toxicity). Diuretics: plasma concentration of ciclosporin possiblyincreased by .acetazolamide; increased risk ofhyperkalaemia when ciclosporin given with .potassium-sparingdiuretics and aldosterone antagonists;increased risk of nephrotoxicity and possibly hypermagnesaemiawhen ciclosporin given with thiazidesand related diuretics. Grapefruit Juice: plasma concentration of ciclosporinincreased by .grapefruit juice (increased risk oftoxicity). Hormone Antagonists: metabolism of ciclosporininhibited by .danazol (increased plasma concentration);plasma concentration of ciclosporin reduced bylanreotide and .octreotide. Lipid-regulating Drugs: absorption of ciclosporinreduced by .colesevelam; increased risk of renalimpairment when ciclosporin given withbezafibrate or fenofibrate; increased risk of myopathywhen ciclosporin given with .rosuvastatin (avoidconcomitant use); plasma concentration of bothdrugs may increase when ciclosporin given with.ezetimibe; increased risk of myopathy when ciclosporingiven with .statinsMannitol: possible increased risk of nephrotoxicitywhen ciclosporin given with mannitol. Metoclopramide: plasma concentration of ciclosporinincreased by .metoclopramideMifamurtide: avoidance of ciclosporin advised bymanufacturer of mifamurtide. Modafinil: plasma concentration of ciclosporin reducedby .modafinilOestrogens: plasma concentration of ciclosporin possiblyincreased by oestrogens. Orlistat: absorption of ciclosporin possibly reduced by.orlistat. Potassium Salts: increased risk of hyperkalaemiawhen ciclosporin given with .potassium saltsProgestogens: plasma concentration of ciclosporinpossibly increased by progestogensRanolazine: ciclosporin possibly increases plasmaconcentration of ranolazineSevelamer: plasma concentration of ciclosporin possiblyreduced by sevelamerSirolimus: ciclosporin increases plasma concentrationof sirolimus. Sitaxentan: ciclosporin increases plasma concentrationof .sitaxentan—avoid concomitant use. Sulfinpyrazone: plasma concentration of ciclosporinreduced by .sulfinpyrazone. Tacrolimus: plasma concentration of ciclosporinincreased by .tacrolimus (increased risk of nephrotoxicity)—avoidconcomitant use. Ulcer-healing Drugs: plasma concentration of ciclosporinpossibly increased by .cimetidine; plasmaconcentration of ciclosporin possibly affected byomeprazoleVitamins: plasma concentration of ciclosporin possiblyaffected by vitamin ECidofovir. Antivirals: manufacturers advise avoid concomitantuse of cidofovir with .tenofovirCilazapril see ACE InhibitorsCilostazol. Anagrelide: avoidance of cilostazol advised by manufacturerof .anagrelideAntibacterials: plasma concentration of cilostazolincreased by erythromycin (consider reducing doseof cilostazol)Antifungals: plasma concentration of cilostazolincreased by ketoconazole (consider reducing dose ofcilostazol)Calcium-channel Blockers: plasma concentration ofcilostazol increased by diltiazem (consider reducingdose of cilostazol)Appendix 1: Interactions

684 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsCilostazol (continued)Ulcer-healing Drugs: plasma concentration of cilostazolincreased by omeprazole (consider reducing doseof cilostazol)Cimetidine see Histamine H 2 -antagonistsCinacalcetAntifungals: metabolism of cinacalcet inhibited byketoconazole (increased plasma concentration). Hormone Antagonists: cinacalcet possibly inhibitsmetabolism of .tamoxifen to active metabolite (avoidconcomitant use)Cinnarizine see AntihistaminesCiprofibrate see FibratesCiprofloxacin see QuinolonesCisatracurium see Muscle RelaxantsCisplatin see Platinum CompoundsCitalopram see Antidepressants, SSRIClarithromycin see MacrolidesClemastine see AntihistaminesClindamycin. Muscle Relaxants: clindamycin enhances effects of.non-depolarising muscle relaxants and.suxamethoniumParasympathomimetics: clindamycin antagoniseseffects of neostigmine and pyridostigmineVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Clobazam see Anxiolytics and HypnoticsClomethiazole see Anxiolytics and HypnoticsClomipramine see Antidepressants, TricyclicClonazepam see Anxiolytics and HypnoticsClonidineACE Inhibitors: enhanced hypotensive effect whenclonidine given with ACE inhibitors; previous treatmentwith clonidine possibly delays antihypertensiveeffect of captoprilAdrenergic Neurone Blockers: enhanced hypotensiveeffect when clonidine given with adrenergic neuroneblockersAlcohol: enhanced hypotensive effect when clonidinegiven with alcoholAldesleukin: enhanced hypotensive effect when clonidinegiven with aldesleukinAlpha-blockers: enhanced hypotensive effect whenclonidine given with alpha-blockersAnaesthetics, General: enhanced hypotensive effectwhen clonidine given with general anaestheticsAnalgesics: hypotensive effect of clonidine antagonisedby NSAIDsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when clonidine given with angiotensin-IIreceptor antagonists. Antidepressants: enhanced hypotensive effect whenclonidine given with MAOIs; hypotensive effect ofclonidine possibly antagonised by mirtazapine;hypotensive effect of clonidine antagonised by.tricyclics, also increased risk of hypertension onclonidine withdrawalAntipsychotics: enhanced hypotensive effect whenclonidine given with phenothiazinesAnxiolytics and Hypnotics: enhanced hypotensiveeffect when clonidine given with anxiolytics andhypnotics. Beta-blockers: increased risk of withdrawal hypertensionwhen clonidine given with .beta-blockers(withdraw beta-blockers several days before slowlywithdrawing clonidine)Calcium-channel Blockers: enhanced hypotensiveeffect when clonidine given with calcium-channelblockersCorticosteroids: hypotensive effect of clonidineantagonised by corticosteroidsDiazoxide: enhanced hypotensive effect when clonidinegiven with diazoxideDiuretics: enhanced hypotensive effect when clonidinegiven with diureticsDopaminergics: enhanced hypotensive effect whenclonidine given with levodopaClonidine (continued)Histamine: avoidance of clonidine advised by manufacturerof histamineMethyldopa: enhanced hypotensive effect whenclonidine given with methyldopaMoxisylyte: enhanced hypotensive effect when clonidinegiven with moxisylyteMoxonidine: enhanced hypotensive effect when clonidinegiven with moxonidineMuscle Relaxants: enhanced hypotensive effect whenclonidine given with baclofen or tizanidineNitrates: enhanced hypotensive effect when clonidinegiven with nitratesOestrogens: hypotensive effect of clonidine antagonisedby oestrogensProstaglandins: enhanced hypotensive effect whenclonidine given with alprostadil. Sympathomimetics: possible risk of hypertensionwhen clonidine given with adrenaline(epinephrine) or noradrenaline (norepinephrine);serious adverse events reported with concomitantuse of clonidine and .methylphenidate (causality notestablished)Vasodilator Antihypertensives: enhanced hypotensiveeffect when clonidine given with hydralazine,minoxidil or sodium nitroprussideClopamide see DiureticsClopidogrelAnalgesics: increased risk of bleeding when clopidogrelgiven with NSAIDs or aspirin. Antibacterials: antiplatelet effect of clopidogrel possiblyreduced by .chloramphenicol, .ciprofloxacin and.erythromycin. Anticoagulants: manufacturer of clopidogrel advisesavoid concomitant use with .warfarin; antiplateletaction of clopidogrel enhances anticoagulant effect of.coumarins and .phenindione; increased risk ofbleeding when clopidogrel given with heparins. Antidepressants: antiplatelet effect of clopidogrelpossibly reduced by .fluoxetine, .fluvoxamine and.moclobemide. Antiepileptics: antiplatelet effect of clopidogrel possiblyreduced by .carbamazepine and .oxcarbazepine. Antifungals: antiplatelet effect of clopidogrel possiblyreduced by .fluconazole, .itraconazole,.ketoconazole and .voriconazole. Antivirals: antiplatelet effect of clopidogrel possiblyreduced by .etravirineDipyridamole: increased risk of bleeding when clopidogrelgiven with dipyridamoleIloprost: increased risk of bleeding when clopidogrelgiven with iloprostPrasugrel: possible increased risk of bleeding whenclopidogrel given with prasugrel. Ulcer-healing Drugs: antiplatelet effect of clopidogrelpossibly reduced by .cimetidine, lansoprazole,pantoprazole and rabeprazole; antiplatelet effect ofclopidogrel reduced by .esomeprazole and.omeprazoleClotrimazole see Antifungals, ImidazoleClozapine see AntipsychoticsCo-amoxiclav see PenicillinsCo-beneldopa see LevodopaCo-careldopa see LevodopaCodeine see Opioid AnalgesicsCo-fluampicil see PenicillinsColchicine. Anti-arrhythmics: possible increased risk of colchicinetoxicity when given with .amiodarone. Antibacterials: possible increased risk of colchicinetoxicity when given with .azithromycin,.clarithromycin, .erythromycin and .telithromycin—suspend or reduce dose of colchicine (avoid concomitantuse in hepatic or renal impairment). Antifungals: possible increased risk of colchicinetoxicity when given with .itraconazole and.ketoconazole—suspend or reduce dose of

BNFC 2011–2012 Appendix 1: Interactions 685Colchicine. Antifungals (continued)colchicine (avoid concomitant use in hepatic orrenal impairment). Antivirals: possible increased risk of colchicine toxicitywhen given with .atazanavir, .indinavir and.ritonavir—suspend or reduce dose of colchicine(avoid concomitant use in hepatic or renal impairment). Calcium-channel Blockers: possible increased risk ofcolchicine toxicity when given with .diltiazem and.verapamil—suspend or reduce dose of colchicine(avoid concomitant use in hepatic or renal impairment). Cardiac Glycosides: possible increased risk of myopathywhen colchicine given with .digoxin. Ciclosporin: possible increased risk of nephrotoxicityand myotoxicity when colchicine given with.ciclosporin—suspend or reduce dose of colchicine(avoid concomitant use in hepatic or renal impairment). Grapefruit Juice: possible increased risk of colchicinetoxicity when given with .grapefruit juice. Lipid-regulating Drugs: possible increased risk ofmyopathy when colchicine given with .fibrates or.statinsColesevelamNote Other drugs should be taken at least 4 hours before orafter colesevelam to reduce possible interference withabsorptionAntidiabetics: colesevelam reduces absorption ofglibenclamideAntiepileptics: colesevelam possibly reduces absorptionof phenytoin. Ciclosporin: colesevelam reduces absorption of.ciclosporinOestrogens: colesevelam reduces absorption of ethinylestradiolThyroid Hormones: colesevelam reduces absorption oflevothyroxineColestipolNote Other drugs should be taken at least 1 hour before or4–6 hours after colestipol to reduce possible interferencewith absorptionAntibacterials: colestipol possibly reduces absorptionof tetracyclineBile Acids: colestipol possibly reduces absorption ofbile acidsCardiac Glycosides: colestipol possibly reducesabsorption of cardiac glycosidesDiuretics: colestipol reduces absorption of thiazidesand related diuretics (give at least 2 hours apart)Thyroid Hormones: colestipol reduces absorption ofthyroid hormonesColestyramineNote Other drugs should be taken at least 1 hour before or4–6 hours after colestyramine to reduce possible interferencewith absorptionAnalgesics: colestyramine increases the excretion ofmeloxicam; colestyramine reduces absorption ofparacetamolAntibacterials: colestyramine possibly reducesabsorption of tetracycline; colestyramine antagoniseseffects of oral vancomycin. Anticoagulants: colestyramine may enhance or reduceanticoagulant effect of .coumarins and .phenindioneAntidiabetics: colestyramine possibly enhances hypoglycaemiceffect of acarboseAntiepileptics: colestyramine possibly reducesabsorption of valproateBile Acids: colestyramine possibly reduces absorptionof bile acidsCardiac Glycosides: colestyramine possibly reducesabsorption of cardiac glycosidesDiuretics: colestyramine reduces absorption of thiazidesand related diuretics (give at least 2 hoursapart)Colestyramine (continued)Leflunomide: colestyramine significantly decreaseseffect of leflunomide (enhanced elimination)—avoidunless drug elimination desiredMycophenolate: colestyramine reduces absorption ofmycophenolateRaloxifene: colestyramine reduces absorption ofraloxifene (manufacturer of raloxifene advises avoidconcomitant administration)Thyroid Hormones: colestyramine reduces absorptionof thyroid hormonesColistimethate Sodium see PolymyxinsContraceptives, oral see Oestrogens and ProgestogensCorticosteroidsNote Interactions do not generally apply to corticosteroidsused for topical action (including inhalation) unless specifiedACE Inhibitors: corticosteroids antagonise hypotensiveeffect of ACE inhibitorsAdrenergic Neurone Blockers: corticosteroids antagonisehypotensive effect of adrenergic neuroneblockers. Aldesleukin: avoidance of corticosteroids advised bymanufacturer of .aldesleukinAlpha-blockers: corticosteroids antagonise hypotensiveeffect of alpha-blockersAnalgesics: increased risk of gastro-intestinal bleedingand ulceration when corticosteroids given withNSAIDs; increased risk of gastro-intestinal bleedingand ulceration when corticosteroids given withaspirin, also corticosteroids reduce plasma concentrationof salicylateAngiotensin-II Receptor Antagonists: corticosteroidsantagonise hypotensive effect of angiotensin-IIreceptor antagonistsAntacids: absorption of deflazacort reduced byantacids. Antibacterials: plasma concentration of methylprednisolonepossibly increased by clarithromycin;metabolism of corticosteroids possibly inhibited byerythromycin; metabolism of methylprednisoloneinhibited by erythromycin; corticosteroids possiblyreduce plasma concentration of isoniazid; metabolismof corticosteroids accelerated by .rifamycins(reduced effect). Anticoagulants: corticosteroids may enhance orreduce anticoagulant effect of .coumarins (high-dosecorticosteroids enhance anticoagulant effect); corticosteroidsmay enhance or reduce anticoagulanteffect of phenindioneAntidiabetics: corticosteroids antagonise hypoglycaemiceffect of antidiabetics. Antiepileptics: metabolism of corticosteroids acceleratedby .carbamazepine, .phenobarbital and.phenytoin (reduced effect). Antifungals: metabolism of corticosteroids possiblyinhibited by itraconazole and ketoconazole; plasmaconcentration of active metabolite of ciclesonideincreased by ketoconazole; plasma concentration ofinhaled mometasone increased by ketoconazole;plasma concentration of inhaled and oral budesonideincreased by ketoconazole; metabolism of methylprednisoloneinhibited by ketoconazole; increasedrisk of hypokalaemia when corticosteroids given with.amphotericin—avoid concomitant use unless corticosteroidsneeded to control reactions; plasmaconcentration of inhaled budesonide increased byitraconazole; metabolism of methylprednisolonepossibly inhibited by itraconazole; dexamethasonepossibly reduces plasma concentration of caspofungin—considerincreasing dose of caspofungin. Antivirals: dexamethasone possibly reduces plasmaconcentration of indinavir, lopinavir and saquinavir;plasma concentration of inhaled and intranasalfluticasone possibly increased by nelfinavir; plasmaconcentration of corticosteroids, dexamethasone andprednisolone possibly increased by ritonavir; plasmaconcentration of inhaled and intranasalbudesonide and fluticasone increased by .ritonavirAppendix 1: Interactions

686 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsCorticosteroids (continued)Aprepitant: metabolism of dexamethasone andmethylprednisolone inhibited by aprepitant (reducedose of dexamethasone and methylprednisolone)Beta-blockers: corticosteroids antagonise hypotensiveeffect of beta-blockersCalcium Salts: corticosteroids reduce absorption ofcalcium saltsCalcium-channel Blockers: corticosteroids antagonisehypotensive effect of calcium-channel blockers;plasma concentration of methylprednisoloneincreased by diltiazemCardiac Glycosides: increased risk of hypokalaemiawhen corticosteroids given with cardiac glycosides. Ciclosporin: high-dose methylprednisolone increasesplasma concentration of .ciclosporin (risk of convulsions);plasma concentration of prednisoloneincreased by ciclosporinClonidine: corticosteroids antagonise hypotensiveeffect of clonidineDiazoxide: corticosteroids antagonise hypotensiveeffect of diazoxideDiuretics: corticosteroids antagonise diuretic effect ofdiuretics; increased risk of hypokalaemia whencorticosteroids given with acetazolamide, loopdiuretics or thiazides and related diureticsHistamine: avoidance of corticosteroids advised bymanufacturer of histamineMethyldopa: corticosteroids antagonise hypotensiveeffect of methyldopaMifamurtide: avoidance of corticosteroids advised bymanufacturer of mifamurtideMifepristone: effect of corticosteroids (includinginhaled corticosteroids) may be reduced for 3–4 daysafter mifepristoneMoxonidine: corticosteroids antagonise hypotensiveeffect of moxonidineMuscle Relaxants: corticosteroids possibly antagoniseeffects of pancuronium and vecuroniumNitrates: corticosteroids antagonise hypotensive effectof nitratesOestrogens: plasma concentration of corticosteroidsincreased by oral contraceptives containing oestrogensSodium Benzoate: corticosteroids possibly reduceeffects of sodium benzoateSodium Phenylbutyrate: corticosteroids possiblyreduce effects of sodium phenylbutyrateSomatropin: corticosteroids may inhibit growth-promotingeffect of somatropinSympathomimetics: metabolism of dexamethasoneaccelerated by ephedrineSympathomimetics, Beta 2 : increased risk of hypokalaemiawhen corticosteroids given with high doses ofbeta 2 sympathomimetics—see Hypokalaemia, p. 138Theophylline: increased risk of hypokalaemia whencorticosteroids given with theophylline. Vaccines: high doses of corticosteroids impair immuneresponse to .vaccines, avoid concomitant use withlive vaccines (see p. 599)Vasodilator Antihypertensives: corticosteroids antagonisehypotensive effect of hydralazine, minoxidil andsodium nitroprussideCortisone see CorticosteroidsCo-trimoxazole see Trimethoprim and SulfamethoxazoleCoumarinsNote Change in patient’s clinical condition, particularlyassociated with liver disease, intercurrent illness, or drugadministration, necessitates more frequent testing. Majorchanges in diet (especially involving salads and vegetables)and in alcohol consumption may also affect anticoagulantcontrol. Alcohol: anticoagulant control with coumarins may beaffected by major changes in consumption of.alcoholAllopurinol: anticoagulant effect of coumarins possiblyenhanced by allopurinolCoumarins (continued). Anabolic Steroids: anticoagulant effect of coumarinsenhanced by .anabolic steroids. Analgesics: anticoagulant effect of coumarins possiblyenhanced by .NSAIDs; increased risk of haemorrhagewhen anticoagulants given with intravenous.diclofenac (avoid concomitant use, including lowdoseheparins); increased risk of haemorrhage whenanticoagulants given with .ketorolac (avoid concomitantuse, including low-dose heparins); anticoagulanteffect of coumarins enhanced by.tramadol; increased risk of bleeding when coumarinsgiven with .aspirin (due to antiplatelet effect);anticoagulant effect of coumarins possibly enhancedby prolonged regular use of paracetamol. Anti-arrhythmics: metabolism of coumarins inhibitedby .amiodarone (enhanced anticoagulant effect);anticoagulant effect of coumarins enhanced by.propafenone. Antibacterials: experience in anticoagulant clinicssuggests that INR possibly altered when coumarinsare given with .neomycin (given for local action ongut); anticoagulant effect of coumarins possiblyenhanced by .azithromycin, .aztreonam,.cephalosporins, levofloxacin, .tetracyclines,tigecycline and trimethoprim; anticoagulant effect ofcoumarins enhanced by .chloramphenicol,.ciprofloxacin, .clarithromycin, .erythromycin,.metronidazole, .nalidixic acid, .norfloxacin,.ofloxacin and .sulfonamides; studies have failed todemonstrate an interaction with coumarins, butcommon experience in anticoagulant clinics is thatINR can be altered by a course of broad-spectrumpenicillins such as ampicillin; metabolism of coumarinsaccelerated by .rifamycins (reduced anticoagulanteffect). Antidepressants: anticoagulant effect of warfarinpossibly enhanced by .venlafaxine; anticoagulanteffect of warfarin may be enhanced or reduced bytrazodone; anticoagulant effect of coumarins possiblyenhanced by .SSRIs; anticoagulant effect of coumarinsreduced by .St John’s wort (avoid concomitantuse); anticoagulant effect of warfarin enhanced bymirtazapine; anticoagulant effect of coumarins maybe enhanced or reduced by .tricyclics. Antidiabetics: anticoagulant effect of warfarin possiblyenhanced by exenatide; coumarins possibly enhancehypoglycaemic effect of .sulfonylureas, also possiblechanges to anticoagulant effect. Antiepileptics: metabolism of coumarins acceleratedby .carbamazepine and .phenobarbital (reducedanticoagulant effect); plasma concentration of warfarinreduced by eslicarbazepine; metabolism ofcoumarins accelerated by .phenytoin (possibility ofreduced anticoagulant effect, but enhancement alsoreported); anticoagulant effect of coumarins possiblyenhanced by valproate. Antifungals: anticoagulant effect of coumarinsenhanced by .fluconazole, .itraconazole,.ketoconazole and .voriconazole; anticoagulanteffect of coumarins enhanced by .miconazole(miconazole oral gel and possibly vaginal formulationsabsorbed); anticoagulant effect of coumarinsreduced by .griseofulvinAntimalarials: isolated reports that anticoagulant effectof warfarin may be enhanced by proguanil; plasmaconcentration of both drugs increased when warfaringiven with quinine. Antivirals: anticoagulant effect of warfarin may beenhanced or reduced by atazanavir, .nevirapine and.ritonavir; plasma concentration of warfarin possiblyaffected by .efavirenz; anticoagulant effect ofcoumarins may be enhanced or reduced by fosamprenavir;anticoagulant effect of coumarins possiblyenhanced by .ritonavir; anticoagulant effect of warfarinpossibly enhanced by saquinavirAnxiolytics and Hypnotics: anticoagulant effect ofcoumarins may transiently be enhanced by chloral

BNFC 2011–2012 Appendix 1: Interactions 687Coumarins (continued)Aprepitant: anticoagulant effect of warfarin possiblyreduced by aprepitant. Azathioprine: anticoagulant effect of coumarins possiblyreduced by .azathioprineBosentan: monitoring anticoagulant effect of coumarinsrecommended by manufacturer of bosentan. Clopidogrel: anticoagulant effect of coumarinsenhanced due to antiplatelet action of .clopidogrel;avoidance of warfarin advised by manufacturer of.clopidogrel. Corticosteroids: anticoagulant effect of coumarins maybe enhanced or reduced by .corticosteroids (highdosecorticosteroids enhance anticoagulant effect). Cranberry Juice: anticoagulant effect of coumarinspossibly enhanced by .cranberry juice—avoid concomitantuse. Cytotoxics: anticoagulant effect of coumarins possiblyenhanced by .etoposide, .ifosfamide and .sorafenib;anticoagulant effect of coumarins enhanced by.fluorouracil; anticoagulant effect of warfarin possiblyenhanced by .gefitinib and gemcitabine; anticoagulanteffect of coumarins possibly reduced by.mercaptopurine and .mitotane; increased risk ofbleeding when coumarins given with .erlotinib;replacement of warfarin with a heparin advised bymanufacturer of imatinib (possibility of enhancedwarfarin effect). Dipyridamole: anticoagulant effect of coumarinsenhanced due to antiplatelet action of .dipyridamole. Disulfiram: anticoagulant effect of coumarinsenhanced by .disulfiram. Dopaminergics: anticoagulant effect of warfarinenhanced by .entacapone. Enteral Foods: anticoagulant effect of coumarinsantagonised by vitamin K (present in some .enteralfeeds ). Glucosamine: anticoagulant effect of warfarinenhanced by .glucosamine (avoid concomitant use). Hormone Antagonists: anticoagulant effect of coumarinspossibly enhanced by bicalutamide and.toremifene; metabolism of coumarins inhibited by.danazol (enhanced anticoagulant effect); anticoagulanteffect of coumarins enhanced by.flutamide and .tamoxifenIloprost: anticoagulant effect of coumarins possiblyenhanced by iloprostLactulose: anticoagulant effect of coumarins possiblyenhanced by lactuloseLeflunomide: anticoagulant effect of warfarin possiblyenhanced by leflunomideLeukotriene Receptor Antagonists: anticoagulanteffect of warfarin enhanced by zafirlukast. Levamisole: anticoagulant effect of warfarin possiblyenhanced by .levamisole. Lipid-regulating Drugs: anticoagulant effect of coumarinsmay be enhanced or reduced by.colestyramine; anticoagulant effect of warfarin maybe transiently reduced by atorvastatin; anticoagulanteffect of coumarins enhanced by .fibrates,.fluvastatin and simvastatin; anticoagulant effect ofcoumarins possibly enhanced by ezetimibe and.rosuvastatinMemantine: anticoagulant effect of warfarin possiblyenhanced by memantineOestrogens: anticoagulant effect of coumarins may beenhanced or reduced by oestrogensOrlistat: monitoring anticoagulant effect of coumarinsrecommended by manufacturer of orlistatPrasugrel: possible increased risk of bleeding whencoumarins given with prasugrelProgestogens: anticoagulant effect of coumarins maybe enhanced or reduced by progestogensRaloxifene: anticoagulant effect of coumarins antagonisedby raloxifene. Retinoids: anticoagulant effect of coumarins possiblyreduced by .acitretin. Sitaxentan: anticoagulant effect of coumarinsenhanced by .sitaxentanCoumarins (continued). Sulfinpyrazone: anticoagulant effect of coumarinsenhanced by .sulfinpyrazone. Sympathomimetics: anticoagulant effect of coumarinspossibly enhanced by .methylphenidate. Testolactone: anticoagulant effect of coumarinsenhanced by .testolactone. Testosterone: anticoagulant effect of coumarinsenhanced by .testosterone. Thyroid Hormones: anticoagulant effect of coumarinsenhanced by .thyroid hormonesUbidecarenone: anticoagulant effect of warfarin maybe enhanced or reduced by ubidecarenone. Ulcer-healing Drugs: metabolism of coumarins inhibitedby .cimetidine (enhanced anticoagulant effect);anticoagulant effect of coumarins possibly enhancedby .esomeprazole, .omeprazole and pantoprazole;absorption of coumarins possibly reduced by.sucralfate (reduced anticoagulant effect)Vaccines: anticoagulant effect of warfarin possiblyenhanced by influenza vaccine. Vitamins: anticoagulant effect of coumarins possiblyenhanced by .vitamin E; anticoagulant effect ofcoumarins antagonised by .vitamin KCranberry Juice. Anticoagulants: cranberry juice possibly enhancesanticoagulant effect of .coumarins—avoid concomitantuseCyclizine see AntihistaminesCyclopenthiazide see DiureticsCyclopentolate see AntimuscarinicsCyclophosphamideAntifungals: side-effects of cyclophosphamide possiblyincreased by itraconazole. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cardiac Glycosides: cyclophosphamide possiblyreduces absorption of digoxin tablets. Cytotoxics: increased toxicity when high-dose cyclophosphamidegiven with .pentostatin—avoid concomitantuseMuscle Relaxants: cyclophosphamide enhanceseffects of suxamethoniumCycloserine. Alcohol: increased risk of convulsions when cycloserinegiven with .alcoholAntibacterials: increased risk of CNS toxicity whencycloserine given with isoniazidVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Cyproheptadine see AntihistaminesCytarabineAntifungals: cytarabine possibly reduces plasma concentrationof flucytosine. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cardiac Glycosides: cytarabine possibly reducesabsorption of digoxin tabletsCytotoxics: intracellular concentration of cytarabineincreased by fludarabineCytotoxics see individual drugsDabigatran Etexilate. Analgesics: possible increased risk of bleeding whendabigatran etexilate given with .NSAIDs; increasedrisk of haemorrhage when anticoagulants given withintravenous .diclofenac (avoid concomitant use,including low-dose heparins); increased risk ofhaemorrhage when anticoagulants given with.ketorolac (avoid concomitant use, including lowdoseheparins). Anti-arrhythmics: plasma concentration of dabigatranetexilate increased by .amiodarone (reduce dose ofdabigatran etexilate). Calcium-channel Blockers: plasma concentration ofdabigatran etexilate possibly increased by .verapamil(reduce dose of dabigatran etexilate)Appendix 1: Interactions

688 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsDacarbazine. Aldesleukin: avoidance of dacarbazine advised bymanufacturer of .aldesleukin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Dairy ProductsAntibacterials: dairy products reduce absorption ofciprofloxacin and norfloxacin; dairy products reduceabsorption of tetracyclines (except doxycycline andminocycline)Eltrombopag: dairy products possibly reduce absorptionof eltrombopag (give at least 4 hours apart)Dalteparin see HeparinsDanazol. Anticoagulants: danazol inhibits metabolism of.coumarins (enhanced anticoagulant effect). Antiepileptics: danazol inhibits metabolism of.carbamazepine (increased risk of toxicity). Ciclosporin: danazol inhibits metabolism of.ciclosporin (increased plasma concentration). Lipid-regulating Drugs: possible increased risk ofmyopathy when danazol given with .simvastatinTacrolimus: danazol possibly increases plasma concentrationof tacrolimusDantrolene see Muscle RelaxantsDapsoneAntibacterials: plasma concentration of dapsonereduced by rifamycins; plasma concentration of bothdrugs may increase when dapsone given withtrimethoprim. Antivirals: increased risk of ventricular arrhythmiaswhen dapsone given with .saquinavir—avoid concomitantuseProbenecid: excretion of dapsone reduced by probenecid(increased risk of side-effects)Vaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Daptomycin. Ciclosporin: increased risk of myopathy when daptomycingiven with .ciclosporin (preferably avoidconcomitant use). Lipid-regulating Drugs: increased risk of myopathywhen daptomycin given with .fibrates or .statins(preferably avoid concomitant use)Vaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Darifenacin see AntimuscarinicsDarunavirAnti-arrhythmics: darunavir possibly increases plasmaconcentration of lidocaine—avoid concomitant use. Antibacterials: darunavir increases plasma concentrationof .rifabutin (reduce dose of rifabutin); plasmaconcentration of darunavir significantly reduced by.rifampicin—avoid concomitant useAnticoagulants: avoidance of darunavir advised bymanufacturer of rivaroxaban. Antidepressants: darunavir possibly reduces plasmaconcentration of paroxetine and sertraline; plasmaconcentration of darunavir reduced by .St John’swort—avoid concomitant useAntiepileptics: plasma concentration of darunavirpossibly reduced by carbamazepine,phenobarbital and phenytoinAntifungals: plasma concentration of both drugsincreased when darunavir given with ketoconazole. Antimalarials: caution with darunavir advised bymanufacturer of artemether/lumefantrine; darunavirpossibly increases plasma concentration of .quinine(increased risk of toxicity). Antivirals: plasma concentration of darunavir reducedby efavirenz and saquinavir; plasma concentration ofboth drugs increased when darunavir given withindinavir; plasma concentration of darunavir reducedby .lopinavir, also plasma concentration of lopinavirincreased (avoid concomitant use); darunavirincreases plasma concentration of .maraviroc (considerreducing dose of maraviroc)Darunavir (continued). Cytotoxics: darunavir possibly increases plasma concentrationof .everolimus—manufacturer of everolimusadvises avoid concomitant use. Lipid-regulating Drugs: darunavir possibly increasesplasma concentration of pravastatin; possibleincreased risk of myopathy when darunavir givenwith .rosuvastatin—manufacturer of rosuvastatinadvises avoid concomitant use. Ranolazine: darunavir possibly increases plasma concentrationof .ranolazine—manufacturer of ranolazineadvises avoid concomitant useDasatinib. Antibacterials: metabolism of dasatinib accelerated by.rifampicin (reduced plasma concentration—avoidconcomitant use)Antifungals: plasma concentration of dasatinib possiblyincreased by ketoconazole. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Lipid-regulating Drugs: dasatinib possibly increasesplasma concentration of simvastatinUlcer-healing Drugs: plasma concentration of dasatinibpossibly reduced by famotidineDeferasiroxAntacids: absorption of deferasirox possibly reducedby antacids containing aluminium (manufacturer ofdeferasirox advises avoid concomitant use)Antibacterials: plasma concentration of deferasiroxreduced by rifampicinAntidiabetics: deferasirox increases plasma concentrationof repaglinideAnxiolytics and Hypnotics: deferasirox possiblyreduces plasma concentration of midazolamDeflazacort see CorticosteroidsDemeclocycline see TetracyclinesDesferrioxamineAntipsychotics: avoidance of desferrioxamine advisedby manufacturer of levomepromazine; manufacturerof desferrioxamine advises avoid concomitant usewith prochlorperazineDesflurane see Anaesthetics, GeneralDesloratadine see AntihistaminesDesmopressinAnalgesics: effects of desmopressin enhanced byindometacinLoperamide: plasma concentration of oral desmopressinincreased by loperamideDesogestrel see ProgestogensDexamethasone see CorticosteroidsDexamfetamine see SympathomimeticsDexibuprofen see NSAIDsDexketoprofen see NSAIDsDextromethorphan see Opioid AnalgesicsDextropropoxyphene see Opioid AnalgesicsDiamorphine see Opioid AnalgesicsDiazepam see Anxiolytics and HypnoticsDiazoxideACE Inhibitors: enhanced hypotensive effect whendiazoxide given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when diazoxide given with adrenergic neuroneblockersAlcohol: enhanced hypotensive effect when diazoxidegiven with alcoholAldesleukin: enhanced hypotensive effect when diazoxidegiven with aldesleukinAlpha-blockers: enhanced hypotensive effect whendiazoxide given with alpha-blockersAnaesthetics, General: enhanced hypotensive effectwhen diazoxide given with general anaestheticsAnalgesics: hypotensive effect of diazoxide antagonisedby NSAIDsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when diazoxide given with angiotensin-IIreceptor antagonists

BNFC 2011–2012 Appendix 1: Interactions 689Diazoxide (continued)Antidepressants: enhanced hypotensive effect whendiazoxide given with MAOIs or tricyclic-relatedantidepressantsAntidiabetics: diazoxide antagonises hypoglycaemiceffect of antidiabeticsAntiepileptics: diazoxide reduces plasma concentrationof phenytoin, also effect of diazoxide may bereducedAntipsychotics: enhanced hypotensive effect whendiazoxide given with phenothiazinesAnxiolytics and Hypnotics: enhanced hypotensiveeffect when diazoxide given with anxiolytics andhypnoticsBeta-blockers: enhanced hypotensive effect whendiazoxide given with beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when diazoxide given with calcium-channelblockersClonidine: enhanced hypotensive effect when diazoxidegiven with clonidineCorticosteroids: hypotensive effect of diazoxideantagonised by corticosteroidsDiuretics: enhanced hypotensive and hyperglycaemiceffects when diazoxide given with diureticsDopaminergics: enhanced hypotensive effect whendiazoxide given with levodopaMethyldopa: enhanced hypotensive effect when diazoxidegiven with methyldopaMoxisylyte: enhanced hypotensive effect when diazoxidegiven with moxisylyteMoxonidine: enhanced hypotensive effect when diazoxidegiven with moxonidineMuscle Relaxants: enhanced hypotensive effect whendiazoxide given with baclofen or tizanidineNitrates: enhanced hypotensive effect when diazoxidegiven with nitratesProstaglandins: enhanced hypotensive effect whendiazoxide given with alprostadilVasodilator Antihypertensives: enhanced hypotensiveeffect when diazoxide given with hydralazine,minoxidil or sodium nitroprussideDiclofenac see NSAIDsDicycloverine see AntimuscarinicsDidanosineNote Antacids in tablet formulation may affect absorption ofother drugs. Allopurinol: plasma concentration of didanosineincreased by .allopurinol (risk of toxicity)—avoidconcomitant useAnalgesics: plasma concentration of didanosine possiblyreduced by methadone. Antivirals: plasma concentration of didanosine possiblyincreased by ganciclovir; increased risk of side-effectswhen didanosine given with .ribavirin—avoid concomitantuse; increased risk of side-effects whendidanosine given with .stavudine; plasma concentrationof didanosine increased by .tenofovir(increased risk of toxicity)—avoid concomitant use;plasma concentration of didanosine reduced by.tipranavir. Cytotoxics: increased risk of toxicity when didanosinegiven with .hydroxycarbamide—avoid concomitantuseDienogest see ProgestogensDigoxin see Cardiac GlycosidesDihydrocodeine see Opioid AnalgesicsDiltiazem see Calcium-channel BlockersDimethyl sulfoxide. Analgesics: avoid concomitant use of dimethyl sulfoxidewith .sulindacDinoprostone see ProstaglandinsDiphenoxylate see Opioid AnalgesicsDipipanone see Opioid AnalgesicsDipyridamoleAntacids: absorption of dipyridamole possibly reducedby antacidsDipyridamole (continued). Anti-arrhythmics: dipyridamole enhances and extendsthe effects of .adenosine (important risk of toxicity). Anticoagulants: antiplatelet action of dipyridamoleenhances anticoagulant effect of .coumarins and.phenindione; dipyridamole enhances anticoagulanteffect of heparinsClopidogrel: increased risk of bleeding when dipyridamolegiven with clopidogrelCytotoxics: dipyridamole possibly reduces effects offludarabineDisodium Etidronate see BisphosphonatesDisodium Pamidronate see BisphosphonatesDisopyramideAnaesthetics, Local: increased myocardial depressionwhen anti-arrhythmics given with bupivacaine, levobupivacaine,prilocaine or ropivacaine. Anti-arrhythmics: increased myocardial depressionwhen anti-arrhythmics given with other .antiarrhythmics;increased risk of ventricular arrhythmiaswhen disopyramide given with .amiodarone or.dronedarone—avoid concomitant use. Antibacterials: plasma concentration of disopyramidepossibly increased by .clarithromycin (increased riskof toxicity); plasma concentration of disopyramideincreased by .erythromycin (increased risk of toxicity);increased risk of ventricular arrhythmias whendisopyramide given with .moxifloxacin—avoid concomitantuse; metabolism of disopyramide acceleratedby .rifamycins (reduced plasma concentration). Antidepressants: increased risk of ventricular arrhythmiaswhen disopyramide given with .tricyclicsAntidiabetics: disopyramide possibly enhances hypoglycaemiceffect of gliclazide, insulin and metforminAntiepileptics: metabolism of disopyramide acceleratedby phenobarbital (reduced plasma concentration);plasma concentration of disopyramide reducedby phenytoin. Antifungals: increased risk of ventricular arrhythmiaswhen disopyramide given with .ketoconazole—avoidconcomitant use; avoidance of disopyramide advisedby manufacturer of .itraconazole. Antihistamines: increased risk of ventricular arrhythmiaswhen disopyramide given with .mizolastine—avoid concomitant use. Antimalarials: avoidance of disopyramide advised bymanufacturer of .artemether/lumefantrine (risk ofventricular arrhythmias). Antimuscarinics: increased risk of antimuscarinic sideeffectswhen disopyramide given with antimuscarinics;increased risk of ventricular arrhythmias whendisopyramide given with .tolterodine. Antipsychotics: increased risk of ventricular arrhythmiaswhen anti-arrhythmics that prolong the QTinterval given with .antipsychotics that prolong theQT interval; increased risk of ventricular arrhythmiaswhen disopyramide given with .amisulpride,.droperidol, .pimozide or .zuclopenthixol—avoidconcomitant use; possible increased risk of ventriculararrhythmias when disopyramide given with.haloperidol—avoid concomitant use; increased riskof ventricular arrhythmias when disopyramide givenwith .phenothiazines or .sulpiride. Antivirals: plasma concentration of disopyramidepossibly increased by .ritonavir (increased risk oftoxicity); increased risk of ventricular arrhythmiaswhen disopyramide given with .saquinavir—avoidconcomitant use. Atomoxetine: increased risk of ventricular arrhythmiaswhen disopyramide given with .atomoxetine. Beta-blockers: increased myocardial depression whenanti-arrhythmics given with .beta-blockers; increasedrisk of ventricular arrhythmias when disopyramidegiven with .sotalol—avoid concomitant use. Calcium-channel Blockers: increased risk of myocardialdepression and asystole when disopyramidegiven with .verapamil. Cytotoxics: increased risk of ventricular arrhythmiaswhen disopyramide given with .arsenic trioxideAppendix 1: Interactions

690 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsDisopyramide (continued). Diuretics: increased cardiac toxicity with disopyramideif hypokalaemia occurs with .acetazolamide, .loopdiuretics or .thiazides and related diuretics. Ivabradine: increased risk of ventricular arrhythmiaswhen disopyramide given with .ivabradineNitrates: disopyramide reduces effects of sublingualtablets of nitrates (failure to dissolve under tongueowing to dry mouth). Ranolazine: avoidance of disopyramide advised bymanufacturer of .ranolazineDistigmine see ParasympathomimeticsDisulfiramAlcohol: disulfiram reaction when disulfiram given withalcohol (see BNF section 4.10.1)Antibacterials: psychotic reaction reported whendisulfiram given with metronidazole; CNS effects ofdisulfiram possibly increased by isoniazid. Anticoagulants: disulfiram enhances anticoagulanteffect of .coumarinsAntidepressants: increased disulfiram reaction withalcohol reported with concomitant amitriptyline;disulfiram inhibits metabolism of tricyclics (increasedplasma concentration). Antiepileptics: disulfiram inhibits metabolism of.phenytoin (increased risk of toxicity)Anxiolytics and Hypnotics: disulfiram increases risk oftemazepam toxicity; disulfiram inhibits metabolism ofbenzodiazepines (increased sedative effects). Paraldehyde: risk of toxicity when disulfiram givenwith .paraldehydeTheophylline: disulfiram inhibits metabolism of theophylline(increased risk of toxicity)DiureticsNote Since systemic absorption may follow topical applicationof brinzolamide to the eye, the possibility of interactionsshould be borne in mindNote Since systemic absorption may follow topical applicationof dorzolamide to the eye, the possibility of interactionsshould be borne in mind. ACE Inhibitors: enhanced hypotensive effect whendiuretics given with .ACE inhibitors; increased risk ofsevere hyperkalaemia when potassium-sparing diureticsand aldosterone antagonists given with .ACEinhibitors (monitor potassium concentration withlow-dose spironolactone in heart failure)Adrenergic Neurone Blockers: enhanced hypotensiveeffect when diuretics given with adrenergic neuroneblockersAlcohol: enhanced hypotensive effect when diureticsgiven with alcoholAldesleukin: enhanced hypotensive effect when diureticsgiven with aldesleukinAliskiren: plasma concentration of furosemide reducedby aliskiren; increased risk of hyperkalaemia whenpotassium-sparing diuretics and aldosterone antagonistsgiven with aliskirenAllopurinol: increased risk of hypersensitivity whenthiazides and related diuretics given with allopurinolespecially in renal impairment. Alpha-blockers: enhanced hypotensive effect whendiuretics given with .alpha-blockers, also increasedrisk of first-dose hypotension with post-synapticalpha-blockers such as prazosinAnaesthetics, General: enhanced hypotensive effectwhen diuretics given with general anaesthetics. Analgesics: diuretics increase risk of nephrotoxicity ofNSAIDs, also antagonism of diuretic effect; Diureticeffect of potassium canrenoate possibly antagonisedby NSAIDs; possible increased risk of hyperkalaemiawhen potassium-sparing diuretics and aldosteroneantagonists given with NSAIDs; effects of diureticsantagonised by indometacin and ketorolac; increasedrisk of hyperkalaemia when potassium-sparing diureticsand aldosterone antagonists given with indometacin;occasional reports of reduced renal functionwhen triamterene given with .indometacin—avoidconcomitant use; diuretic effect of spironolactoneantagonised by aspirin; increased risk of toxicityDiuretics. Analgesics (continued)when carbonic anhydrase inhibitors given withhigh-dose aspirin. Angiotensin-II Receptor Antagonists: enhancedhypotensive effect when diuretics given with.angiotensin-II receptor antagonists; increased risk ofhyperkalaemia when potassium-sparing diuretics andaldosterone antagonists given with .angiotensin-IIreceptor antagonists. Anti-arrhythmics: plasma concentration of eplerenoneincreased by amiodarone (reduce dose of eplerenone);hypokalaemia caused by acetazolamide, loopdiuretics or thiazides and related diuretics increasescardiac toxicity with amiodarone; hypokalaemiacaused by acetazolamide, loop diuretics or thiazidesand related diuretics increases cardiac toxicity with.disopyramide; hypokalaemia caused by acetazolamide,loop diuretics or thiazides and related diureticsincreases cardiac toxicity with .flecainide;hypokalaemia caused by acetazolamide, loopdiuretics or thiazides and related diuretics antagonisesaction of .lidocaine. Antibacterials: plasma concentration of eplerenoneincreased by .clarithromycin and .telithromycin—avoid concomitant use; plasma concentration ofeplerenone increased by erythromycin (reduce doseof eplerenone); plasma concentration of eplerenonereduced by .rifampicin—avoid concomitant use;avoidance of diuretics advised by manufacturer oflymecycline; increased risk of otoxicity when loopdiuretics given with .aminoglycosides,.polymyxins or .vancomycin; acetazolamide antagoniseseffects of .methenamine; increased risk ofhyperkalaemia when eplerenone given with trimethoprim. Antidepressants: possible increased risk of hypokalaemiawhen loop diuretics or thiazides and relateddiuretics given with reboxetine; enhanced hypotensiveeffect when diuretics given with MAOIs; plasmaconcentration of eplerenone reduced by .St John’swort—avoid concomitant use; increased risk ofpostural hypotension when diuretics given withtricyclicsAntidiabetics: loop diuretics and thiazides and relateddiuretics antagonise hypoglycaemic effect of antidiabetics. Antiepileptics: plasma concentration of eplerenonereduced by .carbamazepine, .phenobarbital and.phenytoin—avoid concomitant use; increased riskof hyponatraemia when diuretics given with carbamazepine;acetazolamide increases plasma concentrationof .carbamazepine; increased risk ofosteomalacia when carbonic anhydrase inhibitorsgiven with phenobarbital or phenytoin; effects offurosemide antagonised by phenytoin; acetazolamidepossibly increases plasma concentration of.phenytoin; hydrochlorothiazide possibly increasesplasma concentration of topiramate. Antifungals: plasma concentration of eplerenoneincreased by .itraconazole and .ketoconazole—avoid concomitant use; increased risk of hypokalaemiawhen loop diuretics or thiazides and relateddiuretics given with amphotericin; hydrochlorothiazideincreases plasma concentration of fluconazole;plasma concentration of eplerenone increasedby fluconazole (reduce dose of eplerenone). Antipsychotics: hypokalaemia caused by diureticsincreases risk of ventricular arrhythmias with.amisulpride; enhanced hypotensive effect whendiuretics given with phenothiazines; hypokalaemiacaused by diuretics increases risk of ventriculararrhythmias with .pimozide (avoid concomitant use). Antivirals: plasma concentration of eplerenoneincreased by .nelfinavir and .ritonavir—avoid concomitantuse; plasma concentration of eplerenoneincreased by saquinavir (reduce dose of eplerenone)Anxiolytics and Hypnotics: enhanced hypotensiveeffect when diuretics given with anxiolytics and

BNFC 2011–2012 Appendix 1: Interactions 691DiureticsAnxiolytics and Hypnotics (continued)hypnotics; administration of parenteral furosemidewith chloral may displace thyroid hormonefrom binding sites. Atomoxetine: hypokalaemia caused by diureticsincreases risk of ventricular arrhythmias with.atomoxetine. Beta-blockers: enhanced hypotensive effect whendiuretics given with beta-blockers; hypokalaemiacaused by loop diuretics or thiazides and relateddiuretics increases risk of ventricular arrhythmiaswith .sotalolCalcium Salts: increased risk of hypercalcaemia whenthiazides and related diuretics given with calciumsaltsCalcium-channel Blockers: enhanced hypotensiveeffect when diuretics given with calcium-channelblockers; plasma concentration of eplerenoneincreased by diltiazem and verapamil (reduce dose ofeplerenone). Cardiac Glycosides: hypokalaemia caused by acetazolamide,loop diuretics or thiazides and relateddiuretics increases cardiac toxicity with .cardiacglycosides; spironolactone increases plasma concentrationof .digoxin; potassium canrenoate possiblyincreases plasma concentration of digoxin. Ciclosporin: increased risk of nephrotoxicity andpossibly hypermagnesaemia when thiazides andrelated diuretics given with ciclosporin; increased riskof hyperkalaemia when potassium-sparing diureticsand aldosterone antagonists given with .ciclosporin;acetazolamide possibly increases plasma concentrationof .ciclosporinClonidine: enhanced hypotensive effect when diureticsgiven with clonidineCorticosteroids: diuretic effect of diuretics antagonisedby corticosteroids; increased risk of hypokalaemiawhen acetazolamide, loop diuretics or thiazides andrelated diuretics given with corticosteroids. Cytotoxics: alkaline urine due to acetazolamideincreases exceretion of methotrexate; hypokalaemiacaused by acetazolamide, loop diuretics or thiazidesand related diuretics increases risk of ventriculararrhythmias with .arsenic trioxide; avoidance ofspironolactone advised by manufacturer of mitotane(antagonism of effect); increased risk of nephrotoxicityand ototoxicity when diuretics given withplatinum compoundsDiazoxide: enhanced hypotensive and hyperglycaemiceffects when diuretics given with diazoxideDiuretics: increased risk of hypokalaemia when loopdiuretics or thiazides and related diuretics given withacetazolamide; profound diuresis possible whenmetolazone given with furosemide; increased risk ofhypokalaemia when thiazides and related diureticsgiven with loop diureticsDopaminergics: enhanced hypotensive effect whendiuretics given with levodopaHormone Antagonists: increased risk of hypercalcaemiawhen thiazides and related diuretics givenwith toremifene; increased risk of hyperkalaemiawhen potassium-sparing diuretics and aldosteroneantagonists given with trilostaneLipid-regulating Drugs: absorption of thiazides andrelated diuretics reduced by colestipol and colestyramine(give at least 2 hours apart). Lithium: loop diuretics and thiazides and relateddiuretics reduce excretion of .lithium (increasedplasma concentration and risk of toxicity)—loopdiuretics safer than thiazides; potassium-sparingdiuretics and aldosterone antagonists reduce excretionof .lithium (increased plasma concentration andrisk of toxicity); acetazolamide increases the excretionof .lithiumMethyldopa: enhanced hypotensive effect when diureticsgiven with methyldopaDiuretics (continued)Moxisylyte: enhanced hypotensive effect when diureticsgiven with moxisylyteMoxonidine: enhanced hypotensive effect when diureticsgiven with moxonidineMuscle Relaxants: enhanced hypotensive effect whendiuretics given with baclofen or tizanidineNitrates: enhanced hypotensive effect when diureticsgiven with nitratesOestrogens: diuretic effect of diuretics antagonised byoestrogens. Potassium Salts: increased risk of hyperkalaemiawhen potassium-sparing diuretics and aldosteroneantagonists given with .potassium saltsProgestogens: risk of hyperkalaemia when potassiumsparingdiuretics and aldosterone antagonists givenwith drospirenone (monitor serum potassium duringfirst cycle)Prostaglandins: enhanced hypotensive effect whendiuretics given with alprostadilSympathomimetics, Beta 2 : increased risk of hypokalaemiawhen acetazolamide, loop diuretics or thiazidesand related diuretics given with high doses ofbeta 2 sympathomimetics—see Hypokalaemia, p. 138. Tacrolimus: increased risk of hyperkalaemia whenpotassium-sparing diuretics and aldosterone antagonistsgiven with .tacrolimusTheophylline: increased risk of hypokalaemia whenacetazolamide, loop diuretics or thiazides and relateddiuretics given with theophyllineVasodilator Antihypertensives: enhanced hypotensiveeffect when diuretics given with hydralazine,minoxidil or sodium nitroprussideVitamins: increased risk of hypercalcaemia whenthiazides and related diuretics given with vitamin DDiuretics, Loop see DiureticsDiuretics, Potassium-sparing and AldosteroneAntagonists see DiureticsDiuretics, Thiazide and related see DiureticsDobutamine see SympathomimeticsDocetaxelAntibacterials: in vitro studies suggest a possibleinteraction between docetaxel and erythromycin(consult docetaxel product literature)Antifungals: in vitro studies suggest a possible interactionbetween docetaxel and ketoconazole (consultdocetaxel product literature). Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Antivirals: plasma concentration of docetaxel possiblyincreased by .ritonavir (increased risk of toxicity)Ciclosporin: in vitro studies suggest a possible interactionbetween docetaxel and ciclosporin (consultdocetaxel product literature)Cytotoxics: possible increased risk of neutropenia whendocetaxel given with lapatinib; plasma concentrationof docetaxel increased by sorafenibDomperidoneAnalgesics: effects of domperidone on gastro-intestinalactivity antagonised by opioid analgesics. Antifungals: risk of arrhythmias with domperidonepossibly increased by .ketoconazoleAntimuscarinics: effects of domperidone on gastrointestinalactivity antagonised by antimuscarinicsDopaminergics: domperidone possibly antagoniseshypoprolactinaemic effects of bromocriptine andcabergolineDonepezil see ParasympathomimeticsDopamine see SympathomimeticsDopaminergics see Amantadine, Apomorphine, Bromocriptine,Cabergoline, Entacapone, Levodopa,Pergolide, Pramipexole, Quinagolide, Rasagiline,Ropinirole, Rotigotine, Selegiline, and TolcaponeDopexamine see SympathomimeticsDoripenem. Antiepileptics: carbapenems reduce plasma concentrationof .valproate—avoid concomitant useAppendix 1: Interactions

692 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsDoripenem (continued)Probenecid: excretion of doripenem reduced by probenecid(manufacturers of doripenem advise avoidconcomitant use)Vaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Dorzolamide see DiureticsDosulepin see Antidepressants, TricyclicDoxapram. Anaesthetics, General: increased risk of arrhythmiaswhen doxapram given with .volatile liquid generalanaesthetics (avoid doxapram for at least 10 minutesafter volatile liquid general anaesthetics)Antidepressants: effects of doxapram enhanced byMAOIsSympathomimetics: increased risk of hypertensionwhen doxapram given with sympathomimeticsTheophylline: increased CNS stimulation when doxapramgiven with theophyllineDoxazosin see Alpha-blockersDoxepin see Antidepressants, TricyclicDoxorubicin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Antivirals: doxorubicin possibly inhibits effects ofstavudineCalcium-channel Blockers: plasma concentration ofdoxorubicin possibly increased by verapamilCardiac Glycosides: doxorubicin possibly reducesabsorption of digoxin tablets. Ciclosporin: increased risk of neurotoxicity whendoxorubicin given with .ciclosporinCytotoxics: plasma concentration of doxorubicin possiblyincreased by sorafenibDoxycycline see TetracyclinesDronedaroneAnaesthetics, Local: increased myocardial depressionwhen anti-arrhythmics given with bupivacaine, levobupivacaine,prilocaine or ropivacaine. Anti-arrhythmics: increased myocardial depressionwhen anti-arrhythmics given with other .antiarrhythmics;increased risk of ventricular arrhythmiaswhen dronedarone given with .amiodarone or.disopyramide—avoid concomitant use. Antibacterials: manufacturer of dronedarone advisesavoid concomitant use with .clarithromycin or.telithromycin (risk of ventricular arrhythmias);plasma concentration of dronedarone possiblyincreased by .erythromycin (increased risk ofventricular arrhythmias—avoid concomitant use);plasma concentration of dronedarone reduced by.rifampicin—avoid concomitant use. Antidepressants: plasma concentration of dronedaronepossibly reduced by .St John’s wort—avoidconcomitant use; manufacturer of dronedaroneadvises avoid concomitant use with .tricyclics (risk ofventricular arrhythmias). Antiepileptics: plasma concentration of dronedaronepossibly reduced by .carbamazepine,.phenobarbital and .phenytoin—avoid concomitantuse. Antifungals: plasma concentration of dronedaroneincreased by .ketoconazole—avoid concomitant use;manufacturer of dronedarone advises avoid concomitantuse with .itraconazole, .posaconazole and.voriconazole. Antipsychotics: increased risk of ventricular arrhythmiaswhen anti-arrhythmics that prolong the QTinterval given with .antipsychotics that prolong theQT interval; manufacturer of dronedarone advisesavoid concomitant use with .phenothiazines (risk ofventricular arrhythmias). Antivirals: manufacturer of dronedarone advises avoidconcomitant use with .ritonavir; increased risk ofventricular arrhythmias when dronedarone givenwith .saquinavir—avoid concomitant use. Beta-blockers: increased myocardial depression whenanti-arrhythmics given with .beta-blockers; drone-Dronedarone. Beta-blockers (continued)darone possibly increases plasma concentrationof metoprolol and propranolol; increased risk ofventricular arrhythmias when dronedarone givenwith .sotalol—avoid concomitant use. Calcium-channel Blockers: plasma concentration ofdronedarone increased by .nifedipine; increased riskof bradycardia and myocardial depression whendronedarone given with .diltiazem and .verapamil. Cardiac Glycosides: dronedarone increases plasmaconcentration of .digoxin (halve dose of digoxin). Grapefruit Juice: plasma concentration of dronedaroneincreased by .grapefruit juice—avoid concomitantuse. Lipid-regulating Drugs: increased risk of myopathywhen dronedarone given with .simvastatinSirolimus: manufacturer of dronedarone advisescaution with sirolimusTacrolimus: manufacturer of dronedarone advisescaution with tacrolimusDroperidol see AntipsychoticsDrospirenone see ProgestogensDrotrecogin Alfa. Anticoagulants: manufacturer of drotrecogin alfaadvises avoid concomitant use with high doses of.heparins—consult product literatureDuloxetineAnalgesics: possible increased serotonergic effectswhen duloxetine given with pethidine or tramadol. Antibacterials: metabolism of duloxetine inhibited by.ciprofloxacin—avoid concomitant use. Antidepressants: metabolism of duloxetine inhibitedby .fluvoxamine—avoid concomitant use; possibleincreased serotonergic effects when duloxetine givenwith SSRIs, St John’s wort, amitriptyline, clomipramine,.moclobemide, tryptophan or venlafaxine;duloxetine should not be started until 2 weeks afterstopping .MAOIs, also MAOIs should not be starteduntil at least 5 days after stopping duloxetine; afterstopping SSRI-related antidepressants do not start.moclobemide for at least 1 week. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrineAtomoxetine: possible increased risk of convulsionswhen antidepressants given with atomoxetine5HT 1 Agonists: possible increased serotonergic effectswhen duloxetine given with 5HT 1 agonistsDutasterideCalcium-channel Blockers: plasma concentration ofdutasteride increased by diltiazem and verapamilDydrogesterone see ProgestogensEdrophonium see ParasympathomimeticsEfavirenzAnalgesics: efavirenz reduces plasma concentration ofmethadoneAntibacterials: increased risk of rash when efavirenzgiven with clarithromycin; efavirenz reduces plasmaconcentration of rifabutin—increase dose of rifabutin;plasma concentration of efavirenz reduced by rifampicin—increasedose of efavirenz. Anticoagulants: efavirenz possibly affects plasmaconcentration of .warfarin. Antidepressants: plasma concentration of efavirenzreduced by .St John’s wort—avoid concomitant useAntiepileptics: plasma concentration of both drugsreduced when efavirenz given with carbamazepine. Antifungals: efavirenz reduces plasma concentration ofitraconazole and .posaconazole; efavirenz reducesplasma concentration of .voriconazole, also plasmaconcentration of efavirenz increased (increase voriconazoledose and reduce efavirenz dose); efavirenzpossibly reduces plasma concentration of caspofungin—considerincreasing dose of caspofungin. Antipsychotics: efavirenz possibly reduces plasmaconcentration of .aripiprazole—increase dose ofaripiprazole; efavirenz possibly increases plasma

BNFC 2011–2012 Appendix 1: Interactions 693Efavirenz. Antipsychotics (continued)concentration of .pimozide (increased risk ofventricular arrhythmias—avoid concomitant use). Antivirals: avoidance of efavirenz advised by manufacturerof .atazanavir (plasma concentration ofatazanavir reduced); efavirenz reduces plasma concentrationof darunavir, fosamprenavir and indinavir;efavirenz possibly reduces plasma concentration of.etravirine—avoid concomitant use; efavirenzreduces plasma concentration of .lopinavir—considerincreasing dose of lopinavir; efavirenz possiblyreduces plasma concentration of .maraviroc—considerincreasing dose of maraviroc; plasma concentrationof efavirenz reduced by nevirapine; toxicity ofefavirenz increased by ritonavir, monitor liver functiontests; efavirenz significantly reduces plasmaconcentration of saquinavir. Anxiolytics and Hypnotics: increased risk of prolongedsedation when efavirenz given with .midazolam—avoid concomitant useCalcium-channel Blockers: efavirenz reduces plasmaconcentration of diltiazem. Ciclosporin: efavirenz possibly reduces plasma concentrationof .ciclosporin. Ergot Alkaloids: increased risk of ergotism whenefavirenz given with .ergot alkaloids—avoid concomitantuseGrapefruit Juice: plasma concentration of efavirenzpossibly increased by grapefruit juiceLipid-regulating Drugs: efavirenz reduces plasmaconcentration of atorvastatin, pravastatin andsimvastatin. Progestogens: efavirenz possibly reduces contraceptiveeffect of .progestogens. Tacrolimus: efavirenz possibly affects plasma concentrationof .tacrolimusEletriptan see 5HT 1 AgonistsEltrombopagAntacids: absorption of eltrombopag reduced byantacids (give at least 4 hours apart)Antivirals: plasma concentration of eltrombopag possiblyreduced by lopinavirCalcium Salts: absorption of eltrombopag possiblyreduced by calcium salts (give at least 4 hours apart)Dairy Products: absorption of eltrombopag possiblyreduced by dairy products (give at least 4 hoursapart)Iron: absorption of eltrombopag possibly reduced byoral iron (give at least 4 hours apart). Lipid-regulating Drugs: eltrombopag increases plasmaconcentration of .rosuvastatin (consider reducingdose of rosuvastatin)Selenium: absorption of eltrombopag possibly reducedby selenium (give at least 4 hours apart)Zinc: absorption of eltrombopag possibly reduced byzinc (give at least 4 hours apart)EmtricitabineAntivirals: manufacturer of emtricitabine advises avoidconcomitant use with lamivudineEnalapril see ACE InhibitorsEnoxaparin see HeparinsEnoximone see Phosphodiesterase InhibitorsEntacapone. Anticoagulants: entacapone enhances anticoagulanteffect of .warfarin. Antidepressants: manufacturer of entacapone advisescaution with moclobemide, paroxetine, tricyclics andvenlafaxine; avoid concomitant use of entacaponewith non-selective .MAOIsDopaminergics: entacapone possibly enhances effectsof apomorphine; entacapone possibly reducesplasma concentration of rasagiline; manufacturer ofentacapone advises max. dose of 10 mg selegiline ifused concomitantlyIron: absorption of entacapone reduced by oral ironMemantine: effects of dopaminergics possiblyenhanced by memantineEntacapone (continued)Methyldopa: entacapone possibly enhances effects ofmethyldopa; antiparkinsonian effect of dopaminergicsantagonised by methyldopaSympathomimetics: entacapone possibly enhanceseffects of adrenaline (epinephrine), dobutamine,dopamine and noradrenaline (norepinephrine)Enteral Foods. Anticoagulants: the presence of vitamin K in someenteral feeds can antagonise the anticoagulant effectof .coumarins and .phenindioneAntiepileptics: enteral feeds possibly reduce absorptionof phenytoinEphedrine see SympathomimeticsEpinephrine (adrenaline) see SympathomimeticsEpirubicin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Ciclosporin: plasma concentration of epirubicinincreased by .ciclosporin. Ulcer-healing Drugs: plasma concentration of epirubicinincreased by .cimetidineEplerenone see DiureticsEprosartan see Angiotensin-II Receptor AntagonistsEptifibatideIloprost: increased risk of bleeding when eptifibatidegiven with iloprostErgometrine see Ergot AlkaloidsErgot AlkaloidsAnaesthetics, General: effects of ergometrine on theparturient uterus reduced by halothane. Antibacterials: increased risk of ergotism when ergotamineand methysergide given with .macrolides or.telithromycin—avoid concomitant use; increasedrisk of ergotism when ergotamine and methysergidegiven with tetracyclinesAntidepressants: possible risk of hypertension whenergotamine and methysergide given with reboxetine. Antifungals: increased risk of ergotism when ergotamineand methysergide given with .imidazoles or.triazoles—avoid concomitant use. Antivirals: plasma concentration of ergot alkaloidspossibly increased by .atazanavir—avoid concomitantuse; increased risk of ergotism when ergotalkaloids given with .efavirenz—avoid concomitantuse; increased risk of ergotism when ergotamine andmethysergide given with .fosamprenavir, .indinavir,.nelfinavir, .ritonavir or .saquinavir—avoid concomitantuseBeta-blockers: increased peripheral vasoconstrictionwhen ergotamine and methysergide given with betablockers. 5HT 1 Agonists: increased risk of vasospasm whenergotamine and methysergide given with .almotriptan,.rizatriptan, .sumatriptan or .zolmitriptan (avoidergotamine and methysergide for 6 hours afteralmotriptan, rizatriptan, sumatriptan or zolmitriptan,avoid almotriptan, rizatriptan, sumatriptan or zolmitriptanfor 24 hours after ergotamine and methysergide);increased risk of vasospasm whenergotamine and methysergide given with .eletriptan,.frovatriptan or .naratriptan (avoid ergotamine andmethysergide for 24 hours after eletriptan,frovatriptan or naratriptan, avoid eletriptan,frovatriptan or naratriptan for 24 hours after ergotamineand methysergide)Sympathomimetics: increased risk of ergotism whenergotamine and methysergide given with sympathomimetics. Ulcer-healing Drugs: increased risk of ergotism whenergotamine and methysergide given with.cimetidine—avoid concomitant useErgotamine and Methysergide see Ergot AlkaloidsErlotinib. Analgesics: increased risk of bleeding when erlotinibgiven with .NSAIDsAppendix 1: Interactions

694 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsErlotinib (continued). Antacids: plasma concentration of erlotinib possiblyreduced by .antacids—give antacids at least 4 hoursbefore or 2 hours after erlotinibAntibacterials: plasma concentration of erlotinibincreased by ciprofloxacin; metabolism of erlotinibaccelerated by rifampicin (reduced plasma concentration). Anticoagulants: increased risk of bleeding whenerlotinib given with .coumarinsAntifungals: metabolism of erlotinib inhibited byketoconazole (increased plasma concentration). Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cytotoxics: plasma concentration of erlotinib possiblyincreased by capecitabine. Ulcer-healing Drugs: manufacturer of erlotinib advisesavoid concomitant use with .cimetidine,.esomeprazole, .famotidine, .lansoprazole,.nizatidine, .pantoprazole and .rabeprazole; plasmaconcentration of erlotinib reduced by .ranitidine—manufacturer of erlotinib advises give at least 2 hoursbefore or 10 hours after ranitidine; plasma concentrationof erlotinib reduced by .omeprazole—manufacturerof erlotinib advises avoid concomitant useErtapenem. Antiepileptics: carbapenems reduce plasma concentrationof .valproate—avoid concomitant useVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Erythromycin see MacrolidesEscitalopram see Antidepressants, SSRIEslicarbazepineAnticoagulants: eslicarbazepine reduces plasma concentrationof warfarin. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wortAntiepileptics: plasma concentration of both drugsreduced when eslicarbazepine given with carbamazepine;manufacturer of eslicarbazepine advisesavoid concomitant use with oxcarbazepine; plasmaconcentration of eslicarbazepine reduced by phenytoin,also plasma concentration of phenytoinincreased. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered). Oestrogens: eslicarbazepine accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistat. Progestogens: eslicarbazepine accelerates metabolismof .progestogens (reduced contraceptive effect—seep. 398)Esmolol see Beta-blockersEsomeprazole see Proton Pump InhibitorsEstradiol see OestrogensEstramustine. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Bisphosphonates: plasma concentration of estramustineincreased by .sodium clodronateEstriol see OestrogensEstrone see OestrogensEtanercept. Abatacept: avoid concomitant use of etanercept with.abataceptEtanercept (continued). Anakinra: avoid concomitant use of etanercept with.anakinra. Vaccines: avoid concomitant use of etanercept withlive .vaccines (see p. 599)Ethinylestradiol see OestrogensEthosuximide. Antibacterials: metabolism of ethosuximide inhibitedby .isoniazid (increased plasma concentration andrisk of toxicity). Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wort. Antiepileptics: plasma concentration of ethosuximidepossibly reduced by carbamazepine and phenobarbital;plasma concentration of ethosuximide possiblyreduced by .phenytoin, also plasma concentration ofphenytoin possibly increased; plasma concentrationof ethosuximide possibly increased by valproate. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistatEtodolac see NSAIDsEtomidate see Anaesthetics, GeneralEtonogestrel see ProgestogensEtoposide. Anticoagulants: etoposide possibly enhances anticoagulanteffect of .coumarinsAntiepileptics: plasma concentration of etoposidepossibly reduced by phenobarbital and phenytoin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Ciclosporin: plasma concentration of etoposide possiblyincreased by ciclosporin (increased risk oftoxicity)Etoricoxib see NSAIDsEtravirine. Antibacterials: plasma concentration of etravirineincreased by .clarithromycin, also plasma concentrationof clarithromycin reduced; plasma concentrationof both drugs reduced when etravirine givenwith .rifabutin; manufacturer of etravirine advisesavoid concomitant use with rifampicinAntidepressants: manufacturer of etravirine advisesavoid concomitant use with St John’s wortAntiepileptics: manufacturer of etravirine advisesavoid concomitant use with carbamazepine,phenobarbital and phenytoin. Antivirals: plasma concentration of etravirine possiblyreduced by .efavirenz and .nevirapine—avoid concomitantuse; etravirine increases plasma concentrationof .fosamprenavir (consider reducing dose offosamprenavir); etravirine possibly reduces plasmaconcentration of .indinavir—avoid concomitant use;etravirine possibly reduces plasma concentration ofmaraviroc; etravirine possibly increases plasma concentrationof nelfinavir—avoid concomitant use;plasma concentration of etravirine reduced by.tipranavir, also plasma concentration of tipranavirincreased (avoid concomitant use)Cardiac Glycosides: etravirine increases plasma concentrationof digoxin. Clopidogrel: etravirine possibly reduces antiplateleteffect of .clopidogrelLipid-regulating Drugs: etravirine possibly reducesplasma concentration of atorvastatinSildenafil: etravirine reduces plasma concentration ofsildenafil

BNFC 2011–2012 Appendix 1: Interactions 695Etynodiol see ProgestogensEverolimus. Antibacterials: plasma concentration of everolimuspossibly increased by .clarithromycin and.telithromycin—manufacturer of everolimus advisesavoid concomitant use; plasma concentration ofeverolimus increased by .erythromycin; plasmaconcentration of everolimus reduced by .rifampicinAntidepressants: plasma concentration of everolimuspossibly reduced by St John’s wort—manufacturer ofeverolimus advises avoid concomitant use. Antifungals: plasma concentration of everolimusincreased by .ketoconazole—avoid concomitant use;plasma concentration of everolimus possiblyincreased by .itraconazole, .posaconazole and.voriconazole—manufacturer of everolimus advisesavoid concomitant use. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Antivirals: plasma concentration of everolimus possiblyincreased by .atazanavir, .darunavir, .indinavir,.nelfinavir, .ritonavir and .saquinavir—manufacturerof everolimus advises avoid concomitant use. Calcium-channel Blockers: plasma concentration ofboth drugs may increase when everolimus given with.verapamil. Ciclosporin: plasma concentration of everolimusincreased by .ciclosporinGrapefruit Juice: manufacturer of everolimus advisesavoid concomitant use with grapefruit juiceExemestaneAntibacterials: plasma concentration of exemestanepossibly reduced by rifampicinEzetimibeAnticoagulants: ezetimibe possibly enhances anticoagulanteffect of coumarins. Ciclosporin: plasma concentration of both drugs mayincrease when ezetimibe given with .ciclosporinLipid-regulating Drugs: increased risk of cholelithiasisand gallbladder disease when ezetimibe given withfibrates—discontinue if suspectedFamciclovirProbenecid: excretion of famciclovir possibly reducedby probenecid (increased plasma concentration)Famotidine see Histamine H 2 -antagonistsFebuxostat. Azathioprine: manufacturer of febuxostat advises avoidconcomitant use with .azathioprine. Cytotoxics: manufacturer of febuxostat advises avoidconcomitant use with .mercaptopurine. Theophylline: manufacturer of febuxostat advisescaution with .theophyllineFelodipine see Calcium-channel BlockersFenbufen see NSAIDsFenofibrate see FibratesFenoprofen see NSAIDsFenoterol see Sympathomimetics, Beta 2Fentanyl see Opioid AnalgesicsFerrous Salts see IronFesoterodine see AntimuscarinicsFexofenadine see AntihistaminesFibrates. Antibacterials: increased risk of myopathy whenfibrates given with .daptomycin (preferably avoidconcomitant use). Anticoagulants: fibrates enhance anticoagulant effectof .coumarins and .phenindione. Antidiabetics: fibrates may improve glucose toleranceand have an additive effect with insulin or sulfonylureas;gemfibrozil possibly enhances hypoglycaemiceffect of nateglinide; increased risk of severe hypoglycaemiawhen gemfibrozil given with.repaglinide—avoid concomitant useCiclosporin: increased risk of renal impairment whenbezafibrate or fenofibrate given with ciclosporin. Colchicine: possible increased risk of myopathy whenfibrates given with .colchicineFibrates (continued). Cytotoxics: gemfibrozil increases plasma concentrationof .bexarotene—avoid concomitant use. Lipid-regulating Drugs: increased risk of cholelithiasisand gallbladder disaese when fibrates given withezetimibe—discontinue if suspected; increased risk ofmyopathy when fibrates given with .statins;increased risk of myopathy when gemfibrozil givenwith .statins (preferably avoid concomitant use)FilgrastimNote Pegfilgrastim interactions as for filgrastimCytotoxics: neutropenia possibly exacerbated whenfilgrastim given with fluorouracilFlavoxate see AntimuscarinicsFlecainideAnaesthetics, Local: increased myocardial depressionwhen anti-arrhythmics given with bupivacaine, levobupivacaine,prilocaine or ropivacaine. Anti-arrhythmics: increased myocardial depressionwhen anti-arrhythmics given with other .antiarrhythmics;plasma concentration of flecainideincreased by .amiodarone (halve dose of flecainide). Antidepressants: plasma concentration of flecainideincreased by fluoxetine; increased risk of ventriculararrhythmias when flecainide given with .tricyclics. Antihistamines: increased risk of ventricular arrhythmiaswhen flecainide given with .mizolastine—avoidconcomitant use. Antimalarials: avoidance of flecainide advised bymanufacturer of .artemether/lumefantrine (risk ofventricular arrhythmias); plasma concentration offlecainide increased by .quinine. Antimuscarinics: increased risk of ventricular arrhythmiaswhen flecainide given with .tolterodine. Antipsychotics: increased risk of ventricular arrhythmiaswhen anti-arrhythmics that prolong the QTinterval given with .antipsychotics that prolong theQT interval; increased risk of arrhythmias whenflecainide given with .clozapine. Antivirals: plasma concentration of flecainide possiblyincreased by .fosamprenavir, .indinavir,.lopinavir and .ritonavir (increased risk of ventriculararrhythmias—avoid concomitant use); increased riskof ventricular arrhythmias when flecainide given with.saquinavir—avoid concomitant use. Beta-blockers: increased risk of myocardial depressionand bradycardia when flecainide given with .betablockers;increased myocardial depression when antiarrhythmicsgiven with .beta-blockers. Calcium-channel Blockers: increased risk of myocardialdepression and asystole when flecainide givenwith .verapamil. Diuretics: increased cardiac toxicity with flecainide ifhypokalaemia occurs with .acetazolamide, .loopdiuretics or .thiazides and related diureticsUlcer-healing Drugs: metabolism of flecainide inhibitedby cimetidine (increased plasma concentration)Flucloxacillin see PenicillinsFluconazole see Antifungals, TriazoleFlucytosineAntifungals: renal excretion of flucytosine decreasedand cellular uptake increased by amphotericin(toxicity possibly increased)Cytotoxics: plasma concentration of flucytosine possiblyreduced by cytarabineFludarabine. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Cytotoxics: fludarabine increases intracellular concentrationof cytarabine; increased pulmonary toxicitywhen fludarabine given with .pentostatin (unacceptablyhigh incidence of fatalities)Dipyridamole: effects of fludarabine possibly reducedby dipyridamoleFludrocortisone see CorticosteroidsFlunisolide see CorticosteroidsAppendix 1: Interactions

696 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsFluoridesCalcium Salts: absorption of fluorides reduced bycalcium saltsFluorouracilNote Capecitabine is a prodrug of fluorouracilNote Tegafur is a prodrug of fluorouracil. Allopurinol: manufacturer of capecitabine advisesavoid concomitant use with .allopurinolAntibacterials: metabolism of fluorouracil inhibited bymetronidazole (increased toxicity). Anticoagulants: fluorouracil enhances anticoagulanteffect of .coumarinsAntiepileptics: fluorouracil possibly inhibits metabolismof phenytoin (increased risk of toxicity). Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cytotoxics: capecitabine possibly increases plasmaconcentration of erlotinibFilgrastim: neutropenia possibly exacerbated whenfluorouracil given with filgrastim. Temoporfin: increased skin photosensitivity whentopical fluorouracil used with .temoporfinUlcer-healing Drugs: metabolism of fluorouracilinhibited by cimetidine (increased plasma concentration)Fluoxetine see Antidepressants, SSRIFlupentixol see AntipsychoticsFluphenazine see AntipsychoticsFlurazepam see Anxiolytics and HypnoticsFlurbiprofen see NSAIDsFlutamide. Anticoagulants: flutamide enhances anticoagulanteffect of .coumarinsFluticasone see CorticosteroidsFluvastatin see StatinsFluvoxamine see Antidepressants, SSRIFolatesAminosalicylates: absorption of folic acid possiblyreduced by sulfasalazineAntiepileptics: folates possibly reduce plasma concentrationof phenobarbital and phenytoin. Cytotoxics: avoidance of folates advised by manufacturerof .raltitrexedFolic Acid see FolatesFolinic Acid see FolatesFormoterol see Sympathomimetics, Beta 2FosamprenavirNote Fosamprenavir is a prodrug of amprenavirAnalgesics: fosamprenavir reduces plasma concentrationof methadone. Anti-arrhythmics: fosamprenavir possibly increasesplasma concentration of .amiodarone,.flecainide and .propafenone (increased risk ofventricular arrhythmias—avoid concomitant use);fosamprenavir possibly increases plasma concentrationof .lidocaine—avoid concomitant use. Antibacterials: fosamprenavir increases plasma concentrationof .rifabutin (reduce dose of rifabutin);plasma concentration of fosamprenavir significantlyreduced by .rifampicin—avoid concomitant use;avoidance of concomitant fosamprenavir in severerenal and hepatic impairment advised by manufacturerof .telithromycinAnticoagulants: fosamprenavir may enhance or reduceanticoagulant effect of coumarins; avoidance offosamprenavir advised by manufacturer of rivaroxaban. Antidepressants: plasma concentration of fosamprenavirreduced by .St John’s wort—avoid concomitantuseAntiepileptics: plasma concentration of fosamprenavirpossibly reduced by carbamazepine and phenobarbitalAntifungals: fosamprenavir increases plasma concentrationof ketoconazole (also plasma concentration offosamprenavir possibly increased); plasma concentrationof both drugs may increase when fosamprenavirgiven with itraconazoleFosamprenavir (continued). Antimalarials: caution with fosamprenavir advised bymanufacturer of artemether/lumefantrine; fosamprenavirpossibly increases plasma concentration of.quinine (increased risk of toxicity)Antimuscarinics: avoidance of fosamprenavir advisedby manufacturer of darifenacin and tolterodine. Antipsychotics: fosamprenavir possibly inhibitsmetabolism of .aripiprazole (reduce dose of aripiprazole);fosamprenavir increases plasma concentrationof .pimozide (increased risk of ventriculararrhythmias—avoid concomitant use). Antivirals: plasma concentration of fosamprenavirreduced by efavirenz and .tipranavir; plasma concentrationof fosamprenavir increased by .etravirine(consider reducing dose of fosamprenavir); plasmaconcentration of fosamprenavir reduced by lopinavir,effect on lopinavir plasma concentration not predictable—avoidconcomitant use; plasma concentrationof fosamprenavir possibly reduced by nevirapine. Anxiolytics and Hypnotics: fosamprenavir possiblyincreases plasma concentration of .midazolam (riskof prolonged sedation—avoid concomitant use oforal midazolam). Ciclosporin: fosamprenavir increases plasma concentrationof .ciclosporin. Ergot Alkaloids: increased risk of ergotism whenfosamprenavir given with .ergotamine and methysergide—avoidconcomitant use. Lipid-regulating Drugs: possible increased risk ofmyopathy when fosamprenavir given with atorvastatin;possible increased risk of myopathy whenfosamprenavir given with .rosuvastatin—manufacturerof rosuvastatin advises avoid concomitant use;possible increased risk of myopathy when fosamprenavirgiven with .simvastatin—avoid concomitantuse. Ranolazine: fosamprenavir possibly increases plasmaconcentration of .ranolazine—manufacturer ofranolazine advises avoid concomitant useSildenafil: fosamprenavir possibly increases plasmaconcentration of sildenafil. Tacrolimus: fosamprenavir increases plasma concentrationof .tacrolimusTadalafil: fosamprenavir possibly increases plasmaconcentration of tadalafilVardenafil: fosamprenavir possibly increases plasmaconcentration of vardenafilFosaprepitant see AprepitantFoscarnetAntivirals: avoidance of foscarnet advised by manufacturerof lamivudine. Pentamidine Isetionate: increased risk of hypocalcaemiawhen foscarnet given with parenteral .pentamidineisetionateFosinopril see ACE InhibitorsFosphenytoin see PhenytoinFramycetin see AminoglycosidesFrovatriptan see 5HT 1AgonistsFurosemide see DiureticsFusidic Acid. Antivirals: plasma concentration of both drugsincreased when fusidic acid given with .ritonavir—avoid concomitant use. Lipid-regulating Drugs: possible increased risk ofmyopathy when fusidic acid given with atorvastatin;increased risk of myopathy when fusidic acid givenwith .simvastatinSugammadex: fusidic acid possibly reduces responseto sugammadexVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620GabapentinAnalgesics: bioavailability of gabapentin increased bymorphineAntacids: absorption of gabapentin reduced byantacids

BNFC 2011–2012 Appendix 1: Interactions 697Gabapentin (continued). Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wort. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistatGalantamine see ParasympathomimeticsGanciclovirNote Increased risk of myelosuppression with other myelosuppressivedrugs—consult product literatureNote Valganciclovir interactions as for ganciclovir. Antibacterials: increased risk of convulsions whenganciclovir given with .imipenem with cilastatin. Antivirals: ganciclovir possibly increases plasma concentrationof didanosine; avoidance of intravenousganciclovir advised by manufacturer of lamivudine;profound myelosuppression when ganciclovir givenwith .zidovudine (if possible avoid concomitantadministration, particularly during initial ganciclovirtherapy)Mycophenolate: plasma concentration of ganciclovirpossibly increased by mycophenolate, also plasmaconcentration of inactive metabolite of mycophenolatepossibly increasedProbenecid: excretion of ganciclovir reduced by probenecid(increased plasma concentration and risk oftoxicity)Tacrolimus: possible increased risk of nephrotoxicitywhen ganciclovir given with tacrolimusGefitinib. Antibacterials: plasma concentration of gefitinibreduced by .rifampicin—avoid concomitant use. Anticoagulants: gefitinib possibly enhances anticoagulanteffect of .warfarinAntidepressants: manufacturer of gefitinib advisesavoid concomitant use with St John’s wortAntiepileptics: manufacturer of gefitinib advises avoidconcomitant use with carbamazepine,phenobarbital and phenytoinAntifungals: plasma concentration of gefitinibincreased by itraconazole. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Ulcer-healing Drugs: plasma concentration of gefitinibreduced by .ranitidineGemcitabineAnticoagulants: gemcitabine possibly enhances anticoagulanteffect of warfarin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Gemeprost see ProstaglandinsGemfibrozil see FibratesGentamicin see AminoglycosidesGestodene see ProgestogensGlibenclamide see AntidiabeticsGliclazide see AntidiabeticsGlimepiride see AntidiabeticsGlipizide see AntidiabeticsGlucosamine. Anticoagulants: glucosamine enhances anticoagulanteffect of .warfarin (avoid concomitant use)Glyceryl Trinitrate see NitratesGlycopyrronium see AntimuscarinicsGold see Sodium AurothiomalateGolimumab. Abatacept: avoid concomitant use of golimumab with.abataceptGolimumab (continued). Anakinra: avoid concomitant use of golimumab with.anakinra. Vaccines: avoid concomitant use of golimumab withlive .vaccines (see p. 599)Grapefruit Juice. Anti-arrhythmics: grapefruit juice increases plasmaconcentration of amiodarone; grapefruit juiceincreases plasma concentration of .dronedarone—avoid concomitant use. Antihistamines: grapefruit juice increases plasmaconcentration of .rupatadine—avoid concomitantuseAntimalarials: grapefruit juice possibly increasesplasma concentration of artemether/lumefantrineAntivirals: grapefruit juice possibly increases plasmaconcentration of efavirenzAnxiolytics and Hypnotics: grapefruit juice increasesplasma concentration of buspironeCalcium-channel Blockers: grapefruit juice possiblyincreases plasma concentration of amlodipine;grapefruit juice increases plasma concentration offelodipine, isradipine, lacidipine, lercanidipine, nicardipine,nifedipine, nimodipine and verapamil. Ciclosporin: grapefruit juice increases plasma concentrationof .ciclosporin (increased risk of toxicity). Colchicine: grapefruit juice possibly increases risk of.colchicine toxicity. Cytotoxics: avoidance of grapefruit juice advised bymanufacturer of everolimus, .lapatinib, .nilotinib and.pazopanib; grapefruit juice possibly increasesplasma concentration of vinflunine—manufacturer ofvinflunine advises avoid concomitant useIvabradine: grapefruit juice increases plasma concentrationof ivabradine. Lipid-regulating Drugs: grapefruit juice possiblyincreases plasma concentration of atorvastatin;grapefruit juice increases plasma concentration of.simvastatin—avoid concomitant use. Ranolazine: grapefruit juice possibly increases plasmaconcentration of .ranolazine—manufacturer ofranolazine advises avoid concomitant useSildenafil: grapefruit juice possibly increases plasmaconcentration of sildenafil. Sirolimus: grapefruit juice increases plasma concentrationof .sirolimus—avoid concomitant use. Tacrolimus: grapefruit juice increases plasma concentrationof .tacrolimusTadalafil: grapefruit juice possibly increases plasmaconcentration of tadalafil. Tolvaptan: grapefruit juice increases plasma concentrationof .tolvaptan—avoid concomitant use. Vardenafil: grapefruit juice possibly increases plasmaconcentration of .vardenafil—avoid concomitant useGriseofulvinAlcohol: griseofulvin possibly enhances effects ofalcohol. Anticoagulants: griseofulvin reduces anticoagulanteffect of .coumarinsAntiepileptics: absorption of griseofulvin reduced byphenobarbital (reduced effect)Ciclosporin: griseofulvin possibly reduces plasmaconcentration of ciclosporinOestrogens: anecdotal reports of contraceptive failureand menstrual irregularities when griseofulvin givenwith oestrogensProgestogens: anecdotal reports of contraceptivefailure and menstrual irregularities when griseofulvingiven with progestogensGuanethidine see Adrenergic Neurone BlockersHaloperidol see AntipsychoticsHalothane see Anaesthetics, GeneralHeparin see HeparinsHeparinsACE Inhibitors: increased risk of hyperkalaemia whenheparins given with ACE inhibitorsAliskiren: increased risk of hyperkalaemia whenheparins given with aliskirenAppendix 1: Interactions

698 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsHeparins (continued). Analgesics: possible increased risk of bleeding whenheparins given with NSAIDs; increased risk ofhaemorrhage when anticoagulants given with intravenous.diclofenac (avoid concomitant use, includinglow-dose heparins); increased risk of haemorrhagewhen anticoagulants given with .ketorolac (avoidconcomitant use, including low-dose heparins); anticoagulanteffect of heparins enhanced by .aspirinAngiotensin-II Receptor Antagonists: increased risk ofhyperkalaemia when heparins given with angiotensin-IIreceptor antagonistsClopidogrel: increased risk of bleeding when heparinsgiven with clopidogrelDipyridamole: anticoagulant effect of heparinsenhanced by dipyridamole. Drotrecogin Alfa: avoidance of concomitant use of highdoses of heparins with drotrecogin alfa advised bymanufacturer of .drotrecogin alfa—consult productliteratureIloprost: anticoagulant effect of heparins possiblyenhanced by iloprost. Nitrates: anticoagulant effect of heparins reduced byinfusion of .glyceryl trinitrateHistamineAntidepressants: manufacturer of histamine advisesavoid concomitant use with MAOIs; effects of histaminetheoretically antagonised by tricyclics—manufacturerof histamine advises avoid concomitant useAntihistamines: effects of histamine theoreticallyantagonised by antihistamines—manufacturer ofhistamine advises avoid concomitant useAntimalarials: manufacturer of histamine advises avoidconcomitant use with antimalarialsAntipsychotics: effects of histamine theoreticallyantagonised by antipsychotics—manufacturer ofhistamine advises avoid concomitant useAtovaquone: manufacturer of histamine advises avoidconcomitant use with atovaquoneClonidine: manufacturer of histamine advises avoidconcomitant use with clonidineCorticosteroids: manufacturer of histamine advisesavoid concomitant use with corticosteroidsUlcer-healing Drugs: effects of histamine theoreticallyantagonised by histamine H 2 -antagonists—manufacturerof histamine advises avoid concomitant useHistamine H 2 -antagonists. Alpha-blockers: cimetidine and ranitidine antagoniseeffects of .tolazolineAnalgesics: cimetidine inhibits metabolism of opioidanalgesics (increased plasma concentration). Anti-arrhythmics: cimetidine increases plasma concentrationof amiodarone and .propafenone; cimetidineinhibits metabolism of flecainide (increasedplasma concentration); cimetidine increases plasmaconcentration of .lidocaine (increased risk of toxicity)Antibacterials: histamine H 2 -antagonists reduceabsorption of cefpodoxime; cimetidine increasesplasma concentration of erythromycin (increased riskof toxicity, including deafness); cimetidine inhibitsmetabolism of metronidazole (increased plasmaconcentration); metabolism of cimetidine acceleratedby rifampicin (reduced plasma concentration). Anticoagulants: cimetidine inhibits metabolism of.coumarins (enhanced anticoagulant effect)Antidepressants: cimetidine increases plasma concentrationof citalopram, escitalopram,mirtazapine and sertraline; cimetidine inhibitsmetabolism of amitriptyline, doxepin,imipramine and nortriptyline (increased plasmaconcentration); cimetidine increases plasma concentrationof moclobemide (halve dose of moclobemide);cimetidine possibly increases plasma concentrationof tricyclicsAntidiabetics: cimetidine reduces excretion of metformin(increased plasma concentration); cimetidineenhances hypoglycaemic effect of sulfonylureasHistamine H 2 -antagonists (continued). Antiepileptics: cimetidine inhibits metabolism of.carbamazepine, .phenytoin and .valproate(increased plasma concentration). Antifungals: histamine H 2 -antagonists reduce absorptionof itraconazole and ketoconazole; avoidance ofhistamine H 2 -antagonists advised by manufacturer ofposaconazole (plasma concentration of posaconazolepossibly reduced); cimetidine reduces plasma concentrationof .posaconazole; cimetidine increasesplasma concentration of terbinafineAntihistamines: manufacturer of loratadine advisescimetidine possibly increases plasma concentrationof loratadine. Antimalarials: avoidance of cimetidine advised bymanufacturer of .artemether/lumefantrine; cimetidineinhibits metabolism of chloroquine andhydroxychloroquine and quinine (increased plasmaconcentration)Antipsychotics: cimetidine possibly enhances effects ofantipsychotics, chlorpromazine and clozapine. Antivirals: histamine H 2 -antagonists reduce plasmaconcentration of .atazanavir; histamine H 2 -antagonistspossibly increase plasma concentration ofraltegravir—manufacturer of raltegravir advises avoidconcomitant use; cimetidine possibly increasesplasma concentration of saquinavirAnxiolytics and Hypnotics: cimetidine inhibits metabolismof benzodiazepines, clomethiazole and zaleplon(increased plasma concentration); cimetidineincreases plasma concentration of melatoninBeta-blockers: cimetidine increases plasma concentrationof labetalol, metoprolol and propranololCalcium-channel Blockers: cimetidine possibly inhibitsmetabolism of calcium-channel blockers (increasedplasma concentration); cimetidine increases plasmaconcentration of isradipine (halve dose of isradipine). Ciclosporin: cimetidine possibly increases plasmaconcentration of .ciclosporin. Clopidogrel: cimetidine possibly reduces antiplateleteffect of .clopidogrel. Cytotoxics: cimetidine possibly enhances myelosuppressiveeffects of carmustine and lomustine; cimetidineincreases plasma concentration of .epirubicin;cimetidine inhibits metabolism of fluorouracil(increased plasma concentration); famotidine possiblyreduces plasma concentration of dasatinib;avoidance of cimetidine, famotidine and nizatidineadvised by manufacturer of .erlotinib; ranitidinereduces plasma concentration of .erlotinib—manufacturerof erlotinib advises give at least 2 hoursbefore or 10 hours after ranitidine; ranitidine reducesplasma concentration of .gefitinib; histamine H 2 -antagonists possibly reduce absorption of lapatinibDopaminergics: cimetidine reduces excretion of pramipexole(increased plasma concentration). Ergot Alkaloids: increased risk of ergotism whencimetidine given with .ergotamine and methysergide—avoidconcomitant useHistamine: histamine H 2 -antagonists theoreticallyantagonise effects of histamine—manufacturer ofhistamine advises avoid concomitant useHormone Antagonists: absorption of cimetidine possiblydelayed by octreotide5HT 1 Agonists: cimetidine inhibits metabolism ofzolmitriptan (reduce dose of zolmitriptan)Mebendazole: cimetidine possibly inhibits metabolismof mebendazole (increased plasma concentration)Roflumilast: cimetidine inhibits the metabolism ofroflumilastSildenafil: cimetidine increases plasma concentrationof sildenafil (consider reducing dose of sildenafil). Theophylline: cimetidine inhibits metabolism of.theophylline (increased plasma concentration)Thyroid Hormones: cimetidine reduces absorption oflevothyroxine. Ulipristal: avoidance of histamine H 2 -antagonistsadvised by manufacturer of .ulipristal (plasmaconcentration of ulipristal possibly reduced)

BNFC 2011–2012 Appendix 1: Interactions 699Homatropine see AntimuscarinicsHormone Antagonists see Bicalutamide, Danazol,Dutasteride, Exemestane, Flutamide, Lanreotide,Octreotide, Tamoxifen, Toremifene, and Trilostane5HT 1 Agonists. Antibacterials: plasma concentration of eletriptanincreased by .clarithromycin and .erythromycin (riskof toxicity)—avoid concomitant use; metabolism ofzolmitriptan possibly inhibited by quinolones (reducedose of zolmitriptan). Antidepressants: increased risk of CNS toxicity whensumatriptan given with .citalopram, .escitalopram,.fluoxetine, .fluvoxamine or .paroxetine; metabolismof frovatriptan inhibited by fluvoxamine;metabolism of zolmitriptan possibly inhibited byfluvoxamine (reduce dose of zolmitriptan); CNStoxicity reported when sumatriptan given with sertraline;possible increased serotonergic effects when5HT 1 agonists given with duloxetine or venlafaxine;increased risk of CNS toxicity when zolmitriptangiven with .MAOIs; risk of CNS toxicity whenrizatriptan or sumatriptan given with .MAOIs (avoidrizatriptan or sumatriptan for 2 weeks after MAOIs);risk of CNS toxicity when rizatriptan or sumatriptangiven with .moclobemide (avoid rizatriptan orsumatriptan for 2 weeks after moclobemide); risk ofCNS toxicity when zolmitriptan given with.moclobemide (reduce dose of zolmitriptan);increased serotonergic effects when 5HT 1 agonistsgiven with .St John’s wort—avoid concomitant use. Antifungals: plasma concentration of eletriptanincreased by .itraconazole and .ketoconazole (risk oftoxicity)—avoid concomitant use; plasma concentrationof almotriptan increased by ketoconazole(increased risk of toxicity). Antivirals: plasma concentration of eletriptan increasedby .indinavir, .nelfinavir and .ritonavir (risk oftoxicity)—avoid concomitant useBeta-blockers: plasma concentration of rizatriptanincreased by propranolol (manufacturer of rizatriptanadvises halve dose and avoid within 2 hours ofpropranolol)Dopaminergics: avoidance of 5HT 1 agonists advisedby manufacturer of selegiline. Ergot Alkaloids: increased risk of vasospasm wheneletriptan, frovatriptan or naratriptan given with.ergotamine and methysergide (avoid ergotamineand methysergide for 24 hours after eletriptan,frovatriptan or naratriptan, avoid eletriptan,frovatriptan or naratriptan for 24 hours after ergotamineand methysergide); increased risk of vasospasmwhen almotriptan, rizatriptan, sumatriptan orzolmitriptan given with .ergotamine and methysergide(avoid ergotamine and methysergide for 6hours after almotriptan, rizatriptan, sumatriptan orzolmitriptan, avoid almotriptan, rizatriptan,sumatriptan or zolmitriptan for 24 hours after ergotamineand methysergide)Lithium: possible risk of toxicity when sumatriptangiven with lithiumUlcer-healing Drugs: metabolism of zolmitriptaninhibited by cimetidine (reduce dose of zolmitriptan)5HT 3 AntagonistsAnalgesics: ondansetron possibly antagonises effectsof tramadolAntibacterials: metabolism of ondansetron acceleratedby rifampicin (reduced effect)Antiepileptics: metabolism of ondansetron acceleratedby carbamazepine and phenytoin (reduced effect)Hydralazine see Vasodilator AntihypertensivesHydrochlorothiazide see DiureticsHydrocortisone see CorticosteroidsHydroflumethiazide see DiureticsHydromorphone see Opioid AnalgesicsHydrotalcite see AntacidsHydroxocobalaminAntibacterials: response to hydroxocobalamin reducedby chloramphenicolHydroxycarbamide. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Antivirals: increased risk of toxicity when hydroxycarbamidegiven with .didanosine and .stavudine—avoid concomitant useHydroxychloroquine see Chloroquine and HydroxychloroquineHydroxyzine see AntihistaminesHyoscine see AntimuscarinicsIbandronic Acid see BisphosphonatesIbuprofen see NSAIDsIdarubicin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Ciclosporin: plasma concentration of idarubicinincreased by .ciclosporinIfosfamide. Anticoagulants: ifosfamide possibly enhances anticoagulanteffect of .coumarins. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cytotoxics: increased risk of otoxicity when ifosfamidegiven with cisplatinIloprostAnalgesics: increased risk of bleeding when iloprostgiven with NSAIDs or aspirinAnticoagulants: iloprost possibly enhances anticoagulanteffect of coumarins and heparins;increased risk of bleeding when iloprost given withphenindioneClopidogrel: increased risk of bleeding when iloprostgiven with clopidogrelEptifibatide: increased risk of bleeding when iloprostgiven with eptifibatideTirofiban: increased risk of bleeding when iloprostgiven with tirofibanImatinibAnalgesics: manufacturer of imatinib advises cautionwith paracetamol. Antibacterials: plasma concentration of imatinibreduced by .rifampicin—avoid concomitant useAnticoagulants: manufacturer of imatinib advisesreplacement of warfarin with a heparin (possibility ofenhanced warfarin effect). Antidepressants: plasma concentration of imatinibreduced by .St John’s wort—avoid concomitant use. Antiepileptics: plasma concentration of imatinibreduced by .carbamazepine, .oxcarbazepine and.phenytoin—avoid concomitant useAntifungals: plasma concentration of imatinibincreased by ketoconazole. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Ciclosporin: imatinib possibly increases plasma concentrationof ciclosporinLipid-regulating Drugs: imatinib increases plasmaconcentration of simvastatinThyroid Hormones: imatinib possibly reduces plasmaconcentration of levothyroxineImidapril see ACE InhibitorsImipenem with Cilastatin. Antiepileptics: carbapenems reduce plasma concentrationof .valproate—avoid concomitant use. Antivirals: increased risk of convulsions when imipenemwith cilastatin given with .ganciclovirVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Imipramine see Antidepressants, TricyclicImmunoglobulinsNote For advice on immunoglobulins and live virus vaccines,see under Normal Immunoglobulin, p. 622Indacaterol see Sympathomimetics, Beta 2Indapamide see DiureticsIndinavirAldesleukin: plasma concentration of indinavir possiblyincreased by aldesleukinAppendix 1: Interactions

700 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsIndinavir (continued). Anti-arrhythmics: indinavir possibly increases plasmaconcentration of .amiodarone—avoid concomitantuse; indinavir possibly increases plasma concentrationof .flecainide (increased risk of ventriculararrhythmias—avoid concomitant use). Antibacterials: indinavir increases plasma concentrationof .rifabutin—avoid concomitant use; metabolismof indinavir accelerated by .rifampicin(reduced plasma concentration—avoid concomitantuse); avoidance of concomitant indinavir in severerenal and hepatic impairment advised by manufacturerof .telithromycinAnticoagulants: avoidance of indinavir advised bymanufacturer of rivaroxaban. Antidepressants: plasma concentration of indinavirreduced by .St John’s wort—avoid concomitant use. Antiepileptics: plasma concentration of indinavirpossibly reduced by .carbamazepine and .phenytoin,also plasma concentration of carbamazepine andphenytoin possibly increased; plasma concentrationof indinavir possibly reduced by .phenobarbital. Antifungals: plasma concentration of indinavirincreased by .itraconazole and .ketoconazole (considerreducing dose of indinavir). Antimalarials: caution with indinavir advised bymanufacturer of artemether/lumefantrine; indinavirpossibly increases plasma concentration of .quinine(increased risk of toxicity)Antimuscarinics: avoidance of indinavir advised bymanufacturer of darifenacin and tolterodine; manufacturerof fesoterodine advises dose reduction whenindinavir given with fesoterodine—consult fesoterodineproduct literature. Antipsychotics: indinavir possibly inhibits metabolismof .aripiprazole (reduce dose of aripiprazole); indinavirpossibly increases plasma concentration of.pimozide (increased risk of ventricular arrhythmias—avoidconcomitant use). Antivirals: avoid concomitant use of indinavir with.atazanavir; plasma concentration of both drugsincreased when indinavir given with darunavir;plasma concentration of indinavir reduced byefavirenz and nevirapine; plasma concentration ofindinavir possibly reduced by .etravirine—avoidconcomitant use; indinavir increases plasma concentrationof .maraviroc (consider reducing dose ofmaraviroc); combination of indinavir with nelfinavirmay increase plasma concentration of either drug (orboth); plasma concentration of indinavir increased byritonavir; indinavir increases plasma concentration ofsaquinavir. Anxiolytics and Hypnotics: increased risk of prolongedsedation when indinavir given with .alprazolam—avoid concomitant use; indinavir possibly increasesplasma concentration of .midazolam (risk of prolongedsedation—avoid concomitant use of oralmidazolam)Atovaquone: plasma concentration of indinavir possiblyreduced by atovaquone. Ciclosporin: indinavir increases plasma concentrationof .ciclosporin. Colchicine: indinavir possibly increases risk of.colchicine toxicity—suspend or reduce dose ofcolchicine (avoid concomitant use in hepatic or renalimpairment)Corticosteroids: plasma concentration of indinavirpossibly reduced by dexamethasone. Cytotoxics: indinavir possibly increases plasma concentrationof .everolimus—manufacturer of everolimusadvises avoid concomitant use; avoidance ofindinavir advised by manufacturer of .pazopanib. Ergot Alkaloids: increased risk of ergotism whenindinavir given with .ergotamine and methysergide—avoidconcomitant use. 5HT 1 Agonists: indinavir increases plasma concentrationof .eletriptan (risk of toxicity)—avoid concomitantuseIndinavir (continued). Lipid-regulating Drugs: possible increased risk ofmyopathy when indinavir given with atorvastatin;possible increased risk of myopathy when indinavirgiven with .rosuvastatin—manufacturer of rosuvastatinadvises avoid concomitant use; increased risk ofmyopathy when indinavir given with .simvastatin(avoid concomitant use). Ranolazine: indinavir possibly increases plasma concentrationof .ranolazine—manufacturer of ranolazineadvises avoid concomitant use. Sildenafil: indinavir increases plasma concentration of.sildenafil—reduce initial dose of sildenafilTadalafil: indinavir possibly increases plasma concentrationof tadalafil. Vardenafil: indinavir increases plasma concentration of.vardenafil—avoid concomitant useIndometacin see NSAIDsIndoramin see Alpha-blockersInfliximab. Abatacept: avoid concomitant use of infliximab with.abatacept. Anakinra: avoid concomitant use of infliximab with.anakinra. Vaccines: avoid concomitant use of infliximab with live.vaccines (see p. 599)Influenza Vaccine see VaccinesInsulin see AntidiabeticsInterferon Alfa see InterferonsInterferon Gamma see InterferonsInterferonsNote Peginterferon alfa interactions as for interferon alfa. Antivirals: increased risk of peripheral neuropathywhen interferon alfa given with .telbivudine. Theophylline: interferon alfa inhibits metabolism of.theophylline (consider reducing dose of theophylline)Vaccines: manufacturer of interferon gamma advisesavoid concomitant use with vaccinesIpratropium see AntimuscarinicsIrbesartan see Angiotensin-II Receptor AntagonistsIrinotecan. Antidepressants: metabolism of irinotecan acceleratedby .St John’s wort (reduced plasma concentration—avoid concomitant use)Antiepileptics: plasma concentration of irinotecan andits active metabolite reduced by carbamazepine,phenobarbital and phenytoin. Antifungals: plasma concentration of irinotecanreduced by .ketoconazole (but concentration ofactive metabolite of irinotecan increased)—avoidconcomitant use. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Antivirals: metabolism of irinotecan possibly inhibitedby .atazanavir (increased risk of toxicity). Cytotoxics: plasma concentration of active metaboliteof irinotecan increased by .lapatinib—considerreducing dose of irinotecan; plasma concentration ofirinotecan possibly increased by sorafenibIronAntacids: absorption of oral iron reduced by oralmagnesium salts (as magnesium trisilicate)Antibacterials: oral iron reduces absorption of ciprofloxacin,levofloxacin, moxifloxacin, norfloxacin andofloxacin; oral iron reduces absorption of tetracyclines,also absorption of oral iron reduced bytetracyclinesBisphosphonates: oral iron reduces absorption ofbisphosphonatesCalcium Salts: absorption of oral iron reduced bycalcium saltsDopaminergics: oral iron reduces absorption ofentacapone; oral iron possibly reduces absorption oflevodopaEltrombopag: oral iron possibly reduces absorption ofeltrombopag (give at least 4 hours apart)

BNFC 2011–2012 Appendix 1: Interactions 701Iron (continued)Methyldopa: oral iron antagonises hypotensive effectof methyldopaMycophenolate: oral iron reduces absorption ofmycophenolatePenicillamine: oral iron reduces absorption of penicillamineThyroid Hormones: oral iron reduces absorption oflevothyroxine (give at least 2 hours apart)Trientine: absorption of oral iron reduced by trientineZinc: oral iron reduces absorption of zinc, alsoabsorption of oral iron reduced by zincIsocarboxazid see MAOIsIsoflurane see Anaesthetics, GeneralIsometheptene see SympathomimeticsIsoniazidAntacids: absorption of isoniazid reduced by antacidsAntibacterials: increased risk of CNS toxicity whenisoniazid given with cycloserine. Antiepileptics: isoniazid increases plasma concentrationof .carbamazepine (also possibly increasedisoniazid hepatotoxicity); isoniazid inhibits metabolismof .ethosuximide (increased plasma concentrationand risk of toxicity); isoniazid possibly inhibitsmetabolism of phenytoin (increased risk of toxicity)Antifungals: isoniazid possibly reduces plasma concentrationof ketoconazoleAnxiolytics and Hypnotics: isoniazid inhibits themetabolism of diazepamCorticosteroids: plasma concentration of isoniazidpossibly reduced by corticosteroidsDisulfiram: isoniazid possibly increases CNS effects ofdisulfiramDopaminergics: isoniazid possibly reduces effects oflevodopaTheophylline: isoniazid possibly increases plasmaconcentration of theophyllineVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Isosorbide Dinitrate see NitratesIsosorbide Mononitrate see NitratesIsotretinoin see RetinoidsIsradipine see Calcium-channel BlockersItraconazole see Antifungals, TriazoleIvabradine. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen ivabradine given with .amiodarone or.disopyramide. Antibacterials: plasma concentration of ivabradinepossibly increased by .clarithromycin and.telithromycin—avoid concomitant use; increasedrisk of ventricular arrhythmias when ivabradine givenwith .erythromycin—avoid concomitant useAntidepressants: plasma concentration of ivabradinereduced by St John’s wort—avoid concomitant use. Antifungals: plasma concentration of ivabradineincreased by .ketoconazole—avoid concomitant use;plasma concentration of ivabradine increased byfluconazole—reduce initial dose of ivabradine;plasma concentration of ivabradine possiblyincreased by .itraconazole—avoid concomitant use. Antimalarials: increased risk of ventricular arrhythmiaswhen ivabradine given with .mefloquine. Antipsychotics: increased risk of ventricular arrhythmiaswhen ivabradine given with .pimozide. Antivirals: plasma concentration of ivabradine possiblyincreased by .nelfinavir and .ritonavir—avoid concomitantuse. Beta-blockers: increased risk of ventricular arrhythmiaswhen ivabradine given with .sotalol. Calcium-channel Blockers: plasma concentration ofivabradine increased by .diltiazem and .verapamil—avoid concomitant useGrapefruit Juice: plasma concentration of ivabradineincreased by grapefruit juice. Pentamidine Isetionate: increased risk of ventriculararrhythmias when ivabradine given with .pentamidineisetionateKaolinAnalgesics: kaolin possibly reduces absorption ofaspirinAntibacterials: kaolin possibly reduces absorption oftetracyclinesAntimalarials: kaolin reduces absorption of chloroquineand hydroxychloroquineAntipsychotics: kaolin possibly reduces absorption ofphenothiazinesKetamine see Anaesthetics, GeneralKetoconazole see Antifungals, ImidazoleKetoprofen see NSAIDsKetorolac see NSAIDsKetotifen see AntihistaminesLabetalol see Beta-blockersLacidipine see Calcium-channel BlockersLacosamide. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wort. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistatLactuloseAnticoagulants: lactulose possibly enhances anticoagulanteffect of coumarinsLamivudineAntibacterials: plasma concentration of lamivudineincreased by trimethoprim (as co-trimoxazole)—avoid concomitant use of high-dose co-trimoxazoleAntivirals: avoidance of lamivudine advised by manufacturerof emtricitabine; manufacturer of lamivudineadvises avoid concomitant use with foscarnet;manufacturer of lamivudine advises avoid concomitantuse of intravenous ganciclovirLamotrigine. Antibacterials: plasma concentration of lamotriginereduced by .rifampicin. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wortAntiepileptics: plasma concentration of lamotrigineoften reduced by carbamazepine, also plasma concentrationof an active metabolite of carbamazepinesometimes raised (but evidence is conflicting);plasma concentration of lamotrigine reduced byphenobarbital and phenytoin; plasma concentrationof lamotrigine increased by valproate. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered)Antivirals: plasma concentration of lamotrigine possiblyreduced by ritonavir. Oestrogens: plasma concentration of lamotriginereduced by .oestrogens—consider increasing dose oflamotrigine. Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistatProgestogens: plasma concentration of lamotriginepossibly increased by desogestrelAppendix 1: Interactions

702 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsLanreotideAntidiabetics: lanreotide possibly reduces requirementsfor insulin, metformin, repaglinide and sulfonylureasCiclosporin: lanreotide reduces plasma concentrationof ciclosporinLansoprazole see Proton Pump InhibitorsLanthanumAntibacterials: lanthanum possibly reduces absorptionof quinolones (give at least 2 hours before or 4 hoursafter lanthanum)Antifungals: lanthanum possibly reduces absorption ofketoconazole (give at least 2 hours apart)Antimalarials: lanthanum possibly reduces absorptionof chloroquine and hydroxychloroquine (give at least2 hours apart)Thyroid Hormones: lanthanum reduces absorption oflevothyroxine (give at least 2 hours apart)Lapatinib. Antibacterials: manufacturer of lapatinib advises avoidconcomitant use with .rifabutin, .rifampicin and.telithromycin. Antidepressants: manufacturer of lapatinib advisesavoid concomitant use with .St John’s wort. Antidiabetics: manufacturer of lapatinib advises avoidconcomitant use with .repaglinide. Antiepileptics: plasma concentration of lapatinibreduced by .carbamazepine—avoid concomitantuse; manufacturer of lapatinib advises avoid concomitantuse with .phenytoin. Antifungals: plasma concentration of lapatinibincreased by .ketoconazole—avoid concomitant use;manufacturer of lapatinib advises avoid concomitantuse with .itraconazole, .posaconazole and.voriconazole. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis);manufacturer of lapatinib advises avoid concomitantuse with .pimozide. Antivirals: manufacturer of lapatinib advises avoidconcomitant use with .ritonavir and .saquinavir. Cytotoxics: lapatinib increases plasma concentration ofpazopanib; possible increased risk of neutropeniawhen lapatinib given with docetaxel; increased risk ofneutropenia when lapatinib given with .paclitaxel;lapatinib increases plasma concentration of activemetabolite of .irinotecan—consider reducing dose ofirinotecan. Grapefruit Juice: manufacturer of lapatinib advisesavoid concomitant use with .grapefruit juiceUlcer-healing Drugs: absorption of lapatinib possiblyreduced by histamine H 2 -antagonists and protonpump inhibitorsLaronidaseAntimalarials: effects of laronidase possibly inhibitedby chloroquine and hydroxychloroquine (manufacturerof laronidase advises avoid concomitant use)LeflunomideNote Increased risk of toxicity with other haematotoxic andhepatotoxic drugsAntibacterials: plasma concentration of active metaboliteof leflunomide possibly increased by rifampicinAnticoagulants: leflunomide possibly enhances anticoagulanteffect of warfarinAntidiabetics: leflunomide possibly enhances hypoglycaemiceffect of tolbutamideAntiepileptics: leflunomide possibly increases plasmaconcentration of phenytoin. Cytotoxics: risk of toxicity when leflunomide given with.methotrexateLipid-regulating Drugs: the effect of leflunomide issignificantly decreased by colestyramine (enhancedelimination)—avoid unless drug elimination desired. Vaccines: avoid concomitant use of leflunomide withlive .vaccines (see p. 599)LenalidomideCardiac Glycosides: lenalidomide possibly increasesplasma concentration of digoxinLercanidipine see Calcium-channel BlockersLeukotriene Receptor AntagonistsAnalgesics: plasma concentration of zafirlukastincreased by aspirinAntibacterials: plasma concentration of zafirlukastreduced by erythromycinAnticoagulants: zafirlukast enhances anticoagulanteffect of warfarinAntiepileptics: plasma concentration of montelukastreduced by phenobarbitalTheophylline: zafirlukast possibly increases plasmaconcentration of theophylline, also plasma concentrationof zafirlukast reducedLevamisoleAlcohol: possibility of disulfiram-like reaction whenlevamisole given with alcohol. Anticoagulants: levamisole possibly enhances anticoagulanteffect of .warfarinAntiepileptics: levamisole possibly increases plasmaconcentration of phenytoinLevetiracetam. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wortAntiepileptics: levetiracetam possibly increases risk ofcarbamazepine toxicity. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistatLevobunolol see Beta-blockersLevobupivacaineAnti-arrhythmics: increased myocardial depressionwhen levobupivacaine given with anti-arrhythmicsLevocetirizine see AntihistaminesLevodopaACE Inhibitors: enhanced hypotensive effect whenlevodopa given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when levodopa given with adrenergic neuroneblockersAlpha-blockers: enhanced hypotensive effect whenlevodopa given with alpha-blockers. Anaesthetics, General: increased risk of arrhythmiaswhen levodopa given with .volatile liquid generalanaestheticsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when levodopa given with angiotensin-IIreceptor antagonistsAntibacterials: effects of levodopa possibly reduced byisoniazid. Antidepressants: risk of hypertensive crisis whenlevodopa given with .MAOIs, avoid levodopa for atleast 2 weeks after stopping MAOIs; increased risk ofside-effects when levodopa given with moclobemideAntiepileptics: effects of levodopa possibly reduced byphenytoinAntimuscarinics: absorption of levodopa possiblyreduced by antimuscarinicsAntipsychotics: effects of levodopa antagonised byantipsychotics; avoidance of levodopa advised bymanufacturer of amisulpride (antagonism of effect)Anxiolytics and Hypnotics: effects of levodopa possiblyantagonised by benzodiazepinesBeta-blockers: enhanced hypotensive effect whenlevodopa given with beta-blockersBupropion: increased risk of side-effects when levodopagiven with bupropionCalcium-channel Blockers: enhanced hypotensiveeffect when levodopa given with calcium-channelblockers

BNFC 2011–2012 Appendix 1: Interactions 703Levodopa (continued)Clonidine: enhanced hypotensive effect when levodopagiven with clonidineDiazoxide: enhanced hypotensive effect when levodopagiven with diazoxideDiuretics: enhanced hypotensive effect when levodopagiven with diureticsDopaminergics: enhanced effects and increased toxicityof levodopa when given with selegiline (reducedose of levodopa)Iron: absorption of levodopa possibly reduced by oralironMemantine: effects of dopaminergics possiblyenhanced by memantineMethyldopa: enhanced hypotensive effect when levodopagiven with methyldopa; antiparkinsonian effectof dopaminergics antagonised by methyldopaMoxonidine: enhanced hypotensive effect when levodopagiven with moxonidineMuscle Relaxants: possible agitation, confusion andhallucinations when levodopa given with baclofenNitrates: enhanced hypotensive effect when levodopagiven with nitratesVasodilator Antihypertensives: enhanced hypotensiveeffect when levodopa given with hydralazine,minoxidil or sodium nitroprussideVitamins: effects of levodopa reduced by pyridoxinewhen given without dopa-decarboxylase inhibitorLevofloxacin see QuinolonesLevofolinic Acid see FolatesLevomepromazine see AntipsychoticsLevonorgestrel see ProgestogensLevothyroxine see Thyroid HormonesLidocaineNote Interactions less likely when lidocaine used topicallyAnaesthetics, Local: increased myocardial depressionwhen anti-arrhythmics given with bupivacaine, levobupivacaine,prilocaine or ropivacaine. Anti-arrhythmics: increased myocardial depressionwhen anti-arrhythmics given with other .antiarrhythmics. Antipsychotics: increased risk of ventricular arrhythmiaswhen anti-arrhythmics that prolong the QTinterval given with .antipsychotics that prolong theQT interval. Antivirals: plasma concentration of lidocaine possiblyincreased by .atazanavir and lopinavir; plasmaconcentration of lidocaine possibly increased bydarunavir and .fosamprenavir—avoid concomitantuse; increased risk of ventricular arrhythmias whenlidocaine given with .saquinavir—avoid concomitantuse. Beta-blockers: increased myocardial depression whenanti-arrhythmics given with .beta-blockers; increasedrisk of lidocaine toxicity when given with.propranolol. Diuretics: action of lidocaine antagonised by hypokalaemiacaused by .acetazolamide, .loop diuretics or.thiazides and related diureticsMuscle Relaxants: neuromuscular blockade enhancedand prolonged when lidocaine given with suxamethonium. Ulcer-healing Drugs: plasma concentration of lidocaineincreased by .cimetidine (increased risk oftoxicity)LinezolidNote Linezolid is a reversible, non-selective MAO inhibitor—seeinteractions of MAOIsAntibacterials: plasma concentration of linezolidreduced by rifampicin (possible therapeutic failure oflinezolid)Vaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Liothyronine see Thyroid HormonesLipid-regulating Drugs see Colesevelam, Colestipol,Colestyramine, Ezetimibe, Fibrates, Nicotinic Acid,and StatinsLiraglutide see AntidiabeticsLisinopril see ACE InhibitorsLithium. ACE Inhibitors: excretion of lithium reduced by .ACEinhibitors (increased plasma concentration). Analgesics: excretion of lithium reduced by .NSAIDs(increased risk of toxicity); excretion of lithiumreduced by .ketorolac (increased risk of toxicity)—avoid concomitant use. Angiotensin-II Receptor Antagonists: excretion oflithium reduced by .angiotensin-II receptor antagonists(increased plasma concentration)Antacids: excretion of lithium increased by sodiumbicarbonate (reduced plasma concentration). Anti-arrhythmics: avoidance of lithium advised bymanufacturer of .amiodarone (risk of ventriculararrhythmias)Antibacterials: increased risk of lithium toxicity whengiven with metronidazole. Antidepressants: possible increased serotonergiceffects when lithium given with venlafaxine;increased risk of CNS effects when lithium given with.SSRIs (lithium toxicity reported); risk of toxicitywhen lithium given with tricyclicsAntiepileptics: neurotoxicity may occur when lithiumgiven with carbamazepine or phenytoin withoutincreased plasma concentration of lithium; plasmaconcentration of lithium possibly affected by topiramateAntipsychotics: increased risk of extrapyramidal sideeffectsand possibly neurotoxicity when lithium givenwith clozapine, flupentixol, haloperidol,phenothiazines or zuclopenthixol; possible risk oftoxicity when lithium given with olanzapine;increased risk of extrapyramidal side-effects whenlithium given with sulpirideAnxiolytics and Hypnotics: increased risk of neurotoxicitywhen lithium given with clonazepamCalcium-channel Blockers: neurotoxicity may occurwhen lithium given with diltiazem or verapamilwithout increased plasma concentration of lithium. Cytotoxics: increased risk of ventricular arrhythmiaswhen lithium given with .arsenic trioxide. Diuretics: excretion of lithium increased by.acetazolamide; excretion of lithium reduced by.loop diuretics and .thiazides and related diuretics(increased plasma concentration and risk of toxicity)—loopdiuretics safer than thiazides; excretion oflithium reduced by .potassium-sparing diuretics andaldosterone antagonists (increased plasma concentrationand risk of toxicity)5HT 1 Agonists: possible risk of toxicity when lithiumgiven with sumatriptan. Methyldopa: neurotoxicity may occur when lithiumgiven with .methyldopa without increased plasmaconcentration of lithiumMuscle Relaxants: lithium enhances effects of musclerelaxants; hyperkinesis caused by lithium possiblyaggravated by baclofenParasympathomimetics: lithium antagonises effects ofneostigmine and pyridostigmineTheophylline: excretion of lithium increased by theophylline(reduced plasma concentration)Lofepramine see Antidepressants, TricyclicLofexidineAlcohol: increased sedative effect when lofexidinegiven with alcoholAnxiolytics and Hypnotics: increased sedative effectwhen lofexidine given with anxiolytics and hypnoticsLomustine. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Ulcer-healing Drugs: myelosuppressive effects oflomustine possibly enhanced by cimetidineLoperamideDesmopressin: loperamide increases plasma concentrationof oral desmopressinAppendix 1: Interactions

704 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsLopinavirNote In combination with ritonavir as Kaletra c (ritonavir ispresent to inhibit lopinavir metabolism and increase plasmalopinavirconcentration)—see also Ritonavir. Anti-arrhythmics: lopinavir possibly increases plasmaconcentration of .flecainide (increased risk ofventricular arrhythmias—avoid concomitant use);lopinavir possibly increases plasma concentration oflidocaine. Antibacterials: plasma concentration of lopinavirreduced by .rifampicin—avoid concomitant use;avoidance of concomitant lopinavir in severe renaland hepatic impairment advised by manufacturer of.telithromycinAnticoagulants: avoidance of lopinavir advised bymanufacturer of rivaroxaban. Antidepressants: plasma concentration of lopinavirreduced by .St John’s wort—avoid concomitant use. Antiepileptics: plasma concentration of lopinavirpossibly reduced by carbamazepine,.phenobarbital and phenytoinAntihistamines: lopinavir possibly increases plasmaconcentration of chlorphenamineAntimalarials: caution with lopinavir advised bymanufacturer of artemether/lumefantrineAntimuscarinics: avoidance of lopinavir advised bymanufacturer of darifenacin and tolterodine. Antipsychotics: lopinavir possibly inhibits metabolismof .aripiprazole (reduce dose of aripiprazole). Antivirals: lopinavir reduces plasma concentration of.darunavir, also plasma concentration of lopinavirincreased (avoid concomitant use); plasma concentrationof lopinavir reduced by .efavirenz—considerincreasing dose of lopinavir; lopinavir reducesplasma concentration of fosamprenavir, effect onlopinavir plasma concentration not predictable—avoid concomitant use; lopinavir increases plasmaconcentration of .maraviroc (consider reducing doseof maraviroc); plasma concentration of lopinavirreduced by nelfinavir, also plasma concentration ofactive metabolite of nelfinavir increased; plasmaconcentration of lopinavir possibly reduced by.nevirapine—consider increasing dose of lopinavir;increased risk of ventricular arrhythmias whenlopinavir given with .saquinavir—avoid concomitantuse; lopinavir increases plasma concentration oftenofovir; plasma concentration of lopinavir reducedby .tipranavirCorticosteroids: plasma concentration of lopinavirpossibly reduced by dexamethasoneEltrombopag: lopinavir possibly reduces plasma concentrationof eltrombopag. Lipid-regulating Drugs: possible increased risk ofmyopathy when lopinavir given with atorvastatin;possible increased risk of myopathy when lopinavirgiven with .rosuvastatin—manufacturer of rosuvastatinadvises avoid concomitant use; possibleincreased risk of myopathy when lopinavir given with.simvastatin—avoid concomitant use. Ranolazine: lopinavir possibly increases plasma concentrationof .ranolazine—manufacturer of ranolazineadvises avoid concomitant useSirolimus: lopinavir possibly increases plasma concentrationof sirolimusLoprazolam see Anxiolytics and HypnoticsLoratadine see AntihistaminesLorazepam see Anxiolytics and HypnoticsLormetazepam see Anxiolytics and HypnoticsLosartan see Angiotensin-II Receptor AntagonistsLumefantrine see Artemether with LumefantrineLymecycline see TetracyclinesMacrolidesNote See also TelithromycinNote Interactions do not apply to small amounts oferythromycin used topicallyAnalgesics: erythromycin increases plasma concentrationof alfentanilAntacids: absorption of azithromycin reduced byantacidsMacrolides (continued). Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen parenteral erythromycin given with.amiodarone—avoid concomitant use; clarithromycinpossibly increases plasma concentration of.disopyramide (increased risk of toxicity); erythromycinincreases plasma concentration of.disopyramide (increased risk of toxicity); avoidanceof clarithromycin advised by manufacturer of.dronedarone (risk of ventricular arrhythmias);erythromycin possibly increases plasma concentrationof .dronedarone (increased risk of ventriculararrhythmias—avoid concomitant use). Antibacterials: increased risk of ventricular arrhythmiaswhen parenteral erythromycin given with.moxifloxacin—avoid concomitant use; macrolidespossibly increase plasma concentration of .rifabutin(increased risk of uveitis—reduce rifabutin dose);clarithromycin increases plasma concentration of.rifabutin (increased risk of uveitis—reduce rifabutindose); plasma concentration of clarithromycinreduced by rifamycins. Anticoagulants: clarithromycin and erythromycinenhance anticoagulant effect of .coumarins; azithromycinpossibly enhances anticoagulant effect of.coumarins. Antidepressants: avoidance of macrolides advised bymanufacturer of .reboxetineAntidiabetics: clarithromycin enhances effects ofrepaglinide. Antiepileptics: clarithromycin and erythromycinincrease plasma concentration of .carbamazepine;clarithromycin inhibits metabolism of phenytoin(increased plasma concentration); erythromycinpossibly inhibits metabolism of valproate (increasedplasma concentration)Antifungals: clarithromycin increases plasma concentrationof itraconazole. Antihistamines: manufacturer of loratadine adviseserythromycin possibly increases plasma concentrationof loratadine; macrolides possibly inhibitmetabolism of .mizolastine (avoid concomitant use);erythromycin inhibits metabolism of .mizolastine—avoid concomitant use; erythromycin increasesplasma concentration of rupatadine. Antimalarials: avoidance of macrolides advised bymanufacturer of .artemether/lumefantrineAntimuscarinics: erythromycin possibly increasesplasma concentration of darifenacin; manufacturer offesoterodine advises dose reduction when clarithromycingiven with fesoterodine—consult fesoterodineproduct literature; avoidance of clarithromycin anderythromycin advised by manufacturer of tolterodine. Antipsychotics: avoidance of macrolides advised bymanufacturer of .droperidol (risk of ventriculararrhythmias); increased risk of ventricular arrhythmiaswhen parenteral erythromycin given with.zuclopenthixol—avoid concomitant use; increasedrisk of ventricular arrhythmias when erythromycingiven with .amisulpride—avoid concomitant use;erythromycin possibly increases plasma concentrationof .clozapine (possible increased risk of convulsions);possible increased risk of ventriculararrhythmias when erythromycin given with.pimozide—avoid concomitant use; increased risk ofventricular arrhythmias when clarithromycin givenwith .pimozide—avoid concomitant use; macrolidespossibly increase plasma concentration of quetiapine(reduce dose of quetiapine); increased risk of ventriculararrhythmias when parenteral erythromycingiven with .sulpiride. Antivirals: plasma concentration of both drugsincreased when clarithromycin given with atazanavir;increased risk of rash when clarithromycin given withefavirenz; clarithromycin increases plasma concentrationof .etravirine, also plasma concentration ofclarithromycin reduced; clarithromycin possiblyincreases plasma concentration of .maraviroc (considerreducing dose of maraviroc); plasma concen-

BNFC 2011–2012 Appendix 1: Interactions 705Macrolides. Antivirals (continued)tration of azithromycin increased by nelfinavir(increased risk of toxicity); plasma concentrationof clarithromycin reduced by nevirapine (butconcentration of an active metabolite increased),also plasma concentration of nevirapineincreased; plasma concentration of clarithromycinincreased by .ritonavir (reduce dose ofclarithromycin in renal impairment); plasmaconcentration of azithromycin and erythromycinpossibly increased by ritonavir; increased risk ofventricular arrhythmias when clarithromycin orerythromycin given with .saquinavir—avoidconcomitant use; plasma concentration ofclarithromycin increased by .tipranavir (reducedose of clarithromycin in renal impairment), alsoclarithromycin increases plasma concentration oftipranavir; clarithromycin tablets reduce absorptionof zidovudine (give at least 2 hours apart). Anxiolytics and Hypnotics: clarithromycin anderythromycin inhibit metabolism of .midazolam(increased plasma concentration with increasedsedation); erythromycin increases plasma concentrationof buspirone (reduce dose of buspirone);erythromycin inhibits the metabolism of zopicloneAprepitant: clarithromycin possibly increases plasmaconcentration of aprepitant. Atomoxetine: increased risk of ventricular arrhythmiaswhen parenteral erythromycin given with.atomoxetine. Calcium-channel Blockers: erythromycin possiblyinhibits metabolism of felodipine (increased plasmaconcentration); avoidance of erythromycin advisedby manufacturer of lercanidipine; clarithromycin anderythromycin possibly inhibit metabolism of.verapamil (increased risk of toxicity)Cardiac Glycosides: macrolides increase plasma concentrationof digoxin (increased risk of toxicity). Ciclosporin: macrolides possibly inhibit metabolism of.ciclosporin (increased plasma concentration);clarithromycin and erythromycin inhibit metabolismof .ciclosporin (increased plasma concentration)Cilostazol: erythromycin increases plasma concentrationof cilostazol (consider reducing dose of cilostazol). Clopidogrel: erythromycin possibly reduces antiplateleteffect of .clopidogrel. Colchicine: azithromycin, clarithromycin and erythromycinpossibly increase risk of .colchicine toxicity—suspend or reduce dose of colchicine (avoid concomitantuse in hepatic or renal impairment)Corticosteroids: erythromycin possibly inhibitsmetabolism of corticosteroids; erythromycin inhibitsthe metabolism of methylprednisolone; clarithromycinpossibly increases plasma concentration ofmethylprednisolone. Cytotoxics: clarithromycin possibly increases plasmaconcentration of .everolimus—manufacturer ofeverolimus advises avoid concomitant use; erythromycinincreases plasma concentration of.everolimus; avoidance of clarithromycin advised bymanufacturer of .nilotinib and .pazopanib; in vitrostudies suggest a possible interaction betweenerythromycin and docetaxel (consult docetaxelproduct literature); increased risk of ventriculararrhythmias when erythromycin given with .arsenictrioxide; erythromycin increases toxicity of.vinblastine—avoid concomitant use; possibleincreased risk of neutropenia when clarithromycingiven with .vinorelbine. Diuretics: clarithromycin increases plasma concentrationof .eplerenone—avoid concomitant use;erythromycin increases plasma concentration ofeplerenone (reduce dose of eplerenone)Dopaminergics: macrolides possibly increase plasmaconcentration of bromocriptine andMacrolidesDopaminergics (continued)cabergoline (increased risk of toxicity); erythromycinincreases plasma concentration ofbromocriptine and cabergoline (increased risk oftoxicity). Ergot Alkaloids: increased risk of ergotism whenmacrolides given with .ergotamine and methysergide—avoidconcomitant use. 5HT 1 Agonists: clarithromycin and erythromycinincrease plasma concentration of .eletriptan (risk oftoxicity)—avoid concomitant use. Ivabradine: clarithromycin possibly increases plasmaconcentration of .ivabradine—avoid concomitantuse; increased risk of ventricular arrhythmias whenerythromycin given with .ivabradine—avoid concomitantuseLeukotriene Receptor Antagonists: erythromycinreduces plasma concentration of zafirlukast. Lipid-regulating Drugs: clarithromycin increasesplasma concentration of .atorvastatin and pravastatin;possible increased risk of myopathy whenerythromycin given with atorvastatin; erythromycinincreases plasma concentration of pravastatin;erythromycin reduces plasma concentration of rosuvastatin;increased risk of myopathy whenclarithromycin or erythromycin given with.simvastatin (avoid concomitant use)Oestrogens: erythromycin increases plasma concentrationof estradiolParasympathomimetics: erythromycin increasesplasma concentration of galantamine. Pentamidine Isetionate: increased risk of ventriculararrhythmias when parenteral erythromycin givenwith .pentamidine isetionateProgestogens: erythromycin increases plasma concentrationof dienogest. Ranolazine: clarithromycin possibly increases plasmaconcentration of .ranolazine—manufacturer ofranolazine advises avoid concomitant useSildenafil: clarithromycin possibly increases plasmaconcentration of sildenafil—reduce initial dose ofsildenafil; erythromycin increases plasma concentrationof sildenafil—reduce initial dose of sildenafil. Sirolimus: clarithromycin increases plasma concentrationof .sirolimus—avoid concomitant use; plasmaconcentration of both drugs increased whenerythromycin given with .sirolimus. Tacrolimus: clarithromycin and erythromycin increaseplasma concentration of .tacrolimusTadalafil: clarithromycin and erythromycin possiblyincrease plasma concentration of tadalafil. Theophylline: azithromycin possibly increases plasmaconcentration of theophylline; clarithromycin inhibitsmetabolism of .theophylline (increased plasma concentration);erythromycin increases plasma concentrationof .theophylline (also theophylline mayreduce absorption of oral erythromycin)Ulcer-healing Drugs: plasma concentration oferythromycin increased by cimetidine (increased riskof toxicity, including deafness); plasma concentrationof both drugs increased when clarithromycin givenwith omeprazoleVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Vardenafil: erythromycin increases plasma concentrationof vardenafil (reduce dose of vardenafil)Magnesium (parenteral). Calcium-channel Blockers: profound hypotensionreported with concomitant use of parenteralmagnesium and .nifedipine in pre-eclampsiaMuscle Relaxants: parenteral magnesium enhanceseffects of non-depolarising muscle relaxants andsuxamethoniumMagnesium Salts (oral) see AntacidsMannitolCiclosporin: possible increased risk of nephrotoxicitywhen mannitol given with ciclosporinAppendix 1: Interactions

706 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsMAOIsNote For interactions of reversible MAO-A inhibitors(RIMAs) see Moclobemide, and for interactions of MAO-Binhibitors see Rasagiline and Selegiline; the antibacterialLinezolid is a reversible, non-selective MAO inhibitorACE Inhibitors: MAOIs possibly enhance hypotensiveeffect of ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when MAOIs given with adrenergic neuroneblockers. Alcohol: MAOIs interact with tyramine found in somebeverages containing .alcohol and some dealcoholisedbeverages (hypertensive crisis)—if no tyramine,enhanced hypotensive effectAlpha 2 -adrenoceptor Stimulants: avoidance ofMAOIs advised by manufacturer of apraclonidine andbrimonidine. Alpha-blockers: avoidance of MAOIs advised bymanufacturer of .indoramin; enhanced hypotensiveeffect when MAOIs given with alpha-blockers. Analgesics: CNS excitation or depression (hypertensionor hypotension) when MAOIs given with.pethidine—avoid concomitant use and for 2 weeksafter stopping MAOIs; possible increased serotonergiceffects and increased risk of convulsions whenMAOIs given with .tramadol—some manufacturersadvise avoid concomitant use and for 2 weeks afterstopping MAOIs; avoidance of MAOIs advised bymanufacturer of .nefopam; possible CNS excitationor depression (hypertension or hypotension) whenMAOIs given with .opioid analgesics—some manufacturersadvise avoid concomitant use and for 2weeks after stopping MAOIsAngiotensin-II Receptor Antagonists: MAOIs possiblyenhance hypotensive effect of angiotensin-II receptorantagonists. Antidepressants: increased risk of hypertension andCNS excitation when MAOIs given with .reboxetine(MAOIs should not be started until 1 week afterstopping reboxetine, avoid reboxetine for 2 weeksafter stopping MAOIs); after stopping MAOIs do notstart .citalopram, .escitalopram, .fluvoxamine,.paroxetine or .sertraline for 2 weeks, also MAOIsshould not be started until at least 1 week afterstopping citalopram, escitalopram, fluvoxamine,paroxetine or sertraline; after stopping MAOIs do notstart .fluoxetine for 2 weeks, also MAOIs should notbe started until at least 5 weeks after stoppingfluoxetine; after stopping MAOIs do not start.duloxetine for 2 weeks, also MAOIs should not bestarted until at least 5 days after stopping duloxetine;enhanced CNS effects and toxicity when MAOIsgiven with .venlafaxine (venlafaxine should not bestarted until 2 weeks after stopping MAOIs, avoidMAOIs for 1 week after stopping venlafaxine);increased risk of hypertension and CNS excitationwhen MAOIs given with other .MAOIs (avoid for atleast 2 weeks after stopping previous MAOIs andthen start at a reduced dose); after stopping MAOIsdo not start .moclobemide for at least 1 week;MAOIs increase CNS effects of .SSRIs (risk of serioustoxicity); after stopping MAOIs do not start.mirtazapine for 2 weeks, also MAOIs should not bestarted until at least 2 weeks after stopping mirtazapine;after stopping MAOIs do not start .tricyclicrelatedantidepressants for 2 weeks, also MAOIsshould not be started until at least 1–2 weeks afterstopping tricyclic-related antidepressants; increasedrisk of hypertension and CNS excitation when MAOIsgiven with .tricyclics, tricyclics should not be starteduntil 2 weeks after stopping MAOIs (3 weeks ifstarting clomipramine or imipramine), also MAOIsshould not be started for at least 1–2 weeks afterstopping tricyclics (3 weeks in the case of clomipramineor imipramine); CNS excitation and confusionwhen MAOIs given with .tryptophan (reduce dose oftryptophan)Antidiabetics: MAOIs possibly enhance hypoglycaemiceffect of antidiabetics; MAOIs enhance hypo-MAOIsAntidiabetics (continued)glycaemic effect of insulin, metformin and sulfonylureas. Antiepileptics: MAOIs possibly antagonise anticonvulsanteffect of antiepileptics (convulsivethreshold lowered); avoidance for 2 weeks afterstopping MAOIs advised by manufacturer of.carbamazepine, also antagonism of anticonvulsanteffectAntihistamines: avoidance of promethazine for 2weeks after stopping MAOIs advised by manufacturerof promethazine; increased antimuscarinic andsedative effects when MAOIs given with antihistamines. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrineAntimuscarinics: increased risk of antimuscarinic sideeffectswhen MAOIs given with antimuscarinics. Antipsychotics: CNS effects of MAOIs possiblyincreased by .clozapineAnxiolytics and Hypnotics: avoidance of MAOIsadvised by manufacturer of buspirone; manufacturerof tranylcypromine advises avoid buspirone for 10days after stopping tranylcypromine. Atomoxetine: after stopping MAOIs do not start.atomoxetine for 2 weeks, also MAOIs should not bestarted until at least 2 weeks after stopping atomoxetine;possible increased risk of convulsions whenantidepressants given with atomoxetineBeta-blockers: enhanced hypotensive effect whenMAOIs given with beta-blockers. Bupropion: avoidance of bupropion for 2 weeks afterstopping MAOIs advised by manufacturer of.bupropionCalcium-channel Blockers: enhanced hypotensiveeffect when MAOIs given with calcium-channelblockersClonidine: enhanced hypotensive effect when MAOIsgiven with clonidineDiazoxide: enhanced hypotensive effect when MAOIsgiven with diazoxideDiuretics: enhanced hypotensive effect when MAOIsgiven with diuretics. Dopaminergics: avoid concomitant use of non-selectiveMAOIs with .entacapone; risk of hypertensivecrisis when MAOIs given with .levodopa, avoidlevodopa for at least 2 weeks after stopping MAOIs;risk of hypertensive crisis when MAOIs given with.rasagiline, avoid MAOIs for at least 2 weeks afterstopping rasagiline; enhanced hypotensive effectwhen MAOIs given with .selegiline—manufacturerof selegiline advises avoid concomitant use; avoidconcomitant use of MAOIs with tolcaponeDoxapram: MAOIs enhance effects of doxapramHistamine: avoidance of MAOIs advised by manufacturerof histamine. 5HT 1 Agonists: risk of CNS toxicity when MAOIs givenwith .rizatriptan or .sumatriptan (avoid rizatriptan orsumatriptan for 2 weeks after MAOIs); increased riskof CNS toxicity when MAOIs given with.zolmitriptan. Methyldopa: avoidance of MAOIs advised by manufacturerof .methyldopaMoxonidine: enhanced hypotensive effect whenMAOIs given with moxonidineMuscle Relaxants: phenelzine enhances effects ofsuxamethoniumNicorandil: enhanced hypotensive effect when MAOIsgiven with nicorandilNitrates: enhanced hypotensive effect when MAOIsgiven with nitratesPholcodine: avoidance of pholcodine for 2 weeks afterstopping MAOIs advised by manufacturer of pholcodine. Sympathomimetics: risk of hypertensive crisis whenMAOIs given with .sympathomimetics; risk ofhypertensive crisis when MAOIs given with.methylphenidate, some manufacturers advise

BNFC 2011–2012 Appendix 1: Interactions 707MAOIs. Sympathomimetics (continued)avoid methylphenidate for at least 2 weeks afterstopping MAOIs. Tetrabenazine: risk of CNS excitation and hypertensionwhen MAOIs given with .tetrabenazineVasodilator Antihypertensives: enhanced hypotensiveeffect when MAOIs given with hydralazine,minoxidil or sodium nitroprussideMAOIs, reversible see MoclobemideMaraviroc. Antibacterials: plasma concentration of maravirocpossibly increased by .clarithromycin and.telithromycin (consider reducing dose of maraviroc);plasma concentration of maraviroc reduced by.rifampicin—consider increasing dose of maraviroc. Antidepressants: plasma concentration of maravirocpossibly reduced by .St John’s wort—avoid concomitantuse. Antifungals: plasma concentration of maravirocincreased by .ketoconazole (consider reducing doseof maraviroc). Antivirals: plasma concentration of maravirocincreased by .atazanavir, .darunavir, .indinavir,.lopinavir and .saquinavir (consider reducing dose ofmaraviroc); plasma concentration of maraviroc possiblyreduced by .efavirenz—consider increasingdose of maraviroc; plasma concentration of maravirocpossibly reduced by etravirine; plasma concentrationof maraviroc possibly increased by.nelfinavir (consider reducing dose of maraviroc);plasma concentration of maraviroc increased byritonavirMebendazoleUlcer-healing Drugs: metabolism of mebendazolepossibly inhibited by cimetidine (increased plasmaconcentration)Medroxyprogesterone see ProgestogensMefenamic Acid see NSAIDsMefloquine. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen mefloquine given with .amiodarone—avoid concomitant use. Antibacterials: increased risk of ventricular arrhythmiaswhen mefloquine given with .moxifloxacin—avoid concomitant use; plasma concentration ofmefloquine reduced by .rifampicin—avoid concomitantuse. Antiepileptics: mefloquine antagonises anticonvulsanteffect of .antiepilepticsAntifungals: plasma concentration of mefloquineincreased by ketoconazole. Antimalarials: avoidance of antimalarials advised bymanufacturer of .artemether/lumefantrine;increased risk of convulsions when mefloquine givenwith .chloroquine and hydroxychloroquine;increased risk of convulsions when mefloquine givenwith .quinine (but should not prevent the use ofintravenous quinine in severe cases). Antipsychotics: possible increased risk of ventriculararrhythmias when mefloquine given with.haloperidol—avoid concomitant use; increased riskof ventricular arrhythmias when mefloquine givenwith .pimozide—avoid concomitant use. Atomoxetine: increased risk of ventricular arrhythmiaswhen mefloquine given with .atomoxetineBeta-blockers: increased risk of bradycardia whenmefloquine given with beta-blockersCalcium-channel Blockers: possible increased risk ofbradycardia when mefloquine given with calciumchannelblockersCardiac Glycosides: possible increased risk of bradycardiawhen mefloquine given with digoxinHistamine: avoidance of antimalarials advised bymanufacturer of histamine. Ivabradine: increased risk of ventricular arrhythmiaswhen mefloquine given with .ivabradineMefloquine (continued)Vaccines: antimalarials inactivate oral typhoidvaccine—see p. 620Megestrol see ProgestogensMelatonin see Anxiolytics and HypnoticsMeloxicam see NSAIDsMelphalanAntibacterials: increased risk of melphalan toxicitywhen given with nalidixic acid. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cardiac Glycosides: melphalan possibly reducesabsorption of digoxin tablets. Ciclosporin: increased risk of nephrotoxicity whenmelphalan given with .ciclosporinMemantine. Anaesthetics, General: increased risk of CNS toxicitywhen memantine given with .ketamine (manufacturerof memantine advises avoid concomitant use). Analgesics: increased risk of CNS toxicity whenmemantine given with .dextromethorphan (manufacturerof memantine advises avoid concomitantuse)Anticoagulants: memantine possibly enhances anticoagulanteffect of warfarinAntimuscarinics: memantine possibly enhances effectsof antimuscarinicsAntipsychotics: memantine possibly reduces effects ofantipsychotics. Dopaminergics: memantine possibly enhances effectsof dopaminergics and selegiline; increased risk ofCNS toxicity when memantine given with.amantadine (manufacturer of memantine advisesavoid concomitant use)Muscle Relaxants: memantine possibly modifieseffects of baclofen and dantroleneMepacrineAntimalarials: mepacrine increases plasma concentrationof primaquine (increased risk of toxicity)Meprobamate see Anxiolytics and HypnoticsMeptazinol see Opioid AnalgesicsMercaptopurine. Allopurinol: enhanced effects and increased toxicity ofmercaptopurine when given with .allopurinol(reduce dose of mercaptopurine to one quarter ofusual dose)Aminosalicylates: possible increased risk of leucopeniawhen mercaptopurine given with aminosalicylates. Antibacterials: increased risk of haematological toxicitywhen mercaptopurine given with.sulfamethoxazole (as co-trimoxazole); increased riskof haematological toxicity when mercaptopurinegiven with .trimethoprim (also with co-trimoxazole). Anticoagulants: mercaptopurine possibly reducesanticoagulant effect of .coumarins. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Febuxostat: avoidance of mercaptopurine advised bymanufacturer of .febuxostatMeropenem. Antiepileptics: carbapenems reduce plasma concentrationof .valproate—avoid concomitant useProbenecid: excretion of meropenem reduced byprobenecidVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Mesalazine see AminosalicylatesMestranol see OestrogensMetaraminol see SympathomimeticsMetformin see AntidiabeticsMethadone see Opioid AnalgesicsMethenamineAntacids: avoid concomitant use of methenamine withantacids. Antibacterials: increased risk of crystalluria whenmethenamine given with .sulfonamidesAppendix 1: Interactions

708 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsMethenamine (continued). Diuretics: effects of methenamine antagonised by.acetazolamidePotassium Salts: avoid concomitant use of methenaminewith potassium citrateSodium Citrate: avoid concomitant use of methenaminewith sodium citrateVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Methocarbamol see Muscle RelaxantsMethotrexate. Anaesthetics, General: antifolate effect of methotrexateincreased by .nitrous oxide—avoid concomitantuse. Analgesics: excretion of methotrexate probablyreduced by .NSAIDs (increased risk of toxicity);excretion of methotrexate reduced by .aspirin,.diclofenac, .ibuprofen, .indometacin, .ketoprofen,.meloxicam and .naproxen (increased risk of toxicity). Antibacterials: absorption of methotrexate possiblyreduced by neomycin; excretion of methotrexatepossibly reduced by ciprofloxacin (increased risk oftoxicity); increased risk of haematological toxicitywhen methotrexate given with .sulfamethoxazole (asco-trimoxazole); increased risk of methotrexatetoxicity when given with doxycycline,sulfonamides or tetracycline; excretion of methotrexatereduced by penicillins (increased risk oftoxicity); increased risk of haematological toxicitywhen methotrexate given with .trimethoprim (alsowith co-trimoxazole)Antiepileptics: antifolate effect of methotrexateincreased by phenytoin. Antimalarials: antifolate effect of methotrexateincreased by .pyrimethamine. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cardiac Glycosides: methotrexate possibly reducesabsorption of digoxin tablets. Ciclosporin: risk of toxicity when methotrexate givenwith .ciclosporin. Cytotoxics: increased pulmonary toxicity whenmethotrexate given with .cisplatinDiuretics: excretion of methotrexate increased byalkaline urine due to acetazolamide. Leflunomide: risk of toxicity when methotrexate givenwith .leflunomide. Probenecid: excretion of methotrexate reduced by.probenecid (increased risk of toxicity). Retinoids: plasma concentration of methotrexateincreased by .acitretin (also increased risk ofhepatotoxicity)—avoid concomitant useTheophylline: methotrexate possibly increases plasmaconcentration of theophyllineUlcer-healing Drugs: excretion of methotrexate possiblyreduced by omeprazole (increased risk of toxicity)Methoxamine see SympathomimeticsMethyldopaACE Inhibitors: enhanced hypotensive effect whenmethyldopa given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when methyldopa given with adrenergicneurone blockersAlcohol: enhanced hypotensive effect when methyldopagiven with alcoholAldesleukin: enhanced hypotensive effect whenmethyldopa given with aldesleukinAlpha-blockers: enhanced hypotensive effect whenmethyldopa given with alpha-blockersAnaesthetics, General: enhanced hypotensive effectwhen methyldopa given with general anaestheticsAnalgesics: hypotensive effect of methyldopa antagonisedby NSAIDsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when methyldopa given withangiotensin-II receptor antagonists. Antidepressants: manufacturer of methyldopa advisesavoid concomitant use with .MAOIsMethyldopa (continued)Antipsychotics: enhanced hypotensive effect whenmethyldopa given with antipsychotics (also increasedrisk of extrapyramidal effects)Anxiolytics and Hypnotics: enhanced hypotensiveeffect when methyldopa given with anxiolytics andhypnoticsBeta-blockers: enhanced hypotensive effect whenmethyldopa given with beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when methyldopa given with calcium-channelblockersClonidine: enhanced hypotensive effect when methyldopagiven with clonidineCorticosteroids: hypotensive effect of methyldopaantagonised by corticosteroidsDiazoxide: enhanced hypotensive effect when methyldopagiven with diazoxideDiuretics: enhanced hypotensive effect when methyldopagiven with diureticsDopaminergics: methyldopa antagonises antiparkinsonianeffect of dopaminergics; increased riskof extrapyramidal side-effects when methyldopagiven with amantadine; effects of methyldopa possiblyenhanced by entacapone; enhanced hypotensiveeffect when methyldopa given with levodopaIron: hypotensive effect of methyldopa antagonised byoral iron. Lithium: neurotoxicity may occur when methyldopagiven with .lithium without increased plasma concentrationof lithiumMoxisylyte: enhanced hypotensive effect whenmethyldopa given with moxisylyteMoxonidine: enhanced hypotensive effect whenmethyldopa given with moxonidineMuscle Relaxants: enhanced hypotensive effect whenmethyldopa given with baclofen or tizanidineNitrates: enhanced hypotensive effect when methyldopagiven with nitratesOestrogens: hypotensive effect of methyldopa antagonisedby oestrogensProstaglandins: enhanced hypotensive effect whenmethyldopa given with alprostadil. Sympathomimetics, Beta 2 : acute hypotensionreported when methyldopa given with infusion of.salbutamolVasodilator Antihypertensives: enhanced hypotensiveeffect when methyldopa given with hydralazine,minoxidil or sodium nitroprussideMethylphenidate see SympathomimeticsMethylprednisolone see CorticosteroidsMethysergide see Ergot AlkaloidsMetipranolol see Beta-blockersMetoclopramideAlcohol: metoclopramide possibly increases absorptionof alcoholAnaesthetics, General: metoclopramide enhanceseffects of thiopentalAnalgesics: metoclopramide increases rate of absorptionof aspirin (enhanced effect); effects of metoclopramideon gastro-intestinal activity antagonised byopioid analgesics; metoclopramide increases rate ofabsorption of paracetamolAntidepressants: CNS toxicity reported when metoclopramidegiven with SSRIsAntimuscarinics: effects of metoclopramide on gastrointestinalactivity antagonised by antimuscarinicsAntipsychotics: increased risk of extrapyramidal sideeffectswhen metoclopramide given with antipsychoticsAtovaquone: metoclopramide reduces plasma concentrationof atovaquone. Ciclosporin: metoclopramide increases plasma concentrationof .ciclosporinDopaminergics: metoclopramide antagonises hypoprolactinaemiceffects of bromocriptine and cabergoline;metoclopramide antagonises antiparkinsonianeffect of pergolide; avoidance of metoclopramide

BNFC 2011–2012 Appendix 1: Interactions 709MetoclopramideDopaminergics (continued)advised by manufacturer of ropinirole and rotigotine(antagonism of effect)Muscle Relaxants: metoclopramide enhances effectsof suxamethoniumTetrabenazine: increased risk of extrapyramidal sideeffectswhen metoclopramide given with tetrabenazineMetolazone see DiureticsMetoprolol see Beta-blockersMetronidazoleNote Interactions do not apply to topical metronidazolepreparationsAlcohol: disulfiram-like reaction when metronidazolegiven with alcohol. Anticoagulants: metronidazole enhances anticoagulanteffect of .coumarinsAntiepileptics: metabolism of metronidazole acceleratedby phenobarbital (reduced effect); metronidazolepossibly inhibits metabolism of phenytoin(increased plasma concentration). Cytotoxics: metronidazole increases plasma concentrationof .busulfan (increased risk of toxicity);metronidazole inhibits metabolism of fluorouracil(increased toxicity)Disulfiram: psychotic reaction reported when metronidazolegiven with disulfiramLithium: metronidazole increases risk of lithiumtoxicityMycophenolate: metronidazole possibly reduces bioavailabilityof mycophenolateUlcer-healing Drugs: metabolism of metronidazoleinhibited by cimetidine (increased plasma concentration)Vaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Mianserin see Antidepressants, Tricyclic (related)MicafunginAntifungals: micafungin possibly increases plasmaconcentration of amphotericin; micafungin increasesplasma concentration of itraconazole (considerreducing dose of itraconazole)Calcium-channel Blockers: micafungin increasesplasma concentration of nifedipineCiclosporin: micafungin possibly increases plasmaconcentration of ciclosporinSirolimus: micafungin increases plasma concentrationof sirolimusMiconazole see Antifungals, ImidazoleMidazolam see Anxiolytics and HypnoticsMifamurtideAnalgesics: manufacturer of mifamurtide advises avoidconcomitant use with high doses of NSAIDsCiclosporin: manufacturer of mifamurtide advisesavoid concomitant use with ciclosporinCorticosteroids: manufacturer of mifamurtide advisesavoid concomitant use with corticosteroidsTacrolimus: manufacturer of mifamurtide advises avoidconcomitant use with tacrolimusMifepristoneCorticosteroids: mifepristone may reduce effect ofcorticosteroids (including inhaled corticosteroids) for3–4 daysMilrinone see Phosphodiesterase InhibitorsMinocycline see TetracyclinesMinoxidil see Vasodilator AntihypertensivesMirtazapine. Alcohol: increased sedative effect when mirtazapinegiven with .alcoholAnalgesics: possible increased serotonergic effectswhen mirtazapine given with tramadolAnticoagulants: mirtazapine enhances anticoagulanteffect of warfarin. Antidepressants: possible increased serotonergiceffects when mirtazapine given with fluoxetine,fluvoxamine or venlafaxine; mirtazapine should notbe started until 2 weeks after stopping .MAOIs, alsoMirtazapine. Antidepressants (continued)MAOIs should not be started until at least 2weeks after stopping mirtazapine; after stoppingmirtazapine do not start .moclobemide for atleast 1 weekAntiepileptics: plasma concentration of mirtazapinereduced by carbamazepine and phenytoinAntifungals: plasma concentration of mirtazapineincreased by ketoconazole. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrineAnxiolytics and Hypnotics: increased sedative effectwhen mirtazapine given with anxiolytics and hypnoticsAtomoxetine: possible increased risk of convulsionswhen antidepressants given with atomoxetineClonidine: mirtazapine possibly antagonises hypotensiveeffect of clonidineUlcer-healing Drugs: plasma concentration of mirtazapineincreased by cimetidineMitomycin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Mitotane. Anticoagulants: mitotane possibly reduces anticoagulanteffect of .coumarins. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Diuretics: manufacturer of mitotane advises avoidconcomitant use of spironolactone (antagonism ofeffect)Mitoxantrone. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Ciclosporin: excretion of mitoxantrone reduced byciclosporin (increased plasma concentration)Mivacurium see Muscle RelaxantsMizolastine see AntihistaminesMoclobemide. Analgesics: possible CNS excitation or depression(hypertension or hypotension) when moclobemidegiven with .dextromethorphan or .pethidine—avoidconcomitant use; possible CNS excitation or depression(hypertension or hypotension) when moclobemidegiven with .opioid analgesics—manufacturer ofmoclobemide advises consider reducing dose ofopioid analgesics. Antidepressants: moclobemide should not be startedfor at least 1 week after stopping .MAOIs, .SSRIrelatedantidepressants, .citalopram, .fluvoxamine,.mirtazapine, .paroxetine, .sertraline, .tricyclicrelatedantidepressants or .tricyclics; increased riskof CNS toxicity when moclobemide given with.escitalopram, preferably avoid concomitant use;moclobemide should not be started until 5 weeksafter stopping .fluoxetine; possible increased serotonergiceffects when moclobemide given with.duloxetine. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrineAtomoxetine: possible increased risk of convulsionswhen antidepressants given with atomoxetine. Bupropion: avoidance of moclobemide advised bymanufacturer of .bupropion. Clopidogrel: moclobemide possibly reduces antiplateleteffect of .clopidogrel. Dopaminergics: caution with moclobemide advised bymanufacturer of entacapone; increased risk of sideeffectswhen moclobemide given with levodopa;avoid concomitant use of moclobemide with.selegiline. 5HT 1 Agonists: risk of CNS toxicity when moclobemidegiven with .rizatriptan or .sumatriptan (avoidrizatriptan or sumatriptan for 2 weeks after moclobemide);risk of CNS toxicity when moclobemidegiven with .zolmitriptan (reduce dose of zolmitriptan)Appendix 1: Interactions

710 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsMoclobemide (continued). Sympathomimetics: risk of hypertensive crisis whenmoclobemide given with .sympathomimeticsUlcer-healing Drugs: plasma concentration of moclobemideincreased by cimetidine (halve dose ofmoclobemide)ModafinilAntiepileptics: modafinil possibly increases plasmaconcentration of phenytoin. Ciclosporin: modafinil reduces plasma concentration of.ciclosporin. Oestrogens: modafinil accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398)Moexipril see ACE InhibitorsMometasone see CorticosteroidsMonobactams see AztreonamMontelukast see Leukotriene Receptor AntagonistsMorphine see Opioid AnalgesicsMoxifloxacin see QuinolonesMoxisylyteACE Inhibitors: enhanced hypotensive effect whenmoxisylyte given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when moxisylyte given with adrenergicneurone blockers. Alpha-blockers: possible severe postural hypotensionwhen moxisylyte given with .alpha-blockersAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when moxisylyte given withangiotensin-II receptor antagonists. Beta-blockers: possible severe postural hypotensionwhen moxisylyte given with .beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when moxisylyte given with calcium-channelblockersClonidine: enhanced hypotensive effect when moxisylytegiven with clonidineDiazoxide: enhanced hypotensive effect when moxisylytegiven with diazoxideDiuretics: enhanced hypotensive effect when moxisylytegiven with diureticsMethyldopa: enhanced hypotensive effect when moxisylytegiven with methyldopaMoxonidine: enhanced hypotensive effect when moxisylytegiven with moxonidineNitrates: enhanced hypotensive effect when moxisylytegiven with nitratesVasodilator Antihypertensives: enhanced hypotensiveeffect when moxisylyte given with hydralazine,minoxidil or sodium nitroprussideMoxonidineACE Inhibitors: enhanced hypotensive effect whenmoxonidine given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when moxonidine given with adrenergicneurone blockersAlcohol: enhanced hypotensive effect when moxonidinegiven with alcoholAldesleukin: enhanced hypotensive effect when moxonidinegiven with aldesleukinAlpha-blockers: enhanced hypotensive effect whenmoxonidine given with alpha-blockersAnaesthetics, General: enhanced hypotensive effectwhen moxonidine given with general anaestheticsAnalgesics: hypotensive effect of moxonidine antagonisedby NSAIDsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when moxonidine given withangiotensin-II receptor antagonistsAntidepressants: enhanced hypotensive effect whenmoxonidine given with MAOIs; hypotensive effect ofmoxonidine possibly antagonised by tricyclics (manufacturerof moxonidine advises avoid concomitantuse)Antipsychotics: enhanced hypotensive effect whenmoxonidine given with phenothiazinesMoxonidine (continued)Anxiolytics and Hypnotics: enhanced hypotensiveeffect when moxonidine given with anxiolytics andhypnotics; sedative effects possibly increased whenmoxonidine given with benzodiazepinesBeta-blockers: enhanced hypotensive effect whenmoxonidine given with beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when moxonidine given with calcium-channelblockersClonidine: enhanced hypotensive effect when moxonidinegiven with clonidineCorticosteroids: hypotensive effect of moxonidineantagonised by corticosteroidsDiazoxide: enhanced hypotensive effect when moxonidinegiven with diazoxideDiuretics: enhanced hypotensive effect when moxonidinegiven with diureticsDopaminergics: enhanced hypotensive effect whenmoxonidine given with levodopaMethyldopa: enhanced hypotensive effect when moxonidinegiven with methyldopaMoxisylyte: enhanced hypotensive effect when moxonidinegiven with moxisylyteMuscle Relaxants: enhanced hypotensive effect whenmoxonidine given with baclofen or tizanidineNitrates: enhanced hypotensive effect when moxonidinegiven with nitratesOestrogens: hypotensive effect of moxonidine antagonisedby oestrogensProstaglandins: enhanced hypotensive effect whenmoxonidine given with alprostadilVasodilator Antihypertensives: enhanced hypotensiveeffect when moxonidine given with hydralazine,minoxidil or sodium nitroprussideMuscle RelaxantsACE Inhibitors: enhanced hypotensive effect whenbaclofen or tizanidine given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when baclofen or tizanidine given with adrenergicneurone blockersAlcohol: increased sedative effect when baclofen,methocarbamol or tizanidine given with alcoholAlpha-blockers: enhanced hypotensive effect whenbaclofen or tizanidine given with alpha-blockers. Anaesthetics, General: effects of atracurium enhancedby ketamine; increased risk of myocardial depressionand bradycardia when suxamethonium given with.propofol; effects of non-depolarising musclerelaxants and suxamethonium enhanced by volatileliquid general anaestheticsAnalgesics: excretion of baclofen possibly reduced byNSAIDs (increased risk of toxicity); excretion ofbaclofen reduced by ibuprofen (increased risk oftoxicity); increased sedative effect when baclofengiven with fentanyl or morphineAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when baclofen or tizanidine givenwith angiotensin-II receptor antagonistsAnti-arrhythmics: neuromuscular blockade enhancedand prolonged when suxamethonium given withlidocaine. Antibacterials: effects of non-depolarising musclerelaxants and suxamethonium enhanced by piperacillin;plasma concentration of tizanidine increasedby .ciprofloxacin (increased risk of toxicity)—avoidconcomitant use; plasma concentration of tizanidinepossibly increased by norfloxacin (increased risk oftoxicity); effects of non-depolarising musclerelaxants and suxamethonium enhanced by.aminoglycosides; effects of non-depolarising musclerelaxants and suxamethonium enhanced by.clindamycin; effects of non-depolarising musclerelaxants and suxamethonium enhanced by.polymyxins; effects of suxamethonium enhanced by.vancomycin. Antidepressants: plasma concentration of tizanidineincreased by .fluvoxamine (increased risk of toxicity)—avoidconcomitant use; effects of suxa-

BNFC 2011–2012 Appendix 1: Interactions 711Muscle Relaxants. Antidepressants (continued)methonium enhanced by phenelzine; musclerelaxant effect of baclofen enhanced by tricyclicsAntiepileptics: muscle relaxant effect of non-depolarisingmuscle relaxants antagonised bycarbamazepine and phenytoin (accelerated recoveryfrom neuromuscular blockade)Antimalarials: effects of suxamethonium possiblyenhanced by quinineAntipsychotics: effects of suxamethonium possiblyenhanced by promazineAnxiolytics and Hypnotics: increased sedative effectwhen baclofen or tizanidine given with anxiolyticsand hypnoticsBeta-blockers: enhanced hypotensive effect whenbaclofen given with beta-blockers; possible enhancedhypotensive effect and bradycardia when tizanidinegiven with beta-blockers; effects of muscle relaxantsenhanced by propranololCalcium-channel Blockers: enhanced hypotensiveeffect when baclofen or tizanidine given withcalcium-channel blockers; effects of non-depolarisingmuscle relaxants possibly enhanced by calciumchannelblockers; possible increased risk of ventriculararrhythmias when intravenous dantrolene givenwith diltiazem—manufacturer of diltiazem advisesavoid concomitant use; effects of non-depolarisingmuscle relaxants and suxamethonium enhanced byverapamil; avoidance of intravenous dantroleneadvised by manufacturer of verapamilCardiac Glycosides: possible increased risk of bradycardiawhen tizanidine given with cardiac glycosides;risk of ventricular arrhythmias when suxamethoniumgiven with cardiac glycosidesClonidine: enhanced hypotensive effect whenbaclofen or tizanidine given with clonidineCorticosteroids: effects of pancuronium and vecuroniumpossibly antagonised by corticosteroidsCytotoxics: effects of suxamethonium enhanced bycyclophosphamide and thiotepaDiazoxide: enhanced hypotensive effect whenbaclofen or tizanidine given with diazoxideDiuretics: enhanced hypotensive effect whenbaclofen or tizanidine given with diureticsDopaminergics: possible agitation, confusion andhallucinations when baclofen given with levodopaLithium: effects of muscle relaxants enhanced bylithium; baclofen possibly aggravates hyperkinesiscaused by lithiumMagnesium (parenteral): effects of non-depolarisingmuscle relaxants and suxamethonium enhanced byparenteral magnesiumMemantine: effects of baclofen and dantrolene possiblymodified by memantineMethyldopa: enhanced hypotensive effect whenbaclofen or tizanidine given with methyldopaMetoclopramide: effects of suxamethonium enhancedby metoclopramideMoxonidine: enhanced hypotensive effect whenbaclofen or tizanidine given with moxonidineNitrates: enhanced hypotensive effect whenbaclofen or tizanidine given with nitratesOestrogens: plasma concentration of tizanidine possiblyincreased by oestrogens (increased risk oftoxicity)Parasympathomimetics: effects of non-depolarisingmuscle relaxants possibly antagonised by donepezil;effects of suxamethonium possibly enhanced bydonepezil; effects of non-depolarising muscle relaxantsantagonised by edrophonium, neostigmine,pyridostigmine and rivastigmine; effects of suxamethoniumenhanced by edrophonium, galantamine,neostigmine, pyridostigmine and rivastigmineProgestogens: plasma concentration of tizanidinepossibly increased by progestogens (increased risk oftoxicity)Sympathomimetics, Beta 2 : effects of suxamethoniumenhanced by bambuterolMuscle Relaxants (continued)Vasodilator Antihypertensives: enhanced hypotensiveeffect when baclofen or tizanidine given withhydralazine; enhanced hypotensive effect whenbaclofen or tizanidine given with minoxidil; enhancedhypotensive effect when baclofen or tizanidine givenwith sodium nitroprussideMuscle Relaxants, depolarising see Muscle RelaxantsMuscle Relaxants, non-depolarising see MuscleRelaxantsMycophenolateAntacids: absorption of mycophenolate reduced byantacids. Antibacterials: bioavailability of mycophenolate possiblyreduced by metronidazole and norfloxacin;plasma concentration of active metabolite of mycophenolatereduced by .rifampicinAntivirals: mycophenolate increases plasma concentrationof aciclovir, also plasma concentration ofinactive metabolite of mycophenolate increased;mycophenolate possibly increases plasma concentrationof ganciclovir, also plasma concentration ofinactive metabolite of mycophenolate possiblyincreasedIron: absorption of mycophenolate reduced by oral ironLipid-regulating Drugs: absorption of mycophenolatereduced by colestyramineSevelamer: plasma concentration of mycophenolatepossibly reduced by sevelamerMycophenolate Mofetil see MycophenolateMycophenolate Sodium see MycophenolateMycophenolic Acid see MycophenolateNabumetone see NSAIDsNadolol see Beta-blockersNalidixic Acid see QuinolonesNandrolone see Anabolic SteroidsNaproxen see NSAIDsNaratriptan see 5HT 1 AgonistsNateglinide see AntidiabeticsNebivolol see Beta-blockersNefopam. Antidepressants: manufacturer of nefopam advisesavoid concomitant use with .MAOIs; side-effectspossibly increased when nefopam given with tricyclicsAntimuscarinics: increased risk of antimuscarinic sideeffectswhen nefopam given with antimuscarinicsNelfinavirAnalgesics: nelfinavir reduces plasma concentration ofmethadone. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen nelfinavir given with .amiodarone—avoid concomitant use. Antibacterials: nelfinavir increases plasma concentrationof azithromycin (increased risk of toxicity);nelfinavir increases plasma concentration of.rifabutin (halve dose of rifabutin); plasma concentrationof nelfinavir significantly reduced by.rifampicin—avoid concomitant use; avoidance ofconcomitant nelfinavir in severe renal and hepaticimpairment advised by manufacturer of.telithromycinAnticoagulants: avoidance of nelfinavir advised bymanufacturer of rivaroxaban. Antidepressants: plasma concentration of nelfinavirreduced by .St John’s wort—avoid concomitant use. Antiepileptics: plasma concentration of nelfinavirpossibly reduced by carbamazepine and.phenobarbital; nelfinavir reduces plasma concentrationof phenytoin. Antimalarials: caution with nelfinavir advised bymanufacturer of artemether/lumefantrine; nelfinavirpossibly increases plasma concentration of .quinine(increased risk of toxicity)Antimuscarinics: avoidance of nelfinavir advised bymanufacturer of darifenacin and tolterodine; manufacturerof fesoterodine advises dose reduction whennelfinavir given with fesoterodine—consult fesoter-Appendix 1: Interactions

712 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsNelfinavirAntimuscarinics (continued)odine product literature; nelfinavir increasesplasma concentration of solifenacin. Antipsychotics: nelfinavir possibly inhibits metabolismof .aripiprazole (reduce dose of aripiprazole); nelfinavirpossibly increases plasma concentration of.pimozide (increased risk of ventricular arrhythmias—avoidconcomitant use). Antivirals: plasma concentration of nelfinavir possiblyincreased by etravirine—avoid concomitant use;combination of nelfinavir with indinavir or ritonavirmay increase plasma concentration of either drug (orboth); nelfinavir reduces plasma concentration oflopinavir, also plasma concentration of active metaboliteof nelfinavir increased; nelfinavir possiblyincreases plasma concentration of .maraviroc (considerreducing dose of maraviroc); nelfinavirincreases plasma concentration of .saquinavir—manufacturer of saquinavir advises avoid concomitantuse. Anxiolytics and Hypnotics: nelfinavir possiblyincreases plasma concentration of .midazolam (riskof prolonged sedation—avoid concomitant use oforal midazolam). Ciclosporin: nelfinavir possibly increases plasma concentrationof .ciclosporinCorticosteroids: nelfinavir possibly increases plasmaconcentration of inhaled and intranasal fluticasone. Cytotoxics: nelfinavir possibly increases plasma concentrationof .everolimus—manufacturer of everolimusadvises avoid concomitant use; avoidance ofnelfinavir advised by manufacturer of .pazopanib;nelfinavir increases plasma concentration of paclitaxel. Diuretics: nelfinavir increases plasma concentration of.eplerenone—avoid concomitant use. Ergot Alkaloids: increased risk of ergotism whennelfinavir given with .ergotamine and methysergide—avoidconcomitant use. 5HT 1 Agonists: nelfinavir increases plasma concentrationof .eletriptan (risk of toxicity)—avoid concomitantuse. Ivabradine: nelfinavir possibly increases plasma concentrationof .ivabradine—avoid concomitant use. Lipid-regulating Drugs: possible increased risk ofmyopathy when nelfinavir given with atorvastatin;possible increased risk of myopathy when nelfinavirgiven with .rosuvastatin—manufacturer of rosuvastatinadvises avoid concomitant use; increased risk ofmyopathy when nelfinavir given with .simvastatin(avoid concomitant use). Oestrogens: nelfinavir accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398)Progestogens: nelfinavir possibly reduces contraceptiveeffect of progestogens. Ranolazine: nelfinavir possibly increases plasma concentrationof .ranolazine—manufacturer of ranolazineadvises avoid concomitant useSildenafil: nelfinavir possibly increases plasma concentrationof sildenafil—reduce initial dose of sildenafil. Tacrolimus: nelfinavir possibly increases plasma concentrationof .tacrolimus. Ulcer-healing Drugs: plasma concentration of nelfinavirreduced by .omeprazole—avoid concomitant useNeomycin see AminoglycosidesNeostigmine see ParasympathomimeticsNevirapineAnalgesics: nevirapine possibly reduces plasma concentrationof methadone. Antibacterials: nevirapine reduces plasma concentrationof clarithromycin (but concentration of an activemetabolite increased), also plasma concentration ofnevirapine increased; nevirapine possibly increasesplasma concentration of rifabutin; plasma concen-Nevirapine. Antibacterials (continued)tration of nevirapine reduced by .rifampicin—avoid concomitant use. Anticoagulants: nevirapine may enhance or reduceanticoagulant effect of .warfarin. Antidepressants: plasma concentration of nevirapinereduced by .St John’s wort—avoid concomitant useAntiepileptics: plasma concentration of nevirapinereduced by carbamazepine. Antifungals: nevirapine reduces plasma concentrationof .ketoconazole—avoid concomitant use; plasmaconcentration of nevirapine increased by.fluconazole; nevirapine possibly reduces plasmaconcentration of caspofungin and itraconazole—consider increasing dose of caspofungin and itraconazole. Antipsychotics: nevirapine possibly reduces plasmaconcentration of .aripiprazole—increase dose ofaripiprazole. Antivirals: nevirapine possibly reduces plasma concentrationof .atazanavir and .etravirine—avoidconcomitant use; nevirapine reduces plasma concentrationof efavirenz and indinavir; nevirapinepossibly reduces plasma concentration of fosamprenavir;nevirapine possibly reduces plasma concentrationof .lopinavir—consider increasing dose oflopinavir. Oestrogens: nevirapine accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398). Progestogens: nevirapine accelerates metabolism of.progestogens (reduced contraceptive effect—seep. 398)Nicardipine see Calcium-channel BlockersNicorandilAlcohol: hypotensive effect of nicorandil possiblyenhanced by alcoholAntidepressants: enhanced hypotensive effect whennicorandil given with MAOIs; hypotensive effect ofnicorandil possibly enhanced by tricyclics. Sildenafil: hypotensive effect of nicorandil significantlyenhanced by .sildenafil (avoid concomitant use). Tadalafil: hypotensive effect of nicorandil significantlyenhanced by .tadalafil (avoid concomitant use). Vardenafil: possible increased hypotensive effect whennicorandil given with .vardenafil—avoid concomitantuseVasodilator Antihypertensives: possible enhancedhypotensive effect when nicorandil given withhydralazine, minoxidil or sodium nitroprussideNicotineAnti-arrhythmics: nicotine possibly enhances effects ofadenosineNicotinic AcidNote Interactions apply to lipid-regulating doses of nicotinicacid. Lipid-regulating Drugs: increased risk of myopathywhen nicotinic acid given with .statins (applies tolipid regulating doses of nicotinic acid)Nifedipine see Calcium-channel BlockersNilotinib. Antibacterials: manufacturer of nilotinib advises avoidconcomitant use with .clarithromycin and.telithromycin; plasma concentration of nilotinibreduced by .rifampicin—avoid concomitant use. Antifungals: plasma concentration of nilotinibincreased by .ketoconazole—avoid concomitant use;manufacturer of nilotinib advises avoid concomitantuse with .itraconazole and .voriconazole. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Antivirals: manufacturer of nilotinib advises avoidconcomitant use with .ritonavirAnxiolytics and Hypnotics: nilotinib increases plasmaconcentration of midazolam. Grapefruit Juice: manufacturer of nilotinib advisesavoid concomitant use with .grapefruit juice

BNFC 2011–2012 Appendix 1: Interactions 713Nimodipine see Calcium-channel BlockersNitratesACE Inhibitors: enhanced hypotensive effect whennitrates given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when nitrates given with adrenergic neuroneblockersAlcohol: enhanced hypotensive effect when nitratesgiven with alcoholAldesleukin: enhanced hypotensive effect whennitrates given with aldesleukinAlpha-blockers: enhanced hypotensive effect whennitrates given with alpha-blockersAnaesthetics, General: enhanced hypotensive effectwhen nitrates given with general anaestheticsAnalgesics: hypotensive effect of nitrates antagonisedby NSAIDsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when nitrates given with angiotensin-IIreceptor antagonistsAnti-arrhythmics: effects of sublingual tablets ofnitrates reduced by disopyramide (failure to dissolveunder tongue owing to dry mouth). Anticoagulants: infusion of glyceryl trinitrate reducesanticoagulant effect of .heparinsAntidepressants: enhanced hypotensive effect whennitrates given with MAOIs; effects of sublingualtablets of nitrates possibly reduced by tricyclicrelatedantidepressants (failure to dissolve undertongue owing to dry mouth); effects of sublingualtablets of nitrates reduced by tricyclics (failure todissolve under tongue owing to dry mouth)Antimuscarinics: effects of sublingual tablets ofnitrates possibly reduced by antimuscarinics (failureto dissolve under tongue owing to dry mouth)Antipsychotics: enhanced hypotensive effect whennitrates given with phenothiazinesAnxiolytics and Hypnotics: enhanced hypotensiveeffect when nitrates given with anxiolytics andhypnoticsBeta-blockers: enhanced hypotensive effect whennitrates given with beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when nitrates given with calcium-channelblockersClonidine: enhanced hypotensive effect when nitratesgiven with clonidineCorticosteroids: hypotensive effect of nitrates antagonisedby corticosteroidsDiazoxide: enhanced hypotensive effect when nitratesgiven with diazoxideDiuretics: enhanced hypotensive effect when nitratesgiven with diureticsDopaminergics: enhanced hypotensive effect whennitrates given with levodopaMethyldopa: enhanced hypotensive effect whennitrates given with methyldopaMoxisylyte: enhanced hypotensive effect when nitratesgiven with moxisylyteMoxonidine: enhanced hypotensive effect whennitrates given with moxonidineMuscle Relaxants: enhanced hypotensive effect whennitrates given with baclofen or tizanidineOestrogens: hypotensive effect of nitrates antagonisedby oestrogensProstaglandins: enhanced hypotensive effect whennitrates given with alprostadil. Sildenafil: hypotensive effect of nitrates significantlyenhanced by .sildenafil (avoid concomitant use). Tadalafil: hypotensive effect of nitrates significantlyenhanced by .tadalafil (avoid concomitant use). Vardenafil: possible increased hypotensive effect whennitrates given with .vardenafil—avoid concomitantuseVasodilator Antihypertensives: enhanced hypotensiveeffect when nitrates given with hydralazine,minoxidil or sodium nitroprussideNitrazepam see Anxiolytics and HypnoticsNitrofurantoinAntacids: absorption of nitrofurantoin reduced by oralmagnesium salts (as magnesium trisilicate)Antibacterials: nitrofurantoin possibly antagoniseseffects of nalidixic acidProbenecid: excretion of nitrofurantoin reduced byprobenecid (increased risk of side-effects)Sulfinpyrazone: excretion of nitrofurantoin reduced bysulfinpyrazone (increased risk of toxicity)Vaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Nitroimidazoles see Metronidazole and TinidazoleNitrous Oxide see Anaesthetics, GeneralNizatidine see Histamine H 2 -antagonistsNoradrenaline (norepinephrine) see SympathomimeticsNorelgestromin see ProgestogensNorepinephrine (noradrenaline) see SympathomimeticsNorethisterone see ProgestogensNorfloxacin see QuinolonesNorgestimate see ProgestogensNorgestrel see ProgestogensNortriptyline see Antidepressants, TricyclicNSAIDsNote See also Aspirin. Interactions do not generally apply totopical NSAIDsACE Inhibitors: increased risk of renal impairmentwhen NSAIDs given with ACE inhibitors, alsohypotensive effect antagonisedAdrenergic Neurone Blockers: NSAIDs antagonisehypotensive effect of adrenergic neurone blockersAliskiren: NSAIDs possibly antagonise hypotensiveeffect of aliskirenAlpha-blockers: NSAIDs antagonise hypotensive effectof alpha-blockers. Analgesics: avoid concomitant use of NSAIDs with.NSAIDs or .aspirin (increased side-effects); avoidconcomitant use of NSAIDs with .ketorolac(increased side-effects and haemorrhage); ibuprofenpossibly reduces antiplatelet effect of aspirinAngiotensin-II Receptor Antagonists: increased risk ofrenal impairment when NSAIDs given with angiotensin-IIreceptor antagonists, also hypotensive effectantagonised. Antibacterials: indometacin possibly increases plasmaconcentration of amikacin and gentamicin in neonates;plasma concentration of celecoxib,diclofenac and etoricoxib reduced by rifampicin;possible increased risk of convulsions when NSAIDsgiven with .quinolones. Anticoagulants: increased risk of haemorrhage whenintravenous diclofenac given with .anticoagulants(avoid concomitant use, including low-dose heparins);increased risk of haemorrhage when ketorolacgiven with .anticoagulants (avoid concomitant use,including low-dose heparins); NSAIDs possiblyenhance anticoagulant effect of .coumarins and.phenindione; possible increased risk of bleedingwhen NSAIDs given with .dabigatran etexilate orheparins. Antidepressants: increased risk of bleeding whenNSAIDs given with .SSRIs or .venlafaxine. Antidiabetics: NSAIDs possibly enhance effects of.sulfonylureasAntifungals: plasma concentration of parecoxibincreased by fluconazole (reduce dose of parecoxib);plasma concentration of celecoxib increased byfluconazole (halve dose of celecoxib); plasma concentrationof flurbiprofen and ibuprofen increased byfluconazole; plasma concentration of diclofenac andibuprofen increased by voriconazoleAntipsychotics: possible severe drowsiness whenindometacin given with haloperidol. Antivirals: plasma concentration of piroxicamincreased by .ritonavir (risk of toxicity)—avoidconcomitant use; plasma concentration of NSAIDspossibly increased by ritonavir; increased risk ofAppendix 1: Interactions

714 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsNSAIDs. Antivirals (continued)haematological toxicity when NSAIDs given withzidovudineBeta-blockers: NSAIDs antagonise hypotensive effectof beta-blockersBisphosphonates: indometacin increases bioavailabilityof tiludronic acidCalcium-channel Blockers: NSAIDs antagonise hypotensiveeffect of calcium-channel blockersCardiac Glycosides: NSAIDs possibly increase plasmaconcentration of cardiac glycosides, also possibleexacerbation of heart failure and reduction of renalfunction. Ciclosporin: increased risk of nephrotoxicity whenNSAIDs given with .ciclosporin; plasma concentrationof diclofenac increased by .ciclosporin (halvedose of diclofenac)Clonidine: NSAIDs antagonise hypotensive effect ofclonidineClopidogrel: increased risk of bleeding when NSAIDsgiven with clopidogrelCorticosteroids: increased risk of gastro-intestinalbleeding and ulceration when NSAIDs given withcorticosteroids. Cytotoxics: NSAIDs probably reduce excretion of.methotrexate (increased risk of toxicity); diclofenac,ibuprofen, indometacin, ketoprofen, meloxicam andnaproxen reduce excretion of .methotrexate(increased risk of toxicity); increased risk of bleedingwhen NSAIDs given with .erlotinibDesmopressin: indometacin enhances effects ofdesmopressinDiazoxide: NSAIDs antagonise hypotensive effect ofdiazoxide. Dimethyl sulfoxide: avoid concomitant use of sulindacwith .dimethyl sulfoxide. Diuretics: risk of nephrotoxicity of NSAIDs increasedby diuretics, also antagonism of diuretic effect;indometacin and ketorolac antagonise effects ofdiuretics; NSAIDs possibly antagonise diuretic effectof potassium canrenoate; occasional reports ofreduced renal function when indometacin given with.triamterene—avoid concomitant use; possibleincreased risk of hyperkalaemia when NSAIDs givenwith potassium-sparing diuretics and aldosteroneantagonists; increased risk of hyperkalaemia whenindometacin given with potassium-sparing diureticsand aldosterone antagonistsIloprost: increased risk of bleeding when NSAIDs givenwith iloprostLipid-regulating Drugs: excretion of meloxicamincreased by colestyramine. Lithium: NSAIDs reduce excretion of .lithium(increased risk of toxicity); ketorolac reduces excretionof .lithium (increased risk of toxicity)—avoidconcomitant useMethyldopa: NSAIDs antagonise hypotensive effect ofmethyldopaMifamurtide: avoidance of high doses of NSAIDsadvised by manufacturer of mifamurtideMoxonidine: NSAIDs antagonise hypotensive effect ofmoxonidineMuscle Relaxants: ibuprofen reduces excretion ofbaclofen (increased risk of toxicity); NSAIDs possiblyreduce excretion of baclofen (increased risk oftoxicity)Nitrates: NSAIDs antagonise hypotensive effect ofnitratesOestrogens: etoricoxib increases plasma concentrationof ethinylestradiolPenicillamine: possible increased risk of nephrotoxicitywhen NSAIDs given with penicillamine. Pentoxifylline: possible increased risk of bleeding whenNSAIDs given with pentoxifylline; increased risk ofbleeding when ketorolac given with .pentoxifylline(avoid concomitant use)Prasugrel: possible increased risk of bleeding whenNSAIDs given with prasugrelNSAIDs (continued). Probenecid: excretion of dexketoprofen, indometacin,ketoprofen and naproxen reduced by .probenecid(increased plasma concentration); excretion of ketorolacreduced by .probenecid (increased plasmaconcentration)—avoid concomitant use. Tacrolimus: possible increased risk of nephrotoxicitywhen NSAIDs given with tacrolimus; increased risk ofnephrotoxicity when ibuprofen given with.tacrolimusVasodilator Antihypertensives: NSAIDs antagonisehypotensive effect of hydralazine, minoxidil andsodium nitroprussideOctreotideAntidiabetics: octreotide possibly reduces requirementsfor insulin, metformin, repaglinide and sulfonylureas. Ciclosporin: octreotide reduces plasma concentrationof .ciclosporinDopaminergics: octreotide increases plasma concentrationof bromocriptineUlcer-healing Drugs: octreotide possibly delaysabsorption of cimetidineOestrogensNote Interactions of combined oral contraceptives may alsoapply to combined contraceptive patches and vaginal rings,see p. 398ACE Inhibitors: oestrogens antagonise hypotensiveeffect of ACE inhibitorsAdrenergic Neurone Blockers: oestrogens antagonisehypotensive effect of adrenergic neurone blockersAlpha-blockers: oestrogens antagonise hypotensiveeffect of alpha-blockersAnalgesics: plasma concentration of ethinylestradiolincreased by etoricoxibAngiotensin-II Receptor Antagonists: oestrogensantagonise hypotensive effect of angiotensin-IIreceptor antagonists. Antibacterials: plasma concentration of estradiolincreased by erythromycin; metabolism of oestrogensaccelerated by .rifamycins (reduced contraceptiveeffect—see p. 398). Anticoagulants: oestrogens may enhance or reduceanticoagulant effect of coumarins; oestrogens antagoniseanticoagulant effect of .phenindione. Antidepressants: contraceptive effect of oestrogensreduced by .St John’s wort (avoid concomitant use);oestrogens antagonise antidepressant effect of tricyclics(but side-effects of tricyclics possiblyincreased due to increased plasma concentration)Antidiabetics: oestrogens antagonise hypoglycaemiceffect of antidiabetics. Antiepileptics: metabolism of oestrogens acceleratedby .carbamazepine, .eslicarbazepine,.oxcarbazepine, .phenobarbital, .phenytoin,.rufinamide and .topiramate (reduced contraceptiveeffect—see p. 398); oestrogens reduce plasma concentrationof .lamotrigine—consider increasing doseof lamotrigine; ethinylestradiol possibly reducesplasma concentration of valproateAntifungals: oestrogens increase plasma concentrationof voriconazole; anecdotal reports of contraceptivefailure and menstrual irregularities when oestrogensgiven with griseofulvin; anecdotal reports of contraceptivefailure when oestrogens given with imidazoles;occasional reports of breakthrough bleedingwhen oestrogens (used for contraception) given withterbinafine. Antivirals: plasma concentration of ethinylestradiolincreased by atazanavir; metabolism of oestrogensaccelerated by .nelfinavir, .nevirapine and .ritonavir(reduced contraceptive effect—see p. 398)Anxiolytics and Hypnotics: oestrogens increaseplasma concentration of melatonin. Aprepitant: possible contraceptive failure of hormonalcontraceptives containing oestrogens when givenwith .aprepitant (alternative contraception recommended)

BNFC 2011–2012 Appendix 1: Interactions 715Oestrogens (continued)Beta-blockers: oestrogens antagonise hypotensiveeffect of beta-blockers. Bosentan: possible contraceptive failure of hormonalcontraceptives containing oestrogens when givenwith .bosentan (alternative contraception recommended)Calcium-channel Blockers: oestrogens antagonisehypotensive effect of calcium-channel blockersCiclosporin: oestrogens possibly increase plasma concentrationof ciclosporinClonidine: oestrogens antagonise hypotensive effect ofclonidineCorticosteroids: oral contraceptives containingoestrogens increase plasma concentration of corticosteroidsDiuretics: oestrogens antagonise diuretic effect ofdiuretics. Dopaminergics: oestrogens increase plasma concentrationof ropinirole; oestrogens increase plasmaconcentration of .selegiline—manufacturer of selegilineadvises avoid concomitant useLipid-regulating Drugs: absorption of ethinylestradiolreduced by colesevelam; plasma concentration ofethinylestradiol increased by atorvastatin and rosuvastatinMethyldopa: oestrogens antagonise hypotensive effectof methyldopa. Modafinil: metabolism of oestrogens accelerated by.modafinil (reduced contraceptive effect—seep. 398)Moxonidine: oestrogens antagonise hypotensive effectof moxonidineMuscle Relaxants: oestrogens possibly increaseplasma concentration of tizanidine (increased risk oftoxicity)Nitrates: oestrogens antagonise hypotensive effect ofnitratesSitaxentan: plasma concentration of oestrogensincreased by sitaxentanSomatropin: oestrogens (when used as oral replacementtherapy) may increase dose requirements ofsomatropinTacrolimus: ethinylestradiol possibly increases plasmaconcentration of tacrolimusTheophylline: oestrogens increase plasma concentrationof theophylline (consider reducing dose oftheophylline)Thyroid Hormones: oestrogens may increase requirementsfor thyroid hormones in hypothyroidismVasodilator Antihypertensives: oestrogens antagonisehypotensive effect of hydralazine, minoxidil andsodium nitroprussideOestrogens, conjugated see OestrogensOfloxacin see QuinolonesOlanzapine see AntipsychoticsOlmesartan see Angiotensin-II Receptor AntagonistsOlsalazine see AminosalicylatesOmeprazole see Proton Pump InhibitorsOndansetron see 5HT 3 AntagonistsOpioid AnalgesicsAlcohol: enhanced hypotensive and sedative effectswhen opioid analgesics given with alcoholAnaesthetics, General: fentanyl inhibits metabolism ofetomidate (consider reducing dose of etomidate);opioid analgesics possibly enhance effects of intravenousgeneral anaesthetics and volatile liquidgeneral anaestheticsAntibacterials: plasma concentration of alfentanilincreased by erythromycin; avoidance of premedicationwith opioid analgesics advised by manufacturerof ciprofloxacin (reduced plasma concentrationof ciprofloxacin) when ciprofloxacin used for surgicalprophylaxis; metabolism of alfentanil, codeine,fentanyl, methadone and morphine accelerated byrifampicin (reduced effect); metabolism of oxycodonepossibly accelerated by rifampicin; metabolism ofoxycodone inhibited by telithromycinOpioid Analgesics (continued). Anticoagulants: tramadol enhances anticoagulanteffect of .coumarins. Antidepressants: plasma concentration of methadonepossibly increased by fluoxetine, fluvoxamine,paroxetine and sertraline; possible increased serotonergiceffects when pethidine or tramadol given withduloxetine; possible increased serotonergic effectswhen tramadol given with mirtazapine or venlafaxine;CNS excitation or depression (hypertension orhypotension) when pethidine given with .MAOIs—avoid concomitant use and for 2 weeks after stoppingMAOIs; possible CNS excitation or depression(hypertension or hypotension) when opioid analgesicsgiven with .MAOIs—some manufacturersadvise avoid concomitant use and for 2 weeks afterstopping MAOIs; possible increased serotonergiceffects and increased risk of convulsions whentramadol given with .MAOIs—some manufacturersadvise avoid concomitant use and for 2 weeks afterstopping MAOIs; possible CNS excitation or depression(hypertension or hypotension) when opioidanalgesics given with .moclobemide—manufacturerof moclobemide advises consider reducing dose ofopioid analgesics; possible CNS excitation ordepression (hypertension or hypotension) whendextromethorphan or pethidine given with.moclobemide—avoid concomitant use; increasedrisk of CNS toxicity when tramadol given with.SSRIs or .tricyclics; plasma concentration ofmethadone possibly reduced by St John’s wort;sedative effects possibly increased when opioidanalgesics given with tricyclics. Antiepileptics: effects of tramadol reduced by carbamazepine;plasma concentration of methadonereduced by carbamazepine and phenobarbital;dextropropoxyphene enhances effects of.carbamazepine; morphine increases bioavailabilityof gabapentin; metabolism of methadone acceleratedby phenytoin (reduced effect and risk of withdrawaleffects). Antifungals: metabolism of buprenorphine inhibited by.ketoconazole (reduce dose of buprenorphine);metabolism of alfentanil inhibited by fluconazole (riskof prolonged or delayed respiratory depression);metabolism of alfentanil possibly inhibited by itraconazole;plasma concentration of alfentanil andmethadone increased by .voriconazole (considerreducing dose of alfentanil and methadone); plasmaconcentration of oxycodone increased by.voriconazole; plasma concentration of fentanylpossibly increased by .triazoles. Antihistamines: sedative effects possibly increasedwhen opioid analgesics given with .sedating antihistaminesAntimuscarinics: possible increased risk of antimuscarinicside-effects when codeine given withantimuscarinics. Antipsychotics: enhanced hypotensive and sedativeeffects when opioid analgesics given with antipsychotics;increased risk of ventricular arrhythmiaswhen methadone given with .antipsychotics thatprolong the QT interval; increased risk of convulsionswhen tramadol given with antipsychotics; increasedrisk of ventricular arrhythmias when methadonegiven with .amisulpride—avoid concomitant use. Antivirals: plasma concentration of methadone possiblyreduced by abacavir and nevirapine; methadonepossibly reduces plasma concentration of didanosine;plasma concentration of methadone reduced byefavirenz, fosamprenavir, nelfinavir and ritonavir;plasma concentration of dextropropoxypheneincreased by .ritonavir (risk of toxicity)—avoidconcomitant use; plasma concentration of buprenorphinepossibly increased by ritonavir; plasmaconcentration of alfentanil and fentanyl increased by.ritonavir; plasma concentration of pethidinereduced by .ritonavir, but plasma concentration oftoxic pethidine metabolite increased (avoid conco-Appendix 1: Interactions

716 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsOpioid Analgesics. Antivirals (continued)mitant use); plasma concentration of morphinepossibly reduced by ritonavir; increased risk ofventricular arrhythmias when alfentanil,fentanyl or methadone given with .saquinavir—avoid concomitant use; buprenorphine possiblyreduces plasma concentration of tipranavir;methadone possibly increases plasma concentrationof zidovudineAnxiolytics and Hypnotics: increased sedative effectwhen opioid analgesics given with anxiolytics andhypnotics; fentanyl possibly inhibits metabolism ofmidazolam. Atomoxetine: increased risk of ventricular arrhythmiaswhen methadone given with .atomoxetine; possibleincreased risk of convulsions when tramadol givenwith atomoxetineBeta-blockers: morphine possibly increases plasmaconcentration of esmololCalcium-channel Blockers: metabolism of alfentanilinhibited by diltiazem (risk of prolonged or delayedrespiratory depression)Domperidone: opioid analgesics antagonise effects ofdomperidone on gastro-intestinal activity. Dopaminergics: avoid concomitant use of dextromethorphanwith .rasagiline; risk of CNS toxicitywhen pethidine given with .rasagiline (avoid pethidinefor 2 weeks after rasagiline); hyperpyrexia andCNS toxicity reported when pethidine given with.selegiline (avoid concomitant use); avoidance ofopioid analgesics advised by manufacturer of selegiline5HT 3 Antagonists: effects of tramadol possibly antagonisedby ondansetron. Memantine: increased risk of CNS toxicity whendextromethorphan given with .memantine (manufacturerof memantine advises avoid concomitantuse)Metoclopramide: opioid analgesics antagonise effectsof metoclopramide on gastro-intestinal activityMuscle Relaxants: increased sedative effect whenfentanyl or morphine given with baclofen. Sodium Oxybate: opioid analgesics enhance effects of.sodium oxybate (avoid concomitant use)Ulcer-healing Drugs: metabolism of opioid analgesicsinhibited by cimetidine (increased plasma concentration)OrlistatAnti-arrhythmics: orlistat possibly reduces plasmaconcentration of amiodaroneAnticoagulants: manufacturer of orlistat recommendsmonitoring anticoagulant effect of coumarinsAntidiabetics: manufacturer of orlistat advises avoidconcomitant use with acarbose. Antiepileptics: possible increased risk of convulsionswhen orlistat given with .antiepileptics. Ciclosporin: orlistat possibly reduces absorption of.ciclosporinThyroid Hormones: possible increased risk of hypothyroidismwhen orlistat given with levothyroxineOrphenadrine see AntimuscarinicsOxaliplatin see Platinum CompoundsOxandrolone see Anabolic SteroidsOxazepam see Anxiolytics and HypnoticsOxcarbazepine. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wortAntiepileptics: oxcarbazepine sometimes reducesplasma concentration of carbamazepine (but concentrationof an active metabolite of carbamazepinemay be increased), also plasma concentration of anactive metabolite of oxcarbazepine often reduced;OxcarbazepineAntiepileptics (continued)avoidance of oxcarbazepine advised by manufacturerof eslicarbazepine; oxcarbazepineincreases plasma concentration ofphenobarbital and phenytoin, also plasma concentrationof an active metabolite of oxcarbazepinereduced; plasma concentration of an activemetabolite of oxcarbazepine sometimes reducedby valproate. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered)Ciclosporin: oxcarbazepine possibly reduces plasmaconcentration of ciclosporin. Clopidogrel: oxcarbazepine possibly reduces antiplateleteffect of .clopidogrel. Cytotoxics: oxcarbazepine reduces plasma concentrationof .imatinib—avoid concomitant use. Oestrogens: oxcarbazepine accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistat. Progestogens: oxcarbazepine accelerates metabolismof .progestogens (reduced contraceptive effect—seep. 398)Oxprenolol see Beta-blockersOxybutynin see AntimuscarinicsOxycodone see Opioid AnalgesicsOxymetazoline see SympathomimeticsOxytetracycline see TetracyclinesOxytocinAnaesthetics, General: oxytocic effect possiblyreduced, also enhanced hypotensive effect and risk ofarrhythmias when oxytocin given with volatile liquidgeneral anaestheticsProstaglandins: uterotonic effect of oxytocin potentiatedby prostaglandinsSympathomimetics: risk of hypertension when oxytocingiven with vasoconstrictor sympathomimetics(due to enhanced vasopressor effect)Paclitaxel. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Antivirals: plasma concentration of paclitaxel increasedby nelfinavir and ritonavir. Cytotoxics: increased risk of neutropenia when paclitaxelgiven with .lapatinibPaliperidone see AntipsychoticsPancreatinAntidiabetics: pancreatin antagonises hypoglycaemiceffect of acarbosePancuronium see Muscle RelaxantsPantoprazole see Proton Pump InhibitorsPapaveretum see Opioid AnalgesicsParacetamolAnticoagulants: prolonged regular use of paracetamolpossibly enhances anticoagulant effect of coumarinsAntiepileptics: metabolism of paracetamol possiblyaccelerated by carbamazepineCytotoxics: paracetamol possibly inhibits metabolismof intravenous busulfan (manufacturer of intravenousbusulfan advises caution within 72 hours of paracetamol);caution with paracetamol advised bymanufacturer of imatinibLipid-regulating Drugs: absorption of paracetamolreduced by colestyramineMetoclopramide: rate of absorption of paracetamolincreased by metoclopramideParaldehyde. Alcohol: increased sedative effect when paraldehydegiven with .alcohol

BNFC 2011–2012 Appendix 1: Interactions 717Paraldehyde (continued). Disulfiram: risk of toxicity when paraldehyde givenwith .disulfiramParasympathomimeticsAnti-arrhythmics: effects of neostigmine and pyridostigminepossibly antagonised by propafenone. Antibacterials: plasma concentration of galantamineincreased by erythromycin; effects ofneostigmine and pyridostigmine antagonised by.aminoglycosides; effects of neostigmine andpyridostigmine antagonised by clindamycin; effectsof neostigmine and pyridostigmine antagonised by.polymyxinsAntidepressants: plasma concentration of galantamineincreased by paroxetineAntifungals: plasma concentration of galantamineincreased by ketoconazoleAntimalarials: effects of neostigmine and pyridostigminemay be diminished because of potential forchloroquine and hydroxychloroquine to increasesymptoms of myasthenia gravisAntimuscarinics: effects of parasympathomimeticsantagonised by antimuscarinicsBeta-blockers: increased risk of arrhythmias whenpilocarpine given with beta-blockers; effects ofneostigmine and pyridostigmine antagonised bypropranololLithium: effects of neostigmine and pyridostigmineantagonised by lithiumMuscle Relaxants: donepezil possibly enhances effectsof suxamethonium; edrophonium, galantamine, neostigmine,pyridostigmine and rivastigmine enhanceeffects of suxamethonium; donepezil possibly antagoniseseffects of non-depolarising muscle relaxants;edrophonium, neostigmine, pyridostigmine and rivastigmineantagonise effects of non-depolarisingmuscle relaxantsParecoxib see NSAIDsParicalcitol see VitaminsParoxetine see Antidepressants, SSRIPazopanib. Antibacterials: manufacturer of pazopanib advisesavoid concomitant use with .clarithromycin,.rifampicin and .telithromycin. Antifungals: manufacturer of pazopanib advises avoidconcomitant use with .itraconazole,.ketoconazole and .voriconazole. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Antivirals: manufacturer of pazopanib advises avoidconcomitant use with .atazanavir, .indinavir,.nelfinavir, .ritonavir and .saquinavirCytotoxics: plasma concentration of pazopanibincreased by lapatinib. Grapefruit Juice: manufacturer of pazopanib advisesavoid concomitant use with .grapefruit juicePegfilgrastim see FilgrastimPeginterferon Alfa see InterferonsPemetrexed. Antimalarials: antifolate effect of pemetrexedincreased by .pyrimethamine. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)PenicillamineAnalgesics: possible increased risk of nephrotoxicitywhen penicillamine given with NSAIDsAntacids: absorption of penicillamine reduced byantacids. Antipsychotics: avoid concomitant use of penicillaminewith .clozapine (increased risk of agranulocytosis)Cardiac Glycosides: penicillamine possibly reducesplasma concentration of digoxinGold: manufacturer of penicillamine advises avoidconcomitant use with sodium aurothiomalate(increased risk of toxicity)Iron: absorption of penicillamine reduced by oral ironPenicillamine (continued)Zinc: penicillamine reduces absorption of zinc, alsoabsorption of penicillamine reduced by zincPenicillinsAllopurinol: increased risk of rash when amoxicillin orampicillin given with allopurinolAntibacterials: absorption of phenoxymethylpenicillinreduced by neomycin; effects of penicillins possiblyantagonised by tetracyclinesAnticoagulants: common experience in anticoagulantclinics is that INR can be altered by a course ofbroad-spectrum penicillins such as ampicillin,although studies have failed to demonstrate aninteraction with coumarins or phenindioneCytotoxics: penicillins reduce excretion of methotrexate(increased risk of toxicity)Muscle Relaxants: piperacillin enhances effects ofnon-depolarising muscle relaxants and suxamethoniumProbenecid: excretion of penicillins reduced by probenecid(increased plasma concentration)Sulfinpyrazone: excretion of penicillins reduced bysulfinpyrazoneVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Pentamidine Isetionate. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen pentamidine isetionate given with.amiodarone—avoid concomitant use. Antibacterials: increased risk of ventricular arrhythmiaswhen pentamidine isetionate given with parenteral.erythromycin; increased risk of ventriculararrhythmias when pentamidine isetionate given with.moxifloxacin—avoid concomitant use. Antidepressants: increased risk of ventricular arrhythmiaswhen pentamidine isetionate given with.tricyclicsAntifungals: possible increased risk of nephrotoxicitywhen pentamidine isetionate given with amphotericin. Antipsychotics: increased risk of ventricular arrhythmiaswhen pentamidine isetionate given with.amisulpride or .droperidol—avoid concomitant use;increased risk of ventricular arrhythmias when pentamidineisetionate given with .phenothiazines. Antivirals: increased risk of hypocalcaemia whenparenteral pentamidine isetionate given with.foscarnet; increased risk of ventricular arrhythmiaswhen pentamidine isetionate given with.saquinavir—avoid concomitant use. Ivabradine: increased risk of ventricular arrhythmiaswhen pentamidine isetionate given with .ivabradinePentazocine see Opioid AnalgesicsPentostatin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Cytotoxics: increased toxicity when pentostatin givenwith high-dose .cyclophosphamide—avoid concomitantuse; increased pulmonary toxicity whenpentostatin given with .fludarabine (unacceptablyhigh incidence of fatalities)Pentoxifylline. Analgesics: possible increased risk of bleeding whenpentoxifylline given with NSAIDs; increased risk ofbleeding when pentoxifylline given with .ketorolac(avoid concomitant use)Theophylline: pentoxifylline increases plasma concentrationof theophyllinePergolideAntipsychotics: effects of pergolide antagonised byantipsychoticsMemantine: effects of dopaminergics possiblyenhanced by memantineMethyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopaMetoclopramide: antiparkinsonian effect of pergolideantagonised by metoclopramidePericyazine see AntipsychoticsAppendix 1: Interactions

718 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsPerindopril see ACE InhibitorsPerphenazine see AntipsychoticsPethidine see Opioid AnalgesicsPhenazocine see Opioid AnalgesicsPhenelzine see MAOIsPhenindioneNote Change in patient’s clinical condition particularlyassociated with liver disease, intercurrent illness, or drugadministration, necessitates more frequent testing. Majorchanges in diet (especially involving salads and vegetables)and in alcohol consumption may also affect anticoagulantcontrol. Alcohol: anticoagulant control with phenindione maybe affected by major changes in consumption of.alcohol. Anabolic Steroids: anticoagulant effect of phenindioneenhanced by .anabolic steroids. Analgesics: anticoagulant effect of phenindione possiblyenhanced by .NSAIDs; increased risk ofhaemorrhage when anticoagulants given with intravenous.diclofenac (avoid concomitant use, includinglow-dose heparins); increased risk of haemorrhagewhen anticoagulants given with .ketorolac (avoidconcomitant use, including low-dose heparins);increased risk of bleeding when phenindione givenwith .aspirin (due to antiplatelet effect). Anti-arrhythmics: metabolism of phenindione inhibitedby .amiodarone (enhanced anticoagulant effect). Antibacterials: experience in anticoagulant clinicssuggests that INR possibly altered when phenindioneis given with .neomycin (given for local action ongut); anticoagulant effect of phenindione possiblyenhanced by levofloxacin and .tetracyclines; studieshave failed to demonstrate an interaction withphenindione, but common experience in anticoagulantclinics is that INR can be altered by acourse of broad-spectrum penicillins such as ampicillin;metabolism of phenindione possibly inhibitedby sulfonamides. Antivirals: anticoagulant effect of phenindione possiblyenhanced by .ritonavir. Clopidogrel: anticoagulant effect of phenindioneenhanced due to antiplatelet action of .clopidogrelCorticosteroids: anticoagulant effect of phenindionemay be enhanced or reduced by corticosteroids. Dipyridamole: anticoagulant effect of phenindioneenhanced due to antiplatelet action of .dipyridamole. Enteral Foods: anticoagulant effect of phenindioneantagonised by vitamin K (present in some .enteralfeeds )Iloprost: increased risk of bleeding when phenindionegiven with iloprost. Lipid-regulating Drugs: anticoagulant effect of phenindionemay be enhanced or reduced by.colestyramine; anticoagulant effect of phenindionepossibly enhanced by .rosuvastatin; anticoagulanteffect of phenindione enhanced by .fibrates. Oestrogens: anticoagulant effect of phenindioneantagonised by .oestrogensPrasugrel: possible increased risk of bleeding whenphenindione given with prasugrel. Progestogens: anticoagulant effect of phenindioneantagonised by .progestogens. Testolactone: anticoagulant effect of phenindioneenhanced by .testolactone. Testosterone: anticoagulant effect of phenindioneenhanced by .testosterone. Thyroid Hormones: anticoagulant effect of phenindioneenhanced by .thyroid hormones. Vitamins: anticoagulant effect of phenindione antagonisedby .vitamin KPhenobarbitalNote Primidone interactions as for phenobarbitalAlcohol: increased sedative effect when phenobarbitalgiven with alcoholAnalgesics: phenobarbital reduces plasma concentrationof methadone. Anti-arrhythmics: phenobarbital accelerates metabolismof disopyramide (reduced plasma concentra-Phenobarbital. Anti-arrhythmics (continued)tion); phenobarbital possibly reduces plasmaconcentration of .dronedarone—avoid concomitantuse. Antibacterials: phenobarbital accelerates metabolismof metronidazole (reduced effect); phenobarbitalpossibly reduces plasma concentration of rifampicin;phenobarbital accelerates metabolism of doxycycline(reduced plasma concentration); phenobarbital possiblyaccelerates metabolism of .chloramphenicol(reduced plasma concentration); phenobarbitalreduces plasma concentration of .telithromycin(avoid during and for 2 weeks after phenobarbital). Anticoagulants: phenobarbital accelerates metabolismof .coumarins (reduced anticoagulant effect). Antidepressants: phenobarbital reduces plasma concentrationof paroxetine; phenobarbital acceleratesmetabolism of .mianserin (reduced plasma concentration);anticonvulsant effect of antiepileptics possiblyantagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wort; phenobarbital possibly acceleratesmetabolism of .tricyclics (reduced plasmaconcentration). Antiepileptics: plasma concentration of phenobarbitalpossibly increased by carbamazepine; phenobarbitalpossibly reduces plasma concentration of ethosuximide,rufinamide and topiramate; phenobarbitalreduces plasma concentration of lamotrigine,tiagabine and zonisamide; plasma concentration ofphenobarbital increased by oxcarbazepine, alsoplasma concentration of an active metabolite ofoxcarbazepine reduced; plasma concentration ofphenobarbital often increased by phenytoin, plasmaconcentration of phenytoin often reduced but may beincreased; plasma concentration of phenobarbitalincreased by .stiripentol; plasma concentration ofphenobarbital increased by valproate (also plasmaconcentration of valproate reduced). Antifungals: phenobarbital possibly reduces plasmaconcentration of itraconazole and .posaconazole;phenobarbital possibly reduces plasma concentrationof .voriconazole—avoid concomitant use; phenobarbitalreduces absorption of griseofulvin (reducedeffect). Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered); phenobarbital accelerates metabolism ofhaloperidol (reduced plasma concentration); plasmaconcentration of both drugs reduced when phenobarbitalgiven with chlorpromazine; phenobarbitalpossibly reduces plasma concentration of.aripiprazole—increase dose of aripiprazole; phenobarbitalpossibly reduces plasma concentration ofclozapine. Antivirals: phenobarbital possibly reduces plasmaconcentration of abacavir, darunavir, fosamprenavir,.indinavir, .lopinavir, .nelfinavir and .saquinavir;avoidance of phenobarbital advised by manufacturerof etravirineAnxiolytics and Hypnotics: phenobarbital oftenreduces plasma concentration of clonazepamAprepitant: phenobarbital possibly reduces plasmaconcentration of aprepitantBeta-blockers: phenobarbital possibly reduces plasmaconcentration of propranolol. Calcium-channel Blockers: phenobarbital probablyreduces effects of .calcium-channel blockers; avoidanceof phenobarbital advised by manufacturer ofisradipine; avoidance of phenobarbital advised by

BNFC 2011–2012 Appendix 1: Interactions 719Phenobarbital. Calcium-channel Blockers (continued)manufacturer of .nimodipine (plasma concentrationof nimodipine reduced). Ciclosporin: phenobarbital accelerates metabolism of.ciclosporin (reduced plasma concentration). Corticosteroids: phenobarbital accelerates metabolismof .corticosteroids (reduced effect)Cytotoxics: avoidance of phenobarbital advised bymanufacturer of gefitinib; phenobarbital possiblyreduces plasma concentration of etoposide; phenobarbitalreduces plasma concentration of irinotecanand its active metabolite. Diuretics: phenobarbital reduces plasma concentrationof .eplerenone—avoid concomitant use; increasedrisk of osteomalacia when phenobarbital given withcarbonic anhydrase inhibitorsFolates: plasma concentration of phenobarbital possiblyreduced by folatesHormone Antagonists: phenobarbital acceleratesmetabolism of toremifene (reduced plasma concentration)Leukotriene Receptor Antagonists: phenobarbitalreduces plasma concentration of montelukast. Oestrogens: phenobarbital accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistat. Progestogens: phenobarbital accelerates metabolismof .progestogens (reduced contraceptive effect—seep. 398)Sodium Oxybate: avoidance of phenobarbital advisedby manufacturer of sodium oxybateSympathomimetics: plasma concentration of phenobarbitalpossibly increased by methylphenidate. Tacrolimus: phenobarbital reduces plasma concentrationof .tacrolimus. Theophylline: phenobarbital accelerates metabolism of.theophylline (reduced effect)Thyroid Hormones: phenobarbital accelerates metabolismof thyroid hormones (may increase requirementsfor thyroid hormones in hypothyroidism). Ulipristal: avoidance of phenobarbital advised bymanufacturer of .ulipristal (contraceptive effect ofulipristal possibly reduced)Vitamins: phenobarbital possibly increases requirementsfor vitamin DPhenothiazines see AntipsychoticsPhenoxybenzamine see Alpha-blockersPhenoxymethylpenicillin see PenicillinsPhentolamine see Alpha-blockersPhenylephrine see SympathomimeticsPhenytoinNote Fosphenytoin interactions as for phenytoinAlcohol: plasma concentration of phenytoin possiblyreduced by chronic heavy consumption of alcoholAnalgesics: phenytoin accelerates metabolism ofmethadone (reduced effect and risk of withdrawaleffects); effects of phenytoin enhanced by aspirinAntacids: absorption of phenytoin reduced by antacids. Anti-arrhythmics: metabolism of phenytoin inhibitedby .amiodarone (increased plasma concentration);phenytoin reduces plasma concentration of disopyramide;phenytoin possibly reduces plasma concentrationof .dronedarone—avoid concomitant use. Antibacterials: metabolism of phenytoin inhibited byclarithromycin (increased plasma concentration);metabolism of phenytoin possibly inhibited bymetronidazole (increased plasma concentration);plasma concentration of phenytoin increased ordecreased by ciprofloxacin; phenytoin acceleratesmetabolism of doxycycline (reduced plasma concentration);plasma concentration of phenytoinincreased by .chloramphenicol (increased risk oftoxicity); metabolism of phenytoin possibly inhibitedby isoniazid (increased risk of toxicity); metabolism ofphenytoin accelerated by .rifamycins (reducedPhenytoin. Antibacterials (continued)plasma concentration); plasma concentration ofphenytoin possibly increased by sulfonamides;phenytoin reduces plasma concentration of.telithromycin (avoid during and for 2 weeks afterphenytoin); plasma concentration of phenytoinincreased by .trimethoprim (also increased antifolateeffect). Anticoagulants: phenytoin accelerates metabolism of.coumarins (possibility of reduced anticoagulanteffect, but enhancement also reported). Antidepressants: plasma concentration of phenytoinincreased by .fluoxetine and .fluvoxamine; phenytoinreduces plasma concentration of .mianserin,mirtazapine and paroxetine; plasma concentration ofphenytoin possibly increased by sertraline, alsoplasma concentration of sertraline possibly reduced;anticonvulsant effect of antiepileptics possiblyantagonised by MAOIs and .tricyclic-related antidepressants(convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wort; phenytoin possibly reducesplasma concentration of .tricyclicsAntidiabetics: plasma concentration of phenytointransiently increased by tolbutamide (possibility oftoxicity). Antiepileptics: plasma concentration of both drugsoften reduced when phenytoin given with carbamazepine,also plasma concentration of phenytoinmay be increased; phenytoin reduces plasma concentrationof eslicarbazepine, also plasma concentrationof phenytoin increased; plasma concentrationof phenytoin possibly increased by .ethosuximide,also plasma concentration of ethosuximide possiblyreduced; phenytoin reduces plasma concentration oflamotrigine, tiagabine and zonisamide; plasma concentrationof phenytoin increased by oxcarbazepine,also plasma concentration of an active metabolite ofoxcarbazepine reduced; phenytoin often increasesplasma concentration of phenobarbital, plasma concentrationof phenytoin often reduced but may beincreased; phenytoin possibly reduces plasma concentrationof rufinamide, also plasma concentrationof phenytoin possibly increased; plasma concentrationof phenytoin increased by .stiripentol; plasmaconcentration of phenytoin increased by .topiramate(also plasma concentration of topiramate reduced);plasma concentration of phenytoin increased orpossibly reduced when given with valproate, alsoplasma concentration of valproate reduced; plasmaconcentration of phenytoin reduced by vigabatrin. Antifungals: phenytoin reduces plasma concentrationof .ketoconazole and .posaconazole; anticonvulsanteffect of phenytoin enhanced by .miconazole(plasma concentration of phenytoin increased);plasma concentration of phenytoin increased by.fluconazole (consider reducing dose of phenytoin);phenytoin reduces plasma concentration of.itraconazole—avoid concomitant use; plasma concentrationof phenytoin increased by .voriconazole,also phenytoin reduces plasma concentration ofvoriconazole (increase dose of voriconazole and alsomonitor for phenytoin toxicity); phenytoin possiblyreduces plasma concentration of caspofungin—considerincreasing dose of caspofungin. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine; anticonvulsanteffect of phenytoin antagonised by.pyrimethamine, also increased antifolate effect. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered); phenytoin reduces plasma concentration ofhaloperidol; plasma concentration of phenytoinAppendix 1: Interactions

720 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsPhenytoin. Antipsychotics (continued)possibly increased or decreased by chlorpromazine;phenytoin possibly reduces plasma concentrationof .aripiprazole—increase dose ofaripiprazole; phenytoin accelerates metabolism ofclozapine and quetiapine (reduced plasma concentration). Antivirals: phenytoin possibly reduces plasma concentrationof abacavir, darunavir, lopinavir andsaquinavir; avoidance of phenytoin advised bymanufacturer of etravirine; phenytoin possiblyreduces plasma concentration of .indinavir, alsoplasma concentration of phenytoin possiblyincreased; plasma concentration of phenytoinreduced by nelfinavir; phenytoin possibly reducesplasma concentration of ritonavir, also plasma concentrationof phenytoin possibly affected; plasmaconcentration of phenytoin increased or decreasedby zidovudineAnxiolytics and Hypnotics: phenytoin often reducesplasma concentration of clonazepam; plasma concentrationof phenytoin increased or decreased bydiazepam; plasma concentration of phenytoin possiblyincreased or decreased by benzodiazepinesAprepitant: phenytoin possibly reduces plasma concentrationof aprepitantBupropion: phenytoin reduces plasma concentration ofbupropion. Calcium-channel Blockers: phenytoin reduces effectsof felodipine and verapamil; avoidance of phenytoinadvised by manufacturer of isradipine; avoidance ofphenytoin advised by manufacturer of nimodipine(plasma concentration of nimodipine possiblyreduced); plasma concentration of phenytoinincreased by .diltiazem but also effect of diltiazemreducedCardiac Glycosides: phenytoin possibly reducesplasma concentration of digoxin. Ciclosporin: phenytoin accelerates metabolism of.ciclosporin (reduced plasma concentration). Corticosteroids: phenytoin accelerates metabolism of.corticosteroids (reduced effect). Cytotoxics: phenytoin possibly reduces plasma concentrationof busulfan and etoposide; metabolism ofphenytoin possibly inhibited by fluorouracil(increased risk of toxicity); phenytoin increases antifolateeffect of methotrexate; plasma concentrationof phenytoin possibly reduced by cisplatin; avoidanceof phenytoin advised by manufacturer of gefitinib and.lapatinib; phenytoin reduces plasma concentrationof .imatinib—avoid concomitant use; phenytoinreduces plasma concentration of irinotecan and itsactive metaboliteDiazoxide: plasma concentration of phenytoin reducedby diazoxide, also effect of diazoxide may be reduced. Disulfiram: metabolism of phenytoin inhibited by.disulfiram (increased risk of toxicity). Diuretics: plasma concentration of phenytoin possiblyincreased by .acetazolamide; phenytoin antagoniseseffects of furosemide; phenytoin reduces plasmaconcentration of .eplerenone—avoid concomitantuse; increased risk of osteomalacia when phenytoingiven with carbonic anhydrase inhibitorsDopaminergics: phenytoin possibly reduces effects oflevodopaEnteral Foods: absorption of phenytoin possiblyreduced by enteral feedsFolates: plasma concentration of phenytoin possiblyreduced by folatesHormone Antagonists: phenytoin possibly acceleratesmetabolism of toremifene5HT 3 Antagonists: phenytoin accelerates metabolismof ondansetron (reduced effect)Leflunomide: plasma concentration of phenytoinpossibly increased by leflunomideLevamisole: plasma concentration of phenytoin possiblyincreased by levamisolePhenytoin (continued)Lipid-regulating Drugs: absorption of phenytoin possiblyreduced by colesevelam; combination ofphenytoin with fluvastatin may increase plasmaconcentration of either drug (or both)Lithium: neurotoxicity may occur when phenytoingiven with lithium without increased plasma concentrationof lithiumModafinil: plasma concentration of phenytoin possiblyincreased by modafinilMuscle Relaxants: phenytoin antagonises musclerelaxant effect of non-depolarising muscle relaxants(accelerated recovery from neuromuscular blockade). Oestrogens: phenytoin accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistat. Progestogens: phenytoin accelerates metabolism of.progestogens (reduced contraceptive effect—seep. 398). Sulfinpyrazone: plasma concentration of phenytoinincreased by .sulfinpyrazoneSympathomimetics: plasma concentration of phenytoinincreased by methylphenidateTacrolimus: phenytoin reduces plasma concentrationof tacrolimus, also plasma concentration of phenytoinpossibly increased. Theophylline: plasma concentration of both drugsreduced when phenytoin given with .theophyllineThyroid Hormones: phenytoin accelerates metabolismof thyroid hormones (may increase requirements inhypothyroidism), also plasma concentration ofphenytoin possibly increasedTibolone: phenytoin accelerates metabolism of tibolone. Ulcer-healing Drugs: metabolism of phenytoin inhibitedby .cimetidine (increased plasma concentration);effects of phenytoin enhanced by .esomeprazole;effects of phenytoin possibly enhanced by omeprazole;absorption of phenytoin reduced by.sucralfate. Ulipristal: avoidance of phenytoin advised by manufacturerof .ulipristal (contraceptive effect of ulipristalpossibly reduced)Vaccines: effects of phenytoin enhanced by influenzavaccineVitamins: phenytoin possibly increases requirementsfor vitamin DPholcodineAntidepressants: manufacturer of pholcodine advisesavoid for 2 weeks after stopping MAOIsPhosphodiesterase Type-3 Inhibitors. Anagrelide: avoidance of enoximone and milrinoneadvised by manufacturer of .anagrelidePhysostigmine see ParasympathomimeticsPilocarpine see ParasympathomimeticsPimozide see AntipsychoticsPindolol see Beta-blockersPioglitazone see AntidiabeticsPiperacillin see PenicillinsPipotiazine see AntipsychoticsPiroxicam see NSAIDsPivmecillinam see PenicillinsPizotifenAdrenergic Neurone Blockers: pizotifen antagoniseshypotensive effect of adrenergic neurone blockersPlatinum Compounds. Aldesleukin: avoidance of cisplatin advised by manufacturerof .aldesleukin. Antibacterials: increased risk of nephrotoxicity andpossibly of ototoxicity when platinum compoundsgiven with .aminoglycosides or .polymyxins;increased risk of nephrotoxicity and ototoxicity whenplatinum compounds given with capreomycin;increased risk of nephrotoxicity and possibly ofototoxicity when cisplatin given with vancomycin

BNFC 2011–2012 Appendix 1: Interactions 721Platinum Compounds (continued)Antiepileptics: cisplatin possibly reduces plasma concentrationof phenytoin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Cytotoxics: increased risk of otoxicity when cisplatingiven with ifosfamide; increased pulmonary toxicitywhen cisplatin given with .bleomycin and.methotrexateDiuretics: increased risk of nephrotoxicity and ototoxicitywhen platinum compounds given with diureticsPolymyxin B see PolymyxinsPolymyxinsAntibacterials: increased risk of nephrotoxicity whencolistimethate sodium or polymyxins given withaminoglycosides; increased risk of nephrotoxicitywhen colistimethate sodium or polymyxins givenwith capreomycin; increased risk of nephrotoxicitywhen polymyxins given with vancomycin; increasedrisk of nephrotoxicity and ototoxicity when colistimethatesodium given with vancomycinAntifungals: increased risk of nephrotoxicity whenpolymyxins given with amphotericin. Ciclosporin: increased risk of nephrotoxicity whenpolymyxins given with .ciclosporin. Cytotoxics: increased risk of nephrotoxicity and possiblyof ototoxicity when polymyxins given with.platinum compounds. Diuretics: increased risk of otoxicity when polymyxinsgiven with .loop diuretics. Muscle Relaxants: polymyxins enhance effects of.non-depolarising muscle relaxants and.suxamethonium. Parasympathomimetics: polymyxins antagoniseeffects of .neostigmine and .pyridostigmineVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Polystyrene Sulphonate ResinsAntacids: risk of intestinal obstruction when polystyrenesulphonate resins given with aluminiumhydroxide; risk of metabolic alkalosis when polystyrenesulphonate resins given with oral magnesiumsaltsThyroid Hormones: polystyrene sulphonate resinsreduce absorption of levothyroxinePosaconazole see Antifungals, TriazolePotassium Canrenoate see DiureticsPotassium AminobenzoateAntibacterials: potassium aminobenzoate inhibitseffects of sulfonamidesPotassium Bicarbonate see Potassium SaltsPotassium Chloride see Potassium SaltsPotassium Citrate see Potassium SaltsPotassium SaltsNote Includes salt substitutes. ACE Inhibitors: increased risk of severe hyperkalaemiawhen potassium salts given with .ACE inhibitorsAliskiren: increased risk of hyperkalaemia whenpotassium salts given with aliskiren. Angiotensin-II Receptor Antagonists: increased risk ofhyperkalaemia when potassium salts given with.angiotensin-II receptor antagonistsAntibacterials: avoid concomitant use of potassiumcitrate with methenamine. Ciclosporin: increased risk of hyperkalaemia whenpotassium salts given with .ciclosporin. Diuretics: increased risk of hyperkalaemia whenpotassium salts given with .potassium-sparing diureticsand aldosterone antagonists. Tacrolimus: increased risk of hyperkalaemia whenpotassium salts given with .tacrolimusPramipexoleAntipsychotics: manufacturer of pramipexole advisesavoid concomitant use of antipsychotics (antagonismof effect)Memantine: effects of dopaminergics possiblyenhanced by memantinePramipexole (continued)Methyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopaUlcer-healing Drugs: excretion of pramipexole reducedby cimetidine (increased plasma concentration)PrasugrelAnalgesics: possible increased risk of bleeding whenprasugrel given with NSAIDsAnticoagulants: possible increased risk of bleedingwhen prasugrel given with coumarins or phenindioneClopidogrel: possible increased risk of bleeding whenprasugrel given with clopidogrelPravastatin see StatinsPrazosin see Alpha-blockersPrednisolone see CorticosteroidsPrednisone see CorticosteroidsPrilocaineAnti-arrhythmics: increased myocardial depressionwhen prilocaine given with anti-arrhythmicsAntibacterials: increased risk of methaemoglobinaemiawhen prilocaine given with sulfonamidesPrimaquine. Antimalarials: avoidance of antimalarials advised bymanufacturer of .artemether/lumefantrineHistamine: avoidance of antimalarials advised bymanufacturer of histamineMepacrine: plasma concentration of primaquineincreased by mepacrine (increased risk of toxicity)Vaccines: antimalarials inactivate oral typhoidvaccine—see p. 620Primidone see PhenobarbitalProbenecidACE Inhibitors: probenecid reduces excretion ofcaptoprilAnaesthetics, General: probenecid possibly enhanceseffects of thiopental. Analgesics: probenecid reduces excretion of.dexketoprofen, .indometacin, .ketoprofen and.naproxen (increased plasma concentration); probenecidreduces excretion of .ketorolac (increasedplasma concentration)—avoid concomitant use;effects of probenecid antagonised by aspirinAntibacterials: probenecid reduces excretion of doripenem(manufacturers of doripenem advise avoidconcomitant use); probenecid reduces excretion ofmeropenem; probenecid reduces excretion of cephalosporins,ciprofloxacin, nalidixic acid,norfloxacin and penicillins (increased plasma concentration);probenecid reduces excretion ofdapsone and nitrofurantoin (increased risk of sideeffects);effects of probenecid antagonised bypyrazinamide. Antivirals: probenecid reduces excretion of aciclovir(increased plasma concentration); probenecid possiblyreduces excretion of famciclovir (increasedplasma concentration); probenecid reduces excretionof ganciclovir and .zidovudine (increased plasmaconcentration and risk of toxicity)Anxiolytics and Hypnotics: probenecid reducesexcretion of lorazepam (increased plasma concentration);probenecid possibly reduces excretion ofnitrazepam (increased plasma concentration). Cytotoxics: probenecid reduces excretion of.methotrexate (increased risk of toxicity)Sodium Benzoate: probenecid possibly reducesexcretion of conjugate formed by sodium benzoateSodium Phenylbutyrate: probenecid possibly reducesexcretion of conjugate formed by sodium phenylbutyrateProcarbazineAlcohol: disulfiram-like reaction when procarbazinegiven with alcohol. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cardiac Glycosides: procarbazine possibly reducesabsorption of digoxin tabletsProchlorperazine see AntipsychoticsProcyclidine see AntimuscarinicsAppendix 1: Interactions

722 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsProgesterone see ProgestogensProgestogensNote Interactions of combined oral contraceptives may alsoapply to combined contraceptive patches and vaginal rings,see p. 398. For further information on interactions of oralprogestogen-only contraceptives, see also p. 403; parenteralprogestogen-only contraceptives, see also p. 404; the intrauterineprogestogen-only device, see also p. 405; hormonalemergency contraception, see also p. 408. Antibacterials: plasma concentration of dienogestincreased by erythromycin; metabolism of progestogensaccelerated by .rifamycins (reduced contraceptiveeffect—see p. 398). Anticoagulants: progestogens may enhance or reduceanticoagulant effect of coumarins; progestogensantagonise anticoagulant effect of .phenindione. Antidepressants: contraceptive effect of progestogensreduced by .St John’s wort (avoid concomitant use)Antidiabetics: progestogens antagonise hypoglycaemiceffect of antidiabetics. Antiepileptics: metabolism of progestogens acceleratedby .carbamazepine, .eslicarbazepine,.oxcarbazepine, .phenobarbital, .phenytoin,.rufinamide and .topiramate (reduced contraceptiveeffect—see p. 398); desogestrel possibly increasesplasma concentration of lamotrigineAntifungals: progestogens possibly increase plasmaconcentration of voriconazole; anecdotal reports ofcontraceptive failure and menstrual irregularitieswhen progestogens given with griseofulvin; occasionalreports of breakthrough bleeding when progestogens(used for contraception) given withterbinafine. Antivirals: plasma concentration of norethisteroneincreased by atazanavir; contraceptive effect ofprogestogens possibly reduced by .efavirenz andnelfinavir; metabolism of progestogens acceleratedby .nevirapine (reduced contraceptive effect—seep. 398). Aprepitant: possible contraceptive failure of hormonalcontraceptives containing progestogens when givenwith .aprepitant (alternative contraception recommended). Bosentan: possible contraceptive failure of hormonalcontraceptives containing progestogens when givenwith .bosentan (alternative contraception recommended)Ciclosporin: progestogens possibly increase plasmaconcentration of ciclosporinDiuretics: risk of hyperkalaemia when drospirenonegiven with potassium-sparing diuretics and aldosteroneantagonists (monitor serum potassium duringfirst cycle). Dopaminergics: progestogens increase plasma concentrationof .selegiline—manufacturer of selegilineadvises avoid concomitant useLipid-regulating Drugs: plasma concentration of norethisteroneincreased by atorvastatin; plasma concentrationof active metabolite of norgestimateincreased by rosuvastatin; plasma concentration ofnorgestrel increased by rosuvastatinMuscle Relaxants: progestogens possibly increaseplasma concentration of tizanidine (increased risk oftoxicity)Sitaxentan: plasma concentration of progestogensincreased by sitaxentanSugammadex: plasma concentration of progestogenspossibly reduced by sugammadex—manufacturer ofsugammadex advises additional contraceptive precautions. Ulipristal: contraceptive effect of progestogens possiblyreduced by .ulipristalProguanilAntacids: absorption of proguanil reduced by oralmagnesium salts (as magnesium trisilicate)Anticoagulants: isolated reports that proguanil mayenhance anticoagulant effect of warfarin. Antimalarials: avoidance of antimalarials advised bymanufacturer of .artemether/lumefantrine;Proguanil. Antimalarials (continued)increased antifolate effect when proguanil givenwith pyrimethamineHistamine: avoidance of antimalarials advised bymanufacturer of histamineVaccines: antimalarials inactivate oral typhoidvaccine—see p. 620Promazine see AntipsychoticsPromethazine see AntihistaminesPropafenoneAnaesthetics, Local: increased myocardial depressionwhen anti-arrhythmics given with bupivacaine, levobupivacaine,prilocaine or ropivacaine. Anti-arrhythmics: increased myocardial depressionwhen anti-arrhythmics given with other .antiarrhythmics. Antibacterials: metabolism of propafenone acceleratedby .rifampicin (reduced effect). Anticoagulants: propafenone enhances anticoagulanteffect of .coumarins. Antidepressants: metabolism of propafenone possiblyinhibited by paroxetine (increased risk of toxicity);increased risk of arrhythmias when propafenonegiven with .tricyclics. Antihistamines: increased risk of ventricular arrhythmiaswhen propafenone given with .mizolastine—avoid concomitant use. Antipsychotics: increased risk of ventricular arrhythmiaswhen anti-arrhythmics that prolong the QTinterval given with .antipsychotics that prolong theQT interval. Antivirals: plasma concentration of propafenone possiblyincreased by .fosamprenavir (increased risk ofventricular arrhythmias—avoid concomitant use);plasma concentration of propafenone increased by.ritonavir (increased risk of ventricular arrhythmias—avoidconcomitant use); increased risk ofventricular arrhythmias when propafenone givenwith .saquinavir—avoid concomitant use. Beta-blockers: increased myocardial depression whenanti-arrhythmics given with .beta-blockers; propafenoneincreases plasma concentration ofmetoprolol and propranolol. Cardiac Glycosides: propafenone increases plasmaconcentration of .digoxin (halve dose of digoxin)Ciclosporin: propafenone possibly increases plasmaconcentration of ciclosporinParasympathomimetics: propafenone possibly antagoniseseffects of neostigmine and pyridostigmineTheophylline: propafenone increases plasma concentrationof theophylline. Ulcer-healing Drugs: plasma concentration of propafenoneincreased by .cimetidinePropantheline see AntimuscarinicsPropiverine see AntimuscarinicsPropofol see Anaesthetics, GeneralPropranolol see Beta-blockersProstaglandinsACE Inhibitors: enhanced hypotensive effect whenalprostadil given with ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when alprostadil given with adrenergicneurone blockersAlpha-blockers: enhanced hypotensive effect whenalprostadil given with alpha-blockersAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when alprostadil given withangiotensin-II receptor antagonistsBeta-blockers: enhanced hypotensive effect whenalprostadil given with beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when alprostadil given with calcium-channelblockersClonidine: enhanced hypotensive effect when alprostadilgiven with clonidineDiazoxide: enhanced hypotensive effect when alprostadilgiven with diazoxide

BNFC 2011–2012 Appendix 1: Interactions 723Prostaglandins (continued)Diuretics: enhanced hypotensive effect when alprostadilgiven with diureticsMethyldopa: enhanced hypotensive effect whenalprostadil given with methyldopaMoxonidine: enhanced hypotensive effect whenalprostadil given with moxonidineNitrates: enhanced hypotensive effect when alprostadilgiven with nitratesOxytocin: prostaglandins potentiate uterotonic effect ofoxytocinVasodilator Antihypertensives: enhanced hypotensiveeffect when alprostadil given with hydralazine,minoxidil or sodium nitroprussideProtein Kinase Inhibitors see Dasatinib, Erlotinib,Everolimus, Gefitinib, Imatinib, Lapatinib, Nilotinib,Pazopanib, Sorafenib, Sunitinib, and TemsirolimusProton Pump InhibitorsAntacids: absorption of lansoprazole possibly reducedby antacidsAntibacterials: plasma concentration of both drugsincreased when omeprazole given with clarithromycin. Anticoagulants: esomeprazole, omeprazole and pantoprazolepossibly enhance anticoagulant effect of.coumarinsAntidepressants: omeprazole increases plasma concentrationof escitalopram; plasma concentration oflansoprazole possibly increased by fluvoxamine;plasma concentration of omeprazole possiblyreduced by St John’s wort. Antiepileptics: esomeprazole enhances effects of.phenytoin; omeprazole possibly enhances effects ofphenytoinAntifungals: proton pump inhibitors reduce absorptionof itraconazole and ketoconazole; avoidance ofproton pump inhibitors advised by manufacturer ofposaconazole (plasma concentration of posaconazolepossibly reduced); plasma concentration of esomeprazolepossibly increased by voriconazole; plasmaconcentration of omeprazole increased by voriconazole(consider reducing dose of omeprazole)Antipsychotics: omeprazole possibly reduces plasmaconcentration of clozapine. Antivirals: proton pump inhibitors reduce plasmaconcentration of .atazanavir—avoid or adjust dose ofboth drugs (consult product literature); omeprazolereduces plasma concentration of .nelfinavir—avoidconcomitant use; proton pump inhibitors possiblyincrease plasma concentration of raltegravir—manufacturerof raltegravir advises avoid concomitantuse; omeprazole increases plasma concentration of.raltegravir—avoid concomitant use; esomeprazole,lansoprazole, pantoprazole and rabeprazole possiblyincrease plasma concentration of .saquinavir—manufacturerof saquinavir advises avoid concomitantuse; omeprazole increases plasma concentration of.saquinavir—manufacturer of saquinavir advisesavoid concomitant use; plasma concentration ofesomeprazole and omeprazole reduced by.tipranavirAnxiolytics and Hypnotics: esomeprazole and omeprazolepossibly inhibit metabolism of diazepam(increased plasma concentration)Cardiac Glycosides: proton pump inhibitors possiblyslightly increase plasma concentration of digoxinCiclosporin: omeprazole possibly affects plasma concentrationof ciclosporinCilostazol: omeprazole increases plasma concentrationof cilostazol (consider reducing dose of cilostazol). Clopidogrel: esomeprazole and omeprazole reduceantiplatelet effect of .clopidogrel; lansoprazole,pantoprazole and rabeprazole possibly reduce antiplateleteffect of clopidogrel. Cytotoxics: omeprazole possibly reduces excretion ofmethotrexate (increased risk of toxicity); avoidanceof esomeprazole, lansoprazole, pantoprazole andrabeprazole advised by manufacturer of .erlotinib;omeprazole reduces plasma concentration ofProton Pump Inhibitors. Cytotoxics (continued).erlotinib—manufacturer of erlotinib advises avoidconcomitant use; proton pump inhibitors possiblyreduce absorption of lapatinibTacrolimus: omeprazole possibly increases plasmaconcentration of tacrolimusUlcer-healing Drugs: absorption of lansoprazole possiblyreduced by sucralfate. Ulipristal: avoidance of proton pump inhibitors advisedby manufacturer of .ulipristal (plasma concentrationof ulipristal possibly reduced)Pseudoephedrine see SympathomimeticsPyrazinamideProbenecid: pyrazinamide antagonises effects of probenecidSulfinpyrazone: pyrazinamide antagonises effects ofsulfinpyrazoneVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Pyridostigmine see ParasympathomimeticsPyridoxine see VitaminsPyrimethamine. Antibacterials: increased antifolate effect when pyrimethaminegiven with .sulfonamides or.trimethoprim. Antiepileptics: pyrimethamine antagonises anticonvulsanteffect of .phenytoin, also increased antifolateeffect. Antimalarials: avoidance of antimalarials advised bymanufacturer of .artemether/lumefantrine;increased antifolate effect when pyrimethamine givenwith proguanilAntivirals: increased antifolate effect when pyrimethaminegiven with zidovudine. Cytotoxics: pyrimethamine increases antifolate effect of.methotrexate and .pemetrexedHistamine: avoidance of antimalarials advised bymanufacturer of histamineVaccines: antimalarials inactivate oral typhoidvaccine—see p. 620Quetiapine see AntipsychoticsQuinagolideMemantine: effects of dopaminergics possiblyenhanced by memantineMethyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopaQuinapril see ACE InhibitorsQuinine. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen quinine given with .amiodarone—avoidconcomitant use; quinine increases plasma concentrationof .flecainide. Antibacterials: increased risk of ventricular arrhythmiaswhen quinine given with .moxifloxacin—avoidconcomitant use; plasma concentration of quininereduced by .rifampicinAnticoagulants: plasma concentration of both drugsincreased when quinine given with warfarin. Antimalarials: avoidance of antimalarials advised bymanufacturer of .artemether/lumefantrine;increased risk of ventricular arrhythmias whenquinine given with .artemether/lumefantrine;increased risk of convulsions when quinine givenwith .mefloquine (but should not prevent the use ofintravenous quinine in severe cases). Antipsychotics: increased risk of ventricular arrhythmiaswhen quinine given with .droperidol or.pimozide—avoid concomitant use; possibleincreased risk of ventricular arrhythmias whenquinine given with .haloperidol—avoid concomitantuse. Antivirals: plasma concentration of quinine possiblyincreased by .atazanavir, .darunavir, .fosamprenavir,.indinavir, .nelfinavir and .tipranavir (increased riskof toxicity); plasma concentration of quinineincreased by .ritonavir (increased risk of toxicity);increased risk of ventricular arrhythmias whenAppendix 1: Interactions

724 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsQuinine. Antivirals (continued)quinine given with .saquinavir—avoid concomitantuse. Cardiac Glycosides: quinine increases plasma concentrationof .digoxinDopaminergics: quinine possibly increases plasmaconcentration of amantadineHistamine: avoidance of antimalarials advised bymanufacturer of histamineMuscle Relaxants: quinine possibly enhances effects ofsuxamethoniumUlcer-healing Drugs: metabolism of quinine inhibitedby cimetidine (increased plasma concentration)Vaccines: antimalarials inactivate oral typhoidvaccine—see p. 620Quinolones. Analgesics: possible increased risk of convulsionswhen quinolones given with .NSAIDs; manufacturerof ciprofloxacin advises avoid premedication withopioid analgesics (reduced plasma concentration ofciprofloxacin) when ciprofloxacin used for surgicalprophylaxisAntacids: absorption of ciprofloxacin, levofloxacin,moxifloxacin, norfloxacin and ofloxacin reduced byantacids. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen levofloxacin or moxifloxacin given with.amiodarone—avoid concomitant use; increased riskof ventricular arrhythmias when moxifloxacin givenwith .disopyramide—avoid concomitant use. Antibacterials: increased risk of ventricular arrhythmiaswhen moxifloxacin given with parenteral.erythromycin—avoid concomitant use; effects ofnalidixic acid possibly antagonised by nitrofurantoin. Anticoagulants: ciprofloxacin, nalidixic acid,norfloxacin and ofloxacin enhance anticoagulanteffect of .coumarins; levofloxacin possibly enhancesanticoagulant effect of coumarins and phenindione. Antidepressants: ciprofloxacin inhibits metabolism of.duloxetine—avoid concomitant use; avoidance ofciprofloxacin advised by manufacturer of.agomelatine; increased risk of ventricular arrhythmiaswhen moxifloxacin given with .tricyclics—avoid concomitant useAntidiabetics: norfloxacin possibly enhances effects ofglibenclamideAntiepileptics: ciprofloxacin increases or decreasesplasma concentration of phenytoin. Antihistamines: increased risk of ventricular arrhythmiaswhen moxifloxacin given with .mizolastine—avoid concomitant use. Antimalarials: avoidance of quinolones advised bymanufacturer of .artemether/lumefantrine;increased risk of ventricular arrhythmias whenmoxifloxacin given with .chloroquine and hydroxychloroquine,.mefloquine or .quinine—avoid concomitantuse. Antipsychotics: increased risk of ventricular arrhythmiaswhen moxifloxacin given with .benperidol—manufacturer of benperidol advises avoid concomitantuse; increased risk of ventricular arrhythmiaswhen moxifloxacin given with .droperidol,.haloperidol, .phenothiazines, .pimozide or.zuclopenthixol—avoid concomitant use; ciprofloxacinincreases plasma concentration of clozapine;ciprofloxacin possibly increases plasma concentrationof olanzapine. Atomoxetine: increased risk of ventricular arrhythmiaswhen moxifloxacin given with .atomoxetine. Beta-blockers: increased risk of ventricular arrhythmiaswhen moxifloxacin given with .sotalol—avoidconcomitant useCalcium Salts: absorption of ciprofloxacin reduced bycalcium salts. Ciclosporin: increased risk of nephrotoxicity whenquinolones given with .ciclosporin. Clopidogrel: ciprofloxacin possibly reduces antiplateleteffect of .clopidogrelQuinolones (continued). Cytotoxics: nalidixic acid increases risk of melphalantoxicity; ciprofloxacin possibly reduces excretion ofmethotrexate (increased risk of toxicity); ciprofloxacinincreases plasma concentration of erlotinib;increased risk of ventricular arrhythmias whenlevofloxacin or moxifloxacin given with .arsenictrioxideDairy Products: absorption of ciprofloxacin and norfloxacinreduced by dairy productsDopaminergics: ciprofloxacin increases plasma concentrationof rasagiline; ciprofloxacin inhibitsmetabolism of ropinirole (increased plasma concentration)5HT 1 Agonists: quinolones possibly inhibit metabolismof zolmitriptan (reduce dose of zolmitriptan)Iron: absorption of ciprofloxacin, levofloxacin, moxifloxacin,norfloxacin and ofloxacin reduced by oralironLanthanum: absorption of quinolones possibly reducedby lanthanum (give at least 2 hours before or 4 hoursafter lanthanum). Muscle Relaxants: norfloxacin possibly increasesplasma concentration of tizanidine (increased risk oftoxicity); ciprofloxacin increases plasma concentrationof .tizanidine (increased risk of toxicity)—avoidconcomitant useMycophenolate: norfloxacin possibly reduces bioavailabilityof mycophenolate. Pentamidine Isetionate: increased risk of ventriculararrhythmias when moxifloxacin given with .pentamidineisetionate—avoid concomitant useProbenecid: excretion of ciprofloxacin, nalidixicacid and norfloxacin reduced by probenecid(increased plasma concentration)Sevelamer: bioavailability of ciprofloxacin reduced bysevelamerStrontium Ranelate: absorption of quinolones reducedby strontium ranelate (manufacturer of strontiumranelate advises avoid concomitant use). Theophylline: possible increased risk of convulsionswhen quinolones given with .theophylline;ciprofloxacin and norfloxacin increase plasma concentrationof .theophyllineUlcer-healing Drugs: absorption of ciprofloxacin,levofloxacin, moxifloxacin, norfloxacin and ofloxacinreduced by sucralfateVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Zinc: absorption of ciprofloxacin, levofloxacin, moxifloxacin,norfloxacin and ofloxacin reduced by zincRabeprazole see Proton Pump InhibitorsRaloxifeneAnticoagulants: raloxifene antagonises anticoagulanteffect of coumarinsLipid-regulating Drugs: absorption of raloxifenereduced by colestyramine (manufacturer of raloxifeneadvises avoid concomitant administration)Raltegravir. Antibacterials: plasma concentration of raltegravirreduced by .rifampicin—consider increasing dose ofraltegravir. Ulcer-healing Drugs: plasma concentration of raltegravirincreased by .omeprazole—avoid concomitantuse; plasma concentration of raltegravir possiblyincreased by histamine H 2 -antagonists and protonpump inhibitors—manufacturer of raltegravir advisesavoid concomitant useRaltitrexed. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Folates: manufacturer of raltitrexed advises avoidconcomitant use with .folatesRamipril see ACE InhibitorsRanitidine see Histamine H 2 -antagonistsRanolazine. Anti-arrhythmics: manufacturer of ranolazine advisesavoid concomitant use with .disopyramide

BNFC 2011–2012 Appendix 1: Interactions 725Ranolazine (continued). Antibacterials: plasma concentration of ranolazinepossibly increased by .clarithromycin and.telithromycin—manufacturer of ranolazine advisesavoid concomitant use; plasma concentration ofranolazine reduced by .rifampicin—manufacturer ofranolazine advises avoid concomitant useAntidepressants: plasma concentration of ranolazineincreased by paroxetine. Antifungals: plasma concentration of ranolazineincreased by .ketoconazole—avoid concomitant use;plasma concentration of ranolazine possiblyincreased by .itraconazole, .posaconazole and.voriconazole—manufacturer of ranolazine advisesavoid concomitant use. Antivirals: plasma concentration of ranolazine possiblyincreased by .atazanavir, .darunavir, .fosamprenavir,.indinavir, .lopinavir, .nelfinavir, .ritonavir,.saquinavir and .tipranavir—manufacturer of ranolazineadvises avoid concomitant use. Beta-blockers: manufacturer of ranolazine advisesavoid concomitant use with .sotalolCalcium-channel Blockers: plasma concentration ofranolazine increased by diltiazem and verapamil(consider reducing dose of ranolazine)Cardiac Glycosides: ranolazine increases plasma concentrationof digoxinCiclosporin: plasma concentration of ranolazine possiblyincreased by ciclosporin. Grapefruit Juice: plasma concentration of ranolazinepossibly increased by .grapefruit juice—manufacturerof ranolazine advises avoid concomitant useLipid-regulating Drugs: ranolazine increases plasmaconcentration of simvastatin (consider reducing doseof simvastatin)RasagilineNote Rasagiline is a MAO-B inhibitor. Analgesics: avoid concomitant use of rasagiline with.dextromethorphan; risk of CNS toxicity whenrasagiline given with .pethidine (avoid pethidine for 2weeks after rasagiline)Antibacterials: plasma concentration of rasagilineincreased by ciprofloxacin. Antidepressants: after stopping rasagiline do not start.fluoxetine for 2 weeks, also rasagiline should not bestarted until at least 5 weeks after stopping fluoxetine;after stopping rasagiline do not start.fluvoxamine for 2 weeks; risk of hypertensive crisiswhen rasagiline given with .MAOIs, avoid MAOIs forat least 2 weeks after stopping rasagiline; increasedrisk of CNS toxicity when rasagiline given with.SSRIs or .tricyclicsDopaminergics: plasma concentration of rasagilinepossibly reduced by entacaponeMemantine: effects of dopaminergics possiblyenhanced by memantineMethyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopa. Sympathomimetics: avoid concomitant use of rasagilinewith .sympathomimeticsReboxetine. Antibacterials: manufacturer of reboxetine advisesavoid concomitant use with .macrolides. Antidepressants: manufacturer of reboxetine advisesavoid concomitant use with .fluvoxamine; increasedrisk of hypertension and CNS excitation whenreboxetine given with .MAOIs (MAOIs should not bestarted until 1 week after stopping reboxetine, avoidreboxetine for 2 weeks after stopping MAOIs). Antifungals: manufacturer of reboxetine advises avoidconcomitant use with .imidazoles and .triazoles. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrineAtomoxetine: possible increased risk of convulsionswhen antidepressants given with atomoxetineDiuretics: possible increased risk of hypokalaemiawhen reboxetine given with loop diuretics or thiazidesand related diureticsReboxetine (continued)Ergot Alkaloids: possible risk of hypertension whenreboxetine given with ergotamine and methysergideRemifentanil see Opioid AnalgesicsRepaglinide see AntidiabeticsRetinoids. Alcohol: etretinate formed from acitretin in presence of.alcohol (increased risk of teratogenecity in womenof child-bearing potential). Antibacterials: possible increased risk of benignintracranial hypertension when retinoids given with.tetracyclines (avoid concomitant use). Anticoagulants: acitretin possibly reduces anticoagulanteffect of .coumarinsAntiepileptics: isotretinoin possibly reduces plasmaconcentration of carbamazepineAntifungals: plasma concentration of alitretinoinincreased by ketoconazole. Cytotoxics: acitretin increases plasma concentration of.methotrexate (also increased risk of hepatotoxicity)—avoidconcomitant useLipid-regulating Drugs: alitretinoin reduces plasmaconcentration of simvastatinVitamins: risk of hypervitaminosis A when retinoidsgiven with vitamin ARibavirin. Antivirals: effects of ribavirin possibly reduced by.abacavir; increased risk of side-effects when ribaviringiven with .didanosine—avoid concomitantuse; increased risk of toxicity when ribavirin givenwith .stavudine; increased risk of anaemia whenribavirin given with .zidovudine—avoid concomitantuse. Azathioprine: ribavirin possibly enhances myelosuppressiveeffects of .azathioprineRifabutin see RifamycinsRifampicin see RifamycinsRifamycinsACE Inhibitors: rifampicin reduces plasma concentrationof active metabolite of imidapril (reduced antihypertensiveeffect)Analgesics: rifampicin reduces plasma concentrationof celecoxib, diclofenac and etoricoxib; rifampicinaccelerates metabolism of alfentanil, codeine,fentanyl, methadone and morphine (reduced effect);rifampicin possibly accelerates metabolism of oxycodoneAngiotensin-II Receptor Antagonists: rifampicinreduces plasma concentration of losartan and itsactive metaboliteAntacids: absorption of rifampicin reduced by antacids. Anti-arrhythmics: rifamycins accelerate metabolism of.disopyramide (reduced plasma concentration); rifampicinreduces plasma concentration of.dronedarone—avoid concomitant use; rifampicinaccelerates metabolism of .propafenone (reducedeffect). Antibacterials: rifamycins reduce plasma concentrationof clarithromycin and dapsone; plasma concentrationof rifabutin increased by .clarithromycin(increased risk of uveitis—reduce rifabutin dose);rifampicin reduces plasma concentration of doxycycline—considerincreasing dose of doxycycline; rifampicinaccelerates metabolism of chloramphenicol(reduced plasma concentration); rifampicin reducesplasma concentration of linezolid (possible therapeuticfailure of linezolid); plasma concentration ofrifabutin possibly increased by .macrolides(increased risk of uveitis—reduce rifabutin dose);rifampicin reduces plasma concentration of.telithromycin (avoid during and for 2 weeks afterrifampicin); rifampicin possibly reduces plasma concentrationof trimethoprim. Anticoagulants: rifamycins accelerate metabolism of.coumarins (reduced anticoagulant effect); rifampicinreduces plasma concentration of rivaroxaban. Antidiabetics: rifamycins accelerate metabolism of.tolbutamide (reduced effect); rifampicin reducesplasma concentration of nateglinide; rifampicinAppendix 1: Interactions

726 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsRifamycins. Antidiabetics (continued)possibly antagonises hypoglycaemic effect ofrepaglinide; rifamycins possibly acceleratemetabolism of .sulfonylureas (reduced effect). Antiepileptics: rifabutin reduces plasma concentrationof .carbamazepine; rifampicin reduces plasma concentrationof .lamotrigine; plasma concentration ofrifampicin possibly reduced by phenobarbital; rifamycinsaccelerate metabolism of .phenytoin(reduced plasma concentration). Antifungals: rifampicin accelerates metabolism of.ketoconazole (reduced plasma concentration), alsoplasma concentration of rifampicin may be reducedby ketoconazole; plasma concentration of rifabutinincreased by .fluconazole (increased risk of uveitis—reduce rifabutin dose); rifampicin acceleratesmetabolism of .fluconazole (reduced plasma concentration);rifabutin and rifampicin reduce plasmaconcentration of .itraconazole—manufacturer ofitraconazole advises avoid concomitant use; plasmaconcentration of rifabutin increased by.posaconazole (also plasma concentration of posaconazolereduced); rifampicin reduces plasma concentrationof .posaconazole and .terbinafine; plasmaconcentration of rifabutin increased by.voriconazole, also rifabutin reduces plasma concentrationof voriconazole (increase dose of voriconazoleand also monitor for rifabutin toxicity);rifampicin reduces plasma concentration of.voriconazole—avoid concomitant use; rifampicininitially increases and then reduces plasma concentrationof caspofungin (consider increasing dose ofcaspofungin); plasma concentration of rifabutinpossibly increased by .triazoles (increased risk ofuveitis—reduce rifabutin dose)Antihistamines: rifampicin possibly reduces effects offexofenadine. Antimalarials: rifampicin reduces plasma concentrationof .mefloquine—avoid concomitant use; rifampicinreduces plasma concentration of .quinineAntimuscarinics: rifampicin reduces plasma concentrationof active metabolite of fesoterodine. Antipsychotics: rifampicin accelerates metabolism of.haloperidol (reduced plasma concentration);rifabutin and rifampicin possibly reduce plasmaconcentration of .aripiprazole—increase dose ofaripiprazole; rifampicin possibly reduces plasmaconcentration of clozapine. Antivirals: rifampicin possibly reduces plasma concentrationof abacavir and ritonavir; rifampicinreduces plasma concentration of .atazanavir,.lopinavir and .nevirapine—avoid concomitant use;plasma concentration of rifabutin increased by.atazanavir, .darunavir, .fosamprenavir and.tipranavir (reduce dose of rifabutin); rifampicinsignificantly reduces plasma concentration of.darunavir, .fosamprenavir and .nelfinavir—avoidconcomitant use; plasma concentration of rifabutinreduced by efavirenz—increase dose of rifabutin;rifampicin reduces plasma concentration of efavirenz—increasedose of efavirenz; plasma concentrationof both drugs reduced when rifabutin given with.etravirine; avoidance of rifampicin advised bymanufacturer of etravirine and zidovudine; rifampicinaccelerates metabolism of .indinavir (reducedplasma concentration—avoid concomitant use);plasma concentration of rifabutin increased by.indinavir—avoid concomitant use; rifampicinreduces plasma concentration of .maraviroc and.raltegravir—consider increasing dose ofmaraviroc and raltegravir; plasma concentration ofrifabutin increased by .nelfinavir (halve dose ofrifabutin); plasma concentration of rifabutin possiblyincreased by nevirapine; plasma concentration ofrifabutin increased by .ritonavir (increased risk oftoxicity); rifampicin significantly reduces plasmaconcentration of .saquinavir, also risk of hepatotoxi-Rifamycins. Antivirals (continued)city—avoid concomitant use; plasma concentrationof rifabutin increased by .saquinavir (alsoplasma concentration of saquinavir reduced);rifampicin possibly reduces plasma concentrationof .tipranavir—avoid concomitant useAnxiolytics and Hypnotics: rifampicin acceleratesmetabolism of diazepam (reduced plasma concentration);rifampicin possibly accelerates metabolismof benzodiazepines (reduced plasma concentration);rifampicin possibly accelerates metabolism ofbuspirone and zaleplon; rifampicin acceleratesmetabolism of zolpidem (reduced plasma concentrationand reduced effect); rifampicin significantlyreduces plasma concentration of zopicloneAprepitant: rifampicin reduces plasma concentration ofaprepitant. Atovaquone: rifabutin and rifampicin reduce plasmaconcentration of .atovaquone (possible therapeuticfailure of atovaquone)Beta-blockers: rifampicin accelerates metabolism ofbisoprolol and propranolol (plasma concentrationsignificantly reduced); rifampicin reduces plasmaconcentration of carvedilol, celiprolol and metoprolol. Bosentan: rifampicin reduces plasma concentration of.bosentan—avoid concomitant use. Calcium-channel Blockers: rifampicin possibly acceleratesmetabolism of .isradipine and .nicardipine(possible significantly reduced plasma concentration);rifampicin accelerates metabolism of.diltiazem, .nifedipine, .nimodipine and .verapamil(plasma concentration significantly reduced)Cardiac Glycosides: rifampicin possibly reducesplasma concentration of digoxin. Ciclosporin: rifampicin accelerates metabolism of.ciclosporin (reduced plasma concentration). Corticosteroids: rifamycins accelerate metabolism of.corticosteroids (reduced effect). Cytotoxics: rifampicin accelerates metabolism of.dasatinib (reduced plasma concentration—avoidconcomitant use); rifampicin accelerates metabolismof erlotinib and sunitinib (reduced plasma concentration);rifampicin reduces plasma concentration of.everolimus and sorafenib; rifampicin reducesplasma concentration of .gefitinib, .imatinib and.nilotinib—avoid concomitant use; avoidance ofrifabutin and rifampicin advised by manufacturer of.lapatinib; avoidance of rifampicin advised by manufacturerof .pazopanib; rifampicin reduces plasmaconcentration of active metabolite of.temsirolimus—avoid concomitant use; rifampicinpossibly reduces plasma concentration of.vinflunine—manufacturer of vinflunine advisesavoid concomitant useDeferasirox: rifampicin reduces plasma concentrationof deferasirox. Diuretics: rifampicin reduces plasma concentration of.eplerenone—avoid concomitant useHormone Antagonists: rifampicin possibly reducesplasma concentration of exemestane; rifampicinaccelerates metabolism of tamoxifen (reducedplasma concentration)5HT 3 Antagonists: rifampicin accelerates metabolismof ondansetron (reduced effect)Leflunomide: rifampicin possibly increases plasmaconcentration of active metabolite of leflunomideLipid-regulating Drugs: rifampicin possibly reducesplasma concentration of atorvastatin and simvastatin;rifampicin accelerates metabolism of fluvastatin(reduced effect). Mycophenolate: rifampicin reduces plasma concentrationof active metabolite of .mycophenolate. Oestrogens: rifamycins accelerate metabolism of.oestrogens (reduced contraceptive effect—seep. 398)

BNFC 2011–2012 Appendix 1: Interactions 727Rifamycins (continued). Progestogens: rifamycins accelerate metabolism of.progestogens (reduced contraceptive effect—seep. 398). Ranolazine: rifampicin reduces plasma concentrationof .ranolazine—manufacturer of ranolazine advisesavoid concomitant useRoflumilast: rifampicin reduces plasma concentrationof roflumilast—consider increasing dose of roflumilast. Sirolimus: rifabutin and rifampicin reduce plasmaconcentration of .sirolimus—avoid concomitant use. Tacrolimus: rifabutin possibly reduces plasma concentrationof tacrolimus; rifampicin reduces plasmaconcentration of .tacrolimus. Tadalafil: rifampicin reduces plasma concentration of.tadalafil—manufacturer of tadalafil advises avoidconcomitant useTheophylline: rifampicin accelerates metabolism oftheophylline (reduced plasma concentration)Thyroid Hormones: rifampicin accelerates metabolismof levothyroxine (may increase requirements forlevothyroxine in hypothyroidism)Tibolone: rifampicin accelerates metabolism of tibolone(reduced plasma concentration)Tolvaptan: rifampicin reduces plasma concentration oftolvaptanUlcer-healing Drugs: rifampicin accelerates metabolismof cimetidine (reduced plasma concentration). Ulipristal: avoidance of rifampicin advised by manufacturerof .ulipristal (contraceptive effect of ulipristalpossibly reduced)Vaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Risedronate Sodium see BisphosphonatesRisperidone see AntipsychoticsRitodrine see Sympathomimetics, Beta 2Ritonavir. Alpha-blockers: ritonavir possibly increases plasmaconcentration of .alfuzosin—avoid concomitant use. Analgesics: ritonavir possibly increases plasma concentrationof NSAIDs and buprenorphine; ritonavirincreases plasma concentration of.dextropropoxyphene and .piroxicam (risk of toxicity)—avoidconcomitant use; ritonavir increasesplasma concentration of .alfentanil and .fentanyl;ritonavir reduces plasma concentration of methadone;ritonavir possibly reduces plasma concentrationof morphine; ritonavir reduces plasmaconcentration of .pethidine, but increases plasmaconcentration of toxic metabolite of pethidine (avoidconcomitant use). Anti-arrhythmics: ritonavir increases plasma concentrationof .amiodarone and .propafenone (increasedrisk of ventricular arrhythmias—avoid concomitantuse); ritonavir possibly increases plasma concentrationof .disopyramide (increased risk of toxicity);avoidance of ritonavir advised by manufacturer of.dronedarone; ritonavir possibly increases plasmaconcentration of .flecainide (increased risk ofventricular arrhythmias—avoid concomitant use). Antibacterials: ritonavir possibly increases plasmaconcentration of azithromycin and erythromycin;ritonavir increases plasma concentration of.clarithromycin (reduce dose of clarithromycin inrenal impairment); ritonavir increases plasma concentrationof .rifabutin (increased risk of toxicity);plasma concentration of ritonavir possibly reducedby rifampicin; plasma concentration of both drugsincreased when ritonavir given with .fusidic acid—avoid concomitant use; avoidance of concomitantritonavir in severe renal and hepatic impairmentadvised by manufacturer of .telithromycin. Anticoagulants: ritonavir may enhance or reduceanticoagulant effect of .warfarin; ritonavir possiblyenhances anticoagulant effect of .coumarins and.phenindione; ritonavir increases plasma concentrationof .rivaroxaban—manufacturer of rivaroxabanadvises avoid concomitant useRitonavir (continued). Antidepressants: ritonavir possibly reduces plasmaconcentration of paroxetine; ritonavir increasesplasma concentration of .trazodone (increased risk oftoxicity); ritonavir possibly increases plasma concentrationof .SSRIs and .tricyclics; plasma concentrationof ritonavir reduced by .St John’s wort—avoidconcomitant useAntidiabetics: ritonavir possibly increases plasmaconcentration of tolbutamide. Antiepileptics: ritonavir possibly increases plasmaconcentration of .carbamazepine; ritonavir possiblyreduces plasma concentration of lamotrigine; plasmaconcentration of ritonavir possibly reduced byphenytoin, also plasma concentration of phenytoinpossibly affected. Antifungals: combination of ritonavir with.itraconazole or .ketoconazole may increase plasmaconcentration of either drug (or both); plasmaconcentration of ritonavir increased by fluconazole;ritonavir reduces plasma concentration of.voriconazole—avoid concomitant useAntihistamines: ritonavir possibly increases plasmaconcentration of non-sedating antihistamines. Antimalarials: caution with ritonavir advised bymanufacturer of artemether/lumefantrine; ritonavirincreases plasma concentration of .quinine(increased risk of toxicity)Antimuscarinics: avoidance of ritonavir advised bymanufacturer of darifenacin and tolterodine; manufacturerof fesoterodine advises dose reduction whenritonavir given with fesoterodine—consult fesoterodineproduct literature; ritonavir increases plasmaconcentration of solifenacin. Antipsychotics: ritonavir possibly increases plasmaconcentration of .antipsychotics; ritonavir possiblyinhibits metabolism of .aripiprazole (reduce dose ofaripiprazole); ritonavir increases plasma concentrationof .clozapine (increased risk of toxicity)—avoidconcomitant use; ritonavir reduces plasma concentrationof olanzapine—consider increasing dose ofolanzapine; ritonavir increases plasma concentrationof .pimozide (increased risk of ventricular arrhythmias—avoidconcomitant use). Antivirals: ritonavir increases toxicity of efavirenz,monitor liver function tests; ritonavir increasesplasma concentration of indinavir, maraviroc and.saquinavir; combination of ritonavir with nelfinavirmay increase plasma concentration of either drug (orboth). Anxiolytics and Hypnotics: ritonavir possibly increasesplasma concentration of .anxiolytics and hypnotics;ritonavir possibly increases plasma concentration of.alprazolam, .diazepam, .flurazepam and .zolpidem(risk of extreme sedation and respiratory depression—avoidconcomitant use); ritonavir possiblyincreases plasma concentration of .midazolam (riskof prolonged sedation—avoid concomitant use oforal midazolam); ritonavir increases plasma concentrationof buspirone (increased risk of toxicity)Aprepitant: ritonavir possibly increases plasma concentrationof aprepitantBosentan: ritonavir possibly increases plasma concentrationof bosentanBupropion: ritonavir reduces plasma concentration ofbupropion. Calcium-channel Blockers: ritonavir possibly increasesplasma concentration of .calcium-channel blockers;avoidance of ritonavir advised by manufacturer oflercanidipineCardiac Glycosides: ritonavir possibly increasesplasma concentration of digoxin. Ciclosporin: ritonavir possibly increases plasma concentrationof .ciclosporin. Colchicine: ritonavir possibly increases risk of.colchicine toxicity—suspend or reduce dose ofcolchicine (avoid concomitant use in hepatic or renalimpairment)Appendix 1: Interactions

728 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsRitonavir (continued). Corticosteroids: ritonavir possibly increases plasmaconcentration of corticosteroids, dexamethasone andprednisolone; ritonavir increases plasma concentrationof inhaled and intranasal budesonide and.fluticasone. Cytotoxics: ritonavir possibly increases plasma concentrationof .everolimus and .vinflunine—manufacturerof everolimus and vinflunine advises avoidconcomitant use; avoidance of ritonavir advised bymanufacturer of .lapatinib, .nilotinib and.pazopanib; ritonavir possibly increases plasmaconcentration of .docetaxel (increased risk of toxicity);ritonavir increases plasma concentration ofpaclitaxel; ritonavir possibly increases plasma concentrationof vinblastine. Diuretics: ritonavir increases plasma concentration of.eplerenone—avoid concomitant use. Ergot Alkaloids: increased risk of ergotism whenritonavir given with .ergotamine and methysergide—avoid concomitant use. 5HT 1 Agonists: ritonavir increases plasma concentrationof .eletriptan (risk of toxicity)—avoid concomitantuse. Ivabradine: ritonavir possibly increases plasma concentrationof .ivabradine—avoid concomitant use. Lipid-regulating Drugs: possible increased risk ofmyopathy when ritonavir given with atorvastatin;possible increased risk of myopathy when ritonavirgiven with .rosuvastatin—manufacturer of rosuvastatinadvises avoid concomitant use; increased risk ofmyopathy when ritonavir given with .simvastatin(avoid concomitant use). Oestrogens: ritonavir accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398). Ranolazine: ritonavir possibly increases plasma concentrationof .ranolazine—manufacturer of ranolazineadvises avoid concomitant use. Sildenafil: ritonavir significantly increases plasmaconcentration of .sildenafil—avoid concomitant useSympathomimetics: ritonavir possibly increasesplasma concentration of dexamfetamine. Tacrolimus: ritonavir possibly increases plasma concentrationof .tacrolimus. Tadalafil: ritonavir increases plasma concentration of.tadalafil—manufacturer of tadalafil advises avoidconcomitant use. Theophylline: ritonavir accelerates metabolism of.theophylline (reduced plasma concentration). Ulipristal: avoidance of ritonavir advised by manufacturerof .ulipristal (contraceptive effect of ulipristalpossibly reduced). Vardenafil: ritonavir increases plasma concentration of.vardenafil—avoid concomitant useRivaroxaban. Analgesics: increased risk of haemorrhage when anticoagulantsgiven with intravenous .diclofenac (avoidconcomitant use, including low-dose heparins);increased risk of haemorrhage when anticoagulantsgiven with .ketorolac (avoid concomitant use,including low-dose heparins)Antibacterials: plasma concentration of rivaroxabanreduced by rifampicin. Antifungals: plasma concentration of rivaroxabanincreased by .ketoconazole—avoid concomitant use;manufacturer of rivaroxaban advises avoid concomitantuse with itraconazole, posaconazole andvoriconazole. Antivirals: manufacturer of rivaroxaban advises avoidconcomitant use with atazanavir, darunavir, fosamprenavir,indinavir, lopinavir, nelfinavir,saquinavir and tipranavir; plasma concentration ofrivaroxaban increased by .ritonavir—manufacturerof rivaroxaban advises avoid concomitant useRivastigmine see ParasympathomimeticsRizatriptan see 5HT 1 AgonistsRocuronium see Muscle RelaxantsRoflumilastAntibacterials: plasma concentration of roflumilastreduced by rifampicin—consider increasing dose ofroflumilastAntidepressants: metabolism of roflumilast inhibitedby fluvoxamineTheophylline: manufacturer of roflumilast advisesavoid concomitant use with theophyllineUlcer-healing Drugs: metabolism of roflumilast inhibitedby cimetidineRopiniroleAntibacterials: metabolism of ropinirole inhibited byciprofloxacin (increased plasma concentration)Antipsychotics: manufacturer of ropinirole advisesavoid concomitant use of antipsychotics (antagonismof effect)Memantine: effects of dopaminergics possiblyenhanced by memantineMethyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopaMetoclopramide: manufacturer of ropinirole advisesavoid concomitant use of metoclopramide (antagonismof effect)Oestrogens: plasma concentration of ropiniroleincreased by oestrogensRopivacaineAnti-arrhythmics: increased myocardial depressionwhen ropivacaine given with anti-arrhythmicsAntidepressants: metabolism of ropivacaine inhibitedby fluvoxamine—avoid prolonged administration ofropivacaineRosuvastatin see StatinsRotigotineAntipsychotics: manufacturer of rotigotine advisesavoid concomitant use of antipsychotics (antagonismof effect)Memantine: effects of dopaminergics possiblyenhanced by memantineMethyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopaMetoclopramide: manufacturer of rotigotine advisesavoid concomitant use of metoclopramide (antagonismof effect)Rufinamide. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wortAntiepileptics: plasma concentration of both drugspossibly reduced when rufinamide given with carbamazepine;plasma concentration of rufinamide possiblyreduced by phenobarbital; plasmaconcentration of rufinamide possibly reduced byphenytoin, also plasma concentration of phenytoinpossibly increased; plasma concentration of rufinamidepossibly increased by valproate (reduce dose ofrufinamide). Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered). Oestrogens: rufinamide accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistat. Progestogens: rufinamide accelerates metabolism of.progestogens (reduced contraceptive effect—seep. 398)Rupatadine see Antihistamines

BNFC 2011–2012 Appendix 1: Interactions 729St John’s WortAnalgesics: St John’s wort possibly reduces plasmaconcentration of methadone. Anti-arrhythmics: St John’s wort possibly reducesplasma concentration of .dronedarone—avoid concomitantuse. Antibacterials: St John’s wort reduces plasma concentrationof .telithromycin (avoid during and for 2weeks after St John’s wort). Anticoagulants: St John’s wort reduces anticoagulanteffect of .coumarins (avoid concomitant use). Antidepressants: possible increased serotonergiceffects when St John’s wort given with duloxetine orvenlafaxine; St John’s wort reduces plasma concentrationof amitriptyline; increased serotonergic effectswhen St John’s wort given with .SSRIs—avoidconcomitant use. Antiepileptics: avoid concomitant use of St John’s wortwith .antiepileptics. Antifungals: St John’s wort reduces plasma concentrationof .voriconazole—avoid concomitant use. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrine. Antipsychotics: St John’s wort possibly reduces plasmaconcentration of .aripiprazole—increase dose ofaripiprazole. Antivirals: St John’s wort reduces plasma concentrationof .atazanavir, .darunavir, .efavirenz,.fosamprenavir, .indinavir, .lopinavir, .nelfinavir,.nevirapine, .ritonavir and .saquinavir—avoid concomitantuse; avoidance of St John’s wort advised bymanufacturer of etravirine; St John’s wort possiblyreduces plasma concentration of .maraviroc and.tipranavir—avoid concomitant useAnxiolytics and Hypnotics: St John’s wort possiblyreduces plasma concentration of oral midazolam. Aprepitant: avoidance of St John’s wort advised bymanufacturer of .aprepitantAtomoxetine: possible increased risk of convulsionswhen antidepressants given with atomoxetine. Calcium-channel Blockers: St John’s wort possiblyreduces plasma concentration of amlodipine; StJohn’s wort reduces plasma concentration of nifedipine;St John’s wort significantly reduces plasmaconcentration of .verapamil. Cardiac Glycosides: St John’s wort reduces plasmaconcentration of .digoxin—avoid concomitant use. Ciclosporin: St John’s wort reduces plasma concentrationof .ciclosporin—avoid concomitant use. Cytotoxics: St John’s wort possibly reduces plasmaconcentration of everolimus and .vinflunine—manufacturerof everolimus and vinflunine advises avoidconcomitant use; avoidance of St John’s wort advisedby manufacturer of gefitinib and .lapatinib; St John’swort reduces plasma concentration of .imatinib—avoid concomitant use; St John’s wort acceleratesmetabolism of .irinotecan (reduced plasma concentration—avoidconcomitant use). Diuretics: St John’s wort reduces plasma concentrationof .eplerenone—avoid concomitant use. 5HT 1 Agonists: increased serotonergic effects when StJohn’s wort given with .5HT 1 agonists—avoid concomitantuseIvabradine: St John’s wort reduces plasma concentrationof ivabradine—avoid concomitant useLipid-regulating Drugs: St John’s wort reduces plasmaconcentration of simvastatin. Oestrogens: St John’s wort reduces contraceptiveeffect of .oestrogens (avoid concomitant use). Progestogens: St John’s wort reduces contraceptiveeffect of .progestogens (avoid concomitant use). Tacrolimus: St John’s wort reduces plasma concentrationof .tacrolimus—avoid concomitant use. Theophylline: St John’s wort reduces plasma concentrationof .theophylline—avoid concomitant useUlcer-healing Drugs: St John’s wort possibly reducesplasma concentration of omeprazoleSt John’s Wort (continued). Ulipristal: avoidance of St John’s wort advised bymanufacturer of .ulipristal (contraceptive effect ofulipristal possibly reduced)Salbutamol see Sympathomimetics, Beta 2Salmeterol see Sympathomimetics, Beta 2Saquinavir. Analgesics: increased risk of ventricular arrhythmiaswhen saquinavir given with .alfentanil, .fentanyl or.methadone—avoid concomitant use. Anti-arrhythmics: increased risk of ventricular arrhythmiaswhen saquinavir given with .amiodarone,.disopyramide, .dronedarone, .flecainide,.lidocaine or .propafenone—avoid concomitant use. Antibacterials: increased risk of ventricular arrhythmiaswhen saquinavir given with .clarithromycin,.dapsone or .erythromycin—avoid concomitant use;saquinavir increases plasma concentration of.rifabutin (also plasma concentration of saquinavirreduced); plasma concentration of saquinavir significantlyreduced by .rifampicin, also risk of hepatotoxicity—avoidconcomitant use; avoidance ofconcomitant saquinavir in severe renal and hepaticimpairment advised by manufacturer of.telithromycinAnticoagulants: saquinavir possibly enhances anticoagulanteffect of warfarin; avoidance of saquinaviradvised by manufacturer of rivaroxaban. Antidepressants: increased risk of ventricular arrhythmiaswhen saquinavir given with .trazodone or.tricyclics—avoid concomitant use; plasma concentrationof saquinavir reduced by .St John’s wort—avoid concomitant use. Antiepileptics: plasma concentration of saquinavirpossibly reduced by carbamazepine,.phenobarbital and phenytoinAntifungals: plasma concentration of saquinavirincreased by ketoconazole; plasma concentration ofsaquinavir possibly increased by imidazoles andtriazoles. Antihistamines: increased risk of ventricular arrhythmiaswhen saquinavir given with .mizolastine—avoidconcomitant use. Antimalarials: caution with saquinavir advised bymanufacturer of artemether/lumefantrine; increasedrisk of ventricular arrhythmias when saquinavir givenwith .quinine—avoid concomitant useAntimuscarinics: avoidance of saquinavir advised bymanufacturer of darifenacin and tolterodine; manufacturerof fesoterodine advises dose reduction whensaquinavir given with fesoterodine—consult fesoterodineproduct literature. Antipsychotics: increased risk of ventricular arrhythmiaswhen saquinavir given with .clozapine,.haloperidol or .phenothiazines—avoid concomitantuse; saquinavir possibly inhibits metabolism of.aripiprazole (reduce dose of aripiprazole); saquinavirpossibly increases plasma concentration of.pimozide (increased risk of ventricular arrhythmias—avoidconcomitant use). Antivirals: increased risk of ventricular arrhythmiaswhen saquinavir given with .atazanavir or.lopinavir—avoid concomitant use; saquinavirreduces plasma concentration of darunavir; plasmaconcentration of saquinavir significantly reduced byefavirenz; plasma concentration of saquinavirincreased by indinavir and .ritonavir; saquinavirincreases plasma concentration of .maraviroc (considerreducing dose of maraviroc); plasma concentrationof saquinavir increased by .nelfinavir—manufacturer of saquinavir advises avoid concomitantuse; plasma concentration of saquinavir reducedby .tipranavir. Anxiolytics and Hypnotics: saquinavir increasesplasma concentration of .midazolam (risk of prolongedsedation—avoid concomitant use of oralmidazolam)Appendix 1: Interactions

730 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsSaquinavir (continued). Beta-blockers: increased risk of ventricular arrhythmiaswhen saquinavir given with .sotalol—avoidconcomitant use. Ciclosporin: plasma concentration of both drugsincreased when saquinavir given with .ciclosporinCorticosteroids: plasma concentration of saquinavirpossibly reduced by dexamethasone. Cytotoxics: saquinavir possibly increases plasma concentrationof .everolimus—manufacturer of everolimusadvises avoid concomitant use; avoidance ofsaquinavir advised by manufacturer of .lapatinib and.pazopanibDiuretics: saquinavir increases plasma concentration ofeplerenone (reduce dose of eplerenone). Ergot Alkaloids: increased risk of ergotism whensaquinavir given with .ergotamine and methysergide—avoidconcomitant use. Lipid-regulating Drugs: possible increased risk ofmyopathy when saquinavir given with atorvastatin;possible increased risk of myopathy when saquinavirgiven with .rosuvastatin—manufacturer of rosuvastatinadvises avoid concomitant use; increased risk ofmyopathy when saquinavir given with .simvastatin(avoid concomitant use). Pentamidine Isetionate: increased risk of ventriculararrhythmias when saquinavir given with .pentamidineisetionate—avoid concomitant use. Ranolazine: saquinavir possibly increases plasmaconcentration of .ranolazine—manufacturer ofranolazine advises avoid concomitant use. Sildenafil: increased risk of ventricular arrhythmiaswhen saquinavir given with .sildenafil—avoid concomitantuse. Tacrolimus: saquinavir increases plasma concentrationof .tacrolimus (consider reducing dose of tacrolimus). Tadalafil: increased risk of ventricular arrhythmiaswhen saquinavir given with .tadalafil—avoid concomitantuse. Ulcer-healing Drugs: plasma concentration of saquinavirpossibly increased by cimetidine; plasmaconcentration of saquinavir possibly increased by.esomeprazole, .lansoprazole, .pantoprazole and.rabeprazole—manufacturer of saquinavir advisesavoid concomitant use; plasma concentration ofsaquinavir increased by .omeprazole—manufacturerof saquinavir advises avoid concomitant use. Vardenafil: increased risk of ventricular arrhythmiaswhen saquinavir given with .vardenafil—avoid concomitantuseSaxagliptin see AntidiabeticsSelegilineNote Selegiline is a MAO-B inhibitor. Analgesics: hyperpyrexia and CNS toxicity reportedwhen selegiline given with .pethidine (avoid concomitantuse); manufacturer of selegiline advisesavoid concomitant use with opioid analgesics. Antidepressants: manufacturer of selegiline advisesavoid concomitant use with citalopram and escitalopram;increased risk of hypertension and CNSexcitation when selegiline given with .fluoxetine(selegiline should not be started until 5 weeks afterstopping fluoxetine, avoid fluoxetine for 2 weeks afterstopping selegiline); increased risk of hypertensionand CNS excitation when selegiline given with.fluvoxamine, .sertraline or .venlafaxine (selegilineshould not be started until 1 week after stoppingfluvoxamine, sertraline or venlafaxine, avoid fluvoxamine,sertraline or venlafaxine for 2 weeks afterstopping selegiline); increased risk of hypertensionand CNS excitation when selegiline given with.paroxetine (selegiline should not be started until 2weeks after stopping paroxetine, avoid paroxetine for2 weeks after stopping selegiline); enhanced hypotensiveeffect when selegiline given with .MAOIs—manufacturer of selegiline advises avoid concomitantuse; avoid concomitant use of selegiline with.moclobemide; CNS toxicity reported when selegilinegiven with .tricyclicsSelegiline (continued)Dopaminergics: max. dose of 10 mg selegiline advisedby manufacturer of entacapone if used concomitantly;selegiline enhances effects and increasestoxicity of levodopa (reduce dose of levodopa)5HT 1 Agonists: manufacturer of selegiline advisesavoid concomitant use with 5HT 1 agonistsMemantine: effects of dopaminergics and selegilinepossibly enhanced by memantineMethyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopa. Oestrogens: plasma concentration of selegilineincreased by .oestrogens—manufacturer of selegilineadvises avoid concomitant use. Progestogens: plasma concentration of selegilineincreased by .progestogens—manufacturer of selegilineadvises avoid concomitant use. Sympathomimetics: risk of hypertensive crisis whenselegiline given with .dopamineSeleniumEltrombopag: selenium possibly reduces absorption ofeltrombopag (give at least 4 hours apart)Vitamins: absorption of selenium possibly reduced byascorbic acid (give at least 4 hours apart)Sertraline see Antidepressants, SSRISevelamerAntibacterials: sevelamer reduces bioavailability ofciprofloxacinCiclosporin: sevelamer possibly reduces plasma concentrationof ciclosporinMycophenolate: sevelamer possibly reduces plasmaconcentration of mycophenolateTacrolimus: sevelamer possibly reduces plasma concentrationof tacrolimusThyroid Hormones: sevelamer possibly reducesabsorption of levothyroxineSevoflurane see Anaesthetics, GeneralSildenafil. Alpha-blockers: enhanced hypotensive effect whensildenafil given with .alpha-blockers (avoid alphablockersfor 4 hours after sildenafil)—see also underPhosphodiesterase type-5 inhibitors, BNF section7.4.5Antibacterials: plasma concentration of sildenafilpossibly increased by clarithromycin and telithromycin—reduceinitial dose of sildenafil; plasma concentrationof sildenafil increased by erythromycin—reduce initial dose of sildenafilAntifungals: plasma concentration of sildenafilincreased by itraconazole and ketoconazole—reduceinitial dose of sildenafil. Antivirals: side-effects of sildenafil possibly increasedby .atazanavir; plasma concentration of sildenafilreduced by etravirine; plasma concentration ofsildenafil possibly increased by fosamprenavir;plasma concentration of sildenafil increased by.indinavir—reduce initial dose of sildenafil; plasmaconcentration of sildenafil possibly increased bynelfinavir—reduce initial dose of sildenafil; plasmaconcentration of sildenafil significantly increased by.ritonavir—avoid concomitant use; increased risk ofventricular arrhythmias when sildenafil given with.saquinavir—avoid concomitant useBosentan: plasma concentration of sildenafil reducedby bosentanCalcium-channel Blockers: enhanced hypotensiveeffect when sildenafil given with amlodipineGrapefruit Juice: plasma concentration of sildenafilpossibly increased by grapefruit juice. Nicorandil: sildenafil significantly enhances hypotensiveeffect of .nicorandil (avoid concomitant use). Nitrates: sildenafil significantly enhances hypotensiveeffect of .nitrates (avoid concomitant use)Ulcer-healing Drugs: plasma concentration of sildenafilincreased by cimetidine (consider reducing dose ofsildenafil)Simvastatin see Statins

BNFC 2011–2012 Appendix 1: Interactions 731SirolimusAnti-arrhythmics: caution with sirolimus advised bymanufacturer of dronedarone. Antibacterials: plasma concentration of sirolimusincreased by .clarithromycin and .telithromycin—avoid concomitant use; plasma concentration of bothdrugs increased when sirolimus given with.erythromycin; plasma concentration of sirolimusreduced by .rifabutin and .rifampicin—avoid concomitantuse. Antifungals: plasma concentration of sirolimusincreased by .itraconazole, .ketoconazole and.voriconazole—avoid concomitant use; plasma concentrationof sirolimus increased by micafungin and.miconazole; plasma concentration of sirolimuspossibly increased by posaconazole. Antivirals: plasma concentration of sirolimus possiblyincreased by .atazanavir and lopinavir. Calcium-channel Blockers: plasma concentration ofsirolimus increased by .diltiazem; plasma concentrationof both drugs increased when sirolimus givenwith .verapamilCiclosporin: plasma concentration of sirolimusincreased by ciclosporin. Grapefruit Juice: plasma concentration of sirolimusincreased by .grapefruit juice—avoid concomitantuseSitagliptin see AntidiabeticsSitaxentan. Anticoagulants: sitaxentan enhances anticoagulanteffect of .coumarins. Ciclosporin: plasma concentration of sitaxentanincreased by .ciclosporin—avoid concomitant useOestrogens: sitaxentan increases plasma concentrationof oestrogensProgestogens: sitaxentan increases plasma concentrationof progestogensSodium Aurothiomalate. ACE Inhibitors: flushing and hypotension reportedwhen sodium aurothiomalate given with .ACE inhibitorsPenicillamine: avoidance of sodium aurothiomalateadvised by manufacturer of penicillamine (increasedrisk of toxicity)Sodium BenzoateAntiepileptics: effects of sodium benzoate possiblyreduced by valproateAntipsychotics: effects of sodium benzoate possiblyreduced by haloperidolCorticosteroids: effects of sodium benzoate possiblyreduced by corticosteroidsProbenecid: excretion of conjugate formed by sodiumbenzoate possibly reduced by probenecidSodium Bicarbonate see AntacidsSodium CitrateAntibacterials: avoid concomitant use of sodiumcitrate with methenamineSodium Clodronate see BisphosphonatesSodium Nitroprusside see Vasodilator AntihypertensivesSodium Oxybate. Analgesics: effects of sodium oxybate enhanced by.opioid analgesics (avoid concomitant use)Antidepressants: increased risk of side-effects whensodium oxybate given with tricyclicsAntiepileptics: manufacturer of sodium oxybateadvises avoid concomitant use with phenobarbitalAntipsychotics: effects of sodium oxybate possiblyenhanced by antipsychotics. Anxiolytics and Hypnotics: effects of sodium oxybateenhanced by .benzodiazepines (avoid concomitantuse)Sodium PhenylbutyrateAntiepileptics: effects of sodium phenylbutyrate possiblyreduced by valproateAntipsychotics: effects of sodium phenylbutyratepossibly reduced by haloperidolSodium Phenylbutyrate (continued)Corticosteroids: effects of sodium phenylbutyratepossibly reduced by corticosteroidsProbenecid: excretion of conjugate formed by sodiumphenylbutyrate possibly reduced by probenecidSodium Valproate see ValproateSolifenacin see AntimuscarinicsSomatropinCorticosteroids: growth-promoting effect of somatropinmay be inhibited by corticosteroidsOestrogens: increased doses of somatropin may beneeded when given with oestrogens (when used asoral replacement therapy)SorafenibAntibacterials: bioavailability of sorafenib reduced byneomycin; plasma concentration of sorafenibreduced by rifampicin. Anticoagulants: sorafenib possibly enhances anticoagulanteffect of .coumarins. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cytotoxics: sorafenib possibly increases plasma concentrationof doxorubicin and irinotecan; sorafenibincreases plasma concentration of docetaxelSotalol see Beta-blockersSpironolactone see DiureticsStatinsAntacids: absorption of rosuvastatin reduced byantacids. Anti-arrhythmics: increased risk of myopathy whensimvastatin given with .amiodarone or .dronedarone. Antibacterials: plasma concentration ofatorvastatin and pravastatin increased by.clarithromycin; increased risk of myopathy whensimvastatin given with .clarithromycin,.erythromycin or .telithromycin (avoid concomitantuse); plasma concentration of rosuvastatin reducedby erythromycin; possible increased risk of myopathywhen atorvastatin given with erythromycin or fusidicacid; plasma concentration of pravastatin increasedby erythromycin; plasma concentration ofatorvastatin and simvastatin possibly reduced byrifampicin; metabolism of fluvastatin accelerated byrifampicin (reduced effect); increased risk of myopathywhen statins given with .daptomycin (preferablyavoid concomitant use); increased risk ofmyopathy when simvastatin given with .fusidic acid;increased risk of myopathy when atorvastatin givenwith .telithromycin (avoid concomitant use); possibleincreased risk of myopathy when pravastatin givenwith telithromycin. Anticoagulants: atorvastatin may transiently reduceanticoagulant effect of warfarin; rosuvastatin possiblyenhances anticoagulant effect of .coumarins and.phenindione; fluvastatin and simvastatin enhanceanticoagulant effect of .coumarinsAntidepressants: plasma concentration of simvastatinreduced by St John’s wortAntidiabetics: fluvastatin possibly increases plasmaconcentration of glibenclamide. Antiepileptics: plasma concentration of simvastatinreduced by .carbamazepine—consider increasingdose of simvastatin; combination of fluvastatin withphenytoin may increase plasma concentration ofeither drug (or both). Antifungals: increased risk of myopathy when simvastatingiven with .itraconazole, .ketoconazole or.posaconazole (avoid concomitant use); possibleincreased risk of myopathy when simvastatin givenwith .fluconazole or .miconazole—avoid concomitantuse; plasma concentration of fluvastatinincreased by fluconazole; increased risk of myopathywhen atorvastatin given with .itraconazole or.posaconazole (avoid concomitant use); possibleincreased risk of myopathy when simvastatin givenwith voriconazole; possible increased risk of myopathywhen atorvastatin given with imidazoles ortriazolesAppendix 1: Interactions

732 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsStatins (continued). Antivirals: possible increased risk of myopathy whenatorvastatin given with atazanavir, fosamprenavir,indinavir, lopinavir, nelfinavir, ritonavir or saquinavir;possible increased risk of myopathy when rosuvastatingiven with .atazanavir, .darunavir,.fosamprenavir, .indinavir, .lopinavir, .nelfinavir,.ritonavir and .saquinavir—manufacturer of rosuvastatinadvises avoid concomitant use; increasedrisk of myopathy when simvastatin given with.atazanavir, .indinavir, .nelfinavir, .ritonavir or.saquinavir (avoid concomitant use); plasma concentrationof pravastatin possibly increased bydarunavir; plasma concentration of atorvastatin,pravastatin and simvastatin reduced by efavirenz;plasma concentration of atorvastatin possiblyreduced by etravirine; possible increased risk ofmyopathy when simvastatin given with.fosamprenavir or .lopinavir—avoid concomitantuse; plasma concentration of rosuvastatin possiblyincreased by .tipranavir—manufacturer of rosuvastatinadvises avoid concomitant use; plasma concentrationof simvastatin possibly increased by.tipranavir—avoid concomitant use; plasma concentrationof atorvastatin possibly increased by.tipranavir (consider reducing dose of atorvastatin)Bosentan: plasma concentration of simvastatinreduced by bosentan. Calcium-channel Blockers: possible increased risk ofmyopathy when simvastatin given with amlodipine;plasma concentration of atorvastatin and simvastatinincreased by diltiazem—possible increased risk ofmyopathy; increased risk of myopathy when simvastatingiven with .verapamilCardiac Glycosides: atorvastatin possibly increasesplasma concentration of digoxin. Ciclosporin: increased risk of myopathy when statinsgiven with .ciclosporin; increased risk of myopathywhen rosuvastatin given with .ciclosporin (avoidconcomitant use). Colchicine: possible increased risk of myopathy whenstatins given with .colchicineCytotoxics: plasma concentration of simvastatin possiblyincreased by dasatinib; plasma concentration ofsimvastatin increased by imatinib. Eltrombopag: plasma concentration of rosuvastatinincreased by .eltrombopag (consider reducing doseof rosuvastatin). Grapefruit Juice: plasma concentration of atorvastatinpossibly increased by grapefruit juice; plasma concentrationof simvastatin increased by .grapefruitjuice—avoid concomitant use. Hormone Antagonists: possible increased risk ofmyopathy when simvastatin given with .danazol. Lipid-regulating Drugs: increased risk of myopathywhen statins given with .gemfibrozil (preferablyavoid concomitant use); increased risk of myopathywhen statins given with .fibrates; increased risk ofmyopathy when statins given with .nicotinic acid(applies to lipid regulating doses of nicotinic acid)Oestrogens: atorvastatin and rosuvastatin increaseplasma concentration of ethinylestradiolProgestogens: atorvastatin increases plasma concentrationof norethisterone; rosuvastatin increasesplasma concentration of active metabolite of norgestimate;rosuvastatin increases plasma concentrationof norgestrelRanolazine: plasma concentration of simvastatinincreased by ranolazine (consider reducing dose ofsimvastatin)Retinoids: plasma concentration of simvastatinreduced by alitretinoinStavudine. Antivirals: increased risk of side-effects when stavudinegiven with .didanosine; increased risk of toxicitywhen stavudine given with .ribavirin; effects ofstavudine possibly inhibited by .zidovudine (manufacturersadvise avoid concomitant use)Stavudine (continued). Cytotoxics: effects of stavudine possibly inhibited bydoxorubicin; increased risk of toxicity when stavudinegiven with .hydroxycarbamide—avoid concomitantuseStiripentol. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wort. Antiepileptics: stiripentol increases plasma concentrationof .carbamazepine, .phenobarbital and.phenytoin. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered)Anxiolytics and Hypnotics: stiripentol increasesplasma concentration of clobazam. Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistatStreptomycin see AminoglycosidesStrontium RanelateAntibacterials: strontium ranelate reduces absorptionof quinolones and tetracyclines (manufacturer ofstrontium ranelate advises avoid concomitant use)SucralfateAntibacterials: sucralfate reduces absorption of ciprofloxacin,levofloxacin, moxifloxacin, norfloxacin,ofloxacin and tetracyclines. Anticoagulants: sucralfate possibly reduces absorptionof .coumarins (reduced anticoagulant effect). Antiepileptics: sucralfate reduces absorption of.phenytoinAntifungals: sucralfate reduces absorption of ketoconazoleAntipsychotics: sucralfate reduces absorption of sulpirideCardiac Glycosides: sucralfate possibly reducesabsorption of cardiac glycosidesTheophylline: sucralfate possibly reduces absorption oftheophylline (give at least 2 hours apart)Thyroid Hormones: sucralfate reduces absorption oflevothyroxineUlcer-healing Drugs: sucralfate possibly reducesabsorption of lansoprazoleSugammadexAntibacterials: response to sugammadex possiblyreduced by fusidic acidProgestogens: sugammadex possibly reduces plasmaconcentration of progestogens—manufacturer ofsugammadex advises additional contraceptive precautionsSulfadiazine see SulfonamidesSulfadoxine see SulfonamidesSulfamethoxazole see SulfonamidesSulfasalazine see AminosalicylatesSulfinpyrazoneAnalgesics: effects of sulfinpyrazone antagonised byaspirinAntibacterials: sulfinpyrazone reduces excretion ofnitrofurantoin (increased risk of toxicity); sulfinpyrazonereduces excretion of penicillins; effects ofsulfinpyrazone antagonised by pyrazinamide. Anticoagulants: sulfinpyrazone enhances anticoagulanteffect of .coumarins. Antidiabetics: sulfinpyrazone enhances effects of.sulfonylureas. Antiepileptics: sulfinpyrazone increases plasma concentrationof .phenytoinCalcium-channel Blockers: sulfinpyrazone reducesplasma concentration of verapamil

BNFC 2011–2012 Appendix 1: Interactions 733Sulfinpyrazone (continued). Ciclosporin: sulfinpyrazone reduces plasma concentrationof .ciclosporinTheophylline: sulfinpyrazone reduces plasma concentrationof theophyllineSulfonamidesAnaesthetics, General: sulfonamides enhance effectsof thiopentalAnaesthetics, Local: increased risk of methaemoglobinaemiawhen sulfonamides given with prilocaineAnti-arrhythmics: possible increased risk of ventriculararrhythmias when sulfamethoxazole (as co-trimoxazole)given with amiodarone—manufacturer ofamiodarone advises avoid concomitant use of cotrimoxazole. Antibacterials: increased risk of crystalluria whensulfonamides given with .methenamine. Anticoagulants: sulfonamides enhance anticoagulanteffect of .coumarins; sulfonamides possibly inhibitmetabolism of phenindioneAntidiabetics: sulfonamides rarely enhance the effectsof sulfonylureasAntiepileptics: sulfonamides possibly increase plasmaconcentration of phenytoin. Antimalarials: increased antifolate effect when sulfonamidesgiven with .pyrimethamine. Antipsychotics: avoid concomitant use of sulfonamideswith .clozapine (increased risk of agranulocytosis). Azathioprine: increased risk of haematological toxicitywhen sulfamethoxazole (as co-trimoxazole) givenwith .azathioprine. Ciclosporin: increased risk of nephrotoxicity whensulfonamides given with .ciclosporin; sulfadiazinepossibly reduces plasma concentration of.ciclosporin. Cytotoxics: increased risk of haematological toxicitywhen sulfamethoxazole (as co-trimoxazole) givenwith .mercaptopurine or .methotrexate; sulfonamidesincrease risk of methotrexate toxicityPotassium Aminobenzoate: effects of sulfonamidesinhibited by potassium aminobenzoateVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Sulfonylureas see AntidiabeticsSulindac see NSAIDsSulpiride see AntipsychoticsSumatriptan see 5HT 1 AgonistsSunitinibAntibacterials: metabolism of sunitinib accelerated byrifampicin (reduced plasma concentration)Antifungals: metabolism of sunitinib inhibited byketoconazole (increased plasma concentration). Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Suxamethonium see Muscle RelaxantsSympathomimetics. Adrenergic Neurone Blockers: ephedrine, isometheptene,metaraminol, methylphenidate, noradrenaline(norepinephrine), oxymetazoline,phenylephrine, pseudoephedrine and xylometazolineantagonise hypotensive effect of .adrenergic neuroneblockers; dexamfetamine antagonises hypotensiveeffect of .guanethidineAlcohol: effects of methylphenidate possibly enhancedby alcohol. Alpha-blockers: avoid concomitant use of adrenaline(epinephrine) or dopamine with .tolazoline. Anaesthetics, General: increased risk of arrhythmiaswhen adrenaline (epinephrine) given with .volatileliquid general anaesthetics; increased risk of hypertensionwhen methylphenidate given with .volatileliquid general anaesthetics. Anticoagulants: methylphenidate possibly enhancesanticoagulant effect of .coumarins. Antidepressants: risk of hypertensive crisis whenmethylphenidate given with .MAOIs, some manufacturersadvise avoid methylphenidate for at least 2weeks after stopping MAOIs; risk of hypertensiveSympathomimetics. Antidepressants (continued)crisis when sympathomimetics given with.MAOIs or .moclobemide; methylphenidatepossibly inhibits metabolism of SSRIs and tricyclics;increased risk of hypertension andarrhythmias when adrenaline (epinephrine) givenwith .tricyclics (but local anaesthetics with adrenalineappear to be safe); increased risk ofhypertension and arrhythmias when noradrenaline(norepinephrine) given with .tricyclicsAntiepileptics: methylphenidate possibly increasesplasma concentration of phenobarbital; methylphenidateincreases plasma concentration of phenytoinAntipsychotics: hypertensive effect of sympathomimeticsantagonised by antipsychotics; dexamfetaminepossibly antagonises antipsychotic effects ofchlorpromazine; methylphenidate possibly increasesside-effects of risperidoneAntivirals: plasma concentration of dexamfetaminepossibly increased by ritonavir. Beta-blockers: increased risk of severe hypertensionand bradycardia when adrenaline (epinephrine) givenwith non-cardioselective .beta-blockers, alsoresponse to adrenaline (epinephrine) may bereduced; increased risk of severe hypertension andbradycardia when dobutamine given with noncardioselective.beta-blockers; possible increasedrisk of severe hypertension and bradycardia whennoradrenaline (norepinephrine) given with non-cardioselective.beta-blockers. Clonidine: possible risk of hypertension when adrenaline(epinephrine) or noradrenaline (norepinephrine)given with clonidine; serious adverse events reportedwith concomitant use of methylphenidate and.clonidine (causality not established)Corticosteroids: ephedrine accelerates metabolism ofdexamethasone. Dopaminergics: risk of toxicity when isometheptenegiven with .bromocriptine; effects of adrenaline(epinephrine), dobutamine, dopamine and noradrenaline(norepinephrine) possibly enhanced by entacapone;avoid concomitant use of sympathomimeticswith .rasagiline; risk of hypertensive crisis whendopamine given with .selegilineDoxapram: increased risk of hypertension whensympathomimetics given with doxapramErgot Alkaloids: increased risk of ergotism whensympathomimetics given with ergotamine andmethysergideOxytocin: risk of hypertension when vasoconstrictorsympathomimetics given with oxytocin (due toenhanced vasopressor effect). Sympathomimetics: effects of adrenaline (epinephrine)possibly enhanced by .dopexamine; dopexaminepossibly enhances effects of .noradrenaline (norepinephrine)Theophylline: avoidance of ephedrine in childrenadvised by manufacturer of theophyllineSympathomimetics, Beta 2Antifungals: metabolism of salmeterol inhibited byketoconazole (increased plasma concentration)Atomoxetine: Increased risk of cardiovascular sideeffectswhen parenteral salbutamol given withatomoxetineCardiac Glycosides: salbutamol possibly reducesplasma concentration of digoxinCorticosteroids: increased risk of hypokalaemia whenhigh doses of beta 2 sympathomimetics given withcorticosteroids—see Hypokalaemia, p. 138Diuretics: increased risk of hypokalaemia when highdoses of beta 2 sympathomimetics given with acetazolamide,loop diuretics or thiazides and relateddiuretics—see Hypokalaemia, p. 138. Methyldopa: acute hypotension reported when infusionof salbutamol given with .methyldopaMuscle Relaxants: bambuterol enhances effects ofsuxamethoniumAppendix 1: Interactions

734 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsSympathomimetics, Beta 2 (continued)Theophylline: increased risk of hypokalaemia whenhigh doses of beta 2 sympathomimetics given withtheophylline—see Hypokalaemia, p. 138TacrolimusNote Interactions do not generally apply to tacrolimus usedtopically; risk of facial flushing and skin irritation withalcohol consumption (p. 573) does not apply to tacrolimustaken systemically. Analgesics: possible increased risk of nephrotoxicitywhen tacrolimus given with NSAIDs; increased risk ofnephrotoxicity when tacrolimus given with.ibuprofenAngiotensin-II Receptor Antagonists: increased risk ofhyperkalaemia when tacrolimus given with angiotensin-IIreceptor antagonistsAnti-arrhythmics: caution with tacrolimus advised bymanufacturer of dronedarone. Antibacterials: plasma concentration of tacrolimusincreased by .clarithromycin and .erythromycin;plasma concentration of tacrolimus possibly reducedby rifabutin; plasma concentration of tacrolimusreduced by .rifampicin; increased risk of nephrotoxicitywhen tacrolimus given with.aminoglycosides; plasma concentration of tacrolimuspossibly increased by .chloramphenicol and.telithromycin; possible increased risk of nephrotoxicitywhen tacrolimus given with vancomycin. Antidepressants: plasma concentration of tacrolimusreduced by .St John’s wort—avoid concomitant use. Antiepileptics: plasma concentration of tacrolimusreduced by .phenobarbital; plasma concentration oftacrolimus reduced by phenytoin, also plasma concentrationof phenytoin possibly increased. Antifungals: plasma concentration of tacrolimusincreased by .fluconazole, .itraconazole,.ketoconazole, .posaconazole and .voriconazole(consider reducing dose of tacrolimus); increased riskof nephrotoxicity when tacrolimus given with.amphotericin; plasma concentration of tacrolimusreduced by .caspofungin; plasma concentration oftacrolimus possibly increased by .imidazoles. Antipsychotics: avoidance of tacrolimus advised bymanufacturer of .droperidol (risk of ventriculararrhythmias). Antivirals: possible increased risk of nephrotoxicitywhen tacrolimus given with aciclovir or ganciclovir;plasma concentration of tacrolimus possiblyincreased by .atazanavir, .nelfinavir and .ritonavir;plasma concentration of tacrolimus possibly affectedby .efavirenz; plasma concentration of tacrolimusincreased by .fosamprenavir; plasma concentrationof tacrolimus increased by .saquinavir (considerreducing dose of tacrolimus). Calcium-channel Blockers: plasma concentration oftacrolimus possibly increased by felodipine,nicardipine and verapamil; plasma concentration oftacrolimus increased by .diltiazem and .nifedipine. Ciclosporin: tacrolimus increases plasma concentrationof .ciclosporin (increased risk of nephrotoxicity)—avoid concomitant use. Diuretics: increased risk of hyperkalaemia whentacrolimus given with .potassium-sparing diureticsand aldosterone antagonists. Grapefruit Juice: plasma concentration of tacrolimusincreased by .grapefruit juiceHormone Antagonists: plasma concentration oftacrolimus possibly increased by danazolMifamurtide: avoidance of tacrolimus advised bymanufacturer of mifamurtideOestrogens: plasma concentration of tacrolimus possiblyincreased by ethinylestradiol. Potassium Salts: increased risk of hyperkalaemiawhen tacrolimus given with .potassium saltsSevelamer: plasma concentration of tacrolimus possiblyreduced by sevelamerUlcer-healing Drugs: plasma concentration of tacrolimuspossibly increased by omeprazoleTadalafil. Alpha-blockers: enhanced hypotensive effect whentadalafil given with .doxazosin—manufacturer oftadalafil advises avoid concomitant use; enhancedhypotensive effect when tadalafil given with .alphablockers—seealso under Phosphodiesterase type-5inhibitors, BNF section 7.4.5. Antibacterials: plasma concentration of tadalafil possiblyincreased by clarithromycin and erythromycin;plasma concentration of tadalafil reduced by.rifampicin—manufacturer of tadalafil advises avoidconcomitant use. Antifungals: plasma concentration of tadalafilincreased by .ketoconazole—manufacturer of tadalafiladvises avoid concomitant use; plasma concentrationof tadalafil possibly increased by itraconazole. Antivirals: plasma concentration of tadalafil possiblyincreased by fosamprenavir and indinavir; plasmaconcentration of tadalafil increased by .ritonavir—manufacturer of tadalafil advises avoid concomitantuse; increased risk of ventricular arrhythmias whentadalafil given with .saquinavir—avoid concomitantuseBosentan: plasma concentration of tadalafil reducedby bosentanGrapefruit Juice: plasma concentration of tadalafilpossibly increased by grapefruit juice. Nicorandil: tadalafil significantly enhances hypotensiveeffect of .nicorandil (avoid concomitant use). Nitrates: tadalafil significantly enhances hypotensiveeffect of .nitrates (avoid concomitant use)TamoxifenAntibacterials: metabolism of tamoxifen acceleratedby rifampicin (reduced plasma concentration). Anticoagulants: tamoxifen enhances anticoagulanteffect of .coumarins. Antidepressants: metabolism of tamoxifen to activemetabolite possibly inhibited by .fluoxetine and.paroxetine (avoid concomitant use). Antipsychotics: avoidance of tamoxifen advised bymanufacturer of .droperidol (risk of ventriculararrhythmias). Bupropion: metabolism of tamoxifen to active metabolitepossibly inhibited by .bupropion (avoid concomitantuse). Cinacalcet: metabolism of tamoxifen to active metabolitepossibly inhibited by .cinacalcet (avoid concomitantuse)Tamsulosin see Alpha-blockersTaxanes see Docetaxel and PaclitaxelTegafur with uracil see FluorouracilTeicoplaninVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Telbivudine. Interferons: increased risk of peripheral neuropathywhen telbivudine given with .interferon alfaTelithromycinAnalgesics: telithromycin inhibits the metabolism ofoxycodone. Anti-arrhythmics: avoidance of telithromycin advisedby manufacturer of .dronedarone (risk of ventriculararrhythmias). Antibacterials: plasma concentration of telithromycinreduced by .rifampicin (avoid during and for 2 weeksafter rifampicin). Antidepressants: plasma concentration of telithromycinreduced by .St John’s wort (avoid during and for2 weeks after St John’s wort). Antiepileptics: plasma concentration of telithromycinreduced by .carbamazepine, .phenobarbital and.phenytoin (avoid during and for 2 weeks aftercarbamazepine, phenobarbital and phenytoin). Antifungals: manufacturer of telithromycin advisesavoid concomitant use with .ketoconazole in severerenal and hepatic impairment

BNFC 2011–2012 Appendix 1: Interactions 735Telithromycin (continued)Antimuscarinics: manufacturer of fesoterodine advisesdose reduction when telithromycin given withfesoterodine—consult fesoterodine product literature. Antipsychotics: increased risk of ventricular arrhythmiaswhen telithromycin given with .pimozide—avoid concomitant use. Antivirals: manufacturer of telithromycin advises avoidconcomitant use with .atazanavir, .fosamprenavir,.indinavir, .lopinavir, .nelfinavir, .ritonavir,.saquinavir and .tipranavir in severe renal andhepatic impairment; telithromycin possibly increasesplasma concentration of .maraviroc (consider reducingdose of maraviroc). Anxiolytics and Hypnotics: telithromycin inhibitsmetabolism of .midazolam (increased plasma concentrationwith increased sedation)Aprepitant: telithromycin possibly increases plasmaconcentration of aprepitantCardiac Glycosides: telithromycin possibly increasesplasma concentration of digoxin. Ciclosporin: telithromycin possibly increases plasmaconcentration of .ciclosporin. Colchicine: telithromycin possibly increases risk of.colchicine toxicity—suspend or reduce dose ofcolchicine (avoid concomitant use in hepatic or renalimpairment). Cytotoxics: telithromycin possibly increases plasmaconcentration of .everolimus—manufacturer ofeverolimus advises avoid concomitant use; avoidanceof telithromycin advised by manufacturer of.lapatinib, .nilotinib and .pazopanib. Diuretics: telithromycin increases plasma concentrationof .eplerenone—avoid concomitant use. Ergot Alkaloids: increased risk of ergotism whentelithromycin given with .ergotamine and methysergide—avoidconcomitant use. Ivabradine: telithromycin possibly increases plasmaconcentration of .ivabradine—avoid concomitantuse. Lipid-regulating Drugs: increased risk of myopathywhen telithromycin given with .atorvastatin or.simvastatin (avoid concomitant use); possibleincreased risk of myopathy when telithromycin givenwith pravastatin. Ranolazine: telithromycin possibly increases plasmaconcentration of .ranolazine—manufacturer ofranolazine advises avoid concomitant useSildenafil: telithromycin possibly increases plasmaconcentration of sildenafil—reduce initial dose ofsildenafil. Sirolimus: telithromycin increases plasma concentrationof .sirolimus—avoid concomitant use. Tacrolimus: telithromycin possibly increases plasmaconcentration of .tacrolimusVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Telmisartan see Angiotensin-II Receptor AntagonistsTemazepam see Anxiolytics and HypnoticsTemocillin see PenicillinsTemoporfin. Cytotoxics: increased skin photosensitivity whentemoporfin given with topical .fluorouracilTemozolomideAntiepileptics: plasma concentration of temozolomideincreased by valproate. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)TemsirolimusNote The main active metabolite of temsirolimus is sirolimus—seealso interactions of sirolimus and consult productliterature. Antibacterials: plasma concentration of active metaboliteof temsirolimus reduced by .rifampicin—avoidconcomitant use. Antifungals: plasma concentration of active metaboliteof temsirolimus increased by .ketoconazole—avoidconcomitant useTemsirolimus (continued). Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Tenofovir. Antivirals: manufacturer of tenofovir advises avoidconcomitant use with adefovir; tenofovir reducesplasma concentration of atazanavir, also plasmaconcentration of tenofovir possibly increased; manufacturersadvise avoid concomitant use of tenofovirwith .cidofovir; tenofovir increases plasma concentrationof .didanosine (increased risk of toxicity)—avoid concomitant use; plasma concentration oftenofovir increased by lopinavirTenoxicam see NSAIDsTerazosin see Alpha-blockersTerbinafine. Antibacterials: plasma concentration of terbinafinereduced by .rifampicinAntidepressants: terbinafine possibly increases plasmaconcentration of tricyclicsCiclosporin: terbinafine possibly reduces plasma concentrationof ciclosporinOestrogens: occasional reports of breakthroughbleeding when terbinafine given with oestrogens(when used for contraception)Progestogens: occasional reports of breakthroughbleeding when terbinafine given with progestogens(when used for contraception)Ulcer-healing Drugs: plasma concentration of terbinafineincreased by cimetidineTerbutaline see Sympathomimetics, Beta 2Testolactone. Anticoagulants: testolactone enhances anticoagulanteffect of .coumarins and .phenindioneTestosterone. Anticoagulants: testosterone enhances anticoagulanteffect of .coumarins and .phenindioneAntidiabetics: testosterone possibly enhances hypoglycaemiceffect of antidiabeticsTetrabenazine. Antidepressants: risk of CNS excitation and hypertensionwhen tetrabenazine given with .MAOIsAntipsychotics: increased risk of extrapyramidal sideeffectswhen tetrabenazine given with antipsychoticsDopaminergics: increased risk of extrapyramidal sideeffectswhen tetrabenazine given with amantadineMetoclopramide: increased risk of extrapyramidalside-effects when tetrabenazine given with metoclopramideTetracosactide see CorticosteroidsTetracycline see TetracyclinesTetracyclinesACE Inhibitors: absorption of tetracyclines reduced byquinapril tablets (quinapril tablets contain magnesiumcarbonate)Adsorbents: absorption of tetracyclines possiblyreduced by kaolinAntacids: absorption of tetracyclines reduced byantacidsAntibacterials: plasma concentration of doxycyclinereduced by rifampicin—consider increasing dose ofdoxycycline; tetracyclines possibly antagonise effectsof penicillins. Anticoagulants: tetracyclines possibly enhance anticoagulanteffect of .coumarins and .phenindioneAntidiabetics: tetracyclines possibly enhance hypoglycaemiceffect of sulfonylureasAntiepileptics: metabolism of doxycycline acceleratedby carbamazepine (reduced effect); metabolism ofdoxycycline accelerated by phenobarbital andphenytoin (reduced plasma concentration)Atovaquone: tetracycline reduces plasma concentrationof atovaquoneCalcium Salts: absorption of tetracycline reduced bycalcium saltsCytotoxics: doxycycline or tetracycline increase risk ofmethotrexate toxicityAppendix 1: Interactions

736 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsTetracyclines (continued)Dairy Products: absorption of tetracyclines (exceptdoxycycline and minocycline) reduced by dairyproductsDiuretics: manufacturer of lymecycline advises avoidconcomitant use with diureticsErgot Alkaloids: increased risk of ergotism whentetracyclines given with ergotamine and methysergideIron: absorption of tetracyclines reduced by oral iron,also absorption of oral iron reduced by tetracyclinesLipid-regulating Drugs: absorption of tetracyclinepossibly reduced by colestipol and colestyramine. Retinoids: possible increased risk of benign intracranialhypertension when tetracyclines given with.retinoids (avoid concomitant use)Strontium Ranelate: absorption of tetracyclinesreduced by strontium ranelate (manufacturer ofstrontium ranelate advises avoid concomitant use)Ulcer-healing Drugs: absorption of tetracyclinesreduced by sucralfate and tripotassium dicitratobismuthateVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Zinc: absorption of tetracyclines reduced by zinc, alsoabsorption of zinc reduced by tetracyclinesTheophyllineAllopurinol: plasma concentration of theophyllinepossibly increased by allopurinolAnaesthetics, General: increased risk of convulsionswhen theophylline given with ketamine; increasedrisk of arrhythmias when theophylline given withhalothaneAnti-arrhythmics: theophylline antagonises anti-arrhythmiceffect of adenosine; plasma concentration oftheophylline increased by propafenone. Antibacterials: plasma concentration of theophyllinepossibly increased by azithromycin and isoniazid;metabolism of theophylline inhibited by.clarithromycin (increased plasma concentration);plasma concentration of theophylline increased by.erythromycin (also theophylline may reduceabsorption of oral erythromycin); plasma concentrationof theophylline increased by.ciprofloxacin and .norfloxacin; metabolism oftheophylline accelerated by rifampicin (reducedplasma concentration); possible increased risk ofconvulsions when theophylline given with.quinolones. Antidepressants: plasma concentration of theophyllineincreased by .fluvoxamine (concomitant use shouldusually be avoided, but where not possible halvetheophylline dose and monitor plasma-theophyllineconcentration); plasma concentration of theophyllinereduced by .St John’s wort—avoid concomitant use. Antiepileptics: metabolism of theophylline acceleratedby carbamazepine and .phenobarbital (reducedeffect); plasma concentration of both drugs reducedwhen theophylline given with .phenytoin. Antifungals: plasma concentration of theophyllinepossibly increased by .fluconazole and.ketoconazole. Antivirals: plasma concentration of theophylline possiblyincreased by aciclovir; metabolism of theophyllineaccelerated by .ritonavir (reduced plasmaconcentration)Anxiolytics and Hypnotics: theophylline possiblyreduces effects of benzodiazepines. Calcium-channel Blockers: plasma concentration oftheophylline possibly increased by .calcium-channelblockers (enhanced effect); plasma concentration oftheophylline increased by diltiazem; plasma concentrationof theophylline increased by .verapamil(enhanced effect)Corticosteroids: increased risk of hypokalaemia whentheophylline given with corticosteroidsCytotoxics: plasma concentration of theophylline possiblyincreased by methotrexateTheophylline (continued)Disulfiram: metabolism of theophylline inhibited bydisulfiram (increased risk of toxicity)Diuretics: increased risk of hypokalaemia when theophyllinegiven with acetazolamide, loop diuretics orthiazides and related diureticsDoxapram: increased CNS stimulation when theophyllinegiven with doxapram. Febuxostat: caution with theophylline advised bymanufacturer of .febuxostat. Interferons: metabolism of theophylline inhibited by.interferon alfa (consider reducing dose of theophylline)Leukotriene Receptor Antagonists: plasma concentrationof theophylline possibly increased by zafirlukast,also plasma concentration of zafirlukast reducedLithium: theophylline increases excretion of lithium(reduced plasma concentration)Oestrogens: plasma concentration of theophyllineincreased by oestrogens (consider reducing dose oftheophylline)Pentoxifylline: plasma concentration of theophyllineincreased by pentoxifyllineRoflumilast: avoidance of theophylline advised bymanufacturer of roflumilastSulfinpyrazone: plasma concentration of theophyllinereduced by sulfinpyrazoneSympathomimetics: manufacturer of theophyllineadvises avoid concomitant use with ephedrine inchildrenSympathomimetics, Beta 2 : increased risk of hypokalaemiawhen theophylline given with high doses ofbeta 2 sympathomimetics—see Hypokalaemia, p. 138. Ulcer-healing Drugs: metabolism of theophyllineinhibited by .cimetidine (increased plasma concentration);absorption of theophylline possibly reducedby sucralfate (give at least 2 hours apart)Vaccines: plasma concentration of theophylline possiblyincreased by influenza vaccineThiazolidinediones see AntidiabeticsThiopental see Anaesthetics, GeneralThiotepa. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Muscle Relaxants: thiotepa enhances effects of suxamethoniumThioxanthenes see AntipsychoticsThyroid HormonesAntacids: absorption of levothyroxine possibly reducedby antacidsAnti-arrhythmics: for concomitant use of thyroidhormones and amiodarone see p. 83Antibacterials: metabolism of levothyroxine acceleratedby rifampicin (may increase requirements forlevothyroxine in hypothyroidism). Anticoagulants: thyroid hormones enhance anticoagulanteffect of .coumarins and .phenindioneAntidepressants: thyroid hormones enhance effects ofamitriptyline and imipramine; thyroid hormonespossibly enhance effects of tricyclicsAntiepileptics: metabolism of thyroid hormonesaccelerated by carbamazepine and phenobarbital(may increase requirements for thyroid hormones inhypothyroidism); metabolism of thyroid hormonesaccelerated by phenytoin (may increase requirementsin hypothyroidism), also plasma concentration ofphenytoin possibly increasedBeta-blockers: levothyroxine accelerates metabolismof propranololCalcium Salts: absorption of levothyroxine reduced bycalcium saltsCytotoxics: plasma concentration of levothyroxinepossibly reduced by imatinibIron: absorption of levothyroxine reduced by oral iron(give at least 2 hours apart)Lanthanum: absorption of levothyroxine reduced bylanthanum (give at least 2 hours apart)

BNFC 2011–2012 Appendix 1: Interactions 737Thyroid Hormones (continued)Lipid-regulating Drugs: absorption of levothyroxinereduced by colesevelam; absorption of thyroidhormones reduced by colestipol and colestyramineOestrogens: requirements for thyroid hormones inhypothyroidism may be increased by oestrogensOrlistat: possible increased risk of hypothyroidismwhen levothyroxine given with orlistatPolystyrene Sulphonate Resins: absorption oflevothyroxine reduced by polystyrene sulphonateresinsSevelamer: absorption of levothyroxine possiblyreduced by sevelamerUlcer-healing Drugs: absorption of levothyroxinereduced by cimetidine and sucralfateTiagabine. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wortAntiepileptics: plasma concentration of tiagabinereduced by carbamazepine, phenobarbital andphenytoin. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistatTiaprofenic Acid see NSAIDsTiboloneAntibacterials: metabolism of tibolone accelerated byrifampicin (reduced plasma concentration)Antiepileptics: metabolism of tibolone accelerated bycarbamazepine (reduced plasma concentration);metabolism of tibolone accelerated by phenytoinTicarcillin see PenicillinsTigecyclineAnticoagulants: tigecycline possibly enhances anticoagulanteffect of coumarinsVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Tiludronic Acid see BisphosphonatesTimolol see Beta-blockersTinidazoleAlcohol: possibility of disulfiram-like reaction whentinidazole given with alcoholVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Tinzaparin see HeparinsTioguanine. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Cytotoxics: increased risk of hepatotoxicity whentioguanine given with busulfanTiotropium see AntimuscarinicsTipranavirAnalgesics: plasma concentration of tipranavir possiblyreduced by buprenorphineAntacids: absorption of tipranavir reduced by antacids. Antibacterials: tipranavir increases plasma concentrationof .clarithromycin (reduce dose of clarithromycinin renal impairment), also plasmaconcentration of tipranavir increased by clarithromycin;tipranavir increases plasma concentration of.rifabutin (reduce dose of rifabutin); plasma concentrationof tipranavir possibly reduced by.rifampicin—avoid concomitant use; avoidance ofconcomitant tipranavir in severe renal and hepaticimpairment advised by manufacturer of.telithromycinTipranavir (continued)Anticoagulants: avoidance of tipranavir advised bymanufacturer of rivaroxaban. Antidepressants: plasma concentration of tipranavirpossibly reduced by .St John’s wort—avoid concomitantuseAntiepileptics: plasma concentration of tipranavirpossibly reduced by carbamazepineAntifungals: plasma concentration of tipranavirincreased by fluconazole. Antimalarials: caution with tipranavir advised bymanufacturer of artemether/lumefantrine; tipranavirpossibly increases plasma concentration of .quinine(increased risk of toxicity)Antimuscarinics: avoidance of tipranavir advised bymanufacturer of darifenacin. Antivirals: tipranavir reduces plasma concentration of.abacavir, .didanosine, .fosamprenavir, .lopinavir,.saquinavir and .zidovudine; plasma concentrationof tipranavir increased by atazanavir (also plasmaconcentration of atazanavir reduced); tipranavirreduces plasma concentration of .etravirine, alsoplasma concentration of tipranavir increased (avoidconcomitant use). Beta-blockers: manufacturer of tipranavir advisesavoid concomitant use with .metoprolol for heartfailure. Lipid-regulating Drugs: tipranavir possibly increasesplasma concentration of .atorvastatin (considerreducing dose of atorvastatin); tipranavir possiblyincreases plasma concentration of .rosuvastatin—manufacturer of rosuvastatin advises avoid concomitantuse; tipranavir possibly increases plasmaconcentration of .simvastatin—avoid concomitantuse. Ranolazine: tipranavir possibly increases plasma concentrationof .ranolazine—manufacturer of ranolazineadvises avoid concomitant use. Ulcer-healing Drugs: tipranavir reduces plasma concentrationof .esomeprazole and .omeprazoleVitamins: increased risk of bleeding when tipranavirgiven with high doses of vitamin ETirofibanIloprost: increased risk of bleeding when tirofibangiven with iloprostTizanidine see Muscle RelaxantsTobramycin see AminoglycosidesTocilizumab. Vaccines: avoid concomitant use of tocilizumab withlive .vaccines (see p. 599)Tolazoline see Alpha-blockersTolbutamide see AntidiabeticsTolcaponeAntidepressants: avoid concomitant use of tolcaponewith MAOIsMemantine: effects of dopaminergics possiblyenhanced by memantineMethyldopa: antiparkinsonian effect of dopaminergicsantagonised by methyldopaTolfenamic Acid see NSAIDsTolterodine see AntimuscarinicsTolvaptanAntibacterials: plasma concentration of tolvaptanreduced by rifampicinAntifungals: plasma concentration of tolvaptanincreased by ketoconazoleCardiac Glycosides: tolvaptan increases plasma concentrationof digoxin (increased risk of toxicity). Grapefruit Juice: plasma concentration of tolvaptanincreased by .grapefruit juice—avoid concomitantuseTopiramate. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdAppendix 1: Interactions

738 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsTopiramate. Antidepressants (continued)lowered); avoid concomitant use of antiepilepticswith .St John’s wortAntidiabetics: topiramate possibly increases plasmaconcentration of metformin; topiramate possiblyreduces plasma concentration of glibenclamide. Antiepileptics: plasma concentration of topiramateoften reduced by carbamazepine; plasma concentrationof topiramate possibly reduced by phenobarbital;topiramate increases plasma concentration of.phenytoin (also plasma concentration of topiramatereduced); hyperammonaemia and CNS toxicityreported when topiramate given with valproate. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered)Diuretics: plasma concentration of topiramate possiblyincreased by hydrochlorothiazideLithium: topiramate possibly affects plasma concentrationof lithium. Oestrogens: topiramate accelerates metabolism of.oestrogens (reduced contraceptive effect—seep. 398). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistat. Progestogens: topiramate accelerates metabolism of.progestogens (reduced contraceptive effect—seep. 398)Torasemide see DiureticsToremifene. Anticoagulants: toremifene possibly enhances anticoagulanteffect of .coumarinsAntiepileptics: metabolism of toremifene possiblyaccelerated by carbamazepine (reduced plasmaconcentration); metabolism of toremifene acceleratedby phenobarbital (reduced plasma concentration);metabolism of toremifene possibly acceleratedby phenytoinDiuretics: increased risk of hypercalcaemia whentoremifene given with thiazides and related diureticsTrabectedin. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Tramadol see Opioid AnalgesicsTrandolapril see ACE InhibitorsTranylcypromine see MAOIsTrazodone see Antidepressants, Tricyclic (related)Tretinoin see RetinoidsTriamcinolone see CorticosteroidsTriamterene see DiureticsTrientineIron: trientine reduces absorption of oral ironZinc: trientine reduces absorption of zinc, alsoabsorption of trientine reduced by zincTrifluoperazine see AntipsychoticsTrihexyphenidyl see AntimuscarinicsTrilostaneDiuretics: increased risk of hyperkalaemia when trilostanegiven with potassium-sparing diuretics andaldosterone antagonistsTrimethoprimACE Inhibitors: possible increased risk of hyperkalaemiawhen trimethoprim given with ACE inhibitorsAngiotensin-II Receptor Antagonists: possibleincreased risk of hyperkalaemia when trimethoprimgiven with angiotensin-II receptor antagonistsAnti-arrhythmics: possible increased risk of ventriculararrhythmias when trimethoprim (as co-trimoxazole)given with amiodarone—manufacturer of amiodaroneadvises avoid concomitant use of co-trimoxazoleAntibacterials: plasma concentration of trimethoprimpossibly reduced by rifampicin; plasma concentrationTrimethoprimAntibacterials (continued)of both drugs may increase when trimethoprimgiven with dapsoneAnticoagulants: trimethoprim possibly enhances anticoagulanteffect of coumarinsAntidiabetics: trimethoprim possibly enhances hypoglycaemiceffect of repaglinide—manufactureradvises avoid concomitant use; trimethoprim rarelyenhances the effects of sulfonylureas. Antiepileptics: trimethoprim increases plasma concentrationof .phenytoin (also increased antifolateeffect). Antimalarials: increased antifolate effect when trimethoprimgiven with .pyrimethamineAntivirals: trimethoprim (as co-trimoxazole) increasesplasma concentration of lamivudine—avoid concomitantuse of high-dose co-trimoxazole. Azathioprine: increased risk of haematological toxicitywhen trimethoprim (also with co-trimoxazole) givenwith .azathioprineCardiac Glycosides: trimethoprim possibly increasesplasma concentration of digoxin. Ciclosporin: increased risk of nephrotoxicity whentrimethoprim given with .ciclosporin, also plasmaconcentration of ciclosporin reduced by intravenoustrimethoprim. Cytotoxics: increased risk of haematological toxicitywhen trimethoprim (also with co-trimoxazole) givenwith .mercaptopurine or .methotrexateDiuretics: increased risk of hyperkalaemia when trimethoprimgiven with eplerenoneVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Trimipramine see Antidepressants, TricyclicTripotassium DicitratobismuthateAntibacterials: tripotassium dicitratobismuthatereduces absorption of tetracyclinesTropicamide see AntimuscarinicsTrospium see AntimuscarinicsTryptophan. Antidepressants: CNS toxicity reported when tryptophangiven with fluoxetine; possible increasedserotonergic effects when tryptophan given withduloxetine; CNS excitation and confusion whentryptophan given with .MAOIs (reduce dose oftryptophan); agitation and nausea may occur whentryptophan given with .SSRIs. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrineAtomoxetine: possible increased risk of convulsionswhen antidepressants given with atomoxetineTyphoid Vaccine (oral) see VaccinesTyphoid Vaccine (parenteral) see VaccinesUbidecarenoneAnticoagulants: ubidecarenone may enhance orreduce anticoagulant effect of warfarinUlcer-healing Drugs see Histamine H 2-antagonists,Proton Pump Inhibitors, Sucralfate, and TripotassiumDicitratobismuthateUlipristal. Antacids: manufacturer of ulipristal advises avoidconcomitant use with .antacids (plasma concentrationof ulipristal possibly reduced). Antibacterials: manufacturer of ulipristal advises avoidconcomitant use with .rifampicin (contraceptiveeffect of ulipristal possibly reduced). Antidepressants: manufacturer of ulipristal advisesavoid concomitant use with .St John’s wort (contraceptiveeffect of ulipristal possibly reduced). Antiepileptics: manufacturer of ulipristal advises avoidconcomitant use with .carbamazepine,.phenobarbital and .phenytoin (contraceptive effectof ulipristal possibly reduced). Antivirals: manufacturer of ulipristal advises avoidconcomitant use with .ritonavir (contraceptive effectof ulipristal possibly reduced)

BNFC 2011–2012 Appendix 1: Interactions 739Ulipristal (continued). Progestogens: ulipristal possibly reduces contraceptiveeffect of .progestogens. Ulcer-healing Drugs: manufacturer of ulipristal advisesavoid concomitant use with .histamine H 2 -antagonists and .proton pump inhibitors (plasmaconcentration of ulipristal possibly reduced)Ursodeoxycholic Acid see Bile AcidsUstekinumab. Vaccines: avoid concomitant use of ustekinumab withlive .vaccines (see p. 599)VaccinesNote For a general warning on live vaccines and high dosesof corticosteroids or other immunosuppressive drugs, seep. 599; for advice on live vaccines and immunoglobulins, seeunder Normal Immunoglobulin, p. 622. Abatacept: avoid concomitant use of live vaccines with.abatacept (see p. 599). Adalimumab: avoid concomitant use of live vaccineswith .adalimumab (see p. 599). Anakinra: avoid concomitant use of live vaccines with.anakinra (see p. 599)Antibacterials: oral typhoid vaccine inactivated byantibacterials—see p. 620Anticoagulants: influenza vaccine possibly enhancesanticoagulant effect of warfarinAntiepileptics: influenza vaccine enhances effects ofphenytoinAntimalarials: oral typhoid vaccine inactivated byantimalarials—see p. 620. Certolizumab pegol: avoid concomitant use of livevaccines with .certolizumab pegol (see p. 599). Corticosteroids: immune response to vaccinesimpaired by high doses of .corticosteroids, avoidconcomitant use with live vaccines (see p. 599). Etanercept: avoid concomitant use of live vaccineswith .etanercept (see p. 599). Golimumab: avoid concomitant use of live vaccineswith .golimumab (see p. 599). Infliximab: avoid concomitant use of live vaccines with.infliximab (see p. 599)Interferons: avoidance of vaccines advised by manufacturerof interferon gamma. Leflunomide: avoid concomitant use of live vaccineswith .leflunomide (see p. 599)Theophylline: influenza vaccine possibly increasesplasma concentration of theophylline. Tocilizumab: avoid concomitant use of live vaccineswith .tocilizumab (see p. 599). Ustekinumab: avoid concomitant use of live vaccineswith .ustekinumab (see p. 599)Valaciclovir see AciclovirValganciclovir see GanciclovirValproateAnalgesics: effects of valproate enhanced by aspirin. Antibacterials: metabolism of valproate possiblyinhibited by erythromycin (increased plasma concentration);plasma concentration of valproatereduced by .carbapenems—avoid concomitant useAnticoagulants: valproate possibly enhances anticoagulanteffect of coumarins. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wortAntiepileptics: plasma concentration of valproatereduced by carbamazepine, also plasma concentrationof active metabolite of carbamazepine increased;valproate possibly increases plasma concentration ofethosuximide; valproate increases plasma concentrationof lamotrigine; valproate sometimes reducesplasma concentration of an active metabolite ofoxcarbazepine; valproate increases plasma concentrationof phenobarbital (also plasma concentrationof valproate reduced); valproate increases or possiblydecreases plasma concentration of phenytoin, alsoValproateAntiepileptics (continued)plasma concentration of valproate reduced; valproatepossibly increases plasma concentrationof rufinamide (reduce dose of rufinamide);hyperammonaemia and CNS toxicity reportedwhen valproate given with topiramate. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered); valproate possibly increases or decreasesplasma concentration of clozapine; increased risk ofside-effects including neutropenia when valproategiven with .olanzapine; valproate possibly increasesplasma concentration of quetiapineAntivirals: valproate possibly increases plasma concentrationof zidovudine (increased risk of toxicity)Anxiolytics and Hypnotics: plasma concentration ofvalproate possibly increased by clobazam; increasedrisk of side-effects when valproate given with clonazepam;valproate possibly increases plasma concentrationof diazepam and lorazepamBupropion: valproate inhibits the metabolism ofbupropionCytotoxics: valproate increases plasma concentrationof temozolomideLipid-regulating Drugs: absorption of valproate possiblyreduced by colestyramineOestrogens: plasma concentration of valproate possiblyreduced by ethinylestradiol. Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistatSodium Benzoate: valproate possibly reduces effectsof sodium benzoateSodium Phenylbutyrate: valproate possibly reduceseffects of sodium phenylbutyrate. Ulcer-healing Drugs: metabolism of valproate inhibitedby .cimetidine (increased plasma concentration)Valsartan see Angiotensin-II Receptor AntagonistsVancomycinAnaesthetics, General: hypersensitivity-like reactionscan occur when intravenous vancomycin given withgeneral anaesthetics. Antibacterials: increased risk of nephrotoxicity andototoxicity when vancomycin given with.aminoglycosides, capreomycin or colistimethatesodium; increased risk of nephrotoxicity whenvancomycin given with polymyxinsAntifungals: possible increased risk of nephrotoxicitywhen vancomycin given with amphotericin. Ciclosporin: increased risk of nephrotoxicity whenvancomycin given with .ciclosporinCytotoxics: increased risk of nephrotoxicity and possiblyof ototoxicity when vancomycin given withcisplatin. Diuretics: increased risk of otoxicity when vancomycingiven with .loop diureticsLipid-regulating Drugs: effects of oral vancomycinantagonised by colestyramine. Muscle Relaxants: vancomycin enhances effects of.suxamethoniumTacrolimus: possible increased risk of nephrotoxicitywhen vancomycin given with tacrolimusVaccines: antibacterials inactivate oral typhoidvaccine—see p. 620Vardenafil. Alpha-blockers: enhanced hypotensive effect whenvardenafil given with .alpha-blockers (excludestamsulosin)—separate doses by 6 hours—see alsounder Phosphodiesterase type-5 inhibitors, BNFsection 7.4.5Antibacterials: plasma concentration of vardenafilincreased by erythromycin (reduce dose of vardenafil)Appendix 1: Interactions

740 Appendix 1: Interactions BNFC 2011–2012Appendix 1: InteractionsVardenafil (continued). Antifungals: plasma concentration of vardenafilincreased by .ketoconazole—avoid concomitant use;plasma concentration of vardenafil possiblyincreased by .itraconazole—avoid concomitant use. Antivirals: plasma concentration of vardenafil possiblyincreased by fosamprenavir; plasma concentration ofvardenafil increased by .indinavir and .ritonavir—avoid concomitant use; increased risk of ventriculararrhythmias when vardenafil given with.saquinavir—avoid concomitant useCalcium-channel Blockers: enhanced hypotensiveeffect when vardenafil given with nifedipine. Grapefruit Juice: plasma concentration of vardenafilpossibly increased by .grapefruit juice—avoid concomitantuse. Nicorandil: possible increased hypotensive effect whenvardenafil given with .nicorandil—avoid concomitantuse. Nitrates: possible increased hypotensive effect whenvardenafil given with .nitrates—avoid concomitantuseVasodilator AntihypertensivesACE Inhibitors: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith ACE inhibitorsAdrenergic Neurone Blockers: enhanced hypotensiveeffect when hydralazine, minoxidil or sodium nitroprussidegiven with adrenergic neurone blockersAlcohol: enhanced hypotensive effect when hydralazine,minoxidil or sodium nitroprusside given withalcoholAldesleukin: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith aldesleukinAlpha-blockers: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith alpha-blockersAnaesthetics, General: enhanced hypotensive effectwhen hydralazine, minoxidil or sodium nitroprussidegiven with general anaestheticsAnalgesics: hypotensive effect of hydralazine,minoxidil and sodium nitroprusside antagonised byNSAIDsAngiotensin-II Receptor Antagonists: enhancedhypotensive effect when hydralazine, minoxidil orsodium nitroprusside given with angiotensin-IIreceptor antagonistsAntidepressants: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith MAOIs; enhanced hypotensive effect whenhydralazine or sodium nitroprusside given withtricyclic-related antidepressantsAntipsychotics: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith phenothiazinesAnxiolytics and Hypnotics: enhanced hypotensiveeffect when hydralazine, minoxidil or sodium nitroprussidegiven with anxiolytics and hypnoticsBeta-blockers: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith beta-blockersCalcium-channel Blockers: enhanced hypotensiveeffect when hydralazine, minoxidil or sodium nitroprussidegiven with calcium-channel blockersClonidine: enhanced hypotensive effect when hydralazine,minoxidil or sodium nitroprusside given withclonidineCorticosteroids: hypotensive effect of hydralazine,minoxidil and sodium nitroprusside antagonised bycorticosteroidsDiazoxide: enhanced hypotensive effect when hydralazine,minoxidil or sodium nitroprusside given withdiazoxideDiuretics: enhanced hypotensive effect when hydralazine,minoxidil or sodium nitroprusside given withdiureticsVasodilator Antihypertensives (continued)Dopaminergics: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith levodopaMethyldopa: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith methyldopaMoxisylyte: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith moxisylyteMoxonidine: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith moxonidineMuscle Relaxants: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith baclofen; enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith tizanidineNicorandil: possible enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith nicorandilNitrates: enhanced hypotensive effect when hydralazine,minoxidil or sodium nitroprusside given withnitratesOestrogens: hypotensive effect of hydralazine,minoxidil and sodium nitroprusside antagonised byoestrogensProstaglandins: enhanced hypotensive effect whenhydralazine, minoxidil or sodium nitroprusside givenwith alprostadilVasodilator Antihypertensives: enhanced hypotensiveeffect when hydralazine given with minoxidil orsodium nitroprusside; enhanced hypotensive effectwhen minoxidil given with sodium nitroprussideVecuronium see Muscle RelaxantsVenlafaxine. Analgesics: increased risk of bleeding when venlafaxinegiven with .NSAIDs or .aspirin; possibleincreased serotonergic effects when venlafaxinegiven with tramadol. Anticoagulants: venlafaxine possibly enhances anticoagulanteffect of .warfarin. Antidepressants: possible increased serotonergiceffects when venlafaxine given with St John’s wort,duloxetine or mirtazapine; enhanced CNS effects andtoxicity when venlafaxine given with .MAOIs (venlafaxineshould not be started until 2 weeks afterstopping MAOIs, avoid MAOIs for 1 week afterstopping venlafaxine); after stopping SSRI-relatedantidepressants do not start .moclobemide for atleast 1 week. Antimalarials: avoidance of antidepressants advised bymanufacturer of .artemether/lumefantrine. Antipsychotics: venlafaxine increases plasma concentrationof .clozapine and haloperidolAtomoxetine: possible increased risk of convulsionswhen antidepressants given with atomoxetine. Dopaminergics: caution with venlafaxine advised bymanufacturer of entacapone; increased risk ofhypertension and CNS excitation when venlafaxinegiven with .selegiline (selegiline should not bestarted until 1 week after stopping venlafaxine, avoidvenlafaxine for 2 weeks after stopping selegiline)5HT 1 Agonists: possible increased serotonergic effectswhen venlafaxine given with 5HT 1 agonistsLithium: possible increased serotonergic effects whenvenlafaxine given with lithiumVerapamil see Calcium-channel BlockersVigabatrin. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdlowered); avoid concomitant use of antiepilepticswith .St John’s wortAntiepileptics: vigabatrin reduces plasma concentrationof phenytoin

BNFC 2011–2012 Appendix 1: Interactions 741Vigabatrin (continued). Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistatVildagliptin see AntidiabeticsVinblastine. Aldesleukin: avoidance of vinblastine advised bymanufacturer of .aldesleukin. Antibacterials: toxicity of vinblastine increased by.erythromycin—avoid concomitant use. Antifungals: metabolism of vinblastine possibly inhibitedby .posaconazole (increased risk of neurotoxicity). Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Antivirals: plasma concentration of vinblastine possiblyincreased by ritonavirVincristine. Antifungals: metabolism of vincristine possibly inhibitedby .itraconazole and .posaconazole (increasedrisk of neurotoxicity). Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Calcium-channel Blockers: metabolism of vincristinepossibly inhibited by nifedipineCardiac Glycosides: vincristine possibly reducesabsorption of digoxin tabletsVinflunine. Antibacterials: plasma concentration of vinfluninepossibly reduced by .rifampicin—manufacturer ofvinflunine advises avoid concomitant use. Antidepressants: plasma concentration of vinfluninepossibly reduced by .St John’s wort—manufacturerof vinflunine advises avoid concomitant use. Antifungals: plasma concentration of vinflunineincreased by .ketoconazole—manufacturer of vinflunineadvises avoid concomitant use; plasmaconcentration of vinflunine possibly increased by.itraconazole—manufacturer of vinflunine advisesavoid concomitant use. Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis). Antivirals: plasma concentration of vinflunine possiblyincreased by .ritonavir—manufacturer of vinflunineadvises avoid concomitant useGrapefruit Juice: plasma concentration of vinfluninepossibly increased by grapefruit juice—manufacturerof vinflunine advises avoid concomitant useVinorelbine. Antibacterials: possible increased risk of neutropeniawhen vinorelbine given with .clarithromycin. Antifungals: metabolism of vinorelbine possibly inhibitedby .itraconazole (increased risk of neurotoxicity). Antipsychotics: avoid concomitant use of cytotoxicswith .clozapine (increased risk of agranulocytosis)Vitamin A see VitaminsVitamin D see VitaminsVitamin E see VitaminsVitamin K (Phytomenadione) see VitaminsVitaminsAntibacterials: absorption of vitamin A possiblyreduced by neomycin. Anticoagulants: vitamin K antagonises anticoagulanteffect of .coumarins and .phenindione; vitamin Epossibly enhances anticoagulant effect of .coumarinsAntiepileptics: vitamin D requirements possiblyincreased when given with carbamazepine,phenobarbital or phenytoinAntifungals: plasma concentration of paricalcitol possiblyincreased by ketoconazoleAntivirals: increased risk of bleeding when high dosesof vitamin E given with tipranavirVitamins (continued)Ciclosporin: vitamin E possibly affects plasma concentrationof ciclosporinDiuretics: increased risk of hypercalcaemia whenvitamin D given with thiazides and related diureticsDopaminergics: pyridoxine reduces effects of levodopawhen given without dopa-decarboxylase inhibitorRetinoids: risk of hypervitaminosis A when vitamin Agiven with retinoidsSelenium: ascorbic acid possibly reduces absorption ofselenium (give at least 4 hours apart)Voriconazole see Antifungals, TriazoleWarfarin see CoumarinsXipamide see DiureticsXylometazoline see SympathomimeticsZafirlukast see Leukotriene Receptor AntagonistsZaleplon see Anxiolytics and HypnoticsZidovudineNote Increased risk of toxicity with nephrotoxic and myelosuppressivedrugs—for further details consult product literatureAnalgesics: increased risk of haematological toxicitywhen zidovudine given with NSAIDs; plasma concentrationof zidovudine possibly increased bymethadoneAntibacterials: absorption of zidovudine reduced byclarithromycin tablets (give at least 2 hours apart);manufacturer of zidovudine advises avoid concomitantuse with rifampicinAntiepileptics: zidovudine increases or decreasesplasma concentration of phenytoin; plasma concentrationof zidovudine possibly increased by valproate(increased risk of toxicity). Antifungals: plasma concentration of zidovudineincreased by .fluconazole (increased risk of toxicity)Antimalarials: increased antifolate effect when zidovudinegiven with pyrimethamine. Antivirals: profound myelosuppression when zidovudinegiven with .ganciclovir (if possible avoidconcomitant administration, particularly during initialganciclovir therapy); increased risk of anaemia whenzidovudine given with .ribavirin—avoid concomitantuse; zidovudine possibly inhibits effects of .stavudine(manufacturers advise avoid concomitant use);plasma concentration of zidovudine reduced by.tipranavirAtovaquone: metabolism of zidovudine possiblyinhibited by atovaquone (increased plasma concentration). Probenecid: excretion of zidovudine reduced by.probenecid (increased plasma concentration andrisk of toxicity)ZincAntibacterials: zinc reduces absorption of ciprofloxacin,levofloxacin, moxifloxacin, norfloxacin andofloxacin; zinc reduces absorption of tetracyclines,also absorption of zinc reduced by tetracyclinesCalcium Salts: absorption of zinc reduced by calciumsaltsEltrombopag: zinc possibly reduces absorption ofeltrombopag (give at least 4 hours apart)Iron: absorption of zinc reduced by oral iron, alsoabsorption of oral iron reduced by zincPenicillamine: absorption of zinc reduced by penicillamine,also absorption of penicillamine reduced byzincTrientine: absorption of zinc reduced by trientine, alsoabsorption of trientine reduced by zincZoledronic Acid see BisphosphonatesZolmitriptan see 5HT 1 AgonistsZolpidem see Anxiolytics and HypnoticsZonisamide. Antidepressants: anticonvulsant effect of antiepilepticspossibly antagonised by MAOIs and .tricyclic-relatedantidepressants (convulsive threshold lowered); anticonvulsanteffect of antiepileptics antagonised by.SSRIs and .tricyclics (convulsive thresholdAppendix 1: Interactions

742 Appendix 1: Interactions BNFC 2011–2012Zonisamide. Antidepressants (continued)lowered); avoid concomitant use of antiepilepticswith .St John’s wortAntiepileptics: plasma concentration of zonisamidereduced by carbamazepine, phenobarbital andphenytoin. Antimalarials: possible increased risk of convulsionswhen antiepileptics given with chloroquine andhydroxychloroquine; anticonvulsant effect of antiepilepticsantagonised by .mefloquine. Antipsychotics: anticonvulsant effect of antiepilepticsantagonised by .antipsychotics (convulsive thresholdlowered). Orlistat: possible increased risk of convulsions whenantiepileptics given with .orlistatZopiclone see Anxiolytics and HypnoticsZuclopenthixol see AntipsychoticsAppendix 1: Interactions

BNFC 2011–2012 743A2Borderline substancesA2.1 Enteral feeds (non-diseasespecific) 744A2.1.1 Enteral feeds (non-diseasespecific): less than 5 g protein/100 mL 744A2.1.2 Enteral feeds (non-diseasespecific): 5 g (or more) protein/100 mL 747A2.1.3 Enteral feeds (non-diseasespecific): Child under 12 years 750A2.2 Nutritional supplements (nondiseasespecific) 756A2.2.1 Nutritional supplements: lessthan 5 g protein/100 mL 756A2.2.2 Nutritional supplements: 5 g(or more) protein/100 mL 758A2.3 Specialised formulas 763A2.3.1 Specialised formulas: Infantand child 763A2.3.2 Specialised formulas for specificclinical conditions 768A2.4 Feed supplements 771A2.4.1 High-energy supplements 771A2.4.2 Fibre, vitamin, and mineralsupplements 776A2.5 Feed additives 777A2.5.1 Special additives for conditionsof intolerance 777A2.5.2 Feed thickeners and pre-thickeneddrinks 777A2.5.3 Flavouring preparations 777A2.6 Foods for special diets 777A2.6.1 Gluten-free foods 777A2.6.2 Low-protein foods 780A2.7 Nutritional supplements formetabolic diseases 781In certain conditions some foods (and toilet preparations)have characteristics of drugs and the AdvisoryCommittee on Borderline Substances (ACBS) advisesas to the circumstances in which such substances maybe regarded as drugs. Prescriptions issued in accordancewith the Committee’s advice and endorsed‘ACBS’ will normally not be investigated.General Practitioners are reminded that the ACBSrecommends products on the basis that they may beregarded as drugs for the management of specifiedconditions. Doctors should satisfy themselves thatthe products can safely be prescribed, that patientsare adequately monitored and that, where necessary,expert hospital supervision is available.Foods which may be prescribed on FP10, GP10(Scotland), or WP10 (Wales) All the food productslisted in this appendix have ACBS approval. The clinicalcondition for which the product has been approved isincluded with each entry.Note Foods included in this appendix may contain cariogenicsugars and appropriate oral hygiene measures should be taken.Enteral feeds and nutritional supplements Formost enteral feeds and nutritional supplements, themain source of carbohydrate is either maltodextrin orglucose syrup; other carbohydrate sources are listed inthe relevant table, below. Feeds containing residuallactose (less than 1 g lactose/100 mL formula) aredescribed as ‘clinically lactose-free’ or ‘lactose-free’ bysome manufacturers. The presence of lactose (includingresidual lactose) in feeds is indicated in the relevanttable, below. The primary sources of protein or aminoacids are included with each product entry. The fat oroil content is derived from a variety of sources such asvegetables, soya bean, corn, palm nuts, and seeds;where the fat content is derived from animal or fishsources, this information is included in the relevanttable, below. The presence of medium chain triglycerides(MCT) is also noted where the quantityexceeds 30% of the fat content.Enteral feeds and nutritional supplements can containvarying amounts of vitamins, minerals, and trace elements—themanufacturer’s product literature should beconsulted for more detailed information. For furtherinformation on enteral nutrition, see section 9.4.2.Feeds containing vitamin K may affect the INR inchildren receiving warfarin; see interactions: Appendix1 (vitamins).The suitability of food products for patients requiring avegan, kosher, halal, or other compliant diet should beconfirmed with individual manufacturers.Note Feeds containing more than 6 g/100 mL protein or 2 g/100 mL fibre should be avoided in children unless recommendedby an appropriate specialist or dietician.Standard ACBS indications: Disease-related malnutrition,intractable malabsorption, pre-operativepreparation of malnourished patients, dysphagia,proven inflammatory bowel disease, following totalgastrectomy, short-bowel syndrome, bowel fistulaPaediatric ACBS indications: Disease-relatedmalnutrition, intractable malabsorption, growth failure,pre-operative preparation of malnourishedpatients, dysphagia, short-bowel syndrome, bowelfistulaAppendix 2: Borderline substances

Appendix 2: Borderline substancesA2.1 Enteral feeds (non-disease specific)A2.1.1 Enteral feeds (non-disease specific): less than 5 g protein/100 mLA2.1.1.1 Enteral feeds: 1 kcal/mL and less than 5 g protein/100 mLNot suitable for use in child under 1 year unless otherwise stated; not recommended for child 1–6 yearsProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsFresubin c Original(Fresenius Kabi)Fresubin c OriginalFibre(Fresenius Kabi)Isosource c Fibre(Nestlé)Isosource cStandard(Nestlé)Jevity c(Abbott)Novasource c GIControl(Nestlé)Liquid (sip ortube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mL1. Sugar content varies with flavour420 kJ(100 kcal)420 kJ(100 kcal)422 kJ(100 kcal)420 kJ(100 kcal)441 kJ(106 kcal)444 kJ(106 kcal)3.8 gcows’ milksoya3.8 gcows’ milksoya3.8 gcows’ milk4gcows’ milk4gcaseinates4.1 gcows’ milk13.8 g(sugars 3.5 g 1 )13.8 g(sugars 1 g)3.4 g Nil Gluten-freeResidual lactoseContains fish gelatinFeed in flexible pack containsfish oil and fish gelatin3.4 g 2 g Gluten-freeResidual lactoseContains fish oil and fishgelatin13.6 g 3.4 g 1.4 g Gluten-freeResidual lactose13.6 g 3.3 g Nil Gluten-freeResidual lactose14.1 g(sugars470 mg)14.4 g(sugars500 mg)3.47 g 1.76 g Gluten-freeResidual lactose3.5 g(MCT40 %)2.2 g Gluten-freeResidual lactoseACBSIndicationsPresentation& FlavourStandard, p. 743 Bottle: 200 mL = £1.78Black currant, chocolate, mocha,nut, peach, vanillaFlexible pack:500 mL = £3.451000 mL = £6.811500 mL = £10.23Standard, p. 743 except bowel fistula.Not suitable for child under 2 yearsStandard, p. 743Not suitable for child under 2 yearsStandard, p. 743Standard, p. 743 except bowel fistula.Not suitable for child under 2 yearsStandard, p. 743Flexible pack:500 mL = £3.901000 mL = £7.781500 mL = £10.69Flexible pack:500 mL = £3.491000 mL = £6.97Flexible pack:500 mL = £3.071000 mL = £6.13Flexible pack:500 mL = £4.161000 mL = £7.811500 mL = £11.73Flexible pack:500 mL = £4.78744 A2.1 Enteral feeds (non-disease specific) BNFC 2011–2012

Nutrison c(Nutricia Clinical)Nutrison c MultiFibre(Nutricia Clinical)Osmolite c(Abbott)Liquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mL420 kJ(100 kcal)420 kJ(100 kcal)424 kJ(100 kcal)Soya protein formula (see also section A2.3.1)Fresubin c SoyaFibre(Fresenius Kabi)Nutrison c Soya(Nutricia Clinical)Nutrison c SoyaMulti Fibre(Nutricia Clinical)Liquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLPeptide-based formulaPeptamen c(Nestlé)Liquid (sip ortube feed)per 100 mL1. Sugar content varies with flavour420 kJ(100 kcal)420 kJ(100 kcal)420 kJ(100 kcal)420 kJ(100 kcal)4gcows’ milk4gcows’ milk4gcaseinatessoy isolate3.8 gsoya protein4gsoy isolate4gsoy isolate4gwhey peptides12.3 g(sugars 1 g)12.3 g(sugars 1 g)13.6 g(sugars630 mg)13.3 g(sugars 4.1 g)12.3 g(sugars 1 g)12.3 g(sugars700 mg)12.7 g(sugars480 mg 1 )3.9 g Nil Gluten-freeResidual lactose3.9 g 1.5 g Gluten-freeResidual lactose3.4 g Nil Gluten-freeResidual lactose3.6 g 2 g Gluten-freeLactose-freeContains fish oil3.9 g Nil Gluten-freeResidual lactoseMilk protein-free3.9 g 1.5 g Gluten-freeResidual lactoseMilk protein-free3.7 g(MCT70 %)NilGluten-freeResidual lactoseStandard, p. 743Standard, p. 743 except bowel fistulaBottle:500 mL = £3.76Flexible pack:500 mL = £4.171000 mL = £7.321500 mL = £10.97Bottle:500 mL = £4.09Flexible pack:500 mL = £4.511000 mL = £8.161500 mL = £12.25Standard, p. 743 Can: 250 mL = £1.88Bottle:500 mL = £3.571000 mL = £6.811500 mL = £10.22Standard, p. 743; also cows’ milkprotein intolerance, lactose intoleranceStandard, p. 743; also cows’ milkprotein and lactose intoleranceStandard, p. 743 except bowel fistula;also cows’ milk protein andlactose intoleranceShort bowel syndrome, intractablemalabsorption, proven inflammatorybowel disease, bowel fistulaFlexible pack: 500 mL = £4.03Bottle:500 mL = £4.34Flexible pack:1000 mL = £8.69Flexible pack:1500 mL = £14.46Bottle:200 mL = £2.83VanillaFlexible pack:500 mL = £5.861000 mL = £11.00BNFC 2011–2012 A2.1 Enteral feeds (non-disease specific) 745Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.1.1.1 Enteral feeds: 1 kcal/mL and less than 5 g protein/100 mL (product list continued)Not suitable for use in child under 1 year unless otherwise stated; not recommended for child 1–6 yearsProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsPeptisorb c(Nutricia Clinical)Survimed c OPD(Fresenius Kabi)Liquid (tube feed)per 100 mLLiquid (tube feed)per 100 mL425 kJ(100 kcal)420 kJ(100 kcal)4gwhey proteinhydrolysate4.5 glactalbuminhydrolysate17.6 g(sugars 1.7 g)15 g(sugars300 mg)1.7 g(MCT47 %)2.4 g(MCT54 %)NilNilGluten-freeResidual lactoseGluten-freeResidual lactoseContains fish oil and fishgelatinA2.1.1.2 Enteral feeds: Less than 1 kcal/mL and less than 5 g protein/100 mLNot suitable for use in child under 1 year unless otherwise stated; not recommended for child 1–6 yearsProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsAmino acid formula (essential and non-essential amino acids)Elemental 028 cExtra(SHS)Liquid (sip feed)per 100 mLStandard dilution(20 %) of powder(sip or tube feed)per 100 mL360 kJ(86 kcal)2.5 g(proteinequivalent)374 kJ 2.5 g(89 kcal) 1 (proteinequivalent)11 g(sugars 4.7 g)11.8 g(sugars 1.8 g)3.5 g(MCT35 %)3.5 g(MCT35 %)Powder provides protein equivalent 12.5 g, carbohydrate 59 g, fat 17.45 g, energy 1871 kJ (443 kcal)/100 g1. Nutritional values vary with flavour—consult product literature2. Flavouring: see Modjul c Flavour System, p. 777NilNilACBSIndicationsShort bowel syndrome, intractablemalabsorption, proven inflammatorybowel disease, bowel fistulaStandard, p. 743; also growth failureACBSIndicationsShort bowel syndrome, intractablemalabsorption, proven inflammatorybowel disease, bowel fistulaPresentation& FlavourBottle:500 mL = £5.76Flexible pack:500 mL = £6.311000 mL = £11.41Flexible pack:500 mL = £5.75Presentation& FlavourCarton:250 mL = £3.19Grapefruit, orange and pineapple,summer fruitsSachet:100 g = £6.01Banana, citrus, orange,unflavoured 2746 A2.1 Enteral feeds (non-disease specific) BNFC 2011–2012

A2.1.2 Enteral feeds (non-disease specific): 5 g (or more) protein/100 mLA2.1.2.1 Enteral feeds: 1.5 kcal/mL and 5 g (or more) protein/100 mLNot suitable for use in child under 1 year unless otherwise stated; not recommended for child 1–6 yearsProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsFresubin c 2250Complete(Fresenius Kabi)Fresubin c Energy(Fresenius Kabi)Fresubin c EnergyFibre(Fresenius Kabi)Fresubin c HPEnergy(Fresenius Kabi)Isosource c EnergyFibre(Nestlé)Liquid (tubefeed)per 100 mLLiquid (sip feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (sip feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mL630 kJ(150 kcal)630 kJ(150 kcal)630 kJ(150 kcal)630 kJ(150 kcal)630 kJ(150 kcal)630 kJ(150 kcal)630 kJ(150 kcal)5.6 gcows’ milk5.6 gcows’ milk5.6 gcows’ milk5.6 gcows’ milk5.6 gcows’ milk7.5 gcows’ milk4.9 gcows’ milk1. Sugar content varies with flavour2. Strawberry flavour may contain traces of wheat starch and egg18.8 g(sugars 1.5 g)18.8 g(sugars 1 )18.8 g(sugars 1.4 g)18.8 g(sugars 1 )18.8 g(sugars 1.5 g)17 g(sugars 1 g)5.8 g 2 g Gluten-freeResidual lactoseContains fish oil and fishgelatin5.8 g Nil Gluten-free 2Residual lactoseContains fish gelatin5.8 g Nil Gluten-freeResidual lactoseContains fish oil and fishgelatin5.8 g 2 g Gluten-freeResidual lactoseContains fish gelatin5.8 g 2 g Gluten-freeResidual lactoseContains fish oil and fishgelatin5.8 g(MCT57 %)NilGluten-freeResidual lactoseContains fish oil and fishgelatin20.2 g 5.5 g 1.5 g Gluten-freeResidual lactoseACBSIndicationsStandard, p. 743Standard, p. 743Standard, p. 743Standard, p. 743Standard, p. 743Standard, p. 743; also CAPD andhaemodialysisStandard, p. 743 except bowel fistulaPresentation& FlavourFlexible pack:1500 mL = £12.25Bottle:200 mL = £1.78Banana, black currant, cappuccino,chocolate, lemon, neutral,strawberry, tropical fruits, vanillaFlexible pack:500 mL = £4.211000 mL = £8.281500 mL = £11.10Bottle:200 mL = £1.87Banana, caramel, cherry, chocolate,strawberry, vanillaFlexible pack:500 mL = £4.631000 mL = £8.82Flexible pack:500 mL = £4.291000 mL = £8.60Flexible pack:500 mL = £4.081000 mL = £8.17BNFC 2011–2012 A2.1 Enteral feeds (non-disease specific) 747Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.1.2.1 Enteral feeds: 1.5 kcal/mL and 5 g (or more) protein/100 mL (product list continued)Not suitable for use in child under 1 year unless otherwise stated; not recommended for child 1–6 yearsProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsJevity c 1.5 kcal(Abbott)Novasource c GIForte(Nestlé)Nutrison c Energy(Nutricia Clinical)Nutrison c EnergyMulti Fibre(Nutricia Clinical)Osmolite c 1.5 kcal(Abbott)Resource c Energy(Nestlé)Liquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (sip feed)per 100 mL1. Sugar content varies with flavour640 kJ(152 kcal)631 kJ(150 kcal)630 kJ(150 kcal)630 kJ(150 kcal)632 kJ(150 kcal)630 kJ(150 kcal)6.38 gcaseinatesand soy isolate6gcows’ milk6gcows’ milk6gcows’ milk6.25 gcows’ milksoya proteinisolate5.6 gcows’ milk20.1 g(sugars 1.47 g)18.3 g(sugars 1.8 g)18.5 g(sugars 1.5 g)18.5 g(sugars 1.5 g)20 g(sugars 4.9 g)21 g(sugars 5.2 g 1 )4.9 g 2.2 g Gluten-freeResidual lactose5.9 g 2.2 g Gluten-freeResidual lactose5.8 g Nil Gluten-freeResidual lactose5.8 g 1.5 g Gluten-freeResidual lactose5 g Nil Gluten-freeResidual lactose5 g less than500 mgGluten-freeResidual lactoseACBSIndicationsStandard, p. 743Not suitable for child under 2 years;not recommended for child 2–10yearsStandard, p. 743Standard, p. 743Standard, p. 743Standard, p. 743Standard, p. 743Not suitable for use in child under 3yearsPresentation& FlavourFlexible pack:500 mL = £4.921000 mL = £9.401500 mL = £14.67Flexible pack:500 mL = £4.751000 mL = £9.50Bottle:500 mL = £4.38Flexible pack:500 mL = £4.861000 mL = £8.811500 mL = £13.18Bottle:500 mL = £4.90Flexible pack:500 mL = £5.391000 mL = £9.771500 mL = £15.66Flexible pack:500 mL = £4.371000 mL = £8.541500 mL = £12.79Bottle:4 200 mL = £6.97Apricot, banana, chocolate, coffee,strawberry-raspberry, vanilla748 A2.1 Enteral feeds (non-disease specific) BNFC 2011–2012

A2.1.2.2 Enteral feeds: Less than 1.5 kcal/mL and 5 g (or more) protein/100 mLNot suitable for use in child under 1 year unless otherwise stated; not recommended for child 1–6 yearsProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsFresubin c 1000Complete(Fresenius Kabi)Fresubin c 1200Complete(Fresenius Kabi)Fresubin c 1800Complete(Fresenius Kabi)Jevity c Plus(Abbott)Jevity c Plus HP(Abbott)Jevity c Promote(Abbott)Nutrison c MCT(Nutricia Clinical)Nutrison c ProteinPlus(Nutricia Clinical)Nutrison c ProteinPlus Multi Fibre(Nutricia Clinical)Liquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mL420 kJ(100 kcal)500 kJ(120 kcal)500 kJ(120 kcal)504 kJ(120 kcal)547 kJ(130 kcal)427 kJ(101 kcal)420 kJ(100 kcal)525 kJ(125 kcal)525 kJ(125 kcal)5.5 gcows’ milk6gcows’ milk6gcows’ milk5.5 gcaseinatessoy isolates8.13 gcows’ milksoy isolates5.55 gcaseinatessoy isolates5gcows’ milk6.3 gcows’ milk6.3 gcow’s milk12.5 g(sugars 1.1 g)15 g(sugars 1.22 g)15 g(sugars 1.22 g)15.1 g(sugars890 mg)14.2 g(sugars950 mg)12 g(sugars670 mg)12.6 g(sugars 1 g)14.2 g(sugars 1.1 g)14.1 g(sugars 1.1 g)3.1 g 2 g Gluten-freeResidual lactoseContains fish oil4.1 g 2 g Gluten-freeResidual lactoseContains fish oil4.1 g 2 g Gluten-freeResidual lactoseContains fish oil3.93 g 2.2 g Gluten-freeResidual lactose4.33 g 1.5 g Gluten-freeResidual lactose3.32 g 1.7 g Gluten-freeResidual lactose3.3 g(MCT61%)NilGluten-freeResidual lactose4.9 g Nil Gluten-freeResidual lactose4.9 g 1.5 g Gluten-freeResidual lactoseACBSIndicationsStandard, p. 743Standard, p. 743Standard, p. 743Standard, p. 743Not suitable for child under 2 years;not recommended for child 2–10yearsStandard, p. 743; also CAPD,haemodialysisNot suitable for child under 2 years;not recommended for child 2–10yearsStandard, p. 743Not suitable for child under 2 years;not recommended for child 2–10yearsStandard, p. 743Standard, p. 743Disease related malnutritionPresentation& FlavourFlexible pack:1000 mL = £8.82Flexible pack:1000 mL = £11.41Flexible pack:1500 mL = £11.23Flexible pack:500 mL = £4.481000 mL = £9.161500 mL = £13.75Flexible pack:500 mL = £4.57Flexible pack:1000 mL = £8.95Flexible pack:1000 mL = £8.15Flexible pack:1000 mL = £8.39Flexible pack:1000 mL = £9.34BNFC 2011–2012 A2.1 Enteral feeds (non-disease specific) 749Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.1.2.2 Enteral feeds: Less than 1.5 kcal/mL and 5 g (or more) protein/100 mL (product list continued)Not suitable for use in child under 1 year unless otherwise stated; not recommended for child 1–6 yearsProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsNutrison c 1000Complete MultiFibre(Nutricia Clinical)Nutrison c 1200Complete MultiFibre(Nutricia Clinical)Osmolite c Plus(Abbott)Peptamen c HN(Nestlé)Perative c(Abbott)Liquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (sip ortube feed)per 100 mL420 kJ(100 kcal)505 kJ(120 kcal)508 kJ(121 kcal)556 kJ(133 kcal)552 kJ(131 kcal)5.5 gcows’ milk5.5 gcows’ milk5.55 gcaseinates6.6 gwhey proteinhydrolysates6.7 gcaseinatewhey proteinhydrolysates11.3 g(sugars700 mg)15 g(sugars 1.2 g)15.8 g(sugars730 mg)15.6 g(sugars 1.4 g)17.7 g(sugars660 mg)3.7 g 2 g Gluten-freeResidual lactose4.3 g 2 g Gluten-freeResidual lactose3.93 g Nil Gluten-freeResidual lactose4.9 g(MCT70%)3.7 g(MCT42%)NilNilGluten-freeResidual lactoseHydrolysed with pork trypsinGluten-freeResidual lactoseA2.1.2.3 Enteral feeds: More than 1.5 kcal/mL and 5 g (or more) protein/100 mLNot suitable for use in child under 1 year unless otherwise stated; not recommended for child 1–6 yearsProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsEnsure c Twocal(Abbott)Isosource c Energy(Nestlé)Liquid (sip ortube feed)per 100 mLLiquid (tube feed)per 100 mL838 kJ(200 kcal)670 kJ(160 kcal)8.4 gcows’ milk5.7 gcows’ milk21 g(sugars 4.5 g)8.9 g 1 g Gluten-freeResidual lactose20 g 6.2 g Nil Gluten-freeResidual lactoseACBSIndicationsDisease related malnutrition inpatients with low energy and/or lowfluid requirementsStandard, p. 743 except bowel fistulaStandard, p. 743Not suitable for child under 10 yearsShort bowel syndrome, intractablemalabsorption, proven inflammatorybowel disease, bowel fistulaNot suitable for child under 3 yearsStandard, p. 743Not suitable for child under 5 yearsACBSIndicationsStandard, p. 743; also haemodialysisand CAPDStandard, p. 743Presentation& FlavourFlexible pack:1000 mL = £8.85Bottle: 500 mL = £4.80Flexible pack:1000 mL = £9.591500 mL = £14.41Flexible pack:500 mL = £4.181000 mL = £8.061500 mL = £12.07Flexible pack:500 mL = £6.32Flexible pack:500 mL = £5.821000 mL = £11.65Presentation& FlavourBottle:200 mL = £2.14Banana, neutral, strawberry,vanillaFlexible pack:500 mL = £3.771000 mL = £7.53750 A2.1 Enteral feeds (non-disease specific) BNFC 2011–2012

A2.1.3 Enteral feeds (non-disease specific): Child under 12 yearsA2.1.3.1 Enteral feeds, Child: Less than 1 kcal/mL and less than 4 g protein/100 mLProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsNutrini c LowEnergy Multi Fibre(Nutricia Clinical)Nutriprem c 1(Cow & Gate)Nutriprem c 2(Cow & Gate)Liquid (tube feed)per 100 mLLiquid (sip feed)per 100 mLLiquid (sip feed)per 100 mLStandard dilution(15.3%) of powder(sip feed)per 100 mL315 kJ(75 kcal)335 kJ(80 kcal)310 kJ(75 kcal)315 kJ(75 kcal)2.1 gwhey proteinand caseinate2.5 gwhey proteinand casein2gwhey proteinand casein2gwhey proteinand casein9.3 g(sugars600 mg)7.6 g(lactose 6.3 g)7.4 g(lactose 5.8 g)7.4 g(lactose 5.9 g)3.3 g 800 mg Gluten-freeResidual lactoseContains fish oil4.4 g 800 mg Contains soya, fish oil andegg lipid4 g 600 mg Contains soya, fish oil andegg lipid4g(includingMCToil)Powder provides: protein 13 g, carbohydrate 48.3 g, fat 26.7 g, fibre 5.2 g, energy 2030 kJ (485 kcal)/100 gSMA c Gold Prem 2(SMA Nutrition)Standard dilution(14%) of powder(sip feed)per 100 mL305 kJ(73 kcal)1.9 gcows’ milk7.5 gsugars 6.4 gPowder provides: protein 14 g, carbohydrate 54 g, fat 28 g, energy 2180 kJ (524 kcal)/100 gSMA c High Energy(SMA Nutrition)Liquid (sip feed)per 100 mL382 kJ(91 kcal)2gwhey proteinand casein9.8 glactoseACBSIndicationsPaediatric, p. 743 except bowel fistula,in child 1–6 years, body-weight8–20 kgLow birth-weight formulaCatch-up growth in pre-term infants(less than 35 weeks at birth) andsmall for gestational-age infants upto 6 months corrected agePresentation& FlavourBottle: 200 mL = £2.16Flexible pack:500 mL = £5.47Bottle: 60 mLHospital supply onlyCarton: 200 mL = £1.59(Bottle: 100 mL Hospital supplyonly600 mg Can: 900 g = £10.64(5.1-g measuring scoop provided)3.9 g Nil Contains lactose Catch-up growth in preterm andsmall for gestational age infants ondischarge from hospital, up to 6months corrected age4.9 g Nil Contains lactose Disease related malnutrition andmalabsorption, and growth failure inchild from birth to 18 monthsCan: 400 g = £4.57(4.7-g measuring scoop provided)Carton: 250 mL = £2.08BNFC 2011–2012 A2.1 Enteral feeds (non-disease specific) 751Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.1.3.1 Enteral feeds, Child: Less than 1 kcal/mL and less than 4 g protein/100 mL (product list continued)Product Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsAmino acid formula (essential and non-essential amino acids)Emsogen c(SHS)Standard dilution(20 %) of powder(sip or tube feed)per 100 mL368 kJ 2.5 g(88 kcal) 1 proteinequivalent(essentialand nonessentialamino acids)12 g(sugars 1.6 g)3.3 g 2(MCT83 %)Powder provides: protein equivalent 12.5 g, carbohydrate 60 g, fat 16.4 g, energy 1839 kJ (438 kcal)/100 g1. Nutritional values vary with flavour—consult product literature2. Additional source of alpha linolenic acid needed if used as sole source of nutrition3. Flavouring: see Modjul c Flavour System, p. 777A2.1.3.2 Enteral feeds, Child: 1 kcal/mL and less than 4 g protein/100 mLNot suitable for use in child under 1 year unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsClinutren c Junior(Nestlé)Standard dilution(22%) of powder(sip or tube feed)per 100 mL420 kJ(100 kcal)2.97 gwhey proteinand caseinatePowder provides: protein 13.9 g, carbohydrate 62.2 g, fat 18.3 g, energy 1950 kJ (467 kcal)/100 gFrebini c Original(Fresenius Kabi)Frebini c OriginalFibre(Fresenius Kabi)Liquid (tube feed)per 100 mLLiquid (tube feed)per 100 mL420 kJ(100 kcal)420 kJ(100 kcal)2.5 gcows’ milk2.5 gcows’ milkACBSIndicationsNil Lactose-free Short-bowel syndrome, intractablemalabsorption, proven inflammatorybowel disease, bowel fistulaNot suitable for child under 1 year oras sole source of nutrition in child1–5 years13.3 g 3.9 g Nil Gluten-freeResidual lactose12.5 g(sugars700 mg)12.5 g(sugars700 mg)4.4 g Nil Gluten-freeResidual lactoseContains fish oils and fishgelatin4.4 g 750 mg Gluten-freeResidual lactoseContains fish oils and fishgelatinACBSIndicationsStandard, p. 743, and growth failurein child 1–10 yearsStandard, p. 743, and growth failurein child 1–10 years, body-weight 8–30 kgStandard, p. 743, and growth failurein child 1–10 years, body-weight 8–30 kgPresentation& FlavourSachet: 100 g = £6.18Orange, unflavoured 3Presentation& FlavourCan: 400 g = £10.57Vanilla(7.85-g measuring scoop provided)Flexible pack:500 mL = £5.09Flexible pack:500 mL = £5.65752 A2.1 Enteral feeds (non-disease specific) BNFC 2011–2012

Infatrini c(Nutricia Clinical)Nutrini c(Nutricia Clinical)Nutrini c Multi Fibre(Nutricia Clinical)Paediasure c(Abbott)Paediasure c Fibre(Abbott)Paediasure cPeptide(Abbott)Similac c HighEnergy(Abbott)Tentrini c(Nutricia Clinical)Liquid (sip ortube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (sip ortube feed)per 100 mLLiquid (sip ortube feed)per 100 mLLiquid (sip ortube feed)per 100 mLLiquid (sip ortube feed)per 100 mLLiquid (tube feed)per 100 mL415 kJ(100 kcal)420 kJ(100 kcal)420 kJ(100 kcal)2.6 gcows’ milk2.8 gcows’ milk2.8 gwhey proteinand caseinate422 kJ 2.8 g(100 kcal) 1 cows’ milk420 kJ 2.8 g(100 kcal) 1 caseinatesand wheyprotein420 kJ(100 kcal)3gwhey proteinand caseinate419 kJ 2.6 g(100 kcal) 2 cows’ milkand wheyprotein420 kJ(100 kcal)3.3 gwhey proteinand caseinate1. Nutritional values vary with flavour—consult product literature2. Nutritional values vary with pack size—consult product literature10.3 g(lactose 5.2 g)12.3 g(sugars 1 g)12.3 g(sugars800 mg)11.2 g(sugars 3.92 g)10.9 g(sugars 3.84 g)13 g(sugars 2.98 g)10.1 g(sugars 5.6 g)12.3 g(sugars800 mg)5.4 g 800 mg Gluten-freeContains fish oil4.4 g Nil Gluten-freeResidual lactose4.4 g 800 mg Gluten-freeResidual lactoseContains fish oil4.98 g Nil Gluten-freeResidual lactose4.98 g 730 mg Gluten-freeResidual lactose4g(MCT50%)NilGluten-freeResidual lactose5.2 g 400 mg Gluten-freeContains lactoseand soy oil4.2 g Nil Gluten-freeResidual lactoseContains fish oilFailure to thrive, disease-relatedmalnutrition and malabsorption, inchild from birth up to body-weight8 kgStandard, p. 743, and growth failurein child 1–6 years, body-weight 8–20 kgStandard, p. 743, and growth failurein child 1–6 years, body-weight 8–20 kgPaediatric, p. 743 in child 1–10years, body-weight 8–30 kgPaediatric, p. 743 in child 1–10years, body-weight 8–30 kgStandard, p. 743, and growth failurein child 1–10 years, body-weight 8–30 kgIncreased energy requirements, falteringgrowth, and/or need for fluidrestriction, in child body-weight upto 8 kgStandard, p. 743, and growth failurein child 7–12 years, body-weight21–45 kgBottle:100 mL = £1.03200 mL = £1.94Flexible pack:500 mL = £5.25Bottle: 200 mL = £2.58Flexible pack:500 mL = £5.80Bottle:200 mL = £2.58Flexible pack:500 mL = £6.45Bottle: 200 mL = £2.10Banana, chocolate, strawberry,vanillaFlexible pack: 500 mL = £5.24VanillaBottle: 200 mL = £2.30Banana, strawberry, vanillaFlexible pack:500 mL = £5.82VanillaBottle: 200 mL = £3.56VanillaFlexible pack: 500 mL = £8.89VanillaBottle:120 mL = £1.23200 mL = £2.06Bottle or Flexible pack:500 mL = £4.92BNFC 2011–2012 A2.1 Enteral feeds (non-disease specific) 753Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.1.3.2 Enteral feeds, Child: 1 kcal/mL and less than 4 g protein/100 mL (product list continued)Not suitable for use in child under 1 year unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsTentrini c MultiFibre(Nutricia Clinical)Liquid (tube feed)per 100 mL420 kJ(100 kcal)3.3 gwhey proteinand caseinate12.3 g(sugars800 mg)Hydrolysate Formula See also Infant Formula (Hydrolysate), section 2.3.1Nutrini c Peptisorb(Nutricia Clinical)Peptamen c Junior(Nestlé)Liquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLStandard dilution(22%) of powder(sip or tube feed)per 100 mL420 kJ(100 kcal)420 kJ(100 kcal)420 kJ(100 kcal)2.8 gwhey proteinhydrolysate3gwhey proteinhydrolysate3gwhey proteinhydrolysate13.7 g(sugars800 mg)4.2 g 1.1 g Gluten-freeResidual lactoseContains fish oil3.9 g(MCT46 %)13.2 g 4 g(MCT60 %)13.8 g 3.85 g(MCT60 %)Powder provides: protein 13.7 g, carbohydrate 62.9 g, fat 17.5 g, energy 1910 kJ (457 kcal)/100 gNilNilGluten-freeResidual lactoseGluten-freeResidual lactoseHydrolysed with pork trypsinGluten-freeResidual lactoseHydrolysed with bacterialtrypsinA2.1.3.3 Enteral feeds, Child: More than 1 kcal/mL and less than 4 g protein/100 mLNot suitable for use in child under 1 year unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsFortini c(Nutricia Clinical)Fortini c Multifibre(Nutricia Clinical)Fortini c SmoothieMultifibre(Nutricia Clinical)Liquid (sip feed)per 100 mLLiquid (sip feed)per 100 mLLiquid (sip feed)per 100 mL630 kJ(150 kcal)630 kJ(150 kcal)625 kJ(150 kcal)3.4 gcows’ milk3.4 gcows’ milk3.4 gcows’ milk18.8 g(sugars 7.4 g)18.8 g(sugars 7.4 g)19 g(sugars 11.5 g)Nil6.8 g Nil Gluten-freeResidual lactose6.8 g 1.5 g Gluten-freeResidual lactose6.4 g 1.4 g Gluten-freeResidual lactoseACBSIndicationsStandard, p. 743, except bowel fistula,and growth failure in child 7–12 years body-weight 21–45 kgStandard, p. 743, and growth failurein child 1–6 years, body-weight 8–20 kgShort bowel syndrome, intractablemalabsorption, proven inflammatorybowel disease, bowel fistula,in child 1–10 yearsACBSIndicationsDisease-related malnutrition andgrowth failure in child 1–6 years,body-weight 8–20 kgDisease-related malnutrition andgrowth failure in child 1–6 years,body-weight 8–20 kgDisease-related malnutrition andgrowth failure in child 1–6 years,body-weight 8–20 kgPresentation& FlavourBottle or Flexible pack:500 mL = £5.40Flexible pack:500 mL = £8.71Flexible pack:500 mL = £5.86Can: 400 g = £15.36Vanilla(7.86-g measuring scoop provided)Presentation& FlavourBottle: 200 mL = £2.77Strawberry, vanillaBottle: 200 mL = £2.91Banana, chocolate, strawberry,vanilla, and unflavouredBottle: 200 mL = £2.91Berry fruit, summer fruit754 A2.1 Enteral feeds (non-disease specific) BNFC 2011–2012

Frebini c EnergyDrink(Fresenius Kabi)Frebini c Energy(Fresenius Kabi)Frebini c EnergyFibre Drink(Fresenius Kabi)Frebini c EnergyFibre(Fresenius Kabi)Isosource c Junior(Nestlé)Resource c Junior(Nestlé)Liquid (sip feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (sip feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (sip feed)per 100 mL630 kJ(150 kcal)630 kJ(150 kcal)630 kJ(150 kcal)630 kJ(150 kcal)512 kJ(122 kcal)3.8 gcows’ milk3.75 gcows’ milk3.8 gcows’ milk3.75 gcows’ milk2.7 gcows’ milk630 kJ 3g(150 kcal) 2 cows’ milk1. Sugar content varies with flavour2. Nutritional values vary with flavour—consult product literature18.7 g(sugars 4.5 g)18.75 g(sugars830 mg)18.75 g(sugars 4.5 g 1 )18.75 g(sugars830 mg)6.7 g Nil Gluten-freeResidual lactose6.7 g Nil Gluten-freeResidual lactoseContains fish oil and fishgelatin6.7 g 1.1 g Gluten-freeResidual lactose6.7 g 1.13 g Gluten-freeResidual lactoseContains fish oils and fishgelatin17 g 4.7 g Nil Gluten-freeResidual lactose20.6 g(sugars 4.9 g)6.2 g Nil Gluten-freeResidual lactoseA2.1.3.4 Enteral feeds, Child: 1.5 kcal/mL and more than 4 g protein/100 mLNot suitable for use in child under 1 year unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsNutrini c Energy(Nutricia Clinical)Nutrini c EnergyMulti Fibre(Nutricia Clinical)Liquid (tubefeed)per 100 mLLiquid (tube feed)per 100 mL630 kJ(150 kcal)630 kJ(150 kcal)4.1 gcaseinatewhey protein4.1 gcaseinatewhey protein18.5 g(sugars 1.1 g)18.5 g(sugars 1.1 g)6.7 g Nil Gluten-freeResidual lactoseContains fish oil6.7 g 800 mg Gluten-freeResidual lactoseContains fish oilDisease-related malnutrition andgrowth failure in child 1–10 years,body-weight 8–30 kgStandard, p. 743, and failure inchild 1–10 years, body-weight 8–30 kgDisease-related malnutrition andgrowth failure in child 1–10 years,body-weight 8–30 kgStandard, p. 743, and growth failurein child 1–10 years, body-weight 8–30 kgStandard, p. 743, and growth failurein child 1–6 years, body-weight 8–20 kgStandard, p. 743 in child 1–10yearsACBSIndicationsStandard, p. 743, and growth failurein child 1–6 years, body-weight 8–20 kgPaediatric, p. 743 except bowel fistula;also total gastrectomy, in child1–6 years, body-weight 8–20 kgBottle: 200 mL = £2.42Banana, strawberryFlexible pack:500 mL = £6.21Bottle: 200 mL = £2.47Chocolate, vanillaFlexible pack:500 mL = £6.82Flexible pack:500 mL = £4.99Bottle: 200 mL = £1.84Chocolate, strawberry, vanillaPresentation& FlavourBottle: 200 mL = £2.84Flexible pack:500 mL = £7.28Bottle: 200 mL = £3.01Flexible pack:500 mL = £7.50BNFC 2011–2012 A2.1 Enteral feeds (non-disease specific) 755Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.1.3.4 Enteral feeds, Child: 1.5 kcal/mL and more than 4 g protein/100 mL (product list continued)Not suitable for use in child under 1 year unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsPaediasure c Plus(Abbott)Paediasure c PlusFibre(Abbott)Tentrini c Energy(Nutricia Clinical)Tentrini c EnergyMulti Fibre(Nutricia Clinical)Liquid (sip ortube feed)per 100 mLLiquid (sip ortube feed)per 100 mLLiquid (tube feed)per 100 mLLiquid (tube feed)per 100 mL1. Sugar content varies with presentation632 kJ(151 kcal)626 kJ(150 kcal)630 kJ(150 kcal)630 kJ(150 kcal)4.2 gcaseinateswhey protein4.2 gcaseinateswhey protein4.9 gwhey proteinand caseinate4.9 gwhey proteinand caseinateA2.2 Nutritional supplements (non-disease specific)A2.2.1 Nutritional supplements: less than 5 g protein/100 mL16.7 g 1 7.47 g Nil Gluten-freeResidual lactose16.4 g 1 7.47 g 1.1 g Gluten-freeResidual lactose18.5 g(sugars 1.1 g)18.5 g(sugars 1.1 g)6.3 g Nil Gluten-freeResidual lactoseContains fish oil6.3 g 1.1 g Gluten-freeResidual lactoseContains fish oilA2.2.1.1 Nutritional supplements: 1 kcal/mL and less than 5 g protein/100 mLNot suitable for use in child under 1 year; use with caution in child 1–5 years unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsEnsure c(Abbott)Liquid (sip ortube feed)per 100 mL423 kJ 4g(100 kcal) 1 caseinatessoy isolate1. Nutritional values vary with flavour—consult product literature13.6 g(sugars 3.93 g)3.36 g Nil Gluten-freeResidual lactoseACBSIndicationsPaediatric, p. 743 in child 1–10years, body-weight 8–30 kgPaediatric, p. 743 in child 1–10years, body-weight 8–30 kgStandard, p. 743, and growth failure,in child 7–12 years, bodyweight21–45 kgPaediatric, p. 743, and proveninflammatory bowel disease, inchild 7–12 years, body-weight 21–45 kgACBSIndicationsPresentation& FlavourBottle: 200 mL = £2.56Banana, strawberry, vanilla,unflavouredFlexible pack:500 mL = £6.57VanillaBottle: 200 mL = £2.79VanillaFlexible pack:500 mL = £7.00VanillaBottle or Flexible pack:500 mL = £6.07Bottle or Flexible pack:500 mL = £6.70Presentation& FlavourStandard, p. 743 Can: 250 mL = £2.07Chocolate, coffee, vanilla756 A2.2 Nutritional supplements (non-disease specific) BNFC 2011–2012

A2.2.1.2 Nutritional supplements: More than 1 kcal/mL and less than 5 g protein/100 mLNot suitable for use in child under 1 year; use with caution in child 1–5 years unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsEnsure c Plus Juce(Abbott)Fortijuce c(Nutricia Clinical)Paediasure c PlusJuce(Abbott)ProvideXtra c JuiceDrink(Fresenius Kabi)Resource c DessertEnergy(Nestlé)Resource c Fruit(Nestlé)Liquid (sip feed)per 100 mLLiquid (sip feed)per 100 mLLiquid (sip feed)per 100 mLLiquid (sip feed)per 100 mLSemi-solidper 100 gLiquid (sip feed)per 100 mL638 kJ(150 kcal)640 kJ(150 kcal)4.8 gwhey proteinisolate4.0 gcows’ milk638 kJ 4.2 g(150 kcal) 2 cows’ milk525 kJ(125 kcal)671 kJ(160 kcal)520 kJ(125 kcal)3.75 gpea and soyaproteinhydrolysates4.8 gcows’ milk1. Sugar content varies with flavour2. Nutritional values vary with flavour—consult product literature3. Fibre content varies with flavour4gwhey proteinhydrolysate32.7 g(sugars 9.4 g 1 )33.5 g(sugars13.1 g 1 )33.3 g(sugars 9.4 g)Nil Nil Gluten-freeResidual lactoseNon-milk tasteNil Nil Gluten-freeResidual lactoseNon-milk tasteNil Nil Gluten-freeResidual lactoseNon-milk taste27.5 g 1 Nil Nil 3 Gluten-freeLactose-freeNon-milk tasteSweet-flavoured productscontain fish gelatin21.2 g(sugars 9.9 g 1 )27 g(sugars 9.5 g 1 )6.2 g Nil Gluten-freeContains lactoselessthan200 mgless than Gluten-free200 mg 3 Residual lactoseNon-milk tasteACBSIndicationsPresentation& FlavourStandard, p. 743 Bottle: 220 mL = £1.80Apple, fruit punch, lemon-lime,orange, peach, strawberryStandard, p. 743Not suitable for child under 3 yearsNutritional supplement in child 1–10 years, body-weight 8–30 kg withdisease-related malnutrition and, orgrowth failureBottle: 200 mL = £1.85Apple, black currant, forest fruits,lemon, orange, strawberry,tropicalStarter pack (mixed)4 200 mL = £7.40Bottle: 200 mL = £2.77Apple, very berryStandard, p. 743 Carton: 200 mL = £1.75Apple, black currant, carrot-apple,cherry, citrus-cola, lemon-lime,melon, orange-pineapple, tomatoStandard, p. 743; alsoCAPD, haemodialysisStandard, p. 743Not suitable for child under 3 yearsCup: 125 g = £1.47Caramel, chocolate, vanillaBottle:4 200 mL = £7.02Apple, orange, pear-cherry, raspberry-blackcurrantBNFC 2011–2012 A2.2 Nutritional supplements (non-disease specific) 757Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.2.2 Nutritional supplements: 5 g (or more) protein/100 mLA2.2.2.1 Nutritional supplements: 1.5 kcal/mL and 5 g (or more) protein/100 mLNot suitable for use in child under 1 year; use with caution in child 1–5 years unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsEnsure c Plus Fibre(Abbott)Ensure c PlusMilkshake style(Abbott)Ensure c PlusYoghurt style(Abbott)Ensure c PlusCommence(Abbott)Fortisip c Bottle(Nutricia Clinical)Fortisip c MultiFibre(Nutricia Clinical)Fortisip c YoghurtStyle(Nutricia Clinical)Liquid (sip ortube feed)per 100 mLLiquid (sip ortube feed)per 100 mLLiquid (sip feed)per 100 mL642 kJ 6.25 g(153 kcal) 1 cows’ milksoya proteinisolate632 kJ 6.25 g(150 kcal) 1 cows’ milksoya proteinisolate632 kJ 6.25 g(150 kcal) 1 cows’ milk20.2 g(sugars 5.5 g)20.2 g(sugars 5.6 gincl. sucrose)20.2 g(sugars 11.7 g)4.92 g 2.5 g Gluten-freeResidual lactose4.92 g Nil Gluten-freeResidual lactose4.92 g Nil Gluten-freeResidual lactoseStarter pack (5–10 day’s supply), contains: Ensure c Plus Milkshake Style (various flavours), 1 pack (10 220-mL) = £18.52.Liquid (sip feed)per 100 mLLiquid (sip feed)per 100 mLLiquid (sip feed)per 100 mL630 kJ(150 kcal)630 kJ(150 kcal)630 kJ(150 kcal)1. Nutritional values vary with flavour—consult product literature2. Sugar content varies with flavour6gcows’ milk6gcows’ milk6gcows’ milk18.4 g 2 5.8 g Nil Gluten-freeResidual lactose18.4 g(sugars 7.0 g)18.7 g(sugars 10.8 g)5.8 g 2.3 g Gluten-freeResidual lactose5.8 g 200 mg Gluten-freeContains lactoseACBSIndicationsStandard, p. 743; alsoCAPD, haemodialysisStandard, p. 743; also CAPD,haemodialysisStandard, p. 743; also CAPD,haemodialysisStandard, p. 743Not suitable for child under 3 yearsStandard, p. 743Not suitable for child under 3 yearsStandard, p. 743Not suitable for child under 3 yearsPresentation& FlavourBottle: 200 mL = £1.85Banana, chocolate, fruits of theforest, raspberry, strawberry,vanillaCan: 250 mL = £2.35Chicken, mushroomBottle: 220 mL = £1.85Banana, black currant, caramel,chocolate, coffee, fruits of theforest, orange, peach, raspberry,strawberry, vanilla, neutralBottle: 220 mL = £1.85Orange, peach, pineapple, strawberryBottle: 200 mL = £1.85Banana, chocolate, neutral,orange, strawberry, toffee,tropical fruits, vanillaBottle: 200 mL = £1.91Banana, chocolate, orange,strawberry, vanillaBottle: 200 mL = £1.85Peach-orange, raspberry, vanillalemon758 A2.2 Nutritional supplements (non-disease specific) BNFC 2011–2012

Fortisip c Range(Nutricia Clinical)Fresubin c ProteinEnergy Drink(Fresenius Kabi)Fresubin cThickened(Fresenius Kabi)Starter pack contains 4 Fortisip c Bottle, 4 Fortijuce c ,2 Fortisip c Yogurt Style, 1 pack (10 200 mL) = £18.50.Liquid (sip feed)per 100 mLLiquid (sipfeed)per 100 mL1. Sugar content varies with flavour2. Fibre content varies with flavour3. Sugar content varies with consistency4. Fibre content varies with consistency630 kJ(150 kcal)630 kJ(150 kcal)10 gcows’ milk10 gcows’ milk12.4 g(sugars 6.4 g 1 )12.2 g(sugars 7.1 g 3 )6.7 g Nil 2 Gluten-freeResidual lactoseContains fish gelatin6.7 g 480 mg 4 Gluten-freeResidual lactoseA2.2.2.2 Nutritional supplements: Less than 1.5 kcal/mL and 5 g (or more) protein/100 mLNot suitable for use in child under 1 year; use with caution in child 1–5 years unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsClinutren c Dessert(Nestlé)Ensure c PlusCrème(Abbott)Fortimel c Regular(Nutricia Clinical)Fortisip c FruitDessert(Nutricia Clinical)Semi-solidper 100 gSemi-solidper 100 gLiquid (sip feed)per 100 mLSemi-Solidper 100 g520 kJ(125 kcal)9.5 gcows’ milk574 kJ 5.68 g(137 kcal) 3 cow’s milkandsoy proteinisolates420 kJ(100 kcal)560 kJ(133 kcal)10 gcows’ milk1. Sugar content varies with flavour2. Fibre content varies with flavour3. Nutritional values vary with flavour—consult product literature7gwhey isolate15.5 g(sugars 14 g 1 )18.4 g(sugars 12.4 g)10.3 g(sugars 8.1 g 1 )16.7 g(sugars 11.3 g)2.6 g 500 mg 2 Gluten-freeContains lactose4.47 g Nil Gluten-freeResidual lactoseContains soya2.1 g Nil Gluten-freeContains lactoseStandard, p. 743; alsoCAPD, haemodialysisDysphagia or disease-related malnutritionNot suitable for child under 3 years.ACBSIndicationsStandard, p. 743; alsoCAPD, haemodialysisNot suitable for child under 3 yearsStandard, p. 743; alsoCAPD, haemodialysisNot suitable for child under 3 yearsStandard, p. 743Not suitable for child under 3 years4 g 2.6 g Residual lactose Standard, p. 743except bowel fistula; also CAPD,haemodialysisNot suitable for child under 3 yearsBottle: 200 mL = £1.82Cappuccino, chocolate, strawberry,tropical fruits, vanillaBottle: 200 mL = £2.10Syrup (Stage 1) and custard(Stage 2) consistenciesStrawberry, vanillaPresentation& FlavourPot: 4 125 g = £5.88Caramel, chocolate, peach, vanillaPot: 125 g = £1.72Banana, chocolate, neutral,vanillaBottle: 200 mL = £1.57Chocolate, forest fruits, strawberry,vanillaPot: 3 150 g = £6.49Apple, strawberryBNFC 2011–2012 A2.2 Nutritional supplements (non-disease specific) 759Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.2.2.2 Nutritional supplements: Less than 1.5 kcal/mL and 5 g (or more) protein/100 mL (product list continued)Not suitable for use in child under 1 year; use with caution in child 1–5 years unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsOral Impact c(Nestlé)Standard dilutionof powder (74 gin 250 mL water)(sip feed)per 100 mL425 kJ 5.6 g(101 kcal) 1 cows’ milk13.4 g(sugars 7.4 g)Powder provides: protein 16.8 g, carbohydrate 40.2 g, fat 8.3 g, fibre 3 g, energy 1276 kJ (303 kcal)/74 gResource c Protein(Nestlé)Liquid (sip feed)per 100 mL530 kJ 9.4 g(125 kcal) 1 cows’ milk1. Nutritional values vary with flavour—consult product literature14 g(sugars 4.5 g)2.8 g 1 g Residual lactoseContains fish oil3.5 g Nil Gluten-freeContains lactoseA2.2.2.3 Nutritional supplements: More than 1.5 kcal/mL and 5 g (or more) protein/100 mLNot suitable for use in child under 1 year; use with caution in child 1–5 years unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsComplan c Shake(Complan Foods)Powderper 57 g1057 kJ 8.8 g(251 kcal) 1 cows’ milk35.2 g(sugars 22.7 g)8.4 g Trace Gluten-freeContains lactoseACBSIndicationsPre-operative nutritional supplementfor malnourished patients orpatients at risk of malnourishmentNot suitable for child under 3 yearsStandard, p. 743Not suitable for child under 3 yearsACBSIndicationsPresentation& FlavourSachet: 5 74 g = £15.41Citrus, coffee, tropicalBottle: 200 mL = £1.45Apricot, chocolate, forest fruits,strawberry, vanillaPresentation& FlavourStandard, p. 743 Sachet: 4 57 g = £3.44Banana, chocolate, original,strawberry, vanillaStarter pack: 5 57 g = £5.0721.9 gPowder 57 g reconstituted with 200 mL whole milk provides: protein 15.6 g, carbohydrate 44.5 g, fat 16.4 g, energy 1621kJ (387 kcal)Foodlink cPowder1838 kJ57.3 g 13.3 g Nil Contains lactose Standard, p. 743 Carton: 450 g = £3.29Complete(Foodlink)per 100 g (437 kcal) 1 cows’ milkBanana, chocolate, neutral,strawberryRecommended serving = 3 heaped tablespoonfuls in 250 mL water provides: protein 12.5 g, carbohydrate 32.7 g, fat 7.6 g, energy 1048 kJ (249 kcal) 1Foodlink cComplete with Fibre(Foodlink)Powderper 100 g1804 kJ(428 kcal) 1 19.5 gcows’ milk57.1 g(sugars 36.8 g)12.3 g 8 g Contains lactose Standard, p. 743 Sachet: 10 63 g = £6.67Vanilla + fibreRecommended serving = 4 heaped tablespoonfuls in 250 mL water provides: protein 12.3 g, carbohydrate 38 g, fat 7.5 g, fibre 5 g, energy 1137 kJ (270 kcal) 11. Nutritional values vary with flavour—consult product literature760 A2.2 Nutritional supplements (non-disease specific) BNFC 2011–2012

Forticreme cComplete(Nutricia Clinical)Fortisip c Compact(Nutricia Clinical)Fortisip c Extra(Nutricia Clinical)Fresubin c 2 kcal(Fresenius Kabi)Fresubin c 2 kcalFibre(Fresenius Kabi)Fresubin c Crème(Fresenius Kabi)Nutilis c CompleteStage 1(Nutricia Clinical)Renilon c 7.5(Nutricia Clinical)Resource c 2.0Fibre(Nestlé)Resource c DessertFruit(Nestlé)Semi-solidper 100 gLiquid (sip feed)per 100 mLLiquid (sip feed)per 100 mLLiquid (sip feed)per 100 mLLiquid (sip feed)per 100 mLSemi-solidper 100 gLiquid (pre-thickened)per 100 mLLiquid (sip feed)per 100 mLLiquid (sip feed)per 100 mLSemi-solidper 100 g675 kJ(160 kcal)1010 kJ(240 kcal)675 kJ(160 kcal)840 kJ(200 kcal)840 kJ(200 kcal)756 kJ(180 kcal)1010 kJ(240 kcal)840 kJ(200 kcal)9.5 gcows’ milk9.6 gcows’ milk10 gcows’ milk10 gcows’ milk10 gcows’ milk10 gcows’ milk9.6 gcows’ milk7.5 gcows’ milk836 kJ 9g(200 kcal) 2 cows’ milk678 kJ 5g(160 kcal) 2 cows’ milk1. Fibre content varies with flavour2. Nutritional values vary with flavour—consult product literature3. Flavour not suitable for child under 3 years19.2 g(sugars 10.6 g)29.7 g(sugars 15 g)18.1 g(sugars 9 g)22.5 g(sugars 5.8 g)22.5 g(sugars 5.8 g)19 g(sugars 14.4 g)29.1 g(sugars 5.4 g)20 g(sugars 4.8 g)21.4 g(sugars 5.5 g)24 g(sugars 16.4 g)5 g 100 mg 1 Gluten-freeResidual lactoseStandard, p. 743; alsoCAPD, haemodialysisNot suitable for child under 3 years9.3 g Nil Residual lactose Standard, p. 743Not suitable for child under 3 years5.3 g Nil 1 Gluten-freeContains lactose7.8 g Nil Gluten-freeContains lactose7.8 g 1.6 g Gluten-freeContains lactose7.2 g 2 g Gluten-freeResidual lactoseStandard, p. 743Not suitable for child under 3 yearsStandard, p. 743; alsoCAPD, haemodialysisStandard, p. 743; alsoCAPD, haemodialysisStandard, p. 743; alsoCAPD, haemodialysisNot suitable for child under 3 years9.3 g 3.2 g Residual lactose Standard, p. 743Not suitable for child under 3 years10 g Nil Gluten-freeResidual lactose8.7 g 2.5 g Gluten-freeResidual lactose5 g 1.4 g Gluten-freeResidual lactoseStandard, p. 743Not suitable for child under 3 yearsStandard, p. 743Not suitable for child under 6 years;caution in child 6–10 yearsStandard, p. 743; alsoCAPD, haemodialysisPot: 4 125 g = £7.20Banana, chocolate, forest fruits,vanillaBottle: 125 mL = £1.85Apricot, banana, mocha, strawberry,vanillaStarter pack: 6 125 mL =£11.10Bottle: 200 mL = £1.85Chocolate, forest fruits, mocha,strawberry, vanillaStarter pack: forest fruits, 4 200 mL = £7.58Bottle: 200 mL = £1.73Apricot-peach, cappuccino, fruitsof the forest, toffee, vanillaBottle: 200 mL = £1.73Cappuccino, chocolate, lemon,vanillaPot: 4 125 g = £7.08Cappuccino, chocolate, praline,strawberry, vanillaBottle: 125 mL = £2.10Strawberry, vanillaCarton: 125 mL = £1.85Apricot, caramelCarton: 200 mL = £1.80Apricot, coffee, neutral, strawberry,summer fruits, vanillaCup: 3 125 g = £4.41Apple, apple-peach, applestrawberry3BNFC 2011–2012 A2.2 Nutritional supplements (non-disease specific) 761Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.2.2.3 Nutritional supplements: More than 1.5 kcal/mL and 5 g (or more) protein/100 mL (product list continued)Not suitable for use in child under 1 year; use with caution in child 1–5 years unless otherwise statedProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsACBSIndicationsVegenat-med cBalanced Protein(Vegenat)Vegenat-med cHigh Protein(Vegenat)Powderper 110 g servingPowderper 110 g serving1924 kJ(458 kcal) 1 18 gcows’ milk1940 kJ 23.3 g(463 kcal) 1 cows’ milk1. Nutritional values vary with flavour—consult product literature62 g 15.35 g 5.8 g Gluten-freeResidual lactose57.2 g 15.6 g 6 g Gluten-freeResidual lactoseStandard, p. 743 except bowel fistulaNot suitable for child under 14 yearsStandard, p. 743 except bowel fistulaNot suitable for child under 14 yearsPresentation& FlavourSachet:12 110 g = £36.26Apple, chocolate, honey, orangeSachet:12 110 g = £50.76Chicken, chickpea, fish, fishvegetable,ham, lentil, veal,vegetable, winter vegetable12 110 g = £48.95Curry chicken12 110 g = £48.22Lemon, rice with lemon24 55 g = £46.50Rice with apple762 A2.2 Nutritional supplements (non-disease specific) BNFC 2011–2012

A2.3 Specialised formulasA2.3.1 Specialised formulas: Infant and childSpecialised formulas are suitable for infants from birth unless otherwise indicated (see also A2.1.3.1 Enteral feeds (non-disease specific): Child under 12 years)Product Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsACBSIndicationsSpecialised formulas: Infant and child: Amino acid-based formulaPresentation& FlavourACBS Indications: Proven whole protein intolerance, short bowel syndrome, intractable malabsorption, or other gastro-intestinal disorders where an elemental diet is indicatedNeocate c Active(SHS)Standard dilution(21 %) of powderper 300 mL serving(63-g sachetmade up to300 mL withwater)1255 kJ(300 kcal)8.3 gproteinequivalent(essentialand nonessentialamino acids)34 g(sugars 3.1 g 1 )Powder provides: protein equivalent 13.1 g, carbohydrate 54 g, fat 23 g, energy 1992 kJ (475 kcal)/100 gNeocate c Advance(SHS)Standard dilution(25%) of powderper 100 mL420 kJ(100 kcal)2.5 gproteinequivalent(essentialand nonessentialamino acids)14.6 g(sugars 1.3 g 1 )14.5 g Nil Milk protein-free See aboveNutritional supplement onlyNot suitable for child under 1 year3.5 g(MCT35 %)Powder provides: protein equivalent 10 g, carbohydrate 58.5 g, fat 14 g, energy 1683 kJ (400 kcal)/100 gNeocate c LCP(SHS)Standard dilution(14.7%) of powderper 100 mL293 kJ(70 kcal)1.9 gproteinequivalent(essentialand nonessentialamino acids)7.9 g(sugars720 mg)Powder provides: protein equivalent 13 g, carbohydrate 54 g, fat 23 g, energy 1990 kJ (475 kcal)/100 g1. Sugar content varies with flavour2. Flavouring: see Modjul c Flavour System, p. 777Nil Milk protein-free See aboveNot suitable for child under 1 year3.4 g Nil Milk protein-free Cows’ milk allergy, multiple foodprotein intolerance, and conditionsrequiring an elemental dietSachet:15 63 g = £56.04Black currant, unflavoured 2Sachet: 100 g = £4.94Unflavoured 215 50 g = £38.99Banana-vanillaCan:400 g = £23.83(4.9-g measuring scoop provided)BNFC 2011–2012 A2.3 Specialised formulas 763Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.3.1 Specialised formulas: Infant and child (product list continued)Specialised formulas are suitable for infants from birth unless otherwise indicated (see also A2.1.3.1 Enteral feeds (non-disease specific): Child under 12 years)Product Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsNutramigen c AA(Mead Johnson)Standard dilution(13.6 %) of powderper 100 mL286 kJ(68 kcal)1.89 gessential andnon-essentialamino acidsPowder provides: protein 13.9 g, carbohydrate 51 g, fat 26 g, energy 2092 kJ (498 kcal)/100 gSpecialised formulas: Infant and child: Hydrolysate formulaAptamil Pepti c 1(Allergy)(Milupa)Standard dilution(13.6 %) of powderper 100 mL280 kJ(67 kcal)1.6 gwhey hydrolysed7 g 3.6 g Nil Gluten-freeLactose-free7.1 g(sugars 3.5 g)Formerly Aptamil Pepti cPowder provides: protein 11.6 g, carbohydrate 52 g, fat 25.6 g, energy 2025 kJ (484 kcal)/100 gAptamil Pepti c 2(Allergy)(Milupa)Standard dilution(14.3 %) of powderper 100 mL285 kJ(68 kcal)1.6 g 8 g(sugars 3.6 g)Powder provides: protein 11.2 g, carbohydrate 56.1 g, fat 21.8 g, energy 1985 kJ (473 kcal)/100 gCow & Gate Pepti-Junior c(Cow & Gate)Standard dilution(12.8 %) of powderper 100 mL275 kJ(66 kcal)1.8 gwhey hydrolysed6.8 g(sugars 1.1 g)Powder provides: protein 14 g, carbohydrate 53.4 g, fat 27.3 g, energy 2155 kJ (515 kcal)/100 gNutramigen c Lipil 1(Mead Johnson)Standard dilution(13.5 %) of powderper 100 mL280 kJ(68 kcal)1.9 gcasein hydrolysedPowder provides: protein 14 g, carbohydrate 55 g, fat 25 g, energy 2100 kJ (500 kcal)/100 g3.5 g 600 mg Contains lactose and fishoil3.1 g 600 mg Contains lactose and fishoil3.5 g Nil Residual lactoseContains fish oil7.5 g 3.4 g Nil Gluten-freeLactose-freeACBSIndicationsSevere cows’ milk protein intolerance,or multiple food intolerance,and other gastro-intestinal disorderswhere an elemental diet isspecifically indicatedEstablished cows’ milk proteinintolerance, with or without secondarylactose intoleranceEstablished cows’ milk proteinallergy or intoleranceNot suitable for child under 6monthsDisaccharide and/or whole proteinintolerance, or where amino acidsand peptides are indicated in conjunctionwith medium chain triglyceridesDisaccharide and/or whole proteinintolerance where additional mediumchain triglycerides are notincludedPresentation& FlavourCan:400 g = £22.89(4.5-g measuring scoop provided)Can:400 g = £8.62900 g = £19.39(4.5-g measuring scoop provided)Can:900 g = £19.39(4.8-g measuring scoop provided)Can:450 g = £11.01(4.3-g measuring scoop provided)Can:400 g = £9.29(4.5-g measuring scoop provided)764 A2.3 Specialised formulas BNFC 2011–2012

Nutramigen c Lipil 2(Mead Johnson)Standard dilution(14.6 %) of powderper 100 mL285 kJ(68 kcal)1.7 gcasein hydrolysedPowder provides: protein 11.6 g, carbohydrate 59 g, fat 20 g, energy 1950 kJ (466 kcal)/100 gPepdite c297 kJ(SHS)(71 kcal)Standard dilution(15 %) of powderper 100 mL2.1 gproteinequivalent(non-milkhydrolysate)8.6 g 2.9 g Nil Gluten-freeLactose-free7.8 g(sugars700 mg)Powder provides: protein equivalent 13.8 g, carbohydrate 52 g, fat 23.2 g, energy 1977 kJ (472 kcal)/100 gPepdite c 1+(SHS)423 kJ(100 kcal)13 g(sugars 1.2 g)NilStandard dilution(22.8 %) of powderper 100 mL3.1 gproteinequivalent(non-milkhydrolysate,essentialamino acids)3.5 g Nil Lactose-freeContains meat (pork) andsoya derivatives3.9 g(MCT35 %)Powder provides: protein equivalent 13.8 g, carbohydrate 57 g, fat 17.3 g, energy 1844 kJ (439 kcal)/100 gPregestimil c Lipil(Mead Johnson)280 kJ(68 kcal)NilStandard dilution(13.5 %) of powderper 100 mL1.89 gcasein hydrolysed6.9 g 3.8 g(MCT54 %)Powder provides: protein 14 g, carbohydrate 51 g, fat 28 g, energy 2100 kJ (500 kcal)/100 gSpecialised formulas: Infant and child: Residual lactose formulaEnfamil c O-Lac(Mead Johnson)Standard dilution(13%) of powderper 100 mL280 kJ(68 kcal)1.42 gcows’ milkPowder provides: protein 10.9 g, carbohydrate 55 g, fat 28 g, energy 2200 kJ (524 kcal)/100 gGalactomin 17 c(SHS)295 kJ(70 kcal)7.5 g(sugars 1.4 g)Standard dilution(13.6%) of powderper 100 mL1.7 gproteinequivalent(cows’ milk)Powder provides: protein equivalent 12.3 g, carbohydrate 55.3 g, fat 27.2 g, energy 2155 kJ (515 kcal)/100 g1. Flavouring: see Modjul c Flavour System, p. 777Lactose-freeContains meat (pork) andsoya derivativesGluten-freeLactose-free7.2 g 3.7 g Nil Gluten-freeResidual lactoseEstablished disaccharide and/orwhole protein intolerance (whereadditional chain triglycerides are notindicated)Not suitable for child under 6monthsDisaccharide and/or whole proteinintoleranceDisaccharide and/or whole proteinintolerance, or where amino acids orpeptides are indicated in conjunctionwith medium chain triglyceridesNot suitable for child under 1 yearDisaccharide and/or whole proteinintolerance, or where amino acids orpeptides are indicated in conjunctionwith medium chain triglyceridesProven lactose intolerance3.7 g Nil Residual lactose Proven lactose intolerance in preschoolchildren, galactosaemia, andgalactokinase deficiencyCan:400 g = £8.95(4.9-g measuring scoop provided)Can:400 g = £15.05(5-g measuring scoop provided)Can:400 g = £15.81Unflavoured 1Can:400 g = £10.18(4.5-g measuring scoop provided)Can:400 g = £4.16(4.3-g measuring scoop provided)Can:400 g = £14.13Unflavoured 1(4.3-g measuring scoop provided)BNFC 2011–2012 A2.3 Specialised formulas 765Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.3.1 Specialised formulas: Infant and child (product list continued)Specialised formulas are suitable for infants from birth unless otherwise indicated (see also A2.1.3.1 Enteral feeds (non-disease specific): Child under 12 years)Product Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsSMA c LF(SMA Nutrition)Standard dilution(13 %) of powderper 100 mL281 kJ(67 kcal)1.5 gcasein, whey7.2 g(sugars 2.6 g)Powder provides: protein 12 g, carbohydrate 55.6 g, fat 28 g, energy 2185 kJ (522 kcal)/100 gSpecialised formulas: Infant and child: MCT-enhanced formulaCaprilon c(SHS)Standard dilution(12.7 %) of powderper 100 mL277 kJ(66 kcal)1.5 gcows’ milk7g(sugars 1.3 g)Powder provides: protein 11.8 g, carbohydrate 55.1 g, fat 28.3 g, energy 2184 kJ (522 kcal)/100 gMCT Pepdite c(SHS)Standard dilution(15 %) of powderper 100 mL286 kJ(68 kcal)2gproteinequivalent(non-milkpeptides,essentialamino acids)8.8 g(sugars 1.2 g)ACBSIndicationsPresentation& Flavour3.6 g Nil Residual lactose Proven lactose intolerance Can:430 g = £4.60.3.6 g(MCT75 %)2.7 g(MCT75 %)Powder provides: protein equivalent 13.8 g, carbohydrate 59 g, fat 18 g, energy 1903 kJ (453 kcal)/100 gMCT Pepdite c +1(SHS)Standard dilution(20 %) of powderper 100 mL381 kJ(91 kcal)2.8 gproteinequivalent(non-milkpeptides,essentialamino acids)11.8 g(sugars 1.6 g)3.6 g(MCT75 %)Powder provides: protein equivalent 13.8 g, carbohydrate 59 g, fat 18 g, energy 1903 kJ (453 kcal)/100 gMonogen c(SHS)Standard dilution(17.5%) of powderper 100 mL313 kJ(74 kcal)2gproteinequivalent(whey)12 g(sugars 1.2 g)2.1 g(MCT90 %)Powder provides: protein equivalent 11.4 g, carbohydrate 68 g, fat 11.8 g, energy 1786 kJ (424 kcal)/100 g1. Flavouring: see Modjul c Flavour System, p. 777Nil Contains lactose Disorders in which a high intake ofMCT is beneficialNilNilNilGluten-freeLactose-freeContains meat (pork) andsoya derivativesGluten-freeLactose-freeContains meat (pork) andsoya derivativesResidual lactoseSupplementation withessential fatty acids maybe neededDisorders in which a high intake ofMCT is beneficialDisorders in which a high intake ofMCT is beneficialNot suitable for child under 1 yearLong-chain acyl-CoA dehydrogenasedeficiency (LCAD), carnitine palmitoyltransferase deficiency (CPTD),primary and secondary lipoproteinlipase deficiencyCan:420 g = £14.62(4.2-g measuring scoop provided)Can:400 g = £16.39(5-g measuring scoop provided)Can:400 g = £16.39Unflavoured 1Can:400 g = £17.07Unflavoured 1(5-g measuring scoop provided)766 A2.3 Specialised formulas BNFC 2011–2012

Specialised formulas: Infant and child: Soya-based formulaInfaSoy c(Cow & Gate)Standard dilution(12.8 %) of powderper 100 mL275 kJ(66 kcal)1.6 gsoya7g(sugars 1 g)Powder provides: protein 12.8 g, carbohydrate 54.5 g, fat 27.3 g, energy 2150 kJ (514 kcal)/100 gWysoy c(Wyeth)Standard dilution(13.2%) of powderper 100 mL280 kJ(67 kcal)1.8 gsoya proteinisolate6.9 g(sugars 2.5 g)Powder provides: protein 14 g, carbohydrate 54 g, fat 27 g, energy 2155 kJ (515 kcal)/100 gSpecialised formulas: Infant and child: Low calcium formulaLocasol c(SHS)Standard dilution(13.1%) of powderper 100 mL278 kJ(66 kcal)1.9 gcows’ milk7g(sugars 6.9 g)Powder provides: protein 14.6 g, carbohydrate 53.7 g, fat 26.1 g, energy 2125 kJ (508 kcal)/100 gSpecialised formulas: Infant and child: Fructose-based formulaGalactomin 19 c(SHS)Standard dilution(12.9%) of powderper 100 mL288 kJ(69 kcal)1.9 gproteinequivalent(cows’ milk)6.4 g(fructose 6.3 g)3.5 g Nil Lactose-free Proven lactose and associated sucroseintolerance in pre-school children,galactokinase deficiency,galactosaemia, and proven wholecows’ milk sensitivity3.6 g Nil Lactose-free Proven lactose and associated sucroseintolerance in pre-school children,galactokinase deficiency,galactosaemia, and proven wholecows’ milk sensitivity3.4 g Nil Contains lactoseCalcium less than 7 mg/100 mLNo added vitamin D4 g Nil Residual lactose, galactoseand glucosePowder provides: protein equivalent 14.6 g, carbohydrate 49.7 g, fat 30.8 g, energy 2233 kJ (534 kcal)/100 gSpecialised formulas: Infant and child: Pre-thickened infant feedsNote Not to be used for a period of more than 6 months; not to be used in conjunction with any other feed thickener or antacid productsEnfamil c AR(Mead Johnson)Standard dilution(13.5%) of powderper 100 mL285 kJ(68 kcal)1.7 gcows’ milk7.6 g(lactose 4.6 g)Powder provides: protein 12.5 g, carbohydrate 56 g, fat 26 g, energy 2093 kJ (500 kcal)/100 gSMA c Staydown(SMA Nutrition)Standard dilution(12.9%) of powderper 100 mL279 kJ(67 kcal)1.6 gcasein, whey7g(lactose 5 g)Powder provides: protein 12.4 g, carbohydrate 54.3 g, fat 28 g, energy 2166 kJ (518 kcal)/100 g3.5 g Nil Contains lactose, pregelatinisedrice starch3.6 g Nil Contains lactose, precookedcorn starchConditions of calcium intolerancerequiring restriction of calcium andvitamin D intakeConditions of glucose plus galactoseintoleranceSignificant gastro-oesophagealrefluxSignificant gastro-oesophagealrefluxCan:900 g = £7.47(4.3-g measuring scoop provided)Can:430 g = £4.59860 g = £8.75Can:400 g = £19.63(4.4-g measuring scoop provided)Can:400 g = £37.18Can:400 g = £3.12(4.5-g measuring scoop provided)Can:900 g = £6.62BNFC 2011–2012 A2.3 Specialised formulas 767Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.3.2 Specialised formulas for specific clinical conditionsProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsAlicalm c(SHS)Standard dilution(30%) of powderper 100 mL567 kJ(135 kcal)4.5 gcaseinatewhey17.4 g(sugars 3.2 g)Powder provides: protein 15 g, carbohydrate 58 g, fat 17.5 g, energy 1889 kJ (450 kcal)/100 gForticare c(Nutricia Clinical)Liquid (sip feed)per 100 mL675 kJ(160 kcal)9gcows’ milk19.1 g(sugars 13.6 g)Generaid c(SHS)Generaid c Plus(SHS)Powderper 100 gStandard dilution(22 %) of powderper 100 mL1586 kJ(374 kcal)428 kJ(102 kcal)76 gproteinequivalent(whey protein,plusbranchedchain aminoacids)2.4 gproteinequivalent(whey protein,branchedchain aminoacids)5g(sugars 5 g)13.6 g(sugars 1.4 g)ACBSIndications5.3 g Nil Residual lactose Crohn’s diseaseNot suitable for child under 1 year;use as nutritional supplement onlyin children 1–6 years.5.3 g 2.1 g Gluten-freeResidual lactoseContains fish oil5.5 g Nil Electrolytes/100 g:Na + 6.1 mmolK + 10.8 mmolCa 2þ 6.5 mmolP + 6.45 mmol4.2 g(MCT32 %)Powder provides: protein equivalent 11 g, carbohydrate 62 g, fat 19 g, energy 1944 kJ (463 kcal)/100 gHeparon c Junior(SHS)Standard dilution(18%) of powderper 100 mL363 kJ(86 kcal)2gcows’ milk11.6 g(sugars 2.9 g)Powder provides: protein 11.1 g, carbohydrate 64.2 g, fat 19.9 g, energy 2016 kJ (480 kcal)/100 g1. Flavouring: see Modjul c Flavour System, p. 777NilElectrolytes/100 mL:Na + 0.7 mmolK + 2.7 mmolCa 2þ 1.72 mmolP + 1.67 mmol3.6 g Nil Contains lactoseElectrolytes/100 mL:Na + 0.56 mmolK + 1.9 mmolCa 2þ 2.3 mmolP + 1.6 mmolNutritional supplement in patientswith lung cancer undergoingchemotherapy, or with pancreaticcancerNot suitable in child under 3 yearsNutritional supplement for use inchronic liver disease and/or portohepaticencephalopathyEnteral feed or nutritional supplementin children over 1 year withhepatic disordersEnteral feed or nutritional supplementfor children with acute orchronic liver failurePresentation& FlavourPowder:400 g = £18.08VanillaCarton:125 mL = £2.02Cappuccino, orange-lemon,peach-ginger.Tub:400 g = £51.46Unflavoured 1Can:400 g = £18.40Unflavoured 1(5-g measuring scoop provided)Can: 400 g = £18.20(4.5-g measuring scoop provided)768 A2.3 Specialised formulas BNFC 2011–2012

KetoCal c(SHS)Standard dilution(20 %) of powderper 100 mL602 kJ(146 kcal)3.1 gcows’ milkwith additionalaminoacids600 mg(sugars120 mg)Powder provides: protein 15.25 g, carbohydrate 3 g, fat 73 g, energy 3011 kJ (730 kcal)/100 gKetoCal c 4:1 LQ(SHS)Kindergen c(SHS)Liquid (sip ortube feed)per 100 mLStandard dilution(20 %) of powderper 100 mL620 kJ(150 kcal)421 kJ(101 kcal)3.09 gcasein andwhey withadditionalamino acids1.5 gwhey protein610 mg(sugars230 mg)11.8 mg(sugars 1.2 g)Powder provides: protein 7.5 g, carbohydrate 59 g, fat 26.3 g, energy 2104 kJ (504 kcal)/100 gModulen IBD c(Nestlé)Standard dilution(20%) of powder(sip or tube feed)per 100 mL420 kJ(100 kcal)3.6 gcaseinPowder provides: protein 18 g, carbohydrate 54 g, fat 23 g, 2070 kJ (500 kcal)/100 gNepro c(Abbott)838 kJ(200 kcal) 2 7gcows’ milkProSure c(Abbott)Liquid (sip ortube feed)per 100 mLLiquid (sip ortube feed)per 100 mL529 kJ(125 kcal) 2 6.65 gcows’ milk1. Flavouring: see Flavour Mix c , p. 7772. Nutritional values vary with flavour—consult product literature11 g(sugars 3.98 g)20.6 g(sugars 3.26 g)18.3 g(sugars 2.95 g)14.6 g(LCT100 %)14.8 g(LCT100 %)5.3 g(LCT93 %)NilElectrolytes/100 mL:Na + 4.3 mmolK + 4.1 mmolCa 2þ 2.15 mmolP + 2.77 mmol1.12 g Residual lactoseElectrolytes/100 mL:Na + 4.9 mmolK + 4.7 mmolCa 2þ 2.4 mmolP + 3.1 mmolNilElectrolytes/100 mL:Na + 2 mmolK + 0.6 mmolCa 2þ 2.8 mmolP + 3 mmolLow Vitamin A4.7 g Nil Gluten-freeResidual lactose9.6 g 1.56 g Gluten-freeResidual lactoseElectrolytes/100 mL:Na + 3.67 mmolK + 2.72 mmolCa 2þ 3.43 mmolP + 2.23 mmol2.56 g 2.07 g Gluten-freeResidual lactoseContains fish oilEnteral feed or nutritional supplementas part of ketogenic diet inmanagement of epilepsy resistant todrug therapy, in children over 1 year,only on the advice of secondary carephysician with experience of ketogenicdietEnteral feed or nutritional supplementas part of ketogenic diet inmanagement of drug resistant epilepsyor other conditions for which aketogenic diet is indicated in children1–10 years; as a nutritionalsupplement in children over 10yearsEnteral feed or nutritional supplementfor children with chronic renalfailure receiving peritoneal rapidovernight dialysisCrohn’s disease active phase, andin remission if malnourishedEnteral feed or nutritional supplementin patients with chronic renalfailure who are on haemodialysis orCAPD, or with cirrhosis, or otherconditions requiring a high energy,low fluid, low electrolyte diet.Not suitable for child under 1 year;use with caution in child 1–5 yearsNutritional supplement for patientswith pancreatic cancerNot suitable for child under 1 year;use with caution in child 1–4 yearsCan:300 g = £25.62Vanilla, UnflavouredCarton:237 mL = £4.56VanillaTub:400 g = £24.44(5-g measuring scoop provided)Can:400 g = £14.38Unflavoured 1(8.3-g measuring scoop provided)Carton:200 mL = £2.41Strawberry, vanillaFlexible pack:500 mL = £5.22VanillaCarton:240 mL = £2.85VanillaBNFC 2011–2012 A2.3 Specialised formulas 769Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.3.2 Specialised formulas for specific clinical conditions (product list continued)Product Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsRenamil c(KoRa)Renapro c(KoRa)Powder (sip ortube feed whenreconstituted)per 100 gPowderper 100 g2003 kJ(477 kcal)1580 kJ(372 kcal)4.6 gcows’ milkPowder provides: protein 18 g, energy 316 kJ (74 kcal)/20-g sachetRenastart c(Vitaflo)Standard dilution(20%) of powderper 100 mL411 kJ(98 kcal)90 gwhey protein1.5 gcows’ milksoya70.8 g 19.3 g Nil Contains lactoseGluten-freeElectrolytes/100 g:Na + 1.04 mmolK + 0.13 mmolCa 2þ 10.22 mmolP + 1.06 mmolContains no vitamin A orvitamin D800 mg 1 g Nil Gluten-freeResidual lactoseElectrolytes/100 g:Na + 23 mmolK + 2 mmolCa 2þ 4.99 mmolP + 4.84 mmol12.6 g(sugars 1.2 g)Powder provides: protein 7.5 g, carbohydrate 63 g, fat 23.2 g, energy 2053 kJ (491 kcal)/100 gSuplena c(Abbott)Liquid (sip ortube feed)per 100 mL840 kJ(200 kcal)3gcaseinates25.5 g(sugars 2.7 g)4.6 g Nil Contains lactoseElectrolytes/100 mL:Na + 2.1 mmolK + 0.6 mmolCa 2þ 0.58 mmolP + 0.58 mmol9.6 g Nil Gluten-freeResidual lactoseElectrolytes/100 mL:Na + 3.39 mmolK + 2.87 mmolCa 2þ 3.48 mmolP + 2.39 mmolACBSIndicationsEnteral feed or nutritional supplementfor adults and children over 1year with chronic renal failureNutritional supplement for biochemicallyproven hypoproteinaemiaand patients undergoingdialysisNot suitable for child under 1 yearDietary management of renal failurein child from birth to 10 yearsEnteral feed or nutritional supplementin patients with chronic oracute renal failure who are notundergoing dialysis, or with chronicor acute liver disease with fluidrestriction; other conditions requiringhigh energy, low protein, lowelectrolyte, low volume enteral feedNot suitable for child under 1 year;use with caution in child 1–5 yearsPresentation& FlavourSachet:10 100 g = £25.40Sachet:30 20 g = £69.60Powder: 10 100 g = £56.93Unflavoured(7-g measuring scoop provided)Can:237 mL = £2.47Vanilla770 A2.3 Specialised formulas BNFC 2011–2012

A2.4 Feed supplementsA2.4.1 High-energy supplementsA2.4.1.1 High-energy supplements: carbohydrateFlavoured carbohydrate supplements are not suitable for child under 1 year; liquid supplements should be diluted before use in child under 5 yearsACBS Indications: disease-related malnutrition, malabsorption states, or other conditions requiring fortification with a high or readily available carbohydrate supplementProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsCaloreen c(Nestlé)Maxijul c SuperSoluble(SHS)Maxijul c Liquid(SHS)Polycal c(Nutricia Clinical)S.O.S. c(Vitaflo)Powderper 100 gPowderper 100 gLiquidper 100 mLPowderper 100 gLiquidper 100 mLPowderper 100 g1640 kJ(390 kcal)1615 kJ(380 kcal)850 kJ(200 kcal)1630 kJ(384 kcal)1050 kJ(247 kcal)1590 kJ(380 kcal)NilNilNilNilNilNil96 gMaltodextrin95 gGlucose polymer(sugars 8.6 g)50 gGlucose polymer(sugars 4.5 g 1 )96 gMaltodextrin(sugars 6 g)61.9 gMaltodextrin(sugars 12.2 g)95 g(sugars 9 g)Contents of each sachet should be reconstituted with water to a total volume of 200 mL1. Sugar content varies with flavourNil Nil Gluten-freeLactose-freeNil Nil Gluten-freeLactose-freeNil Nil Gluten-freeLactose-freeNil Nil Gluten-freeLactose-freeACBSIndicationsSee aboveNot suitable for child under 3 yearsPresentation& FlavourPowder: 500 g = £3.52Unflavoured(10-g measuring scoop provided)See above Sachets: 4 132 g = £5.44Can:200 g = £2.192.5 kg = £19.2525 kg = £130.76UnflavouredSee aboveNil Nil See above; liquid not suitable forchild under 3 yearsCarton:200 mL = £1.37Orange, unflavouredSee above Can: 400 g = £3.75Neutral(5-g measuring scoop provided)Nil Nil For use as an emergency regimen inthe dietary management of inbornerrors of metabolism in adults andchildren from birthBottle: 200 mL = £1.50Neutral, orangeSachets: 30 21 g (S.O.S. 10) =£6.30; 30 31 g (S.O.S. 15) =£9.30; 30 42 g (S.O.S. 20) =£12.60; 30 52 g (S.O.S. 25) =£15.60BNFC 2011–2012 A2.4 Feed supplements 771Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.4.1.1 High-energy supplements: carbohydrate (product list continued)Flavoured carbohydrate supplements are not suitable for child under 1 year; liquid supplements should be diluted before use in child under 5 yearsACBS Indications: disease-related malnutrition, malabsorption states, or other conditions requiring fortification with a high or readily available carbohydrate supplementProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsVitajoule c(Vitaflo)Powderper 100 g1610 kJ(380 kcal)Nil96 gDried glucosesyrupNil Nil Gluten-freeLactose-freeACBSIndicationsSee aboveA2.4.1.2 High-energy supplements: fatLiquid supplements should be diluted before use in child under 5 yearsACBS indications: disease-related malnutrition, malabsorption states, or other conditions requiring fortification with a high fat (or fat and carbohydrate) supplementProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsCalogen c(Nutricia Clinical)Fresubin c 5 kcalShot(Fresenius Kabi)Liquigen c(SHS)Liquid (emulsion)per 100 mLLiquid (emulsion)per 100 mLLiquid (emulsion)per 100 mL1850 kJ Nil 100 mg 50 g(450 kcal) 1 (LCT100 %)2100 kJ(500 kcal)1850 kJ(450 kcal)1. Nutritional values vary with flavour—consult product literature2. Flavour not suitable for child under 3 yearsNil4.0 g(sucrose)Nil Nil 50 g(MCT97 %)FractionatedcoconutoilNilGluten-freeLactose-free53.8 g 400 mg Gluten-freeLactose-freeNilGluten-freeLactose-freeACBSIndicationsSee aboveSee aboveNot suitable for child under 3 yearsSteatorrhoea associated with cysticfibrosis of the pancreas, intestinallymphangiectasia, intestinal surgery,chronic liver disease, livercirrhosis, other proven malabsorptionsyndromes, ketogenic diet inepilepsy, and in type 1 lipoproteinaemiaNot suitable for child under 1 yearPresentation& FlavourCan:500 g = £3.662.5 kg = £17.8325 kg = £107.39(10-g measuring scoop provided)Presentation& FlavourBottle:200 mL = £4.00500 mL = £9.83Banana 2 , neutral, strawberry 2Bottle:120 mL = £2.55Lemon, neutralBottle:250 mL = £7.79772 A2.4 Feed supplements BNFC 2011–2012

Medium-chainTriglyceride (MCT)Oil(SHS)Liquidper 100 mLFat and CarbohydrateDuobar c(SHS)Duocal c(SHS)Duocal c SuperSoluble(SHS)Energivit c(SHS)Barper 45 gLiquidper 100 mLPowderper 100 gStandard dilution(15%) of powderper 100 mL3515 kJ(855 kcal)1211 kJ(292 kcal)695 kJ(166 kcal)2061 kJ(492 kcal)309 kJ(74 kcal)Nil Nil MCT100 %Less than20 mgPowder provides: carbohydrate 66.7 g, fat 25 g, energy 2059 kJ (492 kcal)/100 gMCT Duocal c(SHS)Powderper 100 g2082 kJ(497 kcal)NilNilNilNil22.5 g(sucrose)23.7 g(sugars 2.1 g)72.7 g(sugars 6.5 g)10 g(sugars900 mg)72 g(sugars 10.1 g)Nil22.5 g Nil Contains phenylalanine180 micrograms/45-g barGluten-freeLactose-free7.9 g(MCT30 %)22.3 g(MCT35 %)Nutritional supplement for steatorrhoeaassociated with cystic fibrosisof the pancreas, intestinal lymphangiectasia,intestinal surgery,chronic liver disease and liver cirrhosis,other proven malabsorptionsyndromes, ketogenic diet in managementof epilepsy, type 1 hyperlipoproteinaemiaSee aboveBottle:500 mL = £12.34Bar:45 g = £1.65Neutral, strawberry, toffeeNil Contains vitamin E See above Bottle:250 mL = £3.37NilGluten-freeLactose-free3.75 g Nil Lactose-freeWith vitamins, minerals,and trace elements23.2 g(MCT83 %)See aboveFor children requiring additionalenergy, vitamins, minerals, andtrace elements following a proteinrestricteddietCan:400 g = £15.20(5-g measuring scoop provided)Can:400 g = £18.49(5-g measuring scoop provided)Nil See above Can:400 g = £18.07A2.4.1.3 High-energy supplements: proteinACBS indications: disease-related malnutrition, malabsorption states, or other conditions requiring fortification with a high fat or carbohydrate (with protein) supplementProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsACBSIndicationsPresentation& FlavourCasilan 90 c(Heinz)Powderper 100 g1572 kJ(370 kcal)90 gcows’ milk300 mg 1 g Nil Gluten-freeElectrolytes/100 g:Na + 1.3 mmolK + 8.7 mmolCa 2þ 35 mmolP + 22.6 mmolNutritional supplement for use inbiochemically proven hypoproteinaemiaCan:250 g = £6.49BNFC 2011–2012 A2.4 Feed supplements 773Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.4.1.3 High-energy supplements: protein (product list continued)ACBS indications: disease-related malnutrition, malabsorption states, or other conditions requiring fortification with a high fat or carbohydrate (with protein) supplementProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsACBSIndicationsPresentation& FlavourProtifar c(Nutricia Clinical)Powderper 100 gPowder provides: protein 2.2 g per 2.5 gVitapro cPowder(Vitaflo)per 100 gProtein and carbohydrateDialamine c(SHS)Standard dilution(20%) of powderper 100 mL1580 kJ(373 kcal)1506 kJ(360 kcal)264 kJ(62 kcal)88.5 gcows’ milk75 gwhey proteinisolate4.3 gproteinequivalent(essentialand nonessentialamino acids)less than 1.5 g 1.6 g Nil Gluten-freeResidual lactoseElectrolytes/100 mL:Na + 1.3 mmolK + 1.28 mmolCa 2þ 33.75 mmolP + 22.58 mmolNutritional supplement for use inbiochemically proven hypoproteinaemia9 g 6 g Nil Contains lactose Biochemically proven hypoproteinaemia11.2 g(sugars 10.2 g)Powder provides: protein equivalent 25 g, carbohydrate 65 g, vitamin C 125 mg, energy 1530 kJ (360 kcal)/100 gProSource c(Nutrinovo)Liquidper 30 mL420 kJ(100 kcal)15 g(sugars 8 g)Protein, fat, and carbohydrateCalogen c Extra(Nutricia Clinical)Liquidper 100 mL1650 kJ(400 kcal)10 gcollagen proteinwhey proteinisolate5gcows’ milk4.5 g(sugars 3.5 g)Nil Nil Contains vitamin C Hypoproteinaemia, chronic renalfailure, wound fistula leakage withexcessive protein loss, conditionsrequiring a controlled nitrogenintake, and haemodialysisNot suitable for child under 6monthsNil Nil Gluten-freeLactose-freeMay contain porcine derivatives40.3 g Nil Residual lactoseContains vitamins, minerals,and trace elementsBiochemically proven hypoproteinaemiaNot recommended for child under 3yearsSee aboveNot suitable for child under 3 years;may require dilution for child 3–5yearsCan:225 g = £7.44Unflavoured(2.5-g measuring scoop provided)Tub:250 g = £7.472 kg = £58.69(5-g measuring scoop provided)Can: 400 g = £61.74OrangeSachet: 100 30 mL = £83.36Citrus-berry, neutral, orangecremeBottle: 200 mL = £4.56Neutral, strawberry774 A2.4 Feed supplements BNFC 2011–2012

Calshake c(Fresenius Kabi)Powderper 87 g1841 kJ(439 kcal) 1 4.1 gcows’ milk56.4 g(sugars 20 g)Powder: one sachet reconstituted with 240 mL whole milk provides approx. 2 kcal/mL and protein 12 gEnshake c(Abbott)Powderper 100 g1893 kJ 8.4 g(450 kcal) 1 cows’ milk,soy proteinisolate69 g(sugars 14.5 g)22 g Nil Contains lactoseGluten-free15.6 g Nil Residual lactoseContains vitamins andmineralsSee aboveNot suitable for child under 1 yearSee aboveNot suitable for child under 1 year;use with caution in child 1–6 yearsPowder: 96.5 g reconstituted with 240 mL whole milk provides approx. 2 kcal/mL and protein 16 gPro-Cal c(Vitaflo)Powderper 100 g2788 kJ(667 kcal)13.5 gcows’ milk27 g 56 g Nil Contains lactose See aboveNot suitable for child under 1 yearPowder 15 g provides: protein 2 g, carbohydrate 4 g, fat 8.4 g, energy 418 kJ (100 kcal)Pro-Cal c Shot(Vitaflo)QuickCal c(Vitaflo)Liquidper 100 mLPowderper 100 g1393 kJ(334 kcal)3263 kJ(780 kcal)6.7 gcows’ milk4.6 gcows’ milkPowder 13 g provides: protein 600 mg, carbohydrate 2.2 g, fat 10 g, energy 418 kJ (100 kcal)Scandishake c Mix(Nutricia Clinical)Powderper 100 g2099 kJ 4.7 g(500 kcal) 1 cows’ milk13.4 g 28.2 g Nil Contains lactoseGluten-freeSee aboveNot suitable for child under 1 year17 g 77 g Nil Contains lactose See aboveNot suitable for child under 1 year65 g(sugars 14.3 g)24.7 g Nil Gluten-freeContains lactoseSee aboveNot suitable for child under 3 yearsPowder: 85 g reconstituted with 240 mL whole milk provides: protein 11.7 g, carbohydrate 66.8 g, fat 30.4 g, energy 2457 kJ (588 kcal)Vitasavoury c Powder2590 kJ 12.7 g 23.5 g52.3 g 6.2 g Contains lactose See above(Vitaflo)per 100 g (619 kcal) 1 cows’ milk (sugars 1.5 g)Not suitable for child under 3 years1. Nutritional values vary with flavour—consult product literature2. Flavour not suitable for child under 3 yearsSachet:87 g = £2.01Banana, neutral, strawberry,vanilla90 g = £2.01ChocolateSachet: 96.5 g = £1.98Banana, chocolate, strawberry,vanillaSachets: 25 15 g = £13.51Tub:510 g = £12.521.5 kg = £25.5012.5 kg = £181.2825 kg = £279.36(15-g measuring scoop provided)Bottle:6 250 mL = £26.76Banana, neutral, strawberry 2Starter pack:3 250 mL = £13.39Sachets:25 13 g = £12.16Sachet:85 g = £2.08Banana, caramel, chocolate,strawberry, vanilla, unflavouredCup (200 kcal):24 33 g = £26.80Sachet (300 kcal)10 50 g = £16.35Chicken, leek and potato, mushroom,vegetableBNFC 2011–2012 A2.4 Feed supplements 775Appendix 2: Borderline substances

Appendix 2: Borderline substancesA2.4.2 Fibre, vitamin, and mineral supplementsProduct Formulation Energy Protein Carbohydrate Fat Fibre SpecialCharacteristicsHigh-fibre supplementsResource cOptifibre c(Nestlé)Powderper 100 g323 kJ(76 kcal)Vitamin and Mineral supplementsMetabolic MineralMixture c(SHS)Paediatric Seravit c(SHS)Powderper 100 gPowderper 100 g729 kJ(175 kcal)1275 kJ(300 kcal)1. Sugar content varies with flavour2. Flavouring: see Modjul c Flavour System, p. 7773. Flavour not suitable for child under 6 monthsNil19 gguar gum, partiallyhydrolysedNil 78 g Gluten-freeLactose-freeNil Nil Nil Nil Contains trace elementsElectrolytes/100 g:Na + 172 mmolK + 212 mmolCa 2þ 205 mmolP + 192 mmolEnergy source: CalciumlactateNil75 g(sugars6.75 g 1 )ACBSIndicationsStandard, p. 743 except dysphagiaNot suitable for child under 5 yearsMineral supplement for syntheticdietsSuitable for infants (but may requirefurther dilution)Nil Nil Vitamin and mineral supplement ininfants and children with restrictivetherapeutic dietsPresentation& FlavourSachet: 16 x 10 g = £7.72Can: 250 g = £9.51(5-g measuring scoop provided)Tub:100 g = £10.67Tub:200 g = £14.37Unflavoured 2200 g = £15.30Pineapple 3(5-g measuring scoop provided)776 A2.4 Feed supplements BNFC 2011–2012

BNFC 2011–2012 A2.5 Feed additives 777A2.5 Feed additivesA2.5.1 Special additives forconditions of intoleranceVitaquick c (Vitaflo)Powder. Modified maize starch. Net price 300 g = £6.66; 2 kg= £33.91; 6 kg = £87.83For thickening of foods in dysphagia. Not suitable for childrenunder 1 year except in cases of failure to thriveA2.5.3 Flavouring preparationsColief c (Forum)Liquid, lactase 50 000 units/g, net price 7-mL dropper bottle= £8.40For the relief of symptoms associated with lactose intolerance ininfants, provided that lactose intolerance is confirmed by thepresence of reducing substances and/or excessive acid in stools, alow concentration of the corresponding disaccharide enzyme onintestinal biopsy or by breath hydrogen test or lactose intolerancetest. For dosage and administration details, consult product literatureFructose(Laevulose)For proven glucose/galactose intoleranceA2.5.2 Feed thickeners and prethickeneddrinksCarobel, Instant c (Cow & Gate)Powder, carob seed flour. Net price 135 g = £2.97For thickening feeds in the treatment of vomitingNutilis c Powder (Nutricia Clinical)Powder, carbohydrate 86 g, energy 1520 kJ (358 kcal)/100 g,modified maize starch, gluten- and lactose-free, net price 20 9-g sachets = £5.88, 225 g = £4.51For thickening of foods in dysphagia. Not suitable for child under 1year except in cases of failure to thriveResource c Thickened Drink (Nestlé)Liquid, carbohydrate 22 g, energy: orange 382 kJ (90 kcal);apple 376 kJ (89 kcal)/100 mL. Flavours; apple or orange,syrup or custard consistencies. Gluten- and lactose-free, netprice 12 114-mL cups = £7.44For dysphagia. Not suitable for children under 1 yearResource c ThickenUp c (Nestlé)Powder, modified maize starch. Gluten- and lactose-free, netprice 227 g = £4.35; 74 4.5-g sachet = £16.66For thickening of foods in dysphagia. Not suitable for childrenunder 1 yearSLO Drinks c (SLO Drinks)Powder, carbohydrate content varies with flavour and chosenconsistency (3 consistencies available), see productliterature. Flavours: black currant, lemon, orange; hot drinks:chocolate, white coffee, net price 25 115 mL = £7.50Nutritional supplement for patient hydration in the dietary managementof dysphagia. Not suitable for children under 3 yearsThick and Easy c (Fresenius Kabi)Powder. Modified maize starch, net price 225-g can = £4.46;100 9-g sachets = £26.35; 4.54 kg = £70.53Thickened Juices, liquid, modified food starch. Flavours:apple or orange, net price 118-mL pot = 57p; apple, blackcurrant, cranberry, kiwi-strawberry, orange, 1.42-litre bottle= £3.61For thickening of foods in dysphagia. Not suitable for childrenunder 1 year except in cases of failure to thriveThixo-D c (Sutherland)Powder, modified maize starch, gluten-free. Net price 375- gtub = £7.15For thickening of foods in dysphagia. Not suitable for childrenunder 1 year except in cases of failure to thriveFlavour Mix c (Nestlé)Powder, flavours: banana, chocolate, coffee, lemon-lime, orstrawberry, net price 60 g = £6.85FlavourPac c (Vitaflo)Powder, flavours: black currant, lemon, orange, tropical orraspberry, net price 30 4-g sachets = £11.54For use with Vitaflo’s range of unflavoured protein substitutes formetabolic diseasesModjul c Flavour System (SHS)Powder, carbohydrate-based flavours, black currant, orange,pineapple, 100 g = £10.24; cherry-vanilla, grapefruit, lemonlime,20 5-g sachets = £10.24For use with unflavoured SHS products based on peptides oramino acids; not suitable for child under 6 monthsA2.6 Foods for special dietsA2.6.1 Gluten-free foodsACBS indications: established gluten-sensitiveenteropathies including steatorrhoea due to glutensensitivity, coeliac disease, and dermatitis herpetiformis.BreadLoavesBarkat c (Gluten Free Foods Ltd)Gluten-free. Loaf, multigrain 500 g = £4.83. Loaf, sliced,wholemeal 500 g = £3.36. Loaf, sliced, part-baked, countrystyle250 g = £3.69. Loaf, sliced, part-baked, white 550 g =£4.88. Rice bread, brown 500 g = £4.83; white 500 g = £4.83Dietary Specials c (Nutrition Point)Gluten-free. Loaf, sliced, multigrain, brown 400 g = £3.01;white 400 g = £3.01Ener-G c (General Dietary)Gluten-free. Loaf, sliced Seattle brown 600 g = £5.28. Ricebread, sliced, brown 474 g = £4.59; white 456 g = £4.59. Riceloaf, sliced 612 g = £4.59. Tapioca bread, sliced 480 g = £4.59Genius Gluten Free c (Genius Foods)Gluten-free. Loaf, unsliced, brown 400 g = £2.49; white 400 g= £2.49Glutafin c (Nutrition Point)Gluten-free. Loaf, sliced, fibre 400 g = £3.41; white 400 g =£3.41Appendix 2: Borderline substances

778 A2.6.1 Gluten-free foods BNFC 2011–2012Appendix 2: Borderline substancesGlutafin c Select (Nutrition Point)Gluten-free. Loaf, sliced, fresh, brown 400 g = £3.25; white400 g = £3.25. Loaf, sliced, fibre 400 g = £3.12; white 400 g =£3.12. Loaf, seeded 400 g = £3.39Juvela c (Juvela)Gluten-free. Loaf, sliced, fresh, fibre 400 g = £2.97; white400 g = £3.23. Loaf, sliced, white 400 g = £3.10; fibre 400 g =£3.10. Loaf, white 400 g = £3.10; fibre 400 g = £3.10. Loaf,part-baked, fibre 400 g = £3.33; white 400 g = £3.46Lifestyle c (Ultrapharm)Gluten-free. Loaf, sliced, brown 400 g = £2.82; high fibre400 g = £2.82; white 400 g = £2.82. Loaf, brown 400 g =£2.82; high fibre 400 g = £2.82; white 400 g = £2.82Livwell c (Livwell)Gluten-free. Loaf, sliced, brown (seeded) 200 g = £2.25;white 200 g = £2.25Pasticely c (GFF Trade)Gluten-free. Loaf, sandwich, sliced, white 260 g = £3.29;rustic, sliced, white 260 g = £3.29Proceli c (Proceli)Gluten-free. Loaf, sliced, white 165 g = £2.30; sandwich155 g = £2.32. Rice bread, brown 220 g = £2.30; sandwich220 g = £2.30Sunnyvale c (Everfresh)Gluten-free. Loaf, mixed grain, sour dough 400 g = £1.91Ultra c (Ultrapharm)Gluten-free. Loaf, white 400 g = £2.46; high fibre 500 g =£3.35Wellfoods c (Wellfoods)Gluten-free. Loaf, sliced 600 g = £4.95; unsliced 600 g =£4.85Baguettes, buns and rollsBarkat c (Gluten Free Foods Ltd)Gluten-free. Baguette, part-baked 200 g = £3.69. Rolls, partbaked2 x 100 g = £3.30; 6 x 50 g = £3.69Ener-G c (General Dietary)Gluten-free. Rolls, dinner 6 = £3.11; white, long 4 55 g =£2.50; round 4 55 g = £2.50Glutafin c (Nutrition Point)Gluten-free. Baguette 2 175 g = £3.20. Rolls, fibre 4 50 g= £3.41; white 4 50 g = £3.41Glutafin c Select (Nutrition Point)Gluten-free. Rolls, fibre 4 65 g = £3.25; white 4 65 g =£3.25. Rolls, part-baked, white 4 50 g = £3.35; long 2 75 g= £2.56Juvela c (Juvela)Gluten-free. Rolls, fresh, fibre 5 85 g = £4.17; white 5 85 g = £4.17. Rolls, fibre 5 85 g = £4.18; white 5 85 g =£4.18. Rolls, part-baked, fibre 5 75 g = £4.33; white 5 75 g = £4.33Lifestyle c (Ultrapharm)Gluten-free. Rolls, brown 5 80 g = £2.82; high fibre 5 80 g = £2.82; white 5 80 g = £2.82Livwell c (Livwell)Gluten-free. Baguette, white 250 g = £2.50. Buns, toasting 4 50 g = £2.50. Rolls, white 4 = £2.25. Rolls, part-baked,circle (bagel) 2 90 g = £2.50; dinner (square) 2 80 g =£2.09Pasticely c (GFF Trade)Gluten-free. Baguette, part–baked, white 160 g = £1.99.Rolls, part-baked, white 2 80 g = 2.39; rustic, part-baked,white 2 105 g = £2.39Proceli c (Proceli)Gluten-free. Baguette, part-baked 2 125 g = £3.24. Buns 4 50 g = £3.26. Lunch rolls, white 8 34 g = £3.26. Rolls,part-baked, white, dinner 4 35 g = £2.18; hotdog 3 35 g =£2.24; long 3 83 g = £2.95Ultra c (Ultrapharm)Gluten-free. Baguette, 2 200 g = £2.46. Rolls, 4 70 g =£2.46Wellfoods c (Wellfoods)Gluten-free. Burger buns 4 75 g = £3.95. Rolls 4 70 g =£3.65Speciality breadsLivwell c (Livwell)Gluten-free. Flat bread (pitta) 4 = £3.00. Tear-drop shape(naan) 2 90 g = £3.00Proceli c (Proceli)Gluten-free. Flat bread (pitta), part-baked 3 40 g = £4.36Cookies and biscuitsBarkat c (Gluten Free Foods Ltd)Gluten-free. Biscuits, coffee-style 200 g = £ 2.86; digestive175 g = £2.20Ener-G c (General Dietary)Gluten-free. Cookies, vanilla 435 g = £5.23Glutafin c (Nutrition Point)Gluten-free. Biscuits, plain 200 g = £3.77; digestive 150 g =£1.94; savoury 125 g = £1.94; savoury shorts 150 g = £2.65;shortbread 100 g = £1.60; sweet (without chocolate or sultanas)150 g = £1.94; tea 150 g = £1.94Juvela c (Juvela)Gluten-free. Biscuits, digestive 150 g = £2.67; savoury 150 g= £3.35; sweet 150 g = £2.52, tea 150 g = £2.67Ultra c (Ultrapharm)Gluten-free. Biscuits, sweet 250 g = £2.93Crackers, crispbreads, and breadsticksBarkat c (Gluten Free Foods Ltd)Gluten-free. Crackers, round (matzo) 200 g = £2.97Dietary Specials c (Nutrition Point)Gluten-free. Cracker bread 150 g = £1.94Glutafin c (Nutrition Point)Gluten-free. Crackers, high fibre 200 g = £2.64; plain 200 g =£3.16; mini 175 g = £2.70Juvela c (Juvela)Gluten-free. Crispbread, plain 200 g = £4.06Ultra c (Ultrapharm)Gluten-free. Crackerbread 200 g = £1.77

BNFC 2011–2012 A2.6.1 Gluten-free foods 779Flour mixes and xanthan gumFlour mixesBarkat c (Gluten Free Foods Ltd)Gluten-free. Flour mix, bread 500 g = £5.74. Plain 750 g =£5.88Dietary Specials c (Nutrition Point)Gluten-free. Flour mix, bread, white 500 g = £5.33. Cake,white 750 g = £5.33. Plain, white 500 g = £5.33Finax c (Drossa)Gluten-free. Flour mix, bread, fibre 1 kg = £9.92Glebe Farm c (Glebe Farm)Gluten-free. Flour mix, bread, brown 375 g = £1.99 (seeded);bread, white and pizza 375 g = £1.99Glutafin c (Nutrition Point)Gluten-free. Flour mix, fibre 500 g = £5.91; white 500 g =£5.91Glutafin Select c (Nutrition Point)Gluten-free. Flour mix, bread, fibre 500 g = £6.06; white500 g = £6.06. Cake 500 g = £6.06. Fibre 500 g = £6.06; white500 g = £5.91. Pastry 500 g = £6.06Heron Foods c (Gluten Free Foods Ltd)Gluten-free. Flour mix, organic, bread, standard 500 g =£8.30; high fibre 500 g = £8.30Il Pane di Anna c (GFF Trade)Gluten-free. Flour mix, bread, white 500 g = £5.25. Cake,white 500 g = £5.25. Pizza base 500 g = £5.25Juvela c (Juvela)Gluten-free. Flour mix, fibre 500 g = £6.44; plain 500 g =£6.44; harvest 500 g = £6.44Orgran c (Community)Gluten-free. Flour mix, bread 450 g = £3.10. Self-raising500 g = £3.10. Pastry and pizza 375 g = £3.80Proceli c (Proceli)Gluten-free. Flour mix, white 1 kg = £9.95Pure c (Innovative)Gluten-free. Flour mix, blended 1 kg = £3.90. Potato starch500 g = £1.55. Rice, brown 500 g = £1.45; white 500 g =£1.55. Tapioca starch 500 g = £2.08. Teff, brown 1 kg = £4.40;white 1 kg = £4.40Tobia c (Tobia Teff)Gluten-free. Flour mix, teff, brown 1 kg = £2.95; white 1 kg =£2.95Tritamyl c (Gluten Free Foods Ltd)Gluten-free. Flour mix, bread, brown 1 kg = £6.60; white 2 kg= £13.20. Plain 2 kg = £13.20Wellfoods c (Wellfoods)Gluten-free. Flour mix, plain 1 kg = £7.65Xanthan gumEner-G c (General Dietary)Gluten-free. Xanthan gum 170 g = £7.25Pure c (Innovative)Gluten-free. Xanthan gum 100 g = £6.00PastaBarkat c (Gluten Free Foods Ltd)Gluten-free. Pasta, animal shapes 500 g = £4.95; macaroni500 g = £4.95; spaghetti 500 g = £4.95; spirals 500 g = £4.95;tagliatelle 500 g = £4.95. Buckwheat, penne 250 g = £2.48;spirals 250 g = £2.48BiAlimenta c (Drossa)Gluten-free. Pasta, potato-based, gnocchi 500 g = £5.59;perle di gnocchi 500 g = £5.60. Tubetti 500 g = £5.90Dietary Specials c (Nutrition Point)Gluten-free. Pasta, fusilli 500 g = £3.44; penne 500 g = £3.44;spaghetti 500 g = £3.44Ener-G c (General Dietary)Gluten-free. Pasta, rice-based, lasagne 454 g = £4.27;macaroni 454 g = £4.27; shells, small 454 g = £4.27 spaghetti454 g = £4.27; vermicelli 300 g = £4.27Glutafin c (Nutrition Point)Gluten-free. Pasta, lasagne 250 g = £3.21; macaroni penne500 g = £6.13; shells 500 g = £6.13; spirals 500 g = £6.13;spaghetti, long 500 g = £6.13; tagliatelle 250 g = £3.21Juvela c (Juvela)Gluten-free. Pasta, fusilli 500 g = £6.31; lasagne 250 g =£3.22; macaroni 500 g = £6.31; spaghetti 500 g = £6.31;tagliatelle 250 g = £3.04. Fibre, penne 500 g = £5.79Orgran c (Community)Gluten-free. Pasta, rice and corn, lasagne 200 g = £3.03;macaroni 250 g = £2.35. Spirals, buckwheat 250 g = £2.35;corn 250 g = £2.35; rice and corn 250 g = £2.35; rice andmillet 250 g = £2.35Pasticely c (GFF Trade)Gluten-free. Pasta, macaroni 500 g = £2.99; elbow 500 g =£2.99; spaghetti 500 g = £2.99Proceli c (Proceli)Gluten-free. Pasta, macaroni penne 250 g = £2.95; puntini 2 250 g = £5.90; spaghetti, short 2 250 g = £5.90; spirals250 g = £2.59Rizopia c (PGR Health Foods)Gluten-free. Pasta, brown rice, fusilli 500 g = £2.60; lasagne375 g = £2.60; penne 500 g = £2.60; spaghetti 500 g = £2.60Ultra c (Ultrapharm)Gluten-free. Pasta, fusilli 250 g = £2.95; penne 250 g = £2.95;spaghetti 250 g = £2.95Pizza basesBarkat c (Gluten Free Foods Ltd)Gluten-free. Pizza crust, rice, brown 150 g = £4.21; white150 g = £4.21Dietary Specials c (Nutrition Point)Gluten-free. Pizza base 2 150 g = £5.27Glutafin c (Nutrition Point)Gluten-free. Pizza base 2 150 g = £5.98Juvela c (Juvela)Gluten-free. Pizza base 2 180 g = £7.70Pasticely c (GFF Trade)Gluten-free. Pizza base 165 g = £2.99Appendix 2: Borderline substances

780 A2.6.2 Low-protein foods BNFC 2011–2012Appendix 2: Borderline substancesProceli c (Proceli)Gluten-free. Pizza base 2 250 g = £3.90Ultra c (Ultrapharm)Gluten-free. Pizza base 2 200 g = £2.65Wellfoods c (Wellfoods)Gluten-free. Pizza base 2 300 g = £8.95A2.6.1.1 Gluten- and wheat-free foodsACBS indications: established gluten-sensitiveenteropathies with coexisting established wheat sensitivityonly.Ener-G c (General Dietary)Gluten-free, wheat-free. Bread loaf, six flour 576 g = £3.60.Rolls, Seattle brown, round (hamburger) 4 119 g = £3.00;long (hot dog) 4 119 g = £3.00. Pizza base, 3 124 g =£3.75Glutafin c (Nutrition Point)Gluten-free, wheat-free. Flour mix, bread 500 g = £6.06;fibre 500 g = £6.06. Cake mix 500 g = £6.06. Crispbread 150 g= £3.82Heron Foods c (Gluten Free Foods Ltd)Gluten-free, wheat-free. Flour mix, organic, bread, fibre500 g = £8.30. Bread and cake mix 500 g = £6.33A2.6.2 Low-protein foodsACBS indications: inherited metabolic disorders,renal or liver failure, requiring a low-protein dietLoprofin c (SHS)Low-protein. Crunch bar 8 41 g = £11.92. Wafers, chocolate100 g = £2.17; vanilla 100 g = £2.17. Crackers 150 g =£3.05, herb 150 g = £3.05PK Foods c (Gluten Free Foods Ltd)Low-protein. Aminex c biscuits 200 g = £4.67; cookies 150 g= £4.67. Cookies, chocolate chip 150 g = £4.67; cinnamon150 g = £4.67; orange 150 g = £4.67. Rusks 200 g = £4.67.Cripsbread 75 g = £2.24Promin c (Firstplay Dietary)Low-protein. Cooked and flavoured Pasta Snax, ready-salted12 25 g = £9.84; salt and vinegar 12 25 g = £9.84; cheeseand onion 12 25 g = £9.84; jalapeno 12 25 g = £9.84Taranis c (Firstplay Dietary)Low-protein. Cake bars, apricot 6 40 g = £5.77, lemon 6 40 g = £5.51, pear 6 40 g = £5.77Vita Bite c (Vitaflo)Low protein. Bar, protein 30 mg (less than 2.5 mg phenylalanine),carbohydrate 15.35 g, fat 8.4 g, energy 572 kJ(137 kcal)/25 g. Chocolate flavoured, 25 g = £1.02Not recommended for any child under 1 yearCerealsLoprofin c (SHS)Low-protein. Breakfast cereal flakes, apple 375 g = £6.70;chocolate 375 g = £6.70; strawberry 375 g = £6.70. Cerealloops 375 g = £6.95Promin c (Firstplay Dietary)Low-protein. Hot breakfast (powder sachets), apple andcinnamon 6 57 g = £7.35, banana 6 57 g = £7.35,chocolate 6 57 g = £7.35; original 6 56 g = £7.35DessertsBreadEner-G c (General Dietary)Low protein, Rice bread, 600 g = £4.71Juvela c (Juvela)Low protein. Loaf, sliced 400 g = £3.19. Rolls 5 70 g =£3.96Loprofin c (SHS)Low protein. Loaf, part-baked, sliced 400 g = £3.35. Rolls,part-baked 4 65 g = £3.52PK Foods c (Gluten Free Foods Ltd)Low protein. Loaf, white, sliced 550 g = £4.40Ultra PKU c (Ultrapharm)Low-protein. Loaf 400 g = £2.65Cake, biscuits, and snacksHarifen c (Ultrapharm)Low protein. Cracker toast, 200 g = £2.75Juvela c (Juvela)Low-protein. Cookies, cinnamon 125 g = £6.67; chocolatechip 110 g = £6.67; orange 125 g = £6.67Loprofin c (SHS)Low-protein. Powder, chocolate 150 g = £4.10; strawberry150 g = £4.10; vanilla 150 g = £4.10PK Foods c (Gluten Free Foods Ltd)Low-protein. Jelly, orange 4 80 g = £7.43, cherry 4 80 g= £7.43ACBS IndicationsPromin c (Firstplay Dietary)Low-protein. Dessert mix, caramel 6 36.5 g = £5.77;custard 6 36.5 g = £5.77; chocolate and banana 6 36.5 g= £5.77; strawberry and vanilla 6 36.5 g = £5.77. Ricepudding imitation, apple 4 69 g = £5.77; banana 4 69 g =£5.77; original 4 69 g = £5.77; strawberry 4 69 g = £5.77Flour mixes and egg substitutesEner-G c (General Dietary)Low-protein. Egg replacer 454 g = £4.34Fate c (Fate)Low protein. All purpose mix 500 g = £6.66. Cake mix, 2 250 g = £6.66; chocolate-flavour 2 250 g = £6.66Juvela c (Juvela)Low-protein. Mix 500 g = £6.82

BNFC 2011–2012 A2.7 Nutritional supplements for metabolic diseases 781Loprofin c (SHS)Low-protein. Mix, plain 500 g = £7.09; chocolate 500 g =£7.50; lemon 500 g = £7.50. Egg replacer 2 250 g = £13.03.Egg-white replacer 100 g = £8.38PK Foods c (Gluten Free Foods Ltd)Low-protein. Flour mix 750 g = £9.91. Egg replacer 350 g =£4.67ACBS IndicationsPastaLoprofin c (SHS)Low-protein. Pasta, animal shapes 500 g = £7.13; conchigle500 g = £7.15; spirals 500 g = £7.42; gnoccetti sardi 500 g =£7.15; lasagne 250 g = £3.61; macaroni elbows 250 g = £3.56;penne 500 g = £7.42; spaghetti 500 g = £7.42; tagliatelle 250 g= £3.56; vermicelli 250 g = £3.69. Rice, imitation 500 g =£7.20Promin c (Firstplay Dietary)Low-protein. Pasta, alphabet shapes 500 g = £6.48; lasagnesheets 200 g = £2.76; macaroni 500 g = £6.48; noodles, flat500 g = £6.48; shells 500 g = £6.48; spaghetti, short-cut 500 g= £6.48; spirals 500 g = £6.48. Rice, imitation 500 g = £6.48.Tricolour pasta, alphabet shapes 500 g = £6.48; shells 500 g= £6.48; spirals 500 g = £6.48Pizza basesJuvela c (Juvela)Low-protein. Pizza base 2 180 g = £7.55Ultra PKU c (Ultrapharm)Low-protein. Pizza base 5 80 g = £2.45Savoury meals and mixesLoprofin c (SHS)Low-protein. Snack pot, curry 47 g = £3.94Promin c (Firstplay Dietary)Low-protein. Burger mix 2 62 g = £5.77; lamb & mint 2 62 g = £5.77. Couscous 500 g = £6.48. Pasta elbows in cheeseand broccoli sauce 4 66 g = £7.54. Pasta meal 500 g =£6.48. Pasta shells in tomato, pepper, and herb sauce 4 72 g= £7.54. Pasta spirals in Moroccan sauce 4 72 g = £7.54.Sausage mix, apple & sage 4 30 g = £6.49; original 4 30 g= £6.49; tomato & basil 4 30 g = £6.49SpreadsTaranis c (Firstplay Dietary)Low-protein. Spread, hazelnut 230 g = £6.80A2.7 Nutritional supplementsfor metabolic diseasesGlutaric aciduria (type 1)GA1 Anamix c Infant (SHS)Powder, protein equivalent (essential and non-essentialamino acids except lysine, and low tryptophan) 13.1 g,carbohydrate 49.5 g, fat 23 g, fibre 5.3 g, energy 1915 kJ(457 kcal)/100 g, with vitamins, minerals, and trace elements;standard dilution (15%) provides protein equivalent2 g, carbohydrate 7.4 g, fat 3.5 g, fibre 800 mg, energy 287 kJ(69 kcal)/100 mL. Unflavoured, net price 400 g = £32.70 (5-gmeasuring scoop provided)Nutritional supplement for the dietary management of provenglutaric aciduria (type 1) in children from birth to 3 yearsGA Gel c (Vitaflo)Gel, protein equivalent (essential and non-essential aminoacids except lysine, and low tryptophan) 8.4 g, carbohydrate8.6 g. fat trace, energy 286 kJ (68 kcal)/20 g, with vitamins,minerals, and trace elements. Unflavoured (flavouring: seeFlavourPac c , p. 777), net price 30 20-g sachets = £149.04Nutritional supplement for dietary management of type 1 glutaricaciduria in children 1–10 years1 XLYS, Low TRY, Maxamaid (SHS)Powder, protein equivalent (essential and non-essentialamino acids except lysine, and low tryptophan) 25 g,carbohydrate 51 g, fat less than 500 mg, energy 1311 kJ(309 kcal)/100 g, with vitamins, minerals, and trace elements.Unflavoured, (flavouring: see Modjul c FlavourSystem, p. 777), net price 500 g = £82.57Nutritional supplement for dietary management of type 1 glutaricaciduriaXLYS, TRY, Glutaridon (SHS)Powder, protein equivalent (essential and non-essentialamino acids except lysine and tryptophan) 79 g, carbohydrate4 g, energy 1411 kJ (332 kcal)/100 g, Lactose-free.Unflavoured, (flavouring: see Modjul c Flavour System,p. 777), net price 2 500 g = £312.84Nutritional supplement for type 1 glutaric aciduria in children andadults; requires additional source of vitamins, minerals and traceelementsGlucogen storage diseaseCorn flour and corn starchFor hypoglycaemia associated with glycogen-storage diseaseGlucose(Dextrose monohydrate)Net price 500 g = £1.18.For glycogen storage disease and sucrose/isomaltose intoleranceGlycosade c (Vitaflo)Powder, protein 200 mg, carbohydrate (maize starch) 47.6 g,fat 100 mg, fibre less than 600 mg, energy 803 kJ (192 kcal)/60 g, net price 30 60-g sachets = £92.03A nutritional supplement for use in the dietary management ofglycogen storage disease and other metabolic conditions where aconstant supply of glucose is essential. Not suitable for use inchildren under 2 yearsHomocystinuria orhypermethionimaemiaHCU Anamix c Infant (SHS)Powder, protein equivalent (essential and non-essentialamino acids except methionine) 13.1 g, carbohydrate 49.5 g,fat 23 g, fibre 5.3 g, energy 1915 kJ (457 kcal)/100 g, withvitamins, minerals, and trace elements; standard dilution(15%) provides protein equivalent 2 g, carbohydrate 7.4 g, fat3,5 g, fibre 800 mg, energy 287 kJ (69 kcal)/100 mL. Unflavoured,net price 400 g = £32.70 (5-g measuring scoopprovided)Nutritional supplement for the dietary management of provenvitamin B 6 non-responsive homocystinuria or hypermethioninaemiain children from birth to 3 years1. Maxamaid products are generally intended for use inchildren 1–8 yearsAppendix 2: Borderline substances

782 A2.7 Nutritional supplements for metabolic diseases BNFC 2011–2012Appendix 2: Borderline substancesHCU cooler c (Vitaflo)Liquid, protein (essential and non-essential amino acidsexcept methionine) 15 g, carbohydrate 7 g, fat 500 mg,energy 386 kJ (92 kcal)/130 mL, with vitamins, minerals andtrace elements. Orange or red flavour, net price 30 130-mLpouch = £277.20A methionine-free protein substitute for use as a nutritionalsupplement in children over 3 years with homocystinuriaHCU Express c (Vitaflo)Powder, protein (essential and non-essential amino acidsexcept methionine) 15 g, carbohydrate 3.8 g, fat 30 mg,energy 315 kJ (75.3 kcal)/25 g with vitamins, minerals andtrace elements. Unflavoured, (flavouring: see Flavour Pac c ,p. 777), net price 30 25- g sachets = £277.88A methionine-free protein substitute for use as a nutritionalsupplement in children over 8 years with homocystinuriaHCU gel c (Vitaflo)Powder, protein (essential and non-essential amino acidsexcept methionine) 8.4 g, carbohydrate 8.6 g, fat 30 mg,energy 286 kJ (68 kcal)/20 g with vitamins, minerals andtrace elements. Unflavoured, (flavouring: see Flavour Pac c ,p. 777), net price 30 20- g sachets = £151.93A methionine-free protein substitute for use as a nutritionalsupplement for the dietary management of children 1–10 yearswith homocystinuriaHCU LV c (SHS)Powder, protein (essential and non-essential amino acidsexcept methionine) 20 g, carbohydrate 2.5 g, fat 190 mg,energy 390 kJ (92 kcal)/27.8-g sachet, with vitamins,minerals, and trace elements. Unflavoured (flavouring: seeModjul c Flavour System, p. 777), or tropical flavour (formulationvaries slightly), net price 30 27.8-g sachets =£434.40Nutritional supplement for the dietary management of hypermethioninaemiaor vitamin B 6 non-responsive homocystinuria inchildren over 8 yearsXMET Homidon (SHS)Powder, protein equivalent (essential and non-essentialamino acids, except methionine) 77 g, carbohydrate 4.5 g, fatnil, energy 1386 kJ (326 kcal)/100 g. Unflavoured,(flavouring: see Modjul c Flavour System, p. 777), net price500 g = £156.42Nutritional supplement for the dietary management of hypermethioninaemiaor homocystinuria in children1 XMET Maxamaid (SHS)Powder, protein equivalent (essential and non-essentialamino acids except methionine) 25 g, carbohydrate 51 g, fatless than 500 mg, energy 1311 kJ (309 kcal)/100 g, withvitamins, minerals, and trace elements. Unflavoured(flavouring: see Modjul c Flavour System, p. 777), net price500 g = £82.57Nutritional supplement for the dietary management of hypermethioninaemiaor homocystinuria2 XMET Maxamum c (SHS)Powder, protein equivalent (essential and non-essentialamino acids except methionine) 39 g, carbohydrate 34 g, fatless than 500 mg, energy 1260 kJ (297 kcal)/100 g, withvitamins, minerals, and trace elements. Unflavoured,(flavouring: see Modjul c Flavour System, p. 777), net price500 g = £132.36Nutritional supplement for the dietary management of hypermethioninaemior homocystinuria1. Maxamaid products are generally intended for use inchildren 1–8 years2. Maxamum products are generally intended for use inchildren over 8 yearsHyperlysinaemiaHYPER LYS Anamix c Infant (SHS)Powder, protein equivalent (essential and non-essentialamino acids except lysine) 13.1 g, carbohydrate 49.5 g, fat23 g, fibre 5.3 g, energy 1915 kJ (457 kcal)/100 g, with vitamins,minerals, and trace elements; standard dilution (15%)provides protein equivalent 2 g, carbohydrate 7.4 g, fat 3.5 g,fibre 800 mg, energy 287 kJ (69 kcal)/100 mL. Unflavoured,net price 400 g = £32.70 (5-g measuring scoop provided)Nutritional supplement for the dietary management of provenhyperlysinaemia in children from birth to 3 years1 XLYS Maxamaid (SHS)Powder, protein equivalent (essential and non-essentialamino acids except lysine) 25 g, carbohydrate 51 g, fat lessthan 500 mg, energy 1311 kJ (309 kcal)/100 g with vitamins,minerals, and trace elements. Unflavoured, (flavouring: seeModjul c Flavour System, p. 777), net price 500 g = £82.57Nutritional supplement for the dietary management of hyperlysinaemiaIsovaleric acidaemiaIVA Anamix c Infant (SHS)Powder, protein equivalent (essential and non-essentialamino acids except leucine) 13.1 g, carbohydrate 49.5 g, fat23 g, fibre 5.3 g, energy 1915 kJ (457 kcal)/100 g, with vitamins,minerals, and trace elements; standard dilution (15%)provides protein equivalent 2 g, carbohydrate 7.4 g, fat 3.5 g,fibre 800 mg, energy 287 kJ (69 kcal)/100 mL. Unflavoured,net price 400 g = £32.70 (5-g measuring scoop provided)Nutritional supplement for the dietary management of provenisovaleric acidaemia or other proven disorders of leucine metabolismin children from birth to 3 yearsXLEU Faladon (SHS)Powder, protein equivalent (essential and non-essentialamino acids except leucine) 77 g, carbohydrate 4.5 g, fat nil,energy 1386 kJ (326 kcal)/100 g. Unflavoured, (flavouring:see Modjul c Flavour System, p. 777), net price 200 g =£62.55Nutritional supplement for the dietary management of isovalericacidaemia in children1 XLEU Maxamaid (SHS)Powder, protein equivalent (essential and non-essentialamino acids except leucine) 25 g, carbohydrate 51 g, fat lessthan 500 mg, energy 1311 kJ (309 kcal)/100 g with vitamins,minerals, and trace elements. Unflavoured, (flavouring: seeModjul c Flavour System, p. 777), net price 500 g = £82.57Nutritional supplement for the dietary management of isovalericacidaemiaMaple syrup urine diseaseIsoleucine Amino Acid Supplement (Vitaflo)Powder, isoleucine 50 mg, carbohydrate 4 g, fat nil, energy64 kJ (15 kcal)/4 g, net price 30 4-g sachets = £44.48Nutritional supplement for use in the dietary management ofmaple syrup urine disease and other inborn errors of amino acidmetabolism in children over 1 year and adultsMSUD Aid III c (SHS)Powder, protein equivalent (essential and non-essentialamino acids except isoleucine, leucine, and valine) 77 g,carbohydrate 4.5 g, fat nil, energy 1386 kJ (326 kcal)/100 g.Unflavoured, (flavouring: see Modjul c Flavour System,p. 777), net price 500 g = £156.42Nutritional supplement for the dietary management of maplesyrup urine disease and related conditions in children and adultswhere it is necessary to limit the intake of branched chain aminoacids

BNFC 2011–2012 A2.7 Nutritional supplements for metabolic diseases 783MSUD Anamix c Infant (SHS)Powder, protein equivalent (essential and non-essentialamino acids except isoleucine, leucine, and valine) 13.1 g,carbohydrate 49.5 g, fat 23 g, fibre 5.3 g, energy 1915 kJ(457 kcal)/100 g, with vitamins, minerals, and trace elements;standard dilution (15%) provides protein equivalent2 g, carbohydrate 7.4 g, fat 3.5 g, fibre 800 mg, energy 287 kJ(69 kcal)/100 mL. Unflavoured, net price 400 g = £32.70 (5-gmeasuring scoop provided)Nutritional supplement for the dietary management of provenmaple syrup urine disease in children from birth to 3 yearsMSUD Anamix c Junior (SHS)Powder, protein equivalent (essential and non-essentialamino acids except isoleucine, leucine, and valine) 8.4 g,carbohydrate 11 g, fat 3.9 g, energy 474 kJ (113 kcal)/29-gsachet, with vitamins, minerals, and trace elements. Unflavoured,(flavouring: see Modjul c Flavour System, p. 777),net price 30 29-g sachets = £166.73Nutritional supplement for the dietary management of maplesyrup urine disease in children 1–10 yearsMSUD Anamix c Junior LQ (SHS)Liquid, protein equivalent (essential and non-essential aminoacids except isoleucine, leucine, and valine) 10 g, carbohydrate8.8 g, fat 4.8 g, fibre 310 mg, energy 497 kJ (118 kcal)/125 mL, with vitamins, minerals, and trace elements. Lactose-free.Orange flavour, net price 125-mL carton = £7.58Nutritional supplement for the dietary management of maplesyrup urine disease in children 1–10 yearsMSUD express c (Vitaflo)Powder, protein equivalent (essential and non-essentialamino acids except leucine, isoleucine, and valine) 15 g,carbohydrate 3.8 g, fat less than 100 mg, energy 315 kJ(75 kcal)/25 g, with vitamins, minerals, and trace elements.Unflavoured, (flavouring: see Flavour Pac c , p. 777), netprice 30 25-g sachets = £271.88Nutritional supplement for the dietary management of maplesyrup urine disease in children over 8 years and adultsMSUD cooler c (Vitaflo)Liquid, protein equivalent (essential and non-essential aminoacids except leucine, isoleucine, and valine) 15 g, carbohydrate7 g, fat 500 mg, energy 386 kJ (92 kcal)/130-mL pouch,with vitamins, minerals, and trace elements. Orange or redflavour, net price 30 130-mL = £277.20Nutritional supplement for the dietary management of maplesyrup urine disease in children over 3 years and adultsMSUD Gel c (Vitaflo)Powder, protein equivalent (essential and non-essentialamino acids except leucine, isoleucine, and valine) 8.4 g,carbohydrate 8.6 g, fat less than 100 mg, energy 286 kJ(68 kcal)/20 g, with vitamins, minerals, and trace elements.Unflavoured, (flavouring: see Flavour Pac c , p. 777), netprice 30 20-g sachets = £151.93Nutritional supplement for the dietary management of maplesyrup urine disease in children 1–10 years1 MSUD Maxamaid c (SHS)Powder, protein equivalent (essential and non-essentialamino acids except isoleucine, leucine, and valine) 25 g,carbohydrate 51 g, fat less than 500 mg, energy 1311 kJ(309 kcal)/100 g, with vitamins, minerals, and trace elements.Unflavoured, (flavouring: see Modjul c FlavourSystem, p. 777), net price 500 g = £82.57Nutritional supplement for the dietary management of maplesyrup urine disease2 MSUD Maxamum c (SHS)Powder, protein equivalent (essential and non-essentialamino acids except isoleucine, leucine, and valine) 39 g,carbohydrate 34 g, fat less than 500 mg, energy 1260 kJ(297 kcal)/100 g, with vitamins, minerals, and trace elements.Orange flavour or unflavoured, (flavouring: seeModjul c Flavour System, p. 777), net price 500 g = £132.36Nutritional supplement for the dietary management of maplesyrup urine diseaseValine Amino Acid Supplement (Vitaflo)Powder, valine 50 mg, carbohydrate 4 g, fat nil, energy 64 kJ(15 kcal)/4 g, net price 30 4-g sachets = £44.48Nutritional supplement for the dietary management of maplesyrup urine disease and other inborn errors of amino acidmetabolism in children over 1 yearMethylmalonic propionic acidaemiaMMA/PA Anamix c Infant (SHS)Powder, protein equivalent (essential and non-essentialamino acids except methionine, threonine, and valine, andlow isoleucine) 13.1 g, carbohydrate 49.5 g, fat 23 g, fibre5.3 g, energy 1915 kJ (457 kcal)/100 g, with vitamins,minerals, and trace elements; standard dilution (15%) providesprotein equivalent 2 g, carbohydrate 7.4 g, fat 3.5 g,fibre 800 mg, energy 287 kJ (69 kcal)/100 mL. Unflavoured,net price 400 g = £32.70 (5-g measuring scoop provided)Nutritional supplement for the dietary management of provenmethylmalonic acidaemia or propionic acidaemia in children frombirth to 3 yearsXMTVI Asadon (SHS)Powder, protein equivalent (essential and non-essentialamino acids except methionine, threonine, and valine, andlow isoleucine) 77 g, carbohydrate 4.5 g, fat nil, energy1386 kJ (326 kcal)/100 g. Unflavoured, (flavouring: seeModjul c Flavour System, p. 777), net price 200 g = £62.55Nutritional supplement for the dietary management of methylmalonicacidaemia or propionic acidaemia in children and adults1 XMTVI Maxamaid (SHS)Powder, protein equivalent (essential and non-essentialamino acids except methionine, threonine, and valine, andlow isoleucine) 25 g, carbohydrate 51 g, fat less than 500 mg,energy 1311 kJ (309 kcal)/100 g, with vitamins, minerals,and trace elements. Unflavoured, (flavouring: see Modjul cFlavour System, p. 777), net price 500 g = £82.57Nutritional supplement for the dietary management of methylmalonicacidaemia or propionic acidaemia2 XMTVI Maxamum (SHS)Powder, protein equivalent (essential and non-essentialamino acids except methionine, threonine, and valine, andlow isoleucine) 39 g, carbohydrate 34 g, fat less than 500 mg,energy 1260 kJ (297 kcal)/100 g, with vitamins, minerals,and trace elements. Unflavoured, (flavouring: see Modjul cFlavour System, p. 777), net price 500 g = £132.36Nutritional supplement for the dietary management of methylmalonicacidaemia or propionic acidaemiaOther inborn errors of metabolismAppendix 2: Borderline substances1. Maxamaid products are generally intended for use inchildren 1–8 years2. Maxamum products are generally intended for use inchildren over 8 yearsCystine Amino Acid Supplement (Vitaflo)Powder, cystine 500 mg, carbohydrate 3.4 g, fat nil, energy63 kJ (15 kcal)/4 g, net price 30 4-g sachets = £44.48Nutritional supplement for the dietary management of inbornerrors of amino acid metabolism in children over 1 year

784 A2.7 Nutritional supplements for metabolic diseases BNFC 2011–2012Appendix 2: Borderline substancesDocOmega c (Vitaflo)Powder, protein (cows’ milk, soya) 100 mg, carbohydrate3.2 g, fat 500 mg (of which docosahexaenoic acid 200 mg),fibre nil, energy 74 kJ (18 kcal)/4 g, with minerals, net price30 x 4-g sachets = £32.20Nutritional supplement for the dietary management of inbornerrors of metabolism for adults and children from birthEAA c Supplement (Vitaflo)Powder, protein equivalent (essential amino acids) 5 g,carbohydrate 4 g, fat nil, energy 151 kJ (36 kcal)/12.5 g, withvitamins, minerals, and trace elements. Tropical flavour, netprice 50 12.5-g sachets = £174.48Nutritional supplement for the dietary management of disordersof protein metabolism including urea cycle disorders in childrenover 3 yearsKeyOmega c (Vitaflo)Powder, protein (cows’ milk, soya) 170 mg, carbohydrate2.8 g, fat 800 mg (of which arachidonic acid 200 mg, docosahexaenoicacid 100 mg), energy 80 kJ (19 kcal)/4 g, netprice 30 4-g sachet = £32.92Nutritional supplement for the dietary management of inbornerrors of metabolismLeucine Amino Acid Supplement (Vitaflo)Powder, leucine 100 mg, carbohydrate 4 g, fat nil, energy64 kJ (15 kcal)/4 g, net price 30 4-g sachets = £44.48Nutritional supplement for the dietary management of inbornerrors of amino acid metabolism in children over 1 yearLow protein drink (Milupa )Powder, protein (cows’ milk) 4.5 g (phenylalanine 100 mg),carbohydrate 59.5 g, fat 29.9 g, fibre nil, energy 2194 kJ(528 kcal)/100 g, with vitamins, minerals, and trace elements.Contains lactose. Net price 400 g = £7.76 (5-g measuringscoop provided)Nutritional supplement for the dietary management of inbornerrors of amino acid metabolism in adults and children over 1 yearNote Termed Milupa c lp-drink by manufacturerPhenylalanine Amino Acid Supplement (Vitaflo)Powder, phenylalanine 50 mg, carbohydrate 3.8 g, energy64 kJ (15 kcal)/4 g, net price 30 4-g sachets = £43.18Nutritional supplement for use in the dietary management ofinborn errors of metabolism onlyProZero c (Vitaflo)Liquid, carbohydrate 8.1 g (of which sugars 3.5 g), fat 3.8 g,energy 278 kJ (66 kcal)/100 mL. Contains lactose. Net price18 250 mL = £22.50; 6 1 litre = £30.00A protein-free nutritional supplement for the dietary managementof inborn errors of metabolism in children over 6 months andadultsPhenylketonuriaAdd-Ins c (SHS)Powder, protein equivalent (containing essential and nonessentialamino acids except phenylalanine) 10 g, carbohydratenil, fat 5.1 g, energy 359 kJ (86 kcal)/18.2-g sachet,with vitamins, minerals, and trace elements. Unflavoured,net price 60 18.2-g sachets = £315.60Nutritional supplement for the dietary management of provenphenylketonuria in children over 4 yearsEasiphen c (SHS)Liquid, protein equivalent (containing essential and nonessentialamino acids except phenylalanine) 6.7 g, carbohydrate5.1 g, fat 2 g, energy 275 kJ (65 kcal)/100 mL withvitamins, minerals, and trace elements. Forest berries ororange flavour, net price 250-mL carton = £8.11Nutritional supplement for the dietary management of provenphenylketonuria in children over 8 yearsLophlex c (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 20 g, carbohydrate 2.5 g,fat 60 mg, fibre 220 mg, energy 385 kJ (91 kcal)/27.8-gsachet, with vitamins, minerals, and trace elements. Flavours:berry, orange, or unflavoured, net price 30 x 27.8-gsachets = £243.60Nutritional supplement for the dietary management of provenphenylketonuria in children over 8 years and adults includingpregnant womenLoprofin c PKU Drink (SHS)Liquid, protein (cows’ milk) 400 mg (phenylalanine 10 mg),lactose 9.4 g, fat 2 g, energy 165 kJ (40 kcal)/100 mL. Netprice 200-mL carton = 61pNutritional supplement for the dietary management of phenylketonuriain children over 1 yearMilupa PKU 2-prima c (Milupa)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 60 g, carbohydrate 10 g,fat nil, energy 1190 kJ (280 kcal)/100 g, with vitamins,minerals, and trace elements. Vanilla flavour, net price 500 g= £131.68Nutritional supplement for the dietary management of phenylketonuriain children 1–8 yearsMilupa PKU 2-secunda c (Milupa)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 70 g, carbohydrate 6.8 g,fat nil, energy 1306 kJ (307 kcal)/100 g, with vitamins,minerals, and trace elements. Vanilla flavour, net price 500 g= £153.62Nutritional supplement for the dietary management of phenylketonuriain children 9–15 yearsMilupa PKU 3-advanta c (Milupa)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 70 g, carbohydrate 4.7 g,fat nil, energy 1270 kJ (299 kcal)/100 g, with vitamins,minerals, and trace elements. Vanilla flavour, net price 500 g= £153.62Nutritional supplement for the dietary management of phenylketonuriain children over 15 yearsPhlexy-10 c Exchange System (SHS)Capsules, protein equivalent (essential and non-essentialamino acids except phenylalanine) 416.5 mg/capsule, netprice 200-cap pack = £35.77Tablets, protein equivalent (essential and non-essentialamino acids except phenylalanine) 833 mg tablet, net price75-tab pack = £23.17Drink Mix, powder, protein equivalent (essential and nonessentialamino acids except phenylalanine) 8.33 g, carbohydrate8.8 g/20-g sachet. Apple-black currant, citrus, ortropical flavour, net price 30 20-g sachet = £107.86Nutritional supplement for the dietary management of phenylketonuriaPhlexy-Vits c (SHS)Powder, vitamins, minerals, and trace elements, net price 30 7-g sachets = £60.00Tablets, vitamins, minerals, and trace elements, net price180-tab pack = £68.26For use as a vitamin and mineral component of restricted therapeuticdiets in children over 11 years and adults with phenylketonuriaand similar amino acid abnormalitiesPK Aid 4 c (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 79 g, carbohydrate 4.5 g,fat nil, energy 1420 kJ (334 kcal)/100 g. Unflavoured,(flavouring: see Modjul c Flavour System, p. 777), net price500 g = £120.24 (5-g measuring scoop provided)Nutritional supplement for the dietary management of phenylketonuriain children and adults

BNFC 2011–2012 A2.7 Nutritional supplements for metabolic diseases 785PKU Anamix c First Spoon (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 5 g, carbohydrate 4.8 g,fat 150 mg, fibre nil, energy 168 kJ (41 kcal)/12.5-g sachet,with vitamins, minerals, and trace elements, net price 30 12.5 g = £81.00Nutritional supplement for the dietary management of provenphenylketonuria in children from 6 months to 5 yearsPKU Anamix c Infant (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 13.1 g, carbohydrate49.5 g, fat 23 g, fibre 5.3 g, energy 1915 kJ (457 kcal)/100 g,with vitamins, minerals, and trace elements; standard dilution(15%) provides protein equivalent 2 g, carbohydrate7.4 g, fat 3.5 g, fibre 800 mg, energy 287 kJ (69 kcal)/100 mL.Unflavoured, net price 400 g = £29.72 (5-g measuring scoopprovided)Nutritional supplement for the dietary management of provenphenylketonuria in children from birth to 3 yearsPKU Anamix c Junior (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 8.4 g, carbohydrate 9.9 g,fat 3.9 g, energy 455 kJ (108 kcal)/29-g sachet, with vitamins,minerals, and trace elements. Flavours: chocolate, pineapple-vanilla,or unflavoured (carbohydrate 11 g, energy 474 kJ(113 kcal)/29-g sachet), net price 30 29-g sachets =£106.20Nutritional supplement for the dietary management of phenylketonuriain children 1–10 yearsPKU Anamix Junior LQ c (SHS)Liquid, protein equivalent (essential and non-essential aminoacids except phenylalanine) 10 g, carbohydrate 8.8 g, fat4.8 g, fibre 310 mg, energy 497 kJ (118 kcal)/125 mL, withvitamins, minerals, and trace elements. Lactose-free. Flavours:Berry, orange, or unflavoured, net price 125-mLcarton = £4.72Nutritional supplement for the dietary supplement of phenyketonuriain children 1–10 yearsPKU cooler10 c (Vitaflo)Liquid, protein equivalent (essential and non-essential aminoacids except phenylalanine) 10 g, carbohydrate 5.1 g, energy258 kJ (62 kcal)/87-mL pouch, with vitamins, minerals, andtrace elements. Unflavoured (white) or flavoured (orange,purple, or red), net price 30 87-mL = £112.80Nutritional supplement for the dietary management of phenylketonuriain children over 3 yearsPKU cooler15 c (Vitaflo)Liquid, protein equivalent (essential and non-essential aminoacids except phenylalanine) 15 g, carbohydrate 7.8 g, energy386 kJ (92 kcal)/130-mL pouch, with vitamins, minerals, andtrace elements. Unflavoured (white) or flavoured (orange,purple, or red), net price 30 x 130 mL = £168.00Nutritional supplement for the dietary management of phenylketonuriain children over 3 yearsPKU cooler20 c (Vitaflo)Liquid, protein equivalent (essential and non-essential aminoacids except phenylalanine) 20 g, carbohydrate 10.2 g,energy 517 kJ (124 kcal)/174-mL pouch, with vitamins,minerals, and trace elements. Unflavoured (white) or flavoured(orange, purple, or red), net price 30 174 mL =£225.60Nutritional supplement for the dietary management of phenylketonuriain children over 3 yearsPKU express c (Vitaflo)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 15 g, carbohydrate 3.8 g,energy 315 kJ (76 kcal)/25 g, with vitamins, minerals, andtrace elements. Lemon, orange, tropical, or unflavoured, netprice 30 x 25-g sachets = £164.84Nutritional supplement for the dietary management of phenylketonuriain children over 8 yearsPKU gel c (Vitaflo)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 8.4 g, carbohydrate 8.6 g,fat less than 100 mg, energy 286 kJ (68 kcal)/20 g, withvitamins, minerals and trace elements. Orange, raspberry, orunflavoured (flavouring: see Flavour Pac c , p. 777), net price30 20-g sachets = £95.03For use as part of the low-protein dietary management ofphenylketonuria in children 1–10 yearsPKU Lophlex c LQ 10 (SHS)Liquid, protein equivalent (essential and non-essential aminoacids except phenylalanine) 10 g, carbohydrate 4.4 g, fibre170 mg, energy 245 kJ (58 kcal)/62.5 mL, with vitamins,minerals, and trace elements. Flavours: berry, citrus, orange,or tropical, net price 60 62.5 mL = £261.00Nutritional supplement for the dietary management of phenylketonuriain children over 4 years and adults including pregnantwomenPKU Lophlex c LQ 20 (SHS)Liquid, protein equivalent (essential and non-essential aminoacids except phenylalanine) 20 g, carbohydrate 8.8 g, fibre340 mg, energy 490 kJ (115 kcal)/125 mL, with vitamins,minerals, and trace elements. Flavours: berry, citrus, orange,or tropical, net price 3 125 mL = £26.04Nutritional supplement for the dietary management of phenylketonuriain children over 4 years and adults including pregnantwomenPKU Start c (Vitaflo)Liquid, protein equivalent (essential and non-essential aminoacids except phenylalanine) 2 g, carbohydrate 8.3 g, fat 2.9 g,energy 286 kJ (68 kcal)/100 mL with vitamins, minerals, andtrace elements. Contains lactose and fish oil. Net price 500-mL bottle = £5.58For the dietary management of phenylketonuria in children under12 monthsSno-Pro c (SHS)Liquid, protein (cows’ milk) 220 mg (phenylalanine 12.5 mg),carbohydrate 8 g, fat 3.8 g, energy 273 kJ (65 kcal)/100 mL.Contains lactose. Net price 200 mL = £1.05Nutritional supplement for the dietary management of phenylketonuria,chronic renal failure and other inborn errors of aminoacid metabolismL-Tyrosine (SHS)Powder, net price 100 g = £18.41Nutritional supplement for the dietary management of phenylketonuriain pregnant women with low plasma tyrosine concentrationsTyrosine Amino Acid Supplement (Vitaflo)Powder, tyrosine 1 g, carbohydrate 2.9 g, energy 62 kJ(15 kcal)/4-g sachet, net price 30 4-g sachets = £4.08Nutritional supplement for the dietary management of phenylketonuriaand other inborn errors of amino acid metabolism1 XP Maxamaid (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 25 g, carbohydrate 51 g,fat less than 500 mg, energy 1311 kJ (309 kcal)/100 g, withvitamins, minerals, and trace elements. Orange flavour, orunflavoured (flavouring; see Modjul c Flavour System,p. 777), net price 500 g = £48.85Nutritional supplement for the dietary management of phenylketonuriain children 1– 8 years1. Maxamaid products are generally intended for use inchildren 1–8 yearsAppendix 2: Borderline substances

786 A2.7 Nutritional supplements for metabolic diseases BNFC 2011–2012Appendix 2: Borderline substances1 XP Maxamum c (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine) 39 g, carbohydrate 34 g,fat less than 500 mg, energy 1260 kJ (297 kcal)/100 g, withvitamins, minerals, and trace elements. Orange, or unflavoured(flavouring; see Modjul c Flavour System, p. 777),net price 30 50-g sachets = £226.50, 500 g = £75.54Nutritional supplement for the dietary management of phenylketonuriain children over 8 yearsTyrosinaemiaMethionine-free TYR Anamix c Infant (SHS)Powder, protein equivalent (essential and non-essentialamino acids except methionine, phenylalanine, and tyrosine)13.1 g, carbohydrate 49.5 g, fat 23 g, fibre 5.3 g, energy1915 kJ (457 kcal)/100 g, with vitamins, minerals, and traceelements; standard dilution (15%) provides protein equivalent2 g, carbohydrate 7.4 g, fat 3.5 g, fibre 800 mg, energy287 kJ (69 kcal)/100 mL. Unflavoured, net price 400 g =£32.70 (5-g measuring scoop provided)Nutritional supplement for the dietary management of proventyrosinaemia type 1 in children from birth to 3 yearsTYR Anamix c Infant (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine and tyrosine) 13.1 g,carbohydrate 49.5 g, fat 23 g, fibre 5.3 g, energy 1915 kJ(457 kcal)/100 g, with vitamins, minerals, and trace elements;standard dilution (15%) provides protein equivalent2 g, carbohydrate 7.4 g, fat 3.5 g, fibre 800 mg, energy 287 kJ(69 kcal)/100 mL. Unflavoured, net price 400 g = £32.70 (5-gmeasuring scoop provided)Nutritional supplement for the dietary management of proventyrosinaemia where plasma-methionine concentrations are normalin children from birth to 3 yearsTYR Anamix c Junior (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine and tyrosine) 8.4 g,carbohydrate 11 g, fat 3.9 g, energy 475 kJ (113 kcal)/29-gsachet, with vitamins, minerals, and trace elements. Unflavoured,net price 30 x 29-g sachets = £173.32Nutritional supplement for the dietary management of proventyrosinaemia in children 1–10 yearsTYR Anamix c Junior LQ (SHS)Liquid, protein equivalent (essential and non-essentialamino acids except phenylalanine and tyrosine) 10 g,carbohydrate 8.8 g, fat 4.8 g, fibre 310 mg, energy500 kJ (119 kcal)/125 mL, with vitamins, minerals andtrace elements. Orange flavour, net price 36 x 125-mLbottle = £272.79Nutritional supplement for the dietary management of tyrosinaemiatype 1 (when nitisinone (NTBC) is used, see section 9.8.1),type II, and type III, in children over 1 yearTYR cooler c (Vitaflo)Liquid, protein equivalent (essential and non-essential aminoacids except tyrosine and phenylalanine) 15 g, carbohydrate7 g, fat 500 mg, energy 386 kJ (92 kcal)/130 mL, with vitamins,minerals, and trace elements. Orange or red flavour,net price 30 130-mL pouch = £277.20Nutritional supplement for the dietary management of tyrosinaemiain children over 8 yearsTYR express c (Vitaflo)Powder, protein equivalent (essential and non-essentialamino acids except tyrosine and phenylalanine) 15 g,carbohydrate 3.8 g, fat less than 100 mg, energy 315 kJ(76 kcal)/25 g, with vitamins, minerals, and trace elements.Unflavoured (flavouring: see Flavour Pac c , p. 777), netprice 30 25-g sachets = £271.88Nutritional supplement for the dietary management of tyrosinaemiain children over 8 years1. Maxamum products are generally intended for use inchildren over 8 yearsTYR Gel c (Vitaflo)Gel, protein equivalent (essential and non-essential aminoacids except tyrosine and phenylalanine) 8.4 g, carbohydrate8.6 g, fat less than 100 mg, energy 286 kJ (68 kcal)/20 g, withvitamins, minerals and trace elements. Unflavoured(flavouring: see Flavour Pac c , p. 777), net price 30 20-gsachets = £151.93Nutritional supplement for the dietary management of tyrosinaemiain children 1–10 years2 XPHEN TYR Maxamaid (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine and tyrosine) 25 g,carbohydrate 51 g, fat less than 500 mg, energy 1311 kJ(309 kcal)/100 g, with vitamins, minerals, and trace elements.Unflavoured (flavouring: see Modjul c FlavourSystem, p. 777), net price 500 g = £82.57Nutritional supplement for the dietary management of tyrosinaemiain children 1–8 yearsXPHEN TYR Tyrosidon (SHS)Powder, protein equivalent (essential and non-essentialamino acids except phenylalanine and tyrosine) 77 g,carbohydrate 4.5 g, fat nil, energy 1386 kJ (326 kcal)/100 g.Unflavoured (flavouring: see Modjul c Flavour System,p. 777), net price 500 g = £156.42Nutritional supplement for the management of tyrosinaemia inchildren and adults where plasma-methionine concentrations arenormalXPTM Tyrosidon (SHS)Powder, protein equivalent (essential and non-essentialamino acids except methionine, phenylalanine, and tyrosine)77 g, carbohydrate 4.5 g, fat nil, energy 1386 kJ (326 kcal)/100 g. Unflavoured (flavouring: see Modjul c FlavourSystem, p. 777), net price 500 g = £156.42Nutritional supplement for the dietary management of tyrosinaemiatype I in children and adults where plasma-methionineconcentrations are above normalUrea cycle disorders (other thanarginase deficiency)L-Arginine (SHS)Powder, net price 100 g = £12.27For use as a supplement in urea cycle disorders other thanarginase deficiency, such as hyperammonaemia types I and II,citrullaemia, arginosuccinic aciduria, and deficiency of N-acetylglutamate synthetaseConditions for which ACBS productscan be prescribedNote This is a list of clinical conditions for which the ACBS hasapproved toilet preparations. For details of the preparations seeChapter 13.BirthmarksSee Disfiguring skin lesions, belowDermatitisAveeno c Bath Oil; Aveeno c Cream; Aveeno c Colloidal;Aveeno c lotion; E45 c Emollient Bath Oil; E45 cEmollient Wash Cream; E45 c LotionDermatitis herpetiformisSee also Gluten-sensitive enteropathies, p. 7772. Maxamaid products are generally intended for use inchildren 1–8 years

BNFC 2011–2012 A2.7 Nutritional supplements for metabolic diseases 787Disfiguring skin lesions (birthmarks, mutilatinglesions, scars, vitiligo)Covermark c classic foundation and finishing powder;Dermacolor c Camouflage cream and fixing powder;Keromask c masking cream and finishing powder; Veil cCover cream and Finishing Powder. (Cleansing Creams,Cleansing Milks, and Cleansing Lotions are excluded)Disinfectants (antiseptics)May be prescribed on an FP10 only when ordered insuch quantities and with such directions as are appropriatefor the treatment of patients, but not for generalhygenic purposesDry mouth (xerostomia)For patients suffering from dry mouth as a result ofhaving (or having undergone) radiotherapy, or siccasyndrome.AS Saliva Orthana c ; Biotène Oralbalance c ; BioXtra c ;Glandosane c ; Saliveze c ; Salivix cFor details of preparations see section 12.3.5, p. 548EczemaSee Dermatitis, abovePhotodermatoses (skin protection in)Delph c Sun Lotion SPF 30; LA Roche-PosayAnthelios c Melt in cream SPF 50 + ; Sunsense Ultra c ;Uvistat c Lipscreen SPF 50, Uvistat c Suncream SPF 30and 50PruritusSee Dermatitis, aboveAppendix 2: Borderline substances

788 BNFC 2011–2012A3Cautionary and advisorylabels for dispensedmedicinesAppendix 3: Cautionary and advisory labelsPreparations in the BNF for Children include codenumbers of the cautionary labels that pharmacists arerecommended to add when dispensing. It is alsoexpected that, when necessary, pharmacists willcounsel children or their carers.Counselling needs to be related to the age, experience,background, and understanding of the child orcarer. The pharmacist should ensure understanding ofhow to take or use the medicine and how to follow thecorrect dosage schedule. Any effects of the medicineon co-ordination, performance of skilled tasks, anyfoods or medicines to be avoided, and what to do if adose is missed should also be explained. Other matters,such as the possibility of staining of the clothes orskin, or discoloration of urine or stools by a medicineshould also be mentioned.For some preparations there is a special need forcounselling, such as an unusual method or time ofadministration or a potential interaction with a commonfood or domestic remedy, and this should bementioned where necessary.Original packs Most preparations are now dispensedin unbroken original packs that include further advicefor the patient in the form of patient information leaflets.The advice in patient information leaflets may be lessappropriate when the medicine is for a child, particularlyfor unlicensed medicines or indications. Pharmacistsshould explain discrepancies to carers, if necessary.The patient information leaflet should only be withheldin exceptional circumstances because it contains otherinformation that should be provided. Label 10 may be ofvalue where appropriate. More general leaflets advisingon the administration of preparations such as eye drops,eye ointments, inhalers, and suppositories are also available.Scope of labels In general, no label recommendationsare provided for injections on the assumption thatthey will be administered by a healthcare professional ora well-instructed child or carer. The labelling is notexhaustive and pharmacists are recommended to usetheir professional discretion in labelling new preparationsand those for which no labels are shown.Individual labelling advice is not given on the administrationof the large variety of antacids. In the absence ofinstructions from the prescriber, and if on enquiry thepatient has had no verbal instructions, the directionsgiven under ‘Dose’ should be used on the label.It is recognised that there may be occasions whenpharmacists will use their knowledge and professionaldiscretion and decide to omit one or more of therecommended labels for a particular child. In this casecounselling is of the utmost importance. There may alsobe an occasion when a prescriber does not wish additionalcautionary labels to be used, in which case theprescription should be endorsed ‘NCL’ (no cautionarylabels). The exact wording that is required insteadshould then be specified on the prescription.Pharmacists label medicines with various wordings inaddition to those directions specified on the prescription.Such labels include ‘Shake the bottle’, ‘For externaluse only’, and ‘Store in a cool place’, as well as ‘Discard .. . . days after opening’ and ‘Do not use after ....’,whichapply particularly to antibiotic mixtures, diluted liquidand topical preparations, and to eye-drops. Althoughnot listed in the BNF for Children these labels shouldcontinue to be used when appropriate; indeed, ‘Forexternal use only’ is a legal requirement on externalliquid preparations, while ‘Keep out of the reach ofchildren’ is a legal requirement on all dispensed medicines.Care should be taken not to obscure other relevantinformation with adhesive labelling.It is the usual practice for patients to take standardtablets with water or other liquid and for this reason noseparate label has been recommended.The label wordings recommended by the BNF forChildren apply to medicines dispensed against a prescription.Children and carers should be made awarethat a dispensed medicine should never be taken by, orshared with, anyone other than for whom the prescriberintended it. Therefore, the BNF for Children does notinclude warnings against the use of a dispensed medicineby persons other than for whom it was specificallyprescribed.The label or labels for each preparation are recommendedafter careful consideration of the informationavailable. However, it is recognised that in some casesthis information may be either incomplete or open to adifferent interpretation. The BNF for Children willtherefore be grateful to receive any constructive commentson the labelling suggested for any preparation.Recommended label wordingsFor BNF for Children 2011–2012, a revised set ofcautionary and advisory labels has been introduced.All of the existing labels have been user-tested, andthe revised wording selected reflects terminologythat is better understood by patients.Wordings which can be given as separate warnings arelabels 1–19, 29–30, and 32. Wordings which can beincorporated in an appropriate position in the directionsfor dosage or administration are labels 21–28. A labelhas been omitted for number 20; labels 31 and 33 nolonger apply to any medicines in the BNF for childrenand have therefore been deleted.

BNFC 2011–2012 Appendix 3: Cautionary and advisory labels 789If separate labels are used it is recommended that thewordings be used without modification. If changes aremade to suit computer requirements, care should betaken to retain the sense of the original.1 Warning: This medicine may make you sleepyTo be used on preparations for children containingantihistamines, or other preparations given to childrenwhere the warnings of label 2 on driving oralcohol would not be appropriate.2 Warning: This medicine may make you sleepy. If thishappens, do not drive or use tools or machines. Donot drink alcoholTo be used on preparations for adults that can causedrowsiness, thereby affecting coordination and theability to drive and operate hazardous machinery;label 1 is more appropriate for children. It is an offenceto drive while under the influence of drink or drugs. Itshould be remembered that children and adolescentsdo, on occasion, consume alcohol and should bemade aware of potential problems.Some of these preparations only cause drowsiness inthe first few days of treatment and some only causedrowsiness in higher doses.In such cases the patient should be told that theadvice applies until the effects have worn off. Howevermany of these preparations can produce a slowing ofreaction time and a loss of mental concentration thatcan have the same effects as drowsiness.Avoidance of alcoholic drink is recommended becausethe effects of CNS depressants are enhanced byalcohol. Strict prohibition however could lead to somepatients not taking the medicine. Pharmacists shouldtherefore explain the risk and encourage compliance,particularly in patients who may think they alreadytolerate the effects of alcohol (see also label 3).Queries from patients with epilepsy regarding fitnessto drive should be referred back to the patient’sdoctor.Side-effects unrelated to drowsiness that may affect apatient’s ability to drive or operate machinery safelyinclude blurred vision, dizziness, or nausea. In general,no label has been recommended to cover thesecases, but the patient should be suitably counselled.3 Warning: This medicine may make you sleepy. If thishappens, do not drive or use tools or machinesTo be used on preparations containing monoamineoxidaseinhibitors; the warning to avoid alcohol anddealcoholised (low alcohol) drink is covered by thepatient information leaflet.Also to be used as for label 2 but where alcohol is notan issue.4 Warning: Do not drink alcoholTo be used on preparations where a reaction such asflushing may occur if alcohol is taken (e.g. metronidazole).Alcohol may also enhance the hypoglycaemiaproduced by some oral antidiabetic drugs but routineapplication of a warning label is not considerednecessary.Patients should be advised not to drink alcohol for aslong as they are receiving/using a course of medication,and in some cases for a period of time after thecourse is finished.5 Do not take indigestion remedies 2 hours before orafter you take this medicineTo be used with label 25 on preparations coated toresist gastric acid (e.g. enteric-coated tablets). This isto avoid the possibility of premature dissolution of thecoating in the presence of an alkaline pH.Label 5 also applies to drugs such as ketoconazolewhere the absorption is significantly affected byantacids. Pharmacists will be aware (from a knowledgeof physiology) that the usual time during whichindigestion remedies should be avoided is at least 2hours before and after the majority of medicines havebeen taken; where a manufacturer advises a differenttime period, this can be followed, and should beexplained to the patient.6 Do not take indigestion remedies, or medicines containingiron or zinc, 2 hours before or after you takethis medicineTo be used on preparations containing ofloxacin andsome other quinolones, doxycycline, lymecycline,minocycline, and penicillamine. These drugs chelatecalcium, iron, and zinc and are less well absorbedwhen taken with calcium-containing antacids or preparationscontaining iron or zinc. Pharmacists will beaware (from a knowledge of physiology) that theseincompatible preparations should be taken at least 2hours apart for the majority of medicines; where amanufacturer advises a different time period, this canbe followed, and should be explained to the patient.7 Do not take milk, indigestion remedies, or medicinescontaining iron or zinc, 2 hours before or after youtake this medicineTo be used on preparations containing ciprofloxacin,norfloxacin, or tetracyclines that chelate calcium, iron,magnesium, and zinc, and are thus less available forabsorption. Pharmacists will be aware (from a knowledgeof physiology) that these incompatible preparationsshould be taken at least 2 hours apart for themajority of medicines; where a manufacturer advises adifferent time period, this can be followed, and shouldbe explained to the patient. Doxycycline, lymecycline,and minocycline are less liable to form chelates andtherefore only require label 6 (see above).8 Warning: Do not stop taking this medicine unlessyour doctor tells you to stopTo be used on preparations that contain a drug whichis required to be taken over long periods without thepatient necessarily perceiving any benefit (e.g. antituberculousdrugs).Also to be used on preparations that contain a drugwhose withdrawal is likely to be a particular hazard(e.g. clonidine for hypertension). Label 10 (see below)is more appropriate for corticosteroids.9 Space the doses evenly throughout the day. Keeptaking this medicine until the course is finished,unless you are told to stopTo be used on preparations where a course of treatmentshould be completed to reduce the incidence ofrelapse or failure of treatment.The preparations are antimicrobial drugs given bymouth. Very occasionally, some may have severe sideeffects(e.g. diarrhoea in patients receiving clindamycin)and in such cases the patient may need to beadvised of reasons for stopping treatment quickly andreturning to the doctor.10 Warning: Read the additional information given withthis medicineTo be used particularly on preparations containinganticoagulants, lithium, and oral corticosteroids. Theappropriate treatment card should be given to thepatient and any necessary explanations given.This label may also be used on other preparations toremind the patient of the instructions that have beengiven.11 Protect your skin from sunlight—even on a bright butcloudy day. Do not use sunbedsTo be used on preparations that may cause phototoxicor photoallergic reactions if the patient is exposed toultraviolet radiation. Many drugs other than thoselisted (e.g. phenothiazines and sulfonamides) may, onrare occasions, cause reactions in susceptiblepatients. Exposure to high intensity ultraviolet radiationfrom sunray lamps and sunbeds is particularlylikely to cause reactions.12 Do not take anything containing aspirin while takingthis medicineTo be used on preparations containing probenecidand sulfinpyrazone whose activity is reduced byaspirin.Label 12 should not be used for anticoagulants sincelabel 10 is more appropriate.Appendix 3: Cautionary and advisory labels

790 Appendix 3: Cautionary and advisory labels BNFC 2011–2012Appendix 3: Cautionary and advisory labels13 Dissolve or mix with water before takingTo be used on preparations that are intended to bedissolved in water (e.g. soluble tablets) or mixed withwater (e.g. powders, granules) before use. In a fewcases other liquids such as fruit juice or milk may beused.14 This medicine may colour your urine. This is harmlessTo be used on preparations that may cause thepatient’s urine to turn an unusual colour. Theseinclude triamterene (blue under some lights), levodopa(dark reddish), and rifampicin (red).15 Caution: flammable. Keep your body away from fire orflames after you have put on the medicineTo be used on preparations containing sufficientflammable solvent to render them flammable ifexposed to a naked flame.16 Dissolve the tablet under your tongue—do not swallow.Store the tablets in this bottle with the captightly closed. Get a new supply 8 weeks afteropeningTo be used on glyceryl trinitrate tablets to remind thepatient not to transfer the tablets to plastic or lesssuitable containers.17 Do not take more than . . . in 24 hoursTo be used on preparations for the treatment of acutemigraine except those containing ergotamine, forwhich label 18 is used. The dose form should bespecified, e.g. tablets or capsules.It may also be used on preparations for which no dosehas been specified by the prescriber.18 Do not take more than . . . in 24 hours. Also, do nottake more than . . . in any one weekTo be used on preparations containing ergotamine.The dose form should be specified, e.g. tablets orsuppositories.19 Warning: This medicine makes you sleepy. If you stillfeel sleepy the next day, do not drive or use tools ormachines. Do not drink alcoholTo be used on preparations containing hypnotics (orsome other drugs with sedative effects) prescribed tobe taken at night. On the rare occasions (e.g. nitrazepamin epilepsy) when hypnotics are prescribed fordaytime administration this label would clearly not beappropriate. Also to be used as an alternative to thelabel 2 wording (the choice being at the discretion ofthe pharmacist) for anxiolytics prescribed to be takenat night.It is hoped that this wording will convey adequatelythe problem of residual morning sedation after taking‘sleeping tablets’.21 Take with or just after food, or a mealTo be used on preparations that are liable to causegastric irritation, or those that are better absorbedwith food.Patients should be advised that a small amount offood is sufficient.22 Take 30 to 60 minutes before foodTo be used on some preparations whose absorption isthereby improved.Most oral antibacterials require label 23 instead (seebelow).23 Take this medicine when your stomach is empty. Thismeans an hour before food or 2 hours after foodTo be used on oral preparations whose absorptionmay be reduced by the presence of food and acid inthe stomach.24 Suck or chew this medicineTo be used on preparations that should be sucked orchewed.The pharmacist should use discretion as to which ofthese words is appropriate.25 Swallow this medicine whole. Do not chew or crushTo be used on preparations that are enteric-coated ordesigned for modified-release.Also to be used on preparations that taste veryunpleasant or may damage the mouth if not swallowedwhole.Patients should be advised (where relevant) that somemodified-release preparations can be broken in half,but that the halved tablet should still be swallowedwhole, and not chewed or crushed.26 Dissolve this medicine under your tongueTo be used on preparations designed for sublingualuse. Patients should be advised to hold under thetongue and avoid swallowing until dissolved. Thebuccal mucosa between the gum and cheek is occasionallyspecified by the prescriber.27 Take with a full glass of waterTo be used on preparations that should be well diluted(e.g. chloral hydrate), where a high fluid intake isrequired (e.g. sulfonamides), or where water isrequired to aid the action (e.g. methylcellulose). Thepatient should be advised that ‘a full glass’ means atleast 150 mL. In most cases fruit juice, tea, or coffeemay be used.28 Spread thinly on the affected skin onlyTo be used on external preparations that should beapplied sparingly (e.g. corticosteroids, dithranol).29 Do not take more than 2 at any one time. Do not takemore than 8 in 24 hoursTo be used on containers of dispensed solid dosepreparations containing paracetamol for adults whenthe instruction on the label indicates that the dose canbe taken on an ‘as required’ basis. The dose formshould be specified, e.g. tablets or capsules.This label has been introduced because of the seriousconsequences of overdosage with paracetamol.30 Contains paracetamol. Do not take anything elsecontaining paracetamol while taking this medicineTo be used on all containers of dispensed preparationscontaining paracetamol.32 Contains aspirin. Do not take anything else containingaspirin while taking this medicineTo be used on containers of dispensed preparationscontaining aspirin when the name on the label doesnot include the word ’aspirin’.

BNFC 2011–2012 791A4Intravenous infusions forneonatal intensive careIntravenous policy A local policy on the dilution ofdrugs with intravenous fluids should be drawn up by amulti-disciplinary team and issued as a document to themembers of staff concerned.Centralised additive services are provided in a numberof hospital pharmacy departments and should be usedin preference to making additions on wards.The information that follows should be read in conjunctionwith local policy documents.Guidelines1. Drugs should only be diluted with infusion fluidwhen constant plasma concentrations are neededor when the administration of a more concentratedsolution would be harmful.2. In general, only one drug should be mixed with aninfusion fluid in a syringe and the componentsshould be compatible. Ready-prepared solutionsshould be used whenever possible. Drugs shouldnot normally be added to blood products, mannitol,or sodium bicarbonate. Only specially formulatedadditives should be used with fat emulsions oramino-acid solutions (section 9.3).3. Solutions should be thoroughly mixed by shakingand checked for absence of particulate matterbefore use.4. Strict asepsis should be maintained throughout andin general the giving set should not be used for morethan 24 hours (for drug admixtures).5. The infusion syringe should be labelled with theneonate’s name and hospital number, the name andquantity of drug, the infusion fluid, and the expirydate and time. If a problem occurs during administration,containers should be retained for a periodafter use in case they are needed for investigation.6. Administration using a suitable motorised syringedriver is advocated for preparations where strictcontrol over administration is required.7. It is good practice to examine intravenous infusionsfrom time to time while they are running. If cloudiness,crystallisation, change of colour, or any othersign of interaction or contamination is observed theinfusion should be discontinued.ProblemsMicrobial contamination The accidental entry andsubsequent growth of micro-organisms converts theinfusion fluid pathway into a potential vehicle for infectionwith micro-organisms, particularly species of Candida,Enterobacter, and Klebsiella. Ready-prepared infusionscontaining the additional drugs, or infusionsprepared by an additive service (when available) shouldtherefore be used in preference to making extemporaneousadditions to infusion containers on wards etc.However, when this is necessary strict aseptic procedureshould be followed.Incompatibility Physical and chemical incompatibilitiesmay occur with loss of potency, increase in toxicity,or other adverse effect. The solutions may becomeopalescent or precipitation may occur, but in manyinstances there is no visual indication of incompatibility.Interaction may take place at any point in the infusionfluid pathway, and the potential for incompatibility isincreased when more than one substance is added tothe infusion fluid.Common incompatibilities Precipitation reactions arenumerous and varied and may occur as a result of pH,concentration changes, ‘salting-out’ effects, complexationor other chemical changes. Precipitation or otherparticle formation must be avoided since, apart fromlack of control of dosage on administration, it mayinitiate or exacerbate adverse effects. This is particularlyimportant in the case of drugs which have been implicatedin either thrombophlebitis (e.g. diazepam) or inskin sloughing or necrosis caused by extravasation (e.g.sodium bicarbonate and parenteral nutrition). It is alsoespecially important to effect solution of colloidal drugsand to prevent their subsequent precipitation in order toavoid a pyrogenic reaction (e.g. amphotericin).It is considered undesirable to mix beta-lactam antibiotics,such as semi-synthetic penicillins and cephalosporins,with proteinaceous materials on the groundsthat immunogenic and allergenic conjugates could beformed.A number of preparations undergo significant loss ofpotency when added singly or in combination to largevolume infusions. Examples include ampicillin in infusionsthat contain glucose or lactates.Blood Because of the large number of incompatibilities,drugs should not be added to blood and blood productsfor infusion purposes. Examples of incompatibility withblood include hypertonic mannitol solutions (irreversiblecrenation of red cells), dextrans (rouleaux formationand interference with cross-matching), glucose (clumpingof red cells), and oxytocin (inactivated).If the giving set is not changed after the administrationof blood, but used for other infusion fluids, a fibrin clotmay form which, apart from blocking the set, increasesthe likelihood of microbial growth.Intravenous fat emulsions These may break downwith coalescence of fat globules and separation ofphases when additions such as antibacterials or electrolytesare made, thus increasing the possibility of embolism.Only specially formulated products such as VitlipidN c (section 9.3) may be added to appropriateintravenous fat emulsions.Appendix 4: Intravenous infusions for neonatal intensive care

792 Appendix 4: Intravenous infusions for neonatal intensive care BNFC 2011–2012Appendix 4: Intravenous infusions for neonatal intensive careOther infusions Infusions that frequently give rise toincompatibility include amino acids, mannitol, and sodiumbicarbonate.MethodReady-prepared infusions should be used wheneveravailable. When dilution of drugs is required to bemade extemporaneously, any product reconstitutioninstructions such as those relating to concentration,vehicle, mixing, and handling precautions should bestrictly followed using an aseptic technique throughout.Once the product has been reconstituted, further dilutionwith the infusion fluid should be made immediatelyin order to minimise microbial contamination and, withcertain products, to prevent degradation or other formulationchange which may occur; e.g. reconstitutedampicillin injection degrades rapidly on standing, andalso may form polymers which could cause sensitivityreactions.It is also important in certain instances that an infusionfluid of specific pH be used (e.g. furosemide injectionrequires dilution in infusions of pH greater than 5.5).When drug dilutions are made it is important to mixthoroughly; additions should not be made to an infusioncontainer that has been connected to a giving set, asmixing is hampered. If the solutions are not thoroughlymixed, a concentrated layer of the drug may form owingto differences in density. Potassium chloride is particularlyprone to this ‘layering’ effect when added withoutadequate mixing to infusions; if such a mixture isadministered it may have a serious effect on the heart.A time limit between dilution and completion of administrationmust be imposed for certain admixtures toguarantee satisfactory drug potency and compatibility.For admixtures in which degradation occurs without theformation of toxic substances, an acceptable limit is thetime taken for 10% decomposition of the drug. Whentoxic substances are produced stricter limits may beimposed. Because of the risk of microbial contaminationa maximum time limit of 24 hours may be appropriatefor additions made elsewhere than in hospital pharmaciesoffering central additive service.Certain injections must be protected from light duringcontinuous infusion to minimise oxidation, e.g. amphotericinand sodium nitroprusside.Table of drugs given by continuousintravenous infusion to neonatesThe table lists key drugs given by continuous intravenousinfusion to neonates.Covers dilution with Glucose intravenous infusion5% and 10% and Sodium chloride intravenous infusion0.9%. Compatibility with glucose 5% and withsodium chloride 0.9% indicates compatibility withSodium chloride and glucose intravenous infusion.Infusion of a large volume of hypotonic solutionshould be avoided, therefore care should be takenif water for injections is used.Adrenaline/Epinephrine (p. 113)Dilute 3 mg/kg body-weight to a final volume of50 mL with Glucose 5% or Sodium Chloride 0.9%; anintravenous infusion rate of 0.1 mL/hour provides adose of 100 nanograms/kg/minute; infuse through acentral venous catheter. Incompatible with bicarbonateand alkaline solutions.Note Usually made up with adrenaline 1 in 1000 (1 mg/mL)solution; this concentration of adrenaline is not licensed forintravenous administrationAlprostadil (Prostin VR c ) (p. 131)Dilute 150 micrograms/kg body-weight to a finalvolume of 50 mL with Glucose 5% or Sodium Chloride0.9%; an intravenous infusion rate of 0.1 mL/hourprovides a dose of 5 nanograms/kg/minute. Undilutedsolution must not come into contact with thebarrel of the plastic syringe; add the required volumeof alprostadil to a volume of infusion fluid in thesyringe, and then make up to final volumeAtracurium besilate (p. 643)Dilute 60 mg/kg body-weight to a final volume of50 mL with Glucose 5% or Sodium Chloride 0.9%; anintravenous infusion rate of 0.1 mL/hour provides adose of 120 micrograms/kg/hour; minimum concentrationof 500 micrograms/mL, max. concentration of5 mg/mLIntravenous infusion information for neonatal intensivecare only; for information in other children, seeindividual drug monographs.Dobutamine (as hydrochloride) (p. 111)Dilute 30 mg/kg body-weight to a final volume of50 mL with Glucose 5% or Sodium Chloride 0.9%; anintravenous infusion rate of 0.5 mL/hour provides adose of 5 micrograms/kg/minute; max. concentrationof 5 mg/mL; infuse higher concentration solutionsthrough central venous catheter only. Incompatiblewith bicarbonate and other strong alkaline solutionsDopamine hydrochloride (p. 111)Dilute 30 mg/kg body-weight to a final volume of50 mL with Glucose 5% or Sodium Chloride 0.9%; anintravenous infusion rate of 0.3 mL/hour provides adose of 3 micrograms/kg/minute; max. concentrationof 3.2 mg/mL; infuse higher concentration solutionsthrough central venous catheter. Incompatible withbicarbonate and other alkaline solutionsEpoprostenol (Flolan c ) (p. 96)Reconstitute the 500-microgram vial using the glycinebuffer diluent provided to make a 10 micrograms/mLconcentrate (pH 10.5); filter the concentrate using thefilter provided; the concentrate can be administeredvia a central venous catheter, or it may be dilutedfurther.Neonate body-weight under 2 kg, using the concentrate,dilute 150 micrograms/kg body-weight to a finalvolume of 50 mL with Sodium Chloride 0.9%; anintravenous infusion rate of 0.1 mL/hour provides adose of 5 nanograms/kg/minute.Neonate body-weight over 2 kg, using the concentrate,dilute 60 micrograms/kg body-weight to a finalvolume of 50 mL with Sodium Chloride 0.9%; anintravenous infusion rate of 0.1 mL/hour provides adose of 2 nanograms/kg/minute.Note Diluted solution stable for 12 hours at room temperature,although some units use for 24 hours and allow for lossof potency. Minimum concentration of 1.43 micrograms/mL

BNFC 2011–2012 Appendix 4: Intravenous infusions for neonatal intensive care 793Glyceryl trinitrate (p. 104)Dilute 3 mg/kg body-weight to a final volume of50 mL with Glucose 5% or Sodium Chloride 0.9%; anintravenous infusion rate of 1 mL/hour provides adose of 1 microgram/kg/minute; max. concentrationof 400 micrograms/mL (but concentration of 1 mg/mL has been used via a central venous catheter).Note Glass or polyethylene apparatus is preferable; loss ofpotency will occur if PVC is usedHeparin (as sodium) (p. 115)Maintenance of umbilical arterial catheter, dilute50 units to a final volume of 50 mL with SodiumChloride 0.45% or use ready-made bag containing500 units in 500 mL Sodium Chloride 0.9%; infuse at0.5 mL/hour.Treatment of thrombosis, dilute 1250 units/kg bodyweightto a final volume of 50 mL with Glucose 5% orSodium Chloride 0.9%; an intravenous infusion rate of1 mL/hour provides a dose of 25 units/kg/hourInsulin (soluble) (p. 352)Dilute 5 units to a final volume of 50 mL with SodiumChloride 0.9% and mix thoroughly; an intravenousinfusion rate of 0.1 mL/kg/hour provides a dose of0.01 units/kg/hour.Note Insulin may be absorbed by plastics, flush giving setwith 5 mL of infusion fluid containing insulinMidazolam (p. 234 and p. 638)Dilute 15 mg/kg body-weight to a final volume of50 mL with Glucose 5% or Sodium Chloride 0.9%; anintravenous infusion rate of 0.1 mL/hour provides adose of 30 micrograms/kg/hourIntravenous infusion information for neonatal intensivecare only; for information in other children, seeindividual drug monographs.Morphine sulphate (p. 207)Dilute 2.5 mg/kg body-weight to a final volume of50 mL with Glucose 5% or 10% or Sodium Chloride0.9%; an intravenous infusion rate of 0.1 mL/hourprovides a dose of 5 micrograms/kg/hourNoradrenaline/Norepinephrine (p. 113)Dilute 600 micrograms (base)/kg body-weight to afinal volume of 50 mL with Glucose 5% or SodiumChloride and Glucose; an intravenous infusion rate of0.1 mL/hour provides a dose of 20 nanograms (base)/kg/minute; infuse through central venous catheter;max. concentration of noradrenaline (base) 40 micrograms/mL(higher concentrations can be used iffluid restricted). Discard if discoloured. Incompatiblewith bicarbonate or alkaline solutions.Note 500 micrograms of noradrenaline base is equivalent to1 mg of acid tartrate. Dose expressed as the baseVecuronium (p. 645)Reconstitute each vial with 5 mL Water for Injectionsto give a 2 mg/mL solution. Dilute 5 mg/kg bodyweightto a final volume of 50 mL with Glucose 5% orSodium Chloride 0.9%; an intravenous infusion rate of0.5 mL/hour provides a dose of 50 micrograms/kg/hour; minimum concentration of 40 micrograms/mLAppendix 4: Intravenous infusions for neonatal intensive care

794 BNFC 2011–2012Dental Practitioners’FormularyDental Practitioners’ FormularyList of Dental PreparationsThe following list has been approved by the appropriateSecretaries of State, and the preparations therein maybe prescribed by dental practitioners on form FP10D(GP14 in Scotland, WP10D in Wales).Sugar-free versions, where available, are preferred.Aciclovir Cream, BPAciclovir Oral Suspension, BP, 200 mg/5 mLAciclovir Tablets, BP, 200 mgAciclovir Tablets, BP, 800 mgAmoxicillin Capsules, BPAmoxicillin Oral Powder, DPFAmoxicillin Oral Suspension, BPAmpicillin Capsules, BPAmpicillin Oral Suspension, BPArtificial Saliva Oral Spray, DPF1Artificial Saliva Substitutes as listed below (to be prescribedonly for indications approved by ACBS):AS Saliva Orthana cGlandosane cBiotene Oralbalance cBioXtra cSaliveze cSalivix c2Aspirin Tablets, Dispersible, BPAzithromycin Oral Suspension, 200 mg/5 mL, DPFBeclometasone Pressurised Inhalation, BP, 50 micrograms/meteredinhalation, CFC-free, as:Clenil Modulite cBenzydamine Mouthwash, BP 0.15%Benzydamine Oromucosal Spray, BP 0.15%Betamethasone Soluble Tablets, 500 micrograms, DPFCarbamazepine Tablets, BPCarmellose Gelatin Paste, DPFCefalexin Capsules, BPCefalexin Oral Suspension, BPCefalexin Tablets, BPCefradine Capsules, BPCetirizine Hydrochloride Tablets, 10 mg, DPFChlorhexidine Gluconate Gel, BPChlorhexidine Mouthwash, BPChlorhexidine Oral Spray, DPFChlorhexidine Oromucosal Solution, Alcohol-free, 0.2%,DPFChlorphenamine Oral Solution, BPChlorphenamine Tablets, BPCholine Salicylate Dental Gel, BPClarithromycin Oral Suspension, 125 mg/5 mL, DPFClarithromycin Oral Suspension, 250 mg/5 mL, DPFClarithromycin Tablets, BPClindamycin Capsules, BP1. Indications approved by the ACBS are: patients sufferingfrom dry mouth as a result of having (or having undergone)radiotherapy or sicca syndrome2. The BP directs that when soluble aspirin tablets areprescribed, dispersible aspirin tablets should be dispensedCo-amoxiclav Tablets, BP, 250/125 (amoxicillin 250 mgas trihydrate, clavulanic acid 125 mg as potassiumsalt)Co-amoxiclav Oral Suspension, BP, 125/31 (amoxicillin125 mg as trihydrate, clavulanic acid 31.25 mg aspotassium salt)/5 mLCo-amoxiclav Oral Suspension, BP, 250/62 (amoxicillin250 mg as trihydrate, clavulanic acid 62.5 mg aspotassium salt)/5 mLDiazepam Oral Solution, BP, 2 mg/5 mLDiazepam Tablets, BPDiclofenac Sodium Tablets, BPDihydrocodeine Tablets, BP, 30 mgDispersible Doxycycline Tablets, BPDoxycycline Capsules, BP, 100 mgDoxycycline Tablets, 20 mg, DPFEphedrine Nasal Drops, BPErythromycin Ethyl Succinate Oral Suspension, BPErythromycin Ethyl Succinate Tablets, BPErythromycin Stearate Tablets, BPErythromycin Tablets, BPFluconazole Capsules, 50 mg, DPFFluconazole Oral Suspension, 50 mg/5 mL, DPFHydrocortisone Cream, BP, 1%Hydrocortisone Oromucosal Tablets, BPHydrogen Peroxide Mouthwash, BPIbuprofen Oral Suspension, BP, sugar-freeIbuprofen Tablets, BPLansoprazole Capsules, DPFLidocaine 5% Ointment, DPFLidocaine Spray 10%, DPFLoratadine Tablets, 10 mg, DPF3Menthol and Eucalyptus Inhalation, BP 1980Metronidazole Oral Suspension, BPMetronidazole Tablets, BPMiconazole Cream, BPMiconazole Oromucosal Gel, BPMiconazole and Hydrocortisone Cream, BPMiconazole and Hydrocortisone Ointment, BPMouthwash Solution-tablets, DPFNitrazepam Tablets, BPNystatin Oral Suspension, BPGastro-resistant Omeprazole Capsules, BPOxytetracycline Tablets, BP4Paracetamol Oral Suspension, BPParacetamol Tablets, BPParacetamol Tablets, Soluble, BPPenciclovir Cream, DPFPhenoxymethylpenicillin Oral Solution, BPPhenoxymethylpenicillin Tablets, BPPromethazine Hydrochloride Tablets, BPPromethazine Oral Solution, BPSaliva Stimulating Tablets, DPF3. This preparation does not appear in subsequent editions ofthe BP4. The BP directs that when Paediatric Paracetamol OralSuspension or Paediatric Paracetamol Mixture is prescribedand no strength stated Paracetamol Oral Suspension120 mg/5 mL should be dispensed

BNFC 2011–2012 Dental Practitioners’ Formulary 795Sodium Chloride Mouthwash, Compound, BPSodium Fluoride Mouthwash, BPSodium Fluoride Oral Drops, BPSodium Fluoride Tablets, BPSodium Fluoride Toothpaste 0.619%, DPFSodium Fluoride Toothpaste 1.1%, DPFSodium Fusidate Ointment, BPTemazepam Oral Solution, BPTemazepam Tablets, BPTetracycline Tablets, BPDental Practitioners’ Formulary

796 BNFC 2011–2012Nurse Prescribers’FormularyNurse Prescribers’ FormularyNurse Prescribers’ Formulary forCommunity PractitionersNurse Prescribers’ Formulary Appendix (AppendixNPF). List of preparations approved by the Secretary ofState which may be prescribed on form FP10P (formHS21(N) in Northern Ireland, form GP10(N) in Scotland,forms FP10(CN) and FP10(PN) in Wales or, when available,WP10CN and WP10PN in Wales) by Nurses forNational Health Service patients.Community practitioners who have completed thenecessary training may only prescribe items appearingin the nurse prescribers’ list set out below. CommunityPractitioner Nurse Prescribers are recommended toprescribe generically, except where this would not beclinically appropriate or where there is no approvedgeneric name.Medicinal PreparationsAlmond Oil Ear Drops, BPArachis Oil Enema, NPF1Aspirin Tablets, Dispersible, 300 mg, BPBisacodyl Suppositories, BP (includes 5-mg and 10-mgstrengths)Bisacodyl Tablets, BPCatheter Maintenance Solution, Chlorhexidine, NPFCatheter Maintenance Solution, Sodium Chloride, NPFCatheter Maintenance Solution, ‘Solution G’, NPFCatheter Maintenance Solution, ‘Solution R’, NPFChlorhexidine Gluconate Alcoholic Solutions containingat least 0.05%Chlorhexidine Gluconate Aqueous Solutions containingat least 0.05%Choline Salicylate Dental Gel, BPClotrimazole Cream 1%, BPCo-danthramer Capsules, NPFCo-danthramer Capsules, Strong, NPFCo-danthramer Oral Suspension, NPFCo-danthramer Oral Suspension, Strong, NPFCo-danthrusate Capsules, BPCo-danthrusate Oral Suspension, NPFCrotamiton Cream, BPCrotamiton Lotion, BPDimeticone barrier creams containing at least 10%Dimeticone Lotion, NPFDocusate Capsules, BPDocusate Enema, NPFDocusate Oral Solution, BPDocusate Oral Solution, Paediatric, BPEconazole Cream 1%, BPEmollients as listed below:Aquadrate c 10% w/w CreamAqueous Cream, BPArachis Oil, BPBalneum c Plus CreamCetraben c Emollient Cream1. Max. 96 tablets; max. pack size 32 tabletsDermamist cDiprobase c CreamDiprobase c OintmentDoublebase cE45 c CreamE45 c Itch Relief CreamEmulsifying Ointment, BPEucerin c Intensive 10% w/w Urea TreatmentCreamEucerin c Intensive 10% w/w Urea TreatmentLotionHydromol c CreamHydromol c Intensive2Hydromol c OintmentHydrous Ointment, BPLipobase cLiquid and White Soft Paraffin Ointment, NPFNeutrogena c Norwegian Formula DermatologicalCreamNutraplus c CreamOilatum c CreamOilatum c Junior CreamParaffin, White Soft, BPParaffin, Yellow Soft, BP3QV c Cream3QV c LotionUltrabase cUnguentum M c2Zerobase c Cream2Zerocream c2Zeroguent c CreamEmollient Bath Additives as listed below:4Balneum c4Balneum Plus c Bath OilCetraben c Emollient Bath AdditiveDermalo c Bath EmollientDiprobath cDoublebase c Emollient Bath AdditiveDoublebase c Emollient Shower GelDoublebase c Emollient Wash GelHydromol c Bath and Shower EmollientOilatum c EmollientOilatum c Junior Bath AdditiveOilatum c Gel3QV c Bath OilQV c WashZerolatum c Emollient Medicinal Bath Oil2Zeroneum c Bath OilZerozole c Bath OilFolic Acid 400 micrograms/5 mL Oral Solution, NPFFolic Acid Tablets 400 micrograms, BP2. Included in the Drug Tariff (Part IXA), the Scottish DrugTariff (Part 2) and the Northern Ireland Drug Tariff (partIII)3. Included in the Drug Tariff (Part IXA) and the NorthernIreland Drug Tariff (part III)4. Except pack sizes that are not to be prescribed under theNHS (see Part XVIIIA of the Drug Tariff, Part XI of theNorthern Ireland Drug Tariff)

BNFC 2011–2012 Nurse Prescribers’ Formulary 797Glycerol Suppositories, BP1Ibuprofen Oral Suspension, BP1Ibuprofen Tablets, BPIspaghula Husk Granules, BPIspaghula Husk Granules, Effervescent, BPIspaghula Husk Oral Powder, BPLactulose Solution, BPLidocaine and Chlorhexidine Gel, BPMacrogol Oral Powder, Compound, NPFMacrogol Oral Powder, Compound, Half-strength, NPFMagnesium Hydroxide Mixture, BPMagnesium Sulphate Paste, BPMalathion aqueous lotions containing at least 0.5%Mebendazole Oral Suspension, NPFMebendazole Tablets, NPFMethylcellulose Tablets, BPMiconazole Cream 2%, BPMiconazole Oromucosal Gel, BPMouthwash Solution-tablets, NPFNicotine Inhalation Cartridge for Oromucosal Use, NPFNicotine Lozenge, NPFNicotine Medicated Chewing Gum, NPFNicotine Nasal Spray, NPFNicotine Sublingual Tablets, NPFNicotine Transdermal Patches, NPFNystatin Oral Suspension, BPOlive Oil Ear Drops, BPParacetamol Oral Suspension, BP (includes 120 mg/5 mL and 250 mg/5 mL strengths—both of which areavailable as sugar-free formulations)2Paracetamol Tablets, BP2Paracetamol Tablets, Soluble, BP (includes 120-mg and500-mg tablets)Permethrin Cream, NPFPhosphates Enema, BPPhosphate suppositories, NPFPiperazine and Senna Powder, NPFPovidone–Iodine Solution, BPSenna Oral Solution, NPFSenna Tablets, BPSenna and Ispaghula Granules, NPFSodium Chloride Solution, Sterile, BPSodium Citrate Compound Enema, NPFSodium Picosulfate Capsules, NPFSodium Picosulfate Elixir, NPFSpermicidal contraceptives as listed below:Gygel c Contraceptive JellySterculia Granules, NPFSterculia and Frangula Granules, NPFTitanium Ointment, BPWater for Injections, BPZinc and Castor Oil Ointment, BPZinc Cream, BPZinc Ointment, BPZinc Oxide and Dimeticone Spray, NPFZinc Oxide Impregnated Medicated Bandage, NPFZinc Oxide Impregnated Medicated Stocking, NPFZinc Paste Bandage, BP 1993Zinc Paste and Ichthammol Bandage, BP 1993Appliances and Reagents (including WoundManagement Products)Community Practitioner Nurse Prescribers in England,Wales and Northern Ireland can prescribe any applianceor reagent in the relevant Drug Tariff. In the ScottishDrug Tariff, Appliances and Reagents which may not beprescribed by Nurses are annotated Nx.Appliances (including Contraceptive Devices 3 ) as listedin Part IXA of the Drug Tariff (Part III of the NorthernIreland Drug Tariff, Part 3 (Appliances) and Part 2(Dressings) of the Scottish Drug Tariff)Incontinence Appliances as listed in Part IXB of theDrug Tariff (Part III of the Northern Ireland Drug Tariff,Part 5 of the Scottish Drug Tariff)Stoma Appliances and Associated Products as listedin Part IXC of the Drug Tariff (Part III of the NorthernIreland Drug Tariff, Part 6 of the Scottish Drug Tariff)Chemical Reagents as listed in Part IXR of the DrugTariff (Part II of the Northern Ireland Drug Tariff, Part 9of the Scottish Drug Tariff)The Drug Tariffs can be accessed online at:National Health Service Drug Tariff for England andWales:www.ppa.org.uk/ppa/edt_intro.htmHealth and Personal Social Services for NorthernIreland Drug Tariff:www.dhsspsni.gov.uk/pas-tariffScottish Drug Tariff: www.isdscotland.org/isd/2245.htmlNurse Independent PrescribingNurse Independent Prescribers (formerly known asExtended Formulary Nurse Prescribers) are able toprescribe any medicine for any medical condition,including some Controlled Drugs (see p. 798).Nurse Independent Prescribers must work within theirown level of professional competence and expertise.They are recommended to prescribe generically, exceptwhere this would not be clinically appropriate or wherethere is no approved non-proprietary name.Nurse Independent Prescribers are also able to prescribeindependently the Controlled Drugs in the tablebelow, solely for the medical conditions indicated.For information on the mixing of medicines by NurseIndependent Prescribers, see Mixing of medicines priorto administration in clinical practice—responding tolegislative changes, National Prescribing Centre, May2010 (available at www.npc.co.uk/policy/mixing/mixing_medicines.htm).Up-to-date information and guidance on nurse independentprescribing is available on the Department ofHealth website atwww.dh.gov.uk/nonmedicalprescribingNurse Prescribers’ Formulary1. Except for indications and doses that are A2. Max. 96 tablets; max. pack size 32 tablets3. Nurse Prescribers in Family Planning Clinics—where it isnot appropriate for nurse prescribers in family planningclinics to prescribe contraceptive devices using formFP10(P) (forms FP10(CN) and FP10(PN), or when availableWP10CN and WP10PN, in Wales), they may prescribeusing the same system as doctors in the clinic

798 Nurse Prescribers’ Formulary BNFC 2011–2012Controlled drugs prescribable by Nurse Independent Prescribers solely for the medicalconditions indicatedNurse Prescribers’ FormularyDrug Indication Route of AdministrationBuprenorphine Transdermal use in palliative care TransdermalChlordiazepoxide hydrochloride Treatment of initial or acute withdrawal symptoms caused Oralby the withdrawal of alcohol from persons habituated to itCodeine phosphate – OralCo-phenotrope – OralDiamorphine hydrochloride Use in palliative care, pain relief in respect of suspected Oral, parenteralmyocardial infarction or for relief of acute or severe painafter trauma, including in either case postoperative painreliefDiazepamUse in palliative care, treatment of initial or acute withdrawalOral, parenteral, rectalsymptoms caused by the withdrawal of alcoholfrom persons habituated to it, tonic-clonic seizuresDihydrocodeine tartrate – OralFentanyl Transdermal use in palliative care TransdermalLorazepam Use in palliative care, tonic-clonic seizures Oral, parenteralMidazolam Use in palliative care, tonic-clonic seizures Parenteral, buccalMorphine hydrochloride Use in palliative care, pain relief in respect of suspected Rectalmyocardial infarction or for relief of acute or severe painafter trauma, including in either case postoperative painreliefMorphine sulphateUse in palliative care, pain relief in respect of suspected Oral, parenteral, rectalmyocardial infarction or for relief of acute or severe painafter trauma, including in either case postoperative painreliefOxycodone hydrochloride Use in palliative care Oral, parenteralNote For the purposes of nurse independent prescribing, palliative care means the care of patients with advanced,progressive illness

BNFC 2011–2012 799Non-medical prescribingA range of non-medical healthcare professionals canprescribe medicines for patients as either Independentor Supplementary Prescribers.Independent prescribers are practitioners responsibleand accountable for the assessment of patients withpreviously undiagnosed or diagnosed conditions andfor decisions about the clinical management required,including prescribing. They are recommended to prescribegenerically, except where this would not beclinically appropriate or where there is no approvednon-proprietary name.Supplementary prescribing is a partnership betweenan independent prescriber (a doctor or a dentist) and asupplementary prescriber to implement an agreedClinical Management Plan for an individual patientwith that patient’s agreement.Independent and Supplementary Prescribers are identifiedby an annotation next to their name in therelevant professional register.Up-to-date information and guidance on non-medicalprescribing is available on the Department of Healthwebsite at www.dh.gov.uk/nonmedicalprescribing.For information on the mixing of medicines byIndependent and Supplementary Prescribers, seeMixing of medicines prior to administration in clinicalpractice—responding to legislative changes,National Prescribing Centre, May 2010 (available atwww.npc.co.uk/policy/mixing/mixing_medicines.htm).For information on the supply and administration ofmedicines to groups of patients using Patient GroupDirections, see p. 3.NursesFor further information on Nurse Independent Prescribing,see Nurse Prescribers’ Formulary, p. 797.OptometristsOptometrist Independent Prescribers can prescribe anylicensed medicine for ocular conditions affecting the eyeand the tissues surrounding the eye, except ControlledDrugs or medicines for parenteral administration. OptometristIndependent Prescribers must work within theirown level of professional competence and expertise.Non-medical prescribingPharmacistsPharmacist Independent Prescribers can prescribe anymedicine, except Controlled Drugs, for any medicalcondition. Pharmacist Independent Prescribers mustwork within their own level of professional competenceand expertise.

800 BNFC 2011–2012Index of manufacturersThe following is an alphabeticallist of manufacturers and theirmedicines information contactdetails. For information on ‘special-order’manufacturers andspecialist importing companiessee p. 809.3M3M Health Care Ltdtel: (01509) 611 611A&HAllen & Hanburys LtdSee GSKADI MedicalADI Medical UKtel: (01628) 485159info@adimedical.co.ukAdvancisAdvancis Medical Ltdtel: (01623) 751 500info@advancis.co.ukAgephaAgepha GmbHtel: (020) 3239 6241uk@agepha.comAlmirallAlmirall Ltdtel: 0800 008 7399almirall@professionalinformation.co.ukAlphashowAlphashow Ltdtel: 0870 240 2775info@alphashow.co.ukAltacorAltacor Ltdtel: (01223) 421 411info@altacor-pharma.comIndex of manufacturersA1 PharmaceuticalsA1 Pharmaceuticals Plctel: (01708) 528 900sales@a1plc.co.ukAbbottAbbott Laboratories Ltdtel: (01628) 773 355ukmedinfo@abbott.comAbbott HealthcareAbbott Healthcare Products Ltdtel: (023) 8046 7000medinfo.shl@abbott.comAbraxisAbraxis BioScience Ltdtel: (020) 7081 0850abraxismedical@idispharma.comABT HealthcareABT Healthcare UK Ltdtel: (01565) 757 783AcorusAcorus Therapeutics Ltdtel: (01244) 625 152enquiries@acorus-therapeutics.comActavisActavis UK Ltdtel: (01271) 311 257medinfo@actavis.co.ukAguettantAguettant Ltdtel: (01934) 835 694info@aguettant.co.ukAir ProductsAir Products plctel: 0800 373 580Alan PharmaceuticalsAlan Pharmaceuticalstel: (020) 7284 2887AlconAlcon Laboratories (UK) Ltdtel: (01442) 341 234AlexionAlexion Pharma UK Ltdtel: (01932) 359 220alexion.uk@alxn.comALK-AbellóALK-Abelló (UK) Ltdtel: (01488) 686 016info@uk.alk-abello.comAllerganAllergan Ltdtel: (01628) 494 026AmdipharmAmdipharm plctel: 0870 777 7675medinfo@amdipharm.comAmgenAmgen Ltdtel: (01223) 420 305gbinfoline@amgen.comArchimedesArchimedes Pharma UK Ltdtel: (0118) 931 5060medicalinformation@archimedespharma.comArdanaArdana Bioscience Ltdtel: (0131) 226 8550info@ardana.co.ukArk TherapeuticsArk Therapeutics Group Plctel: (020) 7388 7722info@arktherapeutics.comAspenAspen Europe GmbHtel: 00800 00404142medinfoenquiries@pharsafer.comActelionActelion Pharmaceuticals UK Ltdtel: (020) 8987 3333medinfo_uk@actelion.comAllergyAllergy Therapeutics Ltdtel: (01903) 844 702Aspen MedicalAspen Medical Europe Ltdtel: (01527) 587 728customers@aspenmedicaleurope.comActivaActiva Healthcaretel: 0845 060 6707advice@activahealthcare.co.ukAllianceAlliance Pharmaceuticals Ltdtel: (01249) 466 966info@alliancepharma.co.ukAS PharmaAS Pharma Ltdtel: 0870 066 4117info@aspharma.co.uk

BNFC 2011–2012 Index of manufacturers 801AspireAspire Pharma Ltdtel: (01730) 234 527info@aspirepharma.co.ukBHRBHR Pharmaceuticals Ltdtel: (024) 7635 3742info@bhr.co.ukBritanniaBritannia Pharmaceuticalstel: 0870 851 0207enquiries@medinformation.co.ukAstellasAstellas Pharma Ltdtel: (01784) 419 615AstraZenecaAstraZeneca UK Ltdtel: 0800 783 0033medical.informationuk@astrazeneca.comAuden MckenzieAuden Mckenzie (Pharma Division) Ltdtel: (01895) 627 420BioenvisionBioenvision Ltdtel: (0131) 248 3555info@bioenvision.comBiogenBiogen Idec Ltdtel: 0800 008 7401BiolitecBiolitec Pharma Ltdtel: (00353) 1463 7415medical.info@biolitec.comBSN MedicalBSN Medical Ltdtel: 0845 122 3600CareFusionCareFusion UK 244 Ltdtel: 0800 043 7546enquiries@chloraprep.co.ukCasen-FleetCasen-Fleettel: (0034) 913 518 800ssi@casenfleet.comAxcanAxcan Pharma SAtel: (0033) 130 461 900Ayrton SaundersAyrton Saunders Ltdtel: (0151) 709 2074info@ayrtons.comBardBard Ltdtel: (01293) 527 888BasileaBasilea Pharmaceuticals Ltdtel: (01483) 790 023ukmedinfo@basilea.comBausch & LombBausch & Lomb UK Ltdtel: (01748) 828 864medicalinformationUK@bausch.comBaxterBaxter Healthcare Ltdtel: (01635) 206 345surecall@baxter.comBayer Consumer CareSee Bayer ScheringBayer Diabetes CareSee Bayer ScheringBayer DiagnosticsSee Bayer ScheringBayer ScheringBayer Schering Pharmatel: (01635) 563 116medical.information@bayer.co.ukBBI HealthcareBBI Healthcaretel: (01792) 229 333info@bbihealthcare.comBeaconBeacon Pharmaceuticals Ltdtel: (01892) 600 930info@beaconpharma.co.ukBeiersdorfBeiersdorf UK Ltdtel: (0121) 329 8800BioMarinBioMarin Europe Ltdtel: (020) 7420 0800biomarin-europe@bmrn.comBiotest UKBiotest (UK) Ltdtel: (0121) 733 3393medicinesinformation@biotestuk.comBlackwellBlackwell Supplies Ltdtel: (01634) 877 620BOCBOC Medicaltel: 0800 111 333Boehringer IngelheimBoehringer Ingelheim Ltdtel: (01344) 424 600medinfo@bra.boehringer-ingelheim.comBootsBoots the Chemiststel: (0115) 959 5165BPC 100The Bolton Pharmaceutical 100 Ltdtel: 0845 602 3907info@bpc100.comBPLBio Products Laboratorytel: (020) 8957 2622medinfo@bpl.co.ukBraunB Braun (Medical) Ltdtel: (0114) 225 9000info.bbmuk@bbraun.comBrayBray Healthcaretel: (01367) 240 736info@bray-healthcare.comBristol-Myers SquibbBristol-Myers Squibb PharmaceuticalsLtdtel: (01895) 523 000medical.information@bms.comC D MedicalC D Medical Ltdtel: (01942) 816 184CelgeneCelgene Ltdtel: 0844 801 0045medinfo.uk.ire@celgene.comCephalonCephalon Ltdtel: 0800 783 4869ukmedinfo@cephalon.comChanelle MedicalChanelle Medical UK Ltdtel: (01233) 822 297Chattem UKChattem UK Ltdtel: (01256) 844 144Chefaro UKChefaro UK Ltdtel: (01480) 421 800ChemidexChemidex Pharma Ltdtel: (01784) 477 167info@chemidex.co.ukChiesiChiesi Ltdtel: (0161) 488 5555medinfo@chiesi.uk.comCHSCambridge Healthcare Supplies Ltdtel: (01603) 735 200customerservices@typharm.comChugaiChugai Pharma UK Ltdtel: (020) 8987 5680Clement ClarkeClement Clarke International Ltdtel: (01279) 414 969resp@clement-clarke.comClinigenClinigen Healthcare Ltdtel: (01748) 902 805clinigenuk@professionalinformation.co.ukIndex of manufacturers

802 Index of manufacturers BNFC 2011–2012Index of manufacturersCliniMedCliniMed Ltdtel: (01628) 535 250enquires@clinimed.co.ukClinisuppliesClinisupplies Ltdtel: (020) 8863 4168info@clinisupplies.co.ukColgate-PalmoliveColgate-Palmolive Ltdtel: (01483) 302 222ColoplastColoplast Ltdtel: (01733) 392 000gbcareteam@coloplast.comCommunityCommunity Foods Ltdtel: (020) 8450 9411email@communityfoods.co.ukComplan FoodsComplan Foods Ltdtel: (020) 7395 7565ConsilientConsilient Health UK Ltdtel: (020) 8956 2310drugsafety@consilienthealth.comConvaTecConvaTec Ltdtel: (01895) 628 400Co-PharmaCo-Pharma Ltdtel: 0870 851 0207co-pharma@medinformation.co.ukCovidienCovidien UK Commercial Ltdtel: (01329) 224 226medicalcustomerservices@covidien.comCow & GateCow & Gatetel: 0845 762 3624careline@inpractice.co.ukCranageCranage Healthcare Ltdtel: (01477) 549 392db@cranagehealth.comCrawfordCrawford Healthcare Ltdtel: (01565) 654 920CrucellCrucell (UK) Ltdtel: 0844 800 3908info@crucell.co.ukCSL BehringCSL Behring UK Ltdtel: (01444) 447 400medinfo@cslbehring.comDaiichi SankyoDaiichi Sankyo UK Ltdtel: (01753) 482 771medinfo@daiichi-sankyo.co.ukDanetreDanetre Health Products Ltdtel: (01327) 310 909enquiries@danetrehealthproducts.comDDDDDD Ltdtel: (01923) 229 251DeeDee Pharmaceuticals Ltdtel: (01978) 661993enquiries@deepharmaceuticalsltd.co.ukDental HealthDental Health Products Ltdtel: (01622) 749 222DentsplyDentsply Ltdtel: (01932) 837 279DermalDermal Laboratories Ltdtel: (01462) 458 866DermatonicsDermatonics Ltdtel: (01480) 462 910sales@dermatonics.co.ukDerma UKDerma UK Ltdtel: (01462) 733 500info@dermauk.co.ukDeVilbissDeVilbiss Healthcare UK Ltdtel: (01384) 446 688DexcelDexcel-Pharma Ltdtel: (01327) 312 266office@dexcelpharma.co.ukDHP HealthcareDHP Healthcare Ltdtel: (01622) 749 222sales@dhphealthcare.co.ukDreamskinDreamskin Health Ltdtel: (01727) 668 288medinfo@dreamskinhealth.co.ukDr FalkDr Falk Pharma UK Ltdtel: (01628) 536 600DrossaDrossa Ltdtel: (020) 3393 0859info@drossa.co.ukDurbinDurbin plctel: (020) 8869 6500info@durbin.co.ukEakinT G Eakintel: (028) 9187 1000mail@eakin.co.ukEasigripEasigrip Ltdtel: (01926) 497 108enquiry@easigrip.co.ukEcolabEcolab UKtel: (0113) 232 0066info.healthcare@ecolab.co.ukEgisEgis Pharmaceuticals UK Ltdtel: (020) 7266 2669enquiries@medimpexuk.comEisaiEisai Ltdtel: (020) 8600 1400lmedinfo@eisai.netEncysiveEncysive (UK) Ltdtel: (01895) 876 168enquiries@encysive.co.ukEspereEspere Healthcare Ltdtel: (01234) 834 614info@esperehealth.co.ukEthiconEthicon Ltdtel: (01506) 594 500EumedicaEumedica S.A.tel: (020) 8444 3377enquiries@eumedica.comEUSA PharmaEUSA Pharma (Europe) Ltdtel: (01438) 740 720medinfo-uk@eusapharma.comEverfreshEverfresh Natural Foodstel: (01296) 425 333FabrePierre Fabre Ltdtel: (01962) 874 435medicalinformation@pierre-fabre.co.ukFateFate Special Foodstel: (01215) 224 433

BNFC 2011–2012 Index of manufacturers 803FentonFenton Pharmaceuticals Ltdtel: (020) 7224 1388mail@Fent-Pharm.co.ukFerndaleFerndale Pharmaceuticals Ltdtel: (01937) 541 122info@ferndalepharma.co.ukFerringFerring Pharmaceuticals (UK)tel: 0844 931 0054medical@ferring.comFirstplay DietaryFirstplay Dietary Foods Ltdtel: (0161) 474 7576FlynnFlynn Pharma Ltdtel: (01438) 727 822medinfo@flynnpharma.comFoodlinkFoodlink (UK) Ltdtel: (01752) 344 544info@foodlinkltd.co.ukFordFord Medical Associates Ltdtel: (01233) 633 224enquiries@fordmedical.co.ukForestForest Laboratories UK Ltdtel: (01322) 421 800medinfo@forest-labs.co.ukForumForum Health Products Ltdtel: (01737) 773 711health@forumgroup.co.ukFoxC. H. Fox Ltdtel: (020) 7240 3111Fresenius KabiFresenius Kabi Ltdtel: (01928) 533 533med.info-uk@fresenius-kabi.comFresenius Medical CareFresenius Medical Care UK Ltdtel: (01623) 445 139medinfo-uk@fmc-ag.comFrontierFrontier Multigatetel: (01495) 233 050multigate@frontier-group.co.ukFyne DynamicsFyne Dynamics Ltdtel: (01279) 423 423info@fyne-dynamics.comGaldermaGalderma (UK) Ltdtel: (01923) 208 950GalenGalen Ltdtel: (028) 3833 4974customer.services@galen.co.ukGE HealthcareGE Healthcaretel: (01494) 544 000GeistlichGeistlich Pharmatel: (01244) 347 534General DietaryGeneral Dietary Ltdtel: (020) 8336 2323GenericsSee MylanGenius FoodsGenius Foods Ltdtel: 0845 874 4000info@geniusglutenfree.comGenopharmLaboratoires Genopharmtel: (0808) 234 2664info@genopharm.euGenusGenus Pharmaceuticalstel: (01635) 568 400info@genuspharma.comGenzymeGenzyme Therapeuticstel: (01865) 405 200ukmedinfo@genzyme.comGFF TradeGF Foods Ltdtel: (01757) 289 207admin@gffdirect.co.ukGileadGilead Sciences Ltdtel: (01223) 897 555ukmedinfo@gilead.comGlebe FarmGlebe Farmtel: (01487) 773 282office@glebe-flour.co.ukGlenwoodGlenwood GmbHtel: (0049) 815 199 8790info@glenwood.deGluten Free Foods LtdGluten Free Foods Ltdtel: (020) 8953 4444info@glutenfree-foods.co.ukGoldshieldGoldshield Pharmaceuticals Ltdtel: 0870 070 3033medicalinformation@goldshieldplc.comGP PharmaSee Derma UKGrifolsGrifols UK Ltdtel: (01223) 395 700reception.uk@grifols.comGrünenthalGrünenthal Ltdtel: 0870 351 8960medicalinformationuk@grunenthal.comGSKGlaxoSmithKlinetel: 0800 221 441customercontactuk@gsk.comGSK Consumer HealthcareGlaxoSmithKline Consumer Healthcaretel: (020) 8047 2500customer.relations@gsk.comH&RH&R Healthcare Ltdtel: (01482) 638 491HamptonHampton Pharmaceuticals Ltdtel: (01923) 251 777HartmannPaul Hartmann Ltdtel: (01706) 363 200info@uk.hartmann.infoHeinzH. J. Heinz Company Ltdtel: (020) 8573 7757farleys_heinz@heinz.co.ukHenleysHenleys Medical Supplies Ltdtel: (01707) 333 164HFA HealthcareHFA Healthcare Ltdtel: 0844 335 8270HK PharmaHK Pharma Ltdtel: (01438) 356 926HollisterHollister Ltdtel: (0118) 989 5000customer.services@hollister.comHospiraHospira UK Ltdtel: (01926) 834 400medinfouk@hospira.comHRA PharmaHRA Pharma UK Ltdtel: 0800 917 9548med.info.uk@hra-pharma.comHuntleighHuntleigh Healthcare Ltdtel: (01582) 413 104IdisIdis Ltdtel: (01932) 824 000mi@idispharma.comIndex of manufacturers

804 Index of manufacturers BNFC 2011–2012INCA-PharmINCA-Pharm UKtel: (01748) 828 812info@inca-pharm.comKappinKappin Ltdtel: (020) 8961 8511orbispv@orbisplc.comLornameadLornamead UK Ltdtel: (01276) 674000lornamead@dhl.comIndex of manufacturersInfaiInfai UK Ltdtel: (01904) 435 228info@infai.co.ukInnovativeInnovative Solutions UK Ltdtel: (01706) 746 713enquiries@innovative-solutions.org.ukInsenseInsense Ltdtel: (01234) 782 870enquiries@insense.co.ukInsightInsight Medical Products Ltdtel: (01666) 500 055info@insightmedical.netIntrapharmIntrapharm Laboratories Ltdtel: (01622) 749 222sales@intraphamlabs.comIpsenIpsen Ltdtel: (01753) 627 777medical.information.uk@ipsen.comIrokoIroko Cardio LLCtel: (001) 267 546 3182IS PharmaceuticalsIS Pharmaceuticals Ltdtel: (01244) 625 152enquiries@ispharma.plc.ukIVAXSee TEVA UKJ&JJohnson & Johnson Ltdtel: (01628) 822 222medinfo@congb.jnj.comJanssenJanssen-Cilag Ltdtel: 0800 731 8450medinfo@janssen-cilag.comJobskinJobskin Ltdtel: (0115) 973 4300dw@jobskin.co.ukJuvelaJuvela (Hero UK) Ltdtel: (0151) 432 5300info@juvela.co.ukK/LK/L Pharmaceuticals Ltdtel: (01294) 215 951KCI MedicalKCI Medical Ltdtel: (01865) 840 600Kestrel OphthalmicsKestrel Ophthalmics Ltdtel: (01202) 658 444info@kestrelophthalmics.co.ukKingKing Pharmaceuticals Ltdtel: (01438) 356 924KoRaKoRa Healthcare Ltdtel: 0845 303 8631info@kora.ieKyowa HakkoKyowa Hakko UK Ltdtel: (01753) 566 020LantorLantor UK Ltdtel: (01204) 855 000help@lantor.co.ukLEOLEO Laboratories Ltdtel: (01844) 347 333medical-info.uk@leo-pharma.comLifeScanLifeScantel: (01494) 658 750LillyEli Lilly & Co Ltdtel: (01256) 315 000ukmedinfo@lilly.comLincoln MedicalLincoln Medical Ltdtel: (01748) 828 785info@lincolnmedical.co.ukLindermaLinderma Ltdtel: (01942) 816 184linderma@virgin.netLipomedLipomed GmbHtel: (0049) 776 155 9222lipomed@lipomed.comLivwellLivwell Ltdtel: 0845 120 0038info@livwell.euL’Oréal ActiveL’Oréal Active Cosmetics UKtel: 0800 055 6822LPCLPC Pharmaceuticals Ltdtel: (01582) 560 393info@lpcpharma.comLundbeckLundbeck Ltdtel: (01908) 638 935ukmedicalinformation@lundbeck.comM & A PharmachemM & A Pharmachem Ltdtel: (01942) 816 184buy@mapharmachem.co.ukManuka MedicalManuka Medical Ltdtel: (01623) 600 669ManxManx Healthcaretel: (01926) 482 511info@manxhealthcare.comMarlboroughMarlborough Pharmaceuticalstel: (01672) 514 187info@marlborough-pharma.co.ukMartindaleMartindale Pharmatel: (01277) 266 600medinfo@martindalepharma.co.ukMASTAMASTAtel: (0113) 238 7500medical@masta.orgMcNeilMcNeil Products Ltdtel: (01628) 822 222MDEMedical Diagnostics Europe Ltdtel: 0845 370 8077info@mdediagnostic.co.ukMead JohnsonMead Johnson Nutritionalstel: (01895) 523 764MeadowMeadow Laboratories Ltdtel: (020) 8597 1203enquiries@meadowlabs.fsnet.co.ukMedaMeda Pharmaceuticals Ltdtel: (01748) 828 810meda@professionalinformation.co.ukMedacMedac (UK)tel: (01786) 458 086info@medac-uk.co.uk

BNFC 2011–2012 Index of manufacturers 805MedicareMedicare Plus International Ltdtel: (020) 8810 8811info@medicare-plus.comMedicomMedicom Healthcare Ltdtel: (01489) 574 119info@medicomhealthcare.comMedihoneyMedihoney (Europe) Ltdtel: 0800 071 3912MSDMerck Sharp & Dohme Ltdtel: (01992) 467 272medicalinformationuk@merck.comMylanMylantel: (01707) 853 000info@mylan.co.ukNagorNagor Ltdtel: (01624) 625 556enquiries@nagor.comNovo NordiskNovo Nordisk Ltdtel: (01293) 613 555customercareuk@novonordisk.comnSPIRE HealthnSPIRE Health Ltdtel: (01992) 526 300info@nspirehealth.comNutricia ClinicalNutricia Clinical Caretel: (01225) 711 688resourcecentre@nutricia.comMedlockMedlock Medical Ltdtel: (0161) 621 2100medical.information@medlockmedical.comMedLogicMedLogic Global Ltdtel: (01752) 209 955enquiries@mlgl.co.ukMenariniA. Menarini Pharma UK SRLtel: (01628) 856 400menarini@medinformation.co.ukMenarini DiagnosticsA. Menarini Diagnosticstel: (0118) 944 4100Merck SeronoMerck Serono Ltdtel: (020) 8818 7200medinfo.uk@merckserono.netMerzMerz Pharma UK Ltdtel: (020) 8236 0000info@merzpharma.co.ukMicro MedicalMicro Medical Ltdtel: (01634) 893 500sales@micromedical.co.ukMilupaMilupa Aptamiltel: 0845 762 3676careline@aptamil4hcps.co.ukMölnlyckeMölnlycke Health Care Ltdtel: (0161) 777 2628info.uk@molnlycke.netMoorfieldsMoorfields Pharmaceuticalstel: (020) 7684 9090MorningsideMorningside Healthcare Ltdtel: (0116) 204 5950MoviantoMovianto UKtel: (01234) 248 500movianto.uk@movianto.comNappNapp Pharmaceuticals Ltdtel: (01223) 424 444NeoceuticalsNeoceuticals Ltdtel: (01748) 828 865NeolabNeolab Ltdtel: (01256) 704 110info@neolab.co.ukNeomedicNeomedic Ltdtel: (01923) 836 379marketing@neomedic.co.ukNestléNestlé Nutritiontel: 00800 6887 4846nestlehealthcarenutrition@uk.nestle.comNewportNewport Pharmaceuticals Ltdtel: (00353) 1890 3011Nipro DiagnosticsNipro Diagnostics (UK) Ltdtel: (01489) 569 469info@homediagnostics-uk.comNordicNordic Pharma UK Ltdtel: (0118) 929 8233info@nordicpharma.co.ukNorgineNorgine Pharmaceuticals Ltdtel: (01895) 826 600NovartisNovartis Pharmaceuticals UK Ltdtel: (01276) 698 370medinfo.uk@novartis.comNovartis Consumer HealthNovartis Consumer Healthtel: (01403) 210 211medicalaffairs.uk@novartis.comNovartis VaccinesNovartis Vaccines Ltdtel: 0845 745 1500service.uk@novartis.comNutrinovoNutrinovo Ltdtel: (01304) 829 068info@nutrinovo.comNutrition PointNutrition Point Ltdtel: (07041) 544 044info@nutritionpoint.co.ukNycomedNycomed UK Ltdtel: 0800 633 5797medinfo@nycomed.comOakMedOakMed Ltdtel: 0800 592 786orders@oakmed.co.ukOctapharmaOctapharma Ltdtel: (0161) 837 3770octapharma@octapharma.co.ukOmronOmron Healthcare (UK) Ltdtel: 0870 750 2771info.omronhealthcare.uk@eu.omron.comOrganonSee MSDOrionOrion Pharma (UK) Ltdtel: (01635) 520 300medicalinformation@orionpharma.comOrphan EuropeOrphan Europe (UK) Ltdtel: (01491) 414 333infouk@orphan-europe.comOtsukaOtsuka Pharmaceutical (UK) Ltdtel: (020) 8756 3100medinfo@otsuka.co.ukOvationOvation Healthcare International Ltdtel: (00353) 1613 9707Owen MumfordOwen Mumford Ltdtel: (01993) 812 021customerservices@owenmumford.co.ukIndex of manufacturers

806 Index of manufacturers BNFC 2011–2012Oxford NutritionOxford Nutrition Ltdtel: (01626) 832 067info@nutrinox.comProceliProcelitel: (01226) 713 044admin@proceli.co.ukRIS ProductsRIS Products Ltdtel: (01438) 840 135info@risproducts.co.ukIndex of manufacturersPaines & ByrnePaines & Byrne Ltdtel: (01784) 419 620PariPARI Medical Ltdtel: (01932) 341 122infouk@pari.deParksideParkside Healthcaretel: (0161) 795 2792PeckfortonPeckforton Pharmaceuticals Ltdtel: (01270) 582 255info@peckforton.comPennPenn Pharmaceuticals Services Ltdtel: (01495) 711 222penn@pennpharm.co.ukPfizerPfizer Ltdtel: (01304) 616 161EUMEDINFO@pfizer.comPGR Health FoodsPGR Health Foods Ltdtel: (01992) 581 715info@pgrhealthfoods.co.ukPharmaciaSee PfizerPharma-GlobalPharma-Global Ltdtel: (00353) 1280 1104eyecare@pharmaglobal.iePharma MarSee IdisPharma NordPharma Nord (UK) Ltdtel: (01670) 519 989uksales@pharmanord.co.ukPharmasurePharmasure Ltdtel: (01923) 233 466info@pharmasure.co.ukProcter & GambleProcter & Gamble (Health and BeautyCare) Ltdtel: (0191) 297 5000ProfileProfile Pharma Ltdtel: 0800 1300 855info@profilepharma.comProStrakanProStrakan Ltdtel: (01896) 664 000medinfo@prostrakan.comProtexProtex Healthcare (UK) Ltdtel: 0870 011 4112orders@protexhealthcare.co.ukRanbaxyRanbaxy UK Ltdtel: (020) 8280 1986medinfoeurope@ranbaxy.comRansomRansom Consumer Healthcaretel: (01462) 437 615info@williamransom.comRatiopharm UKRatiopharm UK Ltdtel: (023) 9231 3592info@ratiopharm.co.ukReckitt BenckiserReckitt Benckiser Healthcaretel: (01482) 326 151info.MIU@reckittbenckiser.comRecordatiRecordati Pharmaceuticals Ltdtel: (01491) 576 336medinfo@recordati.co.ukReSource MedicalReSource Medical UK Ltdtel: (01484) 531 489info@resource-medical.co.ukRespironicsPhilips Respironics (UK) Ltdtel: 0800 130 0840rukmarketing@respironics.comRobinsonsRobinson Healthcare Ltdtel: (01909) 735 064enquiry@robinsonhealthcare.comRocheRoche Products Ltdtel: 0800 328 1629medinfo.uk@roche.comRoche DiagnosticsRoche Diagnostics Ltdtel: (01444) 256 000burgesshill.accu-chek@roche.comRosemontRosemont Pharmaceuticals Ltdtel: 0800 919 312infodesk@rosemontpharma.comRowaRowa Pharmaceuticals Ltdtel: (00353) 275 0077rowa@rowa-pharma.ieS&N Hlth.Smith & Nephew Healthcare Ltdtel: (01482) 222 200advice@smith-nephew.comSallisSallis Healthcare Ltdtel: (0115) 978 7841SandozSandoz Ltdtel: (01276) 698 020sandoz@professionalinformation.co.ukSanochemiaSanochemia Diagnostics UK Ltdtel: (0117) 906 3562Sanofi-AventisSanofi-Aventis Ltdtel: (01483) 505 515uk-medicalinformation@sanofi-aventis.comSanofi PasteurSanofi Pasteur MSD Ltdtel: (01628) 785 291Schering-PloughSee MSDPinewoodPinewood Healthcaretel: (00353) 523 6253info@pinewood.ieRichardsonRichardson Healthcare Ltdtel: 0870 011 1126info@richardsonhealthcare.comSchucoSchuco International Ltdtel: (020) 8368 1642sales@schuco.co.ukPottersPotters Herbal Medicinestel: (01942) 219 960info@pottersherbals.co.ukRiemserRiemser Arzneimittel AGtel: (0049) 383 517 6679info@RIEMSER.deSchülkeSchülke UKtel: (0114) 254 3500mail.uk@schuelke.com

BNFC 2011–2012 Index of manufacturers 807Scope OphthalmicsScope Ophthamics Ltdtel: (0161) 266 1011info@scopeophthalmics.comSNBTSScottish National Blood TransfusionServicetel: (0131) 536 5700contact.pfc@snbts.csa.scot.nhs.ukSynergy HealthcareSynergy Healthcare (UK) Ltdtel: (0161) 624 5641healthcaresolutions@synergyhealthplc.comSD HealthcareSD Healthcaretel: (0161) 776 7626sales@sdhealthcare.comSeptodontSeptodont Ltdtel: (01622) 695 520ServierServier Laboratories Ltdtel: (01753) 666 409medical.information@uk.netgrs.comSovereignSee AmdipharmSpeciality EuropeanSpeciality European Pharma Ltdtel: (020) 7421 7400info@spepharma.comSpectrum TheaSpectrum Thea Pharmaceuticalstel: 0845 521 1290theasupport@spectrum-thea.co.ukSyner-MedSyner-Med (Pharmaceutical Products)Ltdtel: 0845 634 2100mail@syner-med.comSystagenixSystagenix Wound Managementtel: (01344) 871 000TakedaTakeda UK Ltdtel: (01628) 537 900Seven SeasSeven Seas Ltdtel: (01482) 375 234ShermondShermondtel: 0870 242 7701sales@shermond.comShireShire Pharmaceuticals Ltdtel: 0800 055 6614medinfoglobal@shire.comShire HGTShire Human Genetic TherapiesSee ShireSHSSHS International Ltdtel: (0151) 228 8161nutrition@shsint.co.ukSiemensSiemens Healthcare Diagnostics Ltdtel: 0845 600 1966dx-diag_sales-uk.med@siemens.comSigma-TauSigma-Tau Pharma Ltd (UK)tel: 0800 043 1268medical.information@sigma-tau.co.ukSkin Camouflage Co.The Skin Camouflage Company Ltdtel: (01507) 343 091smjcovermark@aol.comSkinniesSkinnies UKtel: (01562) 546 123info@skinniesuk.comSLO DrinksSLO Drinks Ltdtel: 0845 222 2205info@slodrinks.comSMA NutritionSee WyethSpePharmSpePharm UK Ltdtel: 0844 800 7579medinfo.uk@spepharm.comSpiritSpirit Healthcare Ltdtel: 0800 881 5423info@spirit-healthcare.co.ukSquibbSee Bristol-Myers SquibbSSLSSL International plctel: 0870 122 2690medical.information@ssl-international.comSTD PharmaceuticalSTD Pharmaceutical Products Ltdtel: (01432) 373 555enquiries@stdpharm.co.ukSteraidSteraid (Gainsborough) Ltdtel: (01427) 677 659StiefelStiefel Laboratories (UK) Ltdtel: (01628) 612 000general@stiefel.co.ukStragenStragen UK Ltdtel: 0870 351 8744info@stragenuk.comSu-MedSu-Med International UK Ltdtel: (01457) 890 980sales@sumed.co.ukSutherlandSutherland Health Ltdtel: (01635) 874 488Swedish OrphanSwedish Orphan Biovitrum Ltdtel: (01638) 722 380TalleyTalley Group Ltdtel: (01794) 503 500TaroTaro Pharmaceuticals (UK) Ltdtel: 0870 736 9544customerservice@taropharma.co.ukTeofarmaTeofarma S.r.l.tel: (01748) 828 857teofarma@professionalinformation.co.ukTevaTeva Pharmaceuticals Ltdmed.info@tevapharma.co.ukTEVA UKTEVA UK Ltdtel: 0870 502 0304medinfo@tevauk.comThe Medicines CompanyThe Medicines Companytel: 00800 8436 3326GCHS.MI@quintiles.comTherabelTherabel Pharma UK Ltdtel: 0800 066 5446info@therabel.co.ukThe Urology Co.The Urology Company Ltdtel: (020) 3077 5411info@theurologyco.comThomas BlakeThomas Blake Cosmetic Creams Ltdtel: (01207) 279 432sales@veilcover.comThornton & RossThornton & Ross Ltdtel: (01484) 842 217mail@thorntonross.comTillomedTillomed Laboratories Ltdtel: (01480) 402 400info@tillomed.co.ukIndex of manufacturers

808 Index of manufacturers BNFC 2011–2012Index of manufacturersTMCTMC Pharma Services Ltdtel: (01252) 842 255info@tmcpharma.comTobia TeffTobia Teff UK Ltdtel: (020) 7328 2045info@tobiateff.co.ukTorbetTorbet Laboratories Ltdtel: (01603) 735 200torbet@typharm.comTransdermalTransdermal Ltdtel: (020) 8654 2251transdermal@transdermal.co.ukTRB ChemedicaTRB Chemedica (UK) Ltdtel: 0845 330 7556TypharmTypharm Ltdtel: (01603) 735 200customerservices@typharm.comUCB PharmaUCB Pharma Ltdtel: (01753) 534 655medicalinformationuk@ucb.comUltrapharmUltrapharm Ltdtel: (01491) 578 016orders@glutenfree.co.ukUnivarUnivar Ltdtel: (01908) 362 200trientine@univareurope.comUnomedicalUnomedical Ltdtel: (01527) 587 700UrgoUrgo Ltdtel: (01509) 502 051medical@parema.comVegenatc/o Archaelis Ltdtel: 0870 803 2484info@vegenat.co.ukViforVifor Pharma UK Ltdtel: (01276) 853 633medicalinfo_uk@viforpharma.comViiVViiV Healthcare UK LtdSee GSKViridianViridian Pharma Ltdtel: (01633) 400 335info@viridianpharma.co.ukVitafloVitaflo International Ltdtel: (0151) 709 9020vitaflo@vitaflo.co.ukVitalineVitaline Pharmaceuticals UK Ltdtel: (01844) 269 007vitalineinfo@aol.comVitalographVitalograph Ltdtel: (01280) 827 110sales@vitalograph.co.ukWallace CameronWallace Cameron Ltdtel: (01698) 354 600sales@wallacecameron.comWallace MfgWallace Manufacturing Chemists Ltdtel: (01235) 538 700info@alinter.co.ukWarner ChilcottWarner Chilcott UK Ltdtel: (01932) 824 700WaveSenseWaveSense Europe Ltdtel: (01235) 838 639enquiries@wavesense.co.ukWellfoodsWellfoods Ltdtel: (01226) 381 712wellfoods@talk21.comWilliamsWilliams Medical Supplies Ltdtel: (01685) 844 739WinthropWinthrop Pharmaceuticals UK Ltdtel: (01483) 554 101winthrop@professionalinformation.co.ukWockhardtWockhardt UK Ltdtel: (01978) 661 261WyethWyeth Pharmaceuticalstel: (01628) 604 377EUMEDINFO@pfizer.comWynlitWynlit Laboratoriestel: (07903) 370 130WyvernWyvern Medical Ltdtel: (01531) 631 105ZerodermaZeroderma Ltdtel: (01858) 525 643info@ixlpharma.comZooBioticZooBiotic Ltdtel: 0845 230 1810enquiries@zoobiotic.co.uk

BNFC 2011–2012 809Special-orderManufacturersUnlicensed medicines are availablefrom ‘special-order’ manufacturersand specialist importingcompanies; the MHRA maintainsa register of these companies athttp://tinyurl.com/cdslke.Licensed hospital manufacturingunits also manufacture ‘special-order’products as unlicensedmedicines, the principal NHSunits are listed below. A database(Pro-File; www.pro-file.nhs.uk)provides information on all medicinesmanufactured in the NHS;access is restricted to NHS pharmacystaff.The Association of CommercialSpecials Manufacturers may alsobe able to provide further informationabout commercial companies(www.acsm.uk.com).The characteristics of unlicensedformulations may vary, see alsoUnlicensed Medicines (p. 6) andExtemporaneous Preparations(p. 6).The MHRA recommends thatan unlicensed medicine shouldonly be used when a patient hasspecial requirements that cannotbe met by use of a licensedmedicineEnglandLondonBarts and the London NHS TrustMr J. SinghProduction ManagerBarts and the London NHS TrustPathology and Pharmacy BuildingRoyal London Hospital80 Newark StWhitechapelLondon, E1 2ES.tel: (020) 3246 0274 (order)tel: (020) 3246 0399 (enquiry)jasdeep.singh@bartsandthelondon.nhs.ukGuy’s and St. Thomas’ NHSFoundation TrustMr P. ForseyAssociate Chief PharmacistGuy’s and St. Thomas’ NHS FoundationTrustPharmacy DepartmentGuy’s HospitalGreat Maze PondLondon, SE1 9RT.tel: (020) 7188 4992 (order)tel: (020) 7188 5003 (enquiry)fax: (020) 7188 5013paul.forsey@gstt.nhs.ukMoorfields PharmaceuticalsMr N. PreciousTechnical DirectorMoorfields Pharmaceuticals34 Nile StreetLondon, N1 7TP.tel: (020) 7684 9090 (order)tel: (020) 7684 8574 (enquiry)fax: (020) 7502 2332nick.precious@moorfields.nhs.ukNorth West London HospitalsNHS TrustDr K. MiddletonNorth West London Hospitals NHSTrustNorthwick Park HospitalWatford RdHarrowMiddlesex, HA1 3UJ.tel: (020) 8869 2295 (order)tel: (020) 8869 2204/2223 (enquiry)keith.middleton@nhs.netRoyal Free Hampstead NHS TrustMs C. TrehaneProduction ManagerRoyal FreePond StLondon, NW3 2QG.tel: (020) 7830 2424 (order)tel: (020) 7830 2282 (enquiry)fax: (020) 7794 1875christine.trehane@nhs.netSt George’s Healthcare NHS TrustMr V. KumarAssistant Chief PharmacistTechnical ServicesSt George’s HospitalBlackshaw RdTootingLondon, SW17 0QT.tel: (020) 8725 1770/1768fax: (020) 8725 3947vinodh.kumar@stgeorges.nhs.ukUniversity College Hospital NHSFoundation TrustMr T. MurphyProduction ManagerUniversity College Hospital235 Euston RdLondon, NW1 2BU.tel: (020) 7380 9723 (order)tel: (020) 7380 9472 (enquiry)fax: (020) 7380 9726tony.murphy@uclh.nhs.ukMidlands and EasternBurton Hospitals NHS TrustMr P. WilliamsPharmacy Technical and Support ServicesManagerPharmacy Manufacturing UnitQueens HospitalBurton Hospitals NHS TrustBelvedere RdBurton-on-Trent, DE13 0RB.tel: (01283) 511 511 (or 566 333) ext:5115 (order) 5138 (enquiry)fax: (01283) 593 036paul.williams@burtonh-tr.wmids.nhs.ukColchester Hospital UniversityNHS Foundation TrustMs N. RhodesProduction ManagerColchester Hospital University NHSFoundation TrustTuner RdColchester, C04 5JL.tel: (01206) 745 962 (order)tel: (01206) 742 949 (enquiry)fax: (01206) 841 249nicola.rhodes@colchester.nhs.ukIpswich Hospital NHS TrustDr J. HarwoodProduction ManagerPharmacy Manufacturing UnitIpswich Hospital NHS TrustHeath RdIpswich, IP4 5PD.tel: (01473) 703 440 (order)tel: (01473) 703 603 (enquiry)fax: (01473) 703 609john.harwood@ipswichhospital.nhs.ukSpecial-order Manufacturers

810 Special-order Manufacturers BNFC 2011–2012Special-order ManufacturersNottingham University HospitalsNHS TrustMs J. KendallAssistant Head of Pharmacy, Technical,and Logistical ServicesPharmacy Production UnitsNottingham University Hospitals NHSTrustQueens Medical Centre CampusNottingham, NG7 2UH.tel: (0115) 875 4521 (order)tel: (0115) 924 9924 ext: 64177(enquiry)fax: (0115) 970 9780jeanette.kendall@nuh.nhs.ukUniversity Hospital of NorthStaffordshire NHS TrustMs K. FergusonChief TechnicianPharmacy Technical ServicesUniversity Hospital of North StaffordshireNHS TrustCity General SiteStoke-on-Trent, ST4 6QG.tel: (01782) 552 289 (order)tel: (01782) 552 290 (enquiry)fax: (01782) 552 916caroline.ferguson@uhns.nhs.ukNorth EastThe Newcastle upon Tyne HospitalsNHS Foundation TrustMr Y. Hunter-BlairProduction ManagerNewcastle SpecialsPharmacy Production UnitRoyal Victoria InfirmaryQueen Victoria RdNewcastle-upon-Tyne, NE1 4LP.tel: (0191) 282 0395 (order)tel: (0191) 282 0389 (enquiry)fax: (0191) 282 0469yan.hunter-blair@nuth.nhs.ukNorth WestPreston PharmaceuticalsMs A. NutmanAssistant Director of PharmacyPreston PharmaceuticalsRoyal Preston HospitalFulwoodPreston, PR2 9HT.tel: (01772) 523 617 (order)tel: (01772) 522 593 (enquiry)fax: (01772) 523 645angela.nutman@lthtr.nhs.ukStockport PharmaceuticalsMr M. BoothPrincipal Pharmacist/Deputy ChiefPharmacistStockport PharmaceuticalsPharmacy DepartmentStepping Hill HospitalStockportCheshire, SK2 7JE.tel: (0161) 419 5666 (order)tel: (0161) 419 5657 (enquiry)fax: (0161) 419 5426mike.booth@stockport.nhs.ukSouthPortsmouth Hospitals NHS TrustMr R. LucasProduct Development ManagerPharmacy Manufacturing UnitPortsmouth Hospitals NHS TrustUnit D2, Railway Triangle IndustrialEstateWalton RoadFarlington, PortsmouthHampshire, PO6 1TF.tel: (02392) 389 078 (order)tel: (02392) 316 312 (enquiry)fax: (02392) 316 316robert.lucas@porthosp.nhs.ukSouth EastEast Sussex Hospitals NHS TrustMr P. KeenBusiness ManagerEastbourne DGH PharmaceuticalsEastbourne District General HospitalEast Sussex Hospitals NHS TrustKings Drive, EastbourneEast Sussex, BN21 2UD.tel: (01323) 414 906 (order)tel: (01323) 417 400 ext: 3076 (enquiry)fax: (01323) 414 931paul.keen@esht.nhs.ukSouth WestTorbay PMUMr P. BendellPharmacy Manufacturing ServicesManagerTorbay PMUSouth Devon HealthcareKemmings Close, Long RdPaigntonDevon, TQ4 7TW.tel: (01803) 664 707fax: (01803) 664 354phil.bendell@nhs.netYorkshireCalderdale and Huddersfield NHSFoundation TrustDr S. LangfordPharmacy Production DirectorPharmacy Manufacturing UnitHuddersfield Royal InfirmaryGate 2-Acre Mills, School StLindleyHuddersfield, HD3 3ET.tel: (01484) 355 388 (order)tel: (01484) 355 371 (enquiry)fax: (01484) 355 377stephen.langford@cht.nhs.ukNorthern IrelandVictoria PharmaceuticalsMs C. McBrideVictoria PharmaceuticalsBelfast Health and Social Care Trust77 Boucher CrescentBelfast, BT12 6HU.tel: (028) 9063 3310 (sterile)tel: (028) 9055 3407 (non-sterile)fax: (028) 9032 8972 (sterile)fax: (028) 9055 3498 (non-sterile)colette.mcbride@belfasttrust.hscni.netScotlandNHS Greater Glasgow and ClydeMr G. ConkieProduction ManagerWestern InfirmaryDumbarton RdGlasgow, G11 6NT.tel: (0141) 211 2754 (order)tel: (0141) 211 2882 (enquiry)fax: (0141) 211 1967graham.conkie@ggc.scot.nhs.ukTayside PharmaceuticalsDr B. W. MillarGeneral ManagerTayside PharmaceuticalsNinewells HospitalDundee, DD1 9SY.tel: (01382) 632 052 (order)tel: (01382) 632 183 (enquiry)fax: (01382) 632 060baxter.millar@nhs.netWalesCardiff and Vale UniversityHealth BoardMr P. SparkPrincipal Pharmacist (Production)Cardiff and Vale University HealthBoard20 FieldwayCardiff, CF14 4HY.tel: (029) 2074 8120fax: (029) 2074 8130paul.spark@wales.nhs.uk

BNFC 2011–2012 Abacavir—Alfacalcidol 811IndexPrincipal page references areprinted in bold type. Proprietary(trade) names and names of organismsare printed in italic type; wherethe BNF does not include a full entryfor a branded product, the non-proprietaryname is shown in bracketsAAbacavir, 310, 311, 312lamivudine and zidovudinewith, 312lamivudine with, 312Abatacept, 510AbbreviationsLatin, inside back coversymbols, inside back coverunits, 4Abcare, 357Abdominal surgery, antibacterialprophylaxis, 255Abelcet, 306Abetalipoproteinaemia, 485Abidec, 487Abilify, 178Able Spacer, 145Abscess, dental, 252Absence seizures, 217Acanthamoeba keratitis, 518contact lenses, 533Acarbose, 360Acaricides, 592ACBSfoods, 743toilet preparations, 786Accolate, 153Accu-Chek products, 364AccuhalerFlixotide, 150Seretide, 150Serevent, 140Ventolin, 140ACE inhibitors, 100diuretics with, 101heart failure, 100renal function, 101Acea, 587Acetaminophen see ParacetamolAcetazolamidediuretic, 82epilepsy, 231, 527glaucoma, 525, 527intracranial pressure, raised,527Acetic acid, otitis externa, 534Acetylcholine, 532Acetylcysteinecystic fibrosis, 165eye, 530meconium ileus, 165mucolytic, 165paracetamol poisoning, 26, 28Acetylsalicylic acid see AspirinAciclovir, 322, 323herpes simplex, 322eye, 322, 521genital, 395, 591labialis, 591skin, 591herpes stomatitis, 545herpes zoster, 322varicella zoster, 322Acid aspiration, prophylaxis,629Acidex, 38Acidosislactic, 311metabolic, 460, 463Acitretin, 567, 571, 572Acnamino MR, 276Acne, 574infantile, 574, 579systemic treatment, 578topical treatment, 574Acnecide, 575Acnisal, 578Acnocin (co-cyprindiol), 578Acrivastine, 153, 154Acrodermatitis enteropathica,478ACTH see Corticotropin, 382Actidose-Aqua Advance, 26Actilyse, 122Actinic keratoses, 583Actinomycin D see Dactinomycin,422Actiq, 206Activated charcoal, 25Active, 364Actonel, 390Once a Week, 390Actrapid, 352Acular, 533ACWY Vax, 615Acyclovir see AciclovirAdalat preparations, 107, 108Adalimumab, 509, 510Adapalene, 576benzoyl peroxide with, 577Adcal, 472Adcal-D 3 preparations, 484Adcortyl Intra-articular/Intradermal,507Add-Ins, 784Addiphos, 467Addison’s disease, 369Additives see ExcipientsAdditrace, 468Adefovir, 325Adenocor, 84Adenoscan (adenosine), 84Adenosine, 83, 84Adenovirus, 328ADH see Antidiuretic hormone,385ADHD see Attention deficit hyperactivitydisorder, 188Adhesive, tissue, 593Adipine preparations, 108Adoport, 436Adrenal function test, 382Adrenal insufficiency, 369Adrenal suppressionmetyrapone, 391surgery, 371systemic corticosteroids,371topical corticosteroids, 558Adrenalineanaphylaxis, 159, 160, 161bradycardia, 82croup, 137hypotension, 113infusion table (neonatal),792local anaesthesia, 649, 651palliative care, 18self administration, 160Adrenergic neurone blockingdrugs, 98Adrenoceptor agonists, 137Adsorbentsgastro-intestinal, 47poisoning, 25Advagraf, 438Advantage Plus, 364Advate (factor VIII fraction), 124Adverse reactionsprevention of, 13reporting, 12Advisory Committee on BorderlineSubstances see ACBSAdvisory labels see Cautionary andadvisory labelsAeroChamber Plus, 145Agalsidasealfa, 490beta, 490Agammaglobulinaemia, congenital,replacement therapy, 622Agrippal, 612AIDS, 309vaccines and, 600Airomir preparations, 140AirZone, 144Akathisia, 173Aknemin (minocycline), 276Aknemycin Plus, 577Albendazolehookworms, 346hydatid disease, 346larva migrans, 346strongyloidiasis, 347Albumin solution, 464Albunorm preparations (albumin),464Albustix, 363Albuterol see SalbutamolAlclometasone dipropionate,561Alcoholpoisoning by, 26presence of, 3skin, 594Aldactone, 81Aldara, 581Aldioxa, 597Aldosterone antagonists, 80, 81Aldurazyme, 492Alemtuzumab, 439Alendronate sodium see Alendronicacid, 389Alendronic acid, 389Alfacalcidol, 483Index

812 Alfentanil—Anterior BNFC 2011–2012IndexAlfentanil, 640, 641Alginate-containing antacids,38Alglucosidase alfa, 493Alicalm, 768Alimemazineallergic disorders, 153, 155,156premedication, 155, 637Alkalinisation of urine, 412Alkeran, 421Alkylating drugs, 419Allegron, 186Allergy, 153allergen immunotherapy, 157anaphylaxis, 159conjunctivitis, 522corticosteroids in, 371food, 56rhinitis, 153, 538Allopurinol, 417Almond oil, ear, 538Alomide, 523Alpha tocopherol, 485Alpha tocopheryl acetate, 485Alpha 2 -adrenoceptor stimulantscardiovascular, 98eye, 526, 532Alpha-adrenoceptor blockingdrugs, 99urinary tract, 409Alpha-blockers see Alpha-adrenoceptorblocking drugsAlphaderm, 560Alphanate (factor VIII fraction),124AlphaNine (factor IX fraction),125Alphosyl 2 in 1, 584Alphosyl HC, 570Alprostadil, 131infusion table (neonatal), 792Altacite Plus, 37Altargo, 586Alteplase, 122Alternative medicine, 2Alu-Cap, 475Aluminium acetate, ear, 534, 535Aluminium chloride, 597Aluminium hydroxideantacid, 36, 37simeticone with, 37hyperphosphataemia, 475Alvedon (paracetamol), 201Alverine, 40Alvesco, 150Amantadine, 326Ambirix, 608AmBisome, 306leishmaniasis, 340Amethocaine see TetracaineAmetop, 654Amfetaminesabuse, 10poisoning by, 31Amidotrizoates, 65Amikacin, 277, 279tuberculosis, 292Amikin, 279Amilamont (amiloride), 80Amiloride, 80furosemide with, 81hydrochlorothiazide with,81Amino acidsACBS, 781, 782, 783, 784, 786intravenous nutrition, 466Aminobenzoic acid, 479Aminoglycosidesear, 534, 537eye, 518systemic, 276Aminophylline, 76, 142, 143, 144see also TheophyllineAminosalicylates, 48, 49Amiodarone, 82, 83, 84, 85Amisulpride, 177, 178Amitriptylinedepression, 185neuropathic pain, 185, 212palliative care, 18nocturnal enuresis, 185Amix (amoxicillin), 261Amlodipine, 105, 106see also Calcium-channelblockersAmlostin (amlodipine), 106Ammonaps, 495Ammonia, poisoning by, 33Amoebiasis, 339Amoebicabscess, 339dysentery, 339Amoebicides, 339Amoram (amoxicillin), 261, 262Amorolfine, 588, 589Amoxicillin, 261, 262Helicobacter pylori eradication,42pneumococcal infectionprophylaxis, 255Amoxident (amoxicillin), 261Amoxil preparations, 262Amoxycillin see AmoxicillinAmphetamines see AmfetaminesAmphotericin, 300, 301, 305eye, 529infusionlipid formulation, 305, 306liposomal, 306leishmaniasis, 340Ampicillin, 260, 262flucloxacillin with [co-fluampicil],261Amsacrine, 427Amsidine, 427Anabact, 587Anabolic steroids, 381anaemias, 447Anaemias, 442aplastic, 448chronic renal failure, 448haemolytic, 447, 448hypoplastic, 447iron-deficiency, 442megaloblastic, 445sideroblastic, 448Anaesthesiaanalgesics, 639anticholinesterases, 646anticoagulants, oral and, 629antidepressants and, 629antimuscarinics, 635antiviral drugs and, 629corticosteroids, 371, 628dental practice, 629diuretics, 629general, 628inhalational, 632intravenous, 629local, 649adrenaline with, 649dental practice, 649eye, 529mouth, 543neuropathic pain, 212rectal, 66vasoconstrictors with, 649muscle relaxants, 642Anagrelide, 453Anal fissure, 67Analeptics, 162Analgesicscompound, 200non-opioid, 199postoperative, 639NSAIDs, 199, 499anaesthesia, 639palliative care, 17poisoning by, 26rheumatic diseases, 499opioid, 202anaesthesia, 640cough suppressants, 167dependence on, 10equivalent doses, 17neuropathic pain, 212obstetric pain, 203palliative care, 17poisoning by, 28Anapen preparations, 160, 161Anaphylactic shock, 159Anaphylaxis, 159, 160Ancotil, 308Ancylostomiasis, 346Androcur, 380Androgens, 379Andropatch—discontinuedAnectine, 646Anexate, 648Angilol (propranolol), 89Angioedema, 161Angiotensin-converting enzymeinhibitors see ACE inhibitorsAngiotensin-II receptorantagonists, 103Angular cheilitis, 545, 559Anhydrol Forte, 597Anogenital warts, 581Anorectics, 191Anorexia, palliative care, 18Antacids, 36palliative care, 18, 19sodium content, 36surgery, 629Antazoline, 522Antepsin, 44Anterior uveitis, 524

BNFC 2011–2012 Anthelios—Arthrofen 813Anthelios, 582Anthelmintics, 344Anthracyclines, 421Anthralin see DithranolAnthraquinones, 59Anthrax, 297vaccine, 603Anti-androgens, 380Anti-arrhythmic drugs, 82, 83Antibacterialsacne, 575, 576, 578diarrhoea, 47infectionsear, 534eye, 518oral, 244skin, 585vaginal, 394policies, 243principles for selecting, 243prophylaxis (table), 254prophylaxis, surgery, 256therapy, initial (table), 244Antibiotic-associated colitis seeClostridium difficileAntibiotics see AntibacterialsAnticholinergic drugs see AntimuscarinicsAnticholinergic syndrome, 635Anticholinesterases, 512anaesthesia, 646Anticoagulant treatment booklets,119Anticoagulantsoral, 118anaesthesia, 629reversal, 118surgery, 629parenteral, 114Anticonvulsants see AntiepilepticsAntidepressantsanaesthesia, 629choice, 183hyponatraemia and, 184monoamine-oxidase inhibitors,186poisoning by, 29serotonin re-uptake inhibitors,183, 186surgery, 629tricyclic, 184enuresis, 412withdrawal, 184Antidiabetic drugsinsulin, 349oral, 357Antidiarrhoeal drugs see DiarrhoeaAntidiuretic hormone, 385Antiemetics, 192cytotoxic therapy and, 415migraine, 212, 214palliative care, 19Antiepileptics, 215, 217breast-feeding and, 216pregnancy and, 216surgery, 629Antifibrinolytic drugs, 123Antifungal drugs, 300anogenital, 394oropharyngeal, 545skin, 588Antigiardial drugs, 340Antihepatitis B immunoglobulin,624, 625Antihistamines, 153breast-feeding, 153cough preparations, 167eczema, 566eye, 522hypnotic, 170insomnia, 153migraine, 214nasal allergy, 538nausea and vertigo, 193nausea and vomiting, 192pregnancy, 153skilled tasks and, 153, 155skin, 557AntihypertensivesACE inhibitors, 100adrenergic neurone blockers,98alpha-blockers, 99angiotensin-II receptorantagonists, 103beta-blockers, 87calcium-channel blockers, 105centrally-acting, 98vasodilator, 93Anti-inflammatory analgesics seeAnalgesics, NSAIDsAntilymphocyte immunoglobulin,447Antimalarials, 329, 507Antimanic drugs, 181Antimetabolites, 423Antimigraine drugs, 212Antimotility drugs, 46, 47Antimuscarinicsantipsychotics and, 173bronchodilator, 141dystonias, 237eye, 524gastro-intestinal, 39premedication, 635quaternary ammonium, 39urinary tract, 410Antineoplastic drugs, 414see also Cytotoxic drugsAntiperspirants, 597Antiplatelet drugs, 120Antiprotozoal drugs, 329Antipsychotics, 172atypical, 177depot injections, 181equivalent doses, oral, 174high doses (caution), 171mania, 181withdrawal, 172atypical, 177Antirabies immunoglobulin, 625Antiretrovirals, 309, 310, 320non-nucleoside reverse transcriptaseinhibitors, 319nucleoside reverse transcriptaseinhibitors, 311protease inhibitors, 315AntisepticsACBS, 787lozenges, 546mouthwashes, 546skin, 594sprays, oropharynx, 546Antiserum, 602, 622Antispasmodics, 39Antitetanus immunoglobulin, 625Antithymocyte immunoglobulin,433, 434Antithyroid drugs, 367Antituberculous drugs, 290Antitussives, 167Antivaricella–zosterimmunoglobulin, 626Antivenoms, 34Antiviral drugs, 309anaesthesia, 629eye, 521mouth, 545skin, 591surgery, 629Anugesic-HC, 66Anusol preparations, 66Anxiety, 171, 184antipsychotics, 172palliative care, 18Anxiolytics, 169, 171APD see Disodium pamidronate,389, 390Aphthous ulcers, 543Apidra, 353Aplastic anaemia, 448Apnoea neonatalaminophylline, 144caffeine, 162theophylline, 142Appetite suppressants, 191Applications, definition, 551Apraclonidine, 526, 532Apresoline, 94Aprinox (bendroflumethiazide),77Aptamil Pepti preparations, 764Aptivus, 318Aquadrate, 553Aquamol, 552Aquasol-A, 479Aqueous cream, 552Aqueous iodine oral solution, 368Arachis oilenema, 61presence of, 3Aranesp preparations, 449Arcoxia, 503Aredia Dry Powder, 390Argininesupplement, 786urea cycle disorders, 493, 494Argipressin (Pitressin), 388Aripiprazole, 177, 178Arovit, 479Arpicolin, 237Arrhythmias, 82anti-arrhythmics, 83poisoning and, 25supraventricular, 73, 82ventricular, 83Artelac (hypromellose)preparations, 531Artemetherlumefantrine with, 334, 335Artesunate, 330Arthritisjuvenile idiopathic, 507rheumatic, 499septic, 251Arthrofen (ibuprofen), 503Index

814 Arthroxen—Benzhexol BNFC 2011–2012IndexArthroxen (naproxen), 505Articaine, 649, 650Artificial saliva, 548palliative care, 18Artificial tears, 529Arzip (mycophenolate mofetil),433AS Saliva Orthana, 5485-ASA, 49Asacol preparations, 50, 51Ascaricides, 345Ascaris, 345Ascensia products, 357, 364Ascites, 80Ascorbic acid, 481, 482iron excretion, 451Asilone preparations, 37Asmabec preparations, 148Asmanex, 151Asmasal preparations, 140Asparaginase, 427Aspart, insulin see Insulin aspartAspartame, 468presence of, 3Aspergillosis, 300Aspiration, acid, prophylaxis, 629Aspirinantiplatelet, 120, 121Kawasaki syndrome, 120AspleniaHaemophilus influenzae type b(Hib)prophylaxis, 255vaccine, 606influenza vaccine, 611malaria, 332meningococcal vaccine, 606pneumococcalinfection, 255vaccine, 616vaccines and, 602Asthma, 133, 134acute (table), 136allergen immunotherapy, 157beta 2 agonists, 137breast-feeding, 133chronic (table), 135exercise-induced, 137pregnancy, 133prophylaxis, 146, 151sympathomimetics, 137Astringentsear, 534skin, 594Atarax, 156Atazanavir, 310, 315, 316Atenolol, 87, 89see also Beta-adrenoceptorblocking drugssupraventricular tachycardia,82thyrotoxicosis, 367Athlete’s foot, 588Atimos Modulite, 138Ativan (lorazepam), 638Atomoxetine, 188, 189Atonic seizures, 217Atorvastatin, 126, 127Atovaquonemalaria, 336, 337pneumocystis pneumonia, 342,343proguanil with, 337Atracurium, 643infusion table (neonatal), 792Atrial fibrillation, 74, 82, 118Atrial flutter, 82Atriance, 425Atripla, 314Atropine sulphateanaesthesia, 635, 636bradycardia, 635anticholinesterases and, 646beta-blocker poisoning, 30eye, 524ointment—discontinuedorganophosphorus poisoning,33Atrovent preparations, 142Aerocaps—discontinuedAttention deficit hyperactivitydisorder, 188Atypical antipsychotics, 177poisoning by, 31Augmentin preparations, 264Aureocort, 565Autopen, 357Avamys, 540Avaxim, 607Aveeno preparations, 552, 554Aviva, 364Avloclor, 335Avoca, 581Avomine, 194Azactam, 274Azamune (azathioprine), 432Azathioprineauto-immune conditions, 508Crohn’s disease, 54eczema, 572inflammatory bowel disease, 49rheumatic disease, 508systemic lupus erythematosus,508transplant rejection, 431, 432ulcerative colitis, 54vasculitis, 508Azelaic acid, 575Azelastineeye, 522, 523nose, 538, 539Azidothymidine see ZidovudineAzithromycin, 280, 281eye, 518Azopt, 527AZT see ZidovudineAztreonam, 273, 274BBabyhaler, 145Bacillus Calmette-Guérinvaccines, 603Bacitracineye, 520skin, polymyxin with, 586Baclofenchronic spasticity, 514palliative care, 18Bacteroides fragilis infectionsantipseudomonal penicillins in,264clindamycin in, 283metronidazole in, 295Bactroban, 586Nasal, 542Balanced Salt Solution, 531, 532Balneum preparations, 553, 554Balsalazide, 48, 49, 50Bandagesmedicated, 566tubular, 565Barbiturates, anaesthesia, 630Barkat products, 777, 778, 779Barrier preparations, 556Bartter’s syndrome, 80Basiliximab, 433, 434Bath additivesantimicrobial with, 556coal tar, 570emollient, 554, 555, 556Baxan—discontinuedBazetham MR (tamsulosin), 410BCG vaccines, 603BD Micro-Fine products, 357BD Safe-clip, 357Becaplermin, 596, 597Beclometasone Cyclocaps—discontinuedBeclometasone dipropionateasthma, 146, 147, 148chronic, 135mouth ulceration, 543nasal allergy, 539skin, 561Beclomethasone dipropionate seeBeclometasone dipropionateBecodisks, 148Beconase preparations, 539Bedranol SR (propranolol), 89Bee sting allergy preparations,157Begrivac, 612Benadryl Allergy Relief, 154Bendrofluazide see Bendroflumethiazide,77Bendroflumethiazide, 77BeneFIX (factor IX fraction), 125Benerva, 480Benoxinate see Oxybuprocaine,529Benzalkonium, 584cetrimide with, 557chlorhexidine with, 554dimeticone with, 556Benzathine benzylpenicillin, 249,257Benzhexol see Trihexyphenidyl,237

BNFC 2011–2012 Benzodiazepines—Buscopan 815Benzodiazepinesantagonist, 647anxiolytics, 169palliative care, 18clinical procedures, 637epilepsy, 230insomniapalliative care, 19mania, 181muscle spasm, 514neonatal seizures, 217poisoning by, 30premedication, 637Benzoic acid ointment,compound, 588, 589Benzoin tincture, compound, 166Benzoyl peroxideacne, 575clindamycin with, 575hydroxyquinoline with, 575adapalene with, 577Benzydamine, 543Benzyl alcohol, presence of, 3Benzyl benzoate, 592Benzylpenicillin sodium, 257, 258gas-gangrene prophylaxis, 255Beractant, 163Berinert, 162Beriplex P/N (dried prothrombincomplex), 124Beta Prograne (propranolol), 89Beta 2 agonists, 137asthmaacute, 134palliative care, 19Beta-adrenoceptor blocking drugsarrhythmias, 82, 83, 88atrial fibrillation, 82diuretics with, 87eye, 525heart failure, 88hypertension, 87poisoning by, 29thyrotoxicosis, 88, 367verapamil and, 109Beta-adrenoceptor stimulantsasthma, 137Beta-blockers see Beta-adrenoceptorblocking drugsBetacap, 562Beta-Cardone, 92Betacarotene, 583Betadine, 596Betagan, 526Betaine, 495, 496Beta-lactamases, 257Betamethasone, 370, 374mouth, 544skin, 561Betamethasone dipropionate, 562calcipotriol with, 568clotrimazole with, 562salicylic acid with, 562Betamethasone sodium phosphateear, 535eye, 521inflammatory and allergicdisorders, 374mouth, 543nose, 539, 542neomycin with, 542Betamethasone valerateskin, 562clioquinol with, 562fusidic acid with, 562neomycin with, 562Betaxolol, 525, 526Betnesolear, 535eye, 521inflammatory and allergicdisorders, 374mouth, 544nose, 539Betnesol-Near, 535eye, 521ointment—discontinuednose, 542Betnovate preparations, 562Betoptic, 526Bettamousse, 562Bezafibrate, 129, 130Bezalip, 130BiAlimenta products, 779Bicarbonateintravenous, 463oral, 460see also Sodium bicarbonateBiguanides, 359Bile acid sequestrants, 70, 128Bilharziasis, 346Bimatoprost, 526Binocrit, 449BiNovum, 402Biosimilar medicines, 2Biotène Oralbalance, 548Biotin, 479, 496BioXtra, 548Biphosphonates see BisphosphonatesBipolar disorder, 181Birthmarks, ACBS, 787Bisacodyl, 59Bismuth subgallate, 66Bisphosphonateshypercalcaemia, 473osteoporosis, 388Bitesanimal, 253human, 253snake, 34Black triangle symbol, 13Bladderblood clot dissolution, 412irrigations, 412Bleedingmucosal, palliative care, 19variceal, 385Bleo-Kyowa (bleomycin), 421Bleomycin, 421Blepharitis, 518Blood products, 124, 125BM-Accutest, 364Body surface area charts, insideback coverBone metabolism, drugs affecting,388Bone tumours, analgesia, 199Bonefos, 390Bone-marrow suppression, cytotoxicdrugs, 416Bonjela preparations (cholinesalicylate), 544Borderline substances see ACBSBosentan, 95, 96Botox, 238Botulinum antitoxin, 604Botulinum toxin type A, 238hyperhidrosis, 597Botulism antitoxin, 604Bowelcleansing preparations, 64irrigation, 25sterilisation, 277Bradycardia, 82anaesthesia, 635Bramitob, 280Breast-feedingcorticosteroids and, 373epilepsy and, 216prescribing in, 16Breeze products, 364Brevibloc, 90Brevinor, 401Brevoxyl, 575Brexidol, 505Bricanyl preparations, 141Bridion, 647Brimonidine, 526Brinzolamide, 527Broflex, 237Brolene, 520Bronchodilatorsadrenoceptor agonist, 137antimuscarinic, 141compound, 144sympathomimetic, 137theophylline, 142Bronchopulmonary dysplasia, 76,78Bronchospasm, 137Brucellosis, 274, 294Brufen preparations, 503Brugia malayi, 346Buccastem, 195Buclizine, codeine and paracetamolwith, 202Budelin Novolizer, 149Budenofalk, 53Budesonideasthma, 146, 148, 149chronic, 135formoterol with, 149bronchopulmonary dysplasia,148croup, 137, 148inflammatory bowel disease, 48Crohn’s disease, 53ulcerative colitis, 53nasalallergy, 539, 540polyps, 539, 540Budesonide Cyclocaps—discontinuedBumetanide, 78, 79Bupivacaine, 650, 651adrenaline with, 651Buprenorphineintra-operative analgesia, 204pain, 203, 204premedication, 204Burinex, 79Buscopan, 40Index

816 Busilvex—Cetraben BNFC 2011–2012IndexBusilvex, 420Buspirone, 171Busulfan, 419, 420Busulphan see Busulfan, 419, 420Butylcyanoacrylate, 594Butyrophenones, 173CC1-esterase inhibitor, 162Cacit, 472Cacit D3, 484Caffeine, 162Calamine, 557Calceos, 484Calchan MR (nifedipine), 108Calcichew, 472Calcichew D3 preparations, 484Calciferol, 482Calciferol see Ergocalciferol, 482,483Calcijex, 484Calcipotriol, 567, 568betamethasone dipropionatewith, 568Calcitonin, 388, 473Calcitriolpsoriasis, 567, 568, 569vitamin D deficiency, 482, 483,484Calciumcolecalciferol with, 484ergocalciferol with, 482, 483supplements, 471, 472Calcium acetate, 476Calcium and vitamin D tablets,483Calcium balance, maintenance,388Calcium carbonatecolecalciferol with, 484hyperphosphataemia, 476Calcium chloride, 472Calcium folinate, 418, 446Calcium gluconate, 471, 472Calcium lactate, 472Calcium leucovorin see Calciumfolinate, 418, 446Calcium levofolinate, 418, 419Calcium levoleucovorin see Calciumlevofolinate, 418, 419Calcium phosphate, 484Calcium polystyrene sulphonate,458Calcium Resonium, 458Calcium-500, 472Calcium-channel blockers, 105angina, 105hypertension, 105poisoning by, 30pulmonary hypertension, 95Calcium-Sandoz, 472Calcort, 374Calfovit D3, 484Calluses, 580Calmurid, 553Calmurid HC, 560Calogen preparations, 772, 774Caloreen, 771Calpol (paracetamol)preparations, 201Calprofen (ibuprofen), 503Calshake, 775Camcolit, 183Camouflaging preparations, 583Campylobacter enteritis, 245,280Canakinumab, 440, 441Cancidas, 307Candidiasisoropharyngeal, 300, 545perianal, 66skin, 588systemic, 300vaginal, 394vulval, 394vulvovaginal, recurrent, 394Candidosis see CandidiasisCanestenanogenital, 394, 395ear, 536skin, 589HC, 560Cannabinoid, 198Cannabis, regulations, 10Capasal, 584Capillary bleeding, palliative care,18Capimune, 435Caplenal (allopurinol), 417Capoten, 102Capreomycin, 292Caprilon, 766Caprin, 121Caps, contraceptive, 408Captopril, 102see also ACE inhibitorsCarbagen SR, 219Carbaglu, 494Carbalax, 63Carbamazepinebipolar disorder, 181, 218epilepsy, 217, 218, 219neuropathic pain, 212palliative care, 18poisoning, elimination, 25trigeminal neuralgia, 218Carbimazole, 367, 368Carbocisteine, 165, 166cystic fibrosis, 165Carbo-Dome, 569Carbomers, 530Carbomix, 26Carbon monoxide poisoning, 33Carbonic anhydrase inhibitorsdiuresis, 82glaucoma, 527Carboplatin, 429, 430Carboxylase defects, 495Cardene preparations, 107Cardiac arrest, 114, 463Cardiac glycosides, 73Cardiac see also HeartCardiopulmonaryarrest, 114resuscitation, 114charts, inside back coverCardioxane, 417Cardura preparations, 99CareSens, 357CareSens N products, 364Carglumic acid, 493, 494Carmelloseeye, 530Carmize, 530Carnitine, 489, 490Carnitor, 490Carobel, Instant, 777Carteolol, 526Carticaine see Articaine, 649, 650Carvedilol, 87, 88, 89, 90see also Beta-adrenoceptorblocking drugsCascara, 59Casilan-90, 773Caspofungin, 300, 301, 306, 307Castor oil, 59Catacrom, 523Catapres, 98Catheter maintenance, 412Catheter patency solutionschlorhexidine, 412sodium chloride, 412solution G, 412solution R, 412Cautionary and advisory labels,788counselling, 788NCL, 788original packs, 788recommended wording, insideback coverCeanel Concentrate, 584Cefaclor, 266, 267Cefadroxil, 266, 267Cefalexin, 266, 267, 268Cefixime, 266, 268Cefotaxime, 266, 268, 269Cefpodoxime, 266, 269Cefradine, 266, 269Ceftazidime, 266, 269, 270eye drops, 529Ceftriaxone, 266, 270, 271meningococcal meningitisprophylaxis, 254Cefuroxime, 266, 271eye drops, 529Celevac, 58CellCept, 433Cellulitis, 253Celluvisc, 530Celsentri, 321Celvapan, 612Central nervous systemstimulants, 188Ceph... see also Cef...Cephalosporins, 266Ceporex, 268Ceprotin (protein C concentrate),125Cepton, 595Cerazette, 404Cerebral oedema, 81, 370Cerezyme, 491Cernevit, 468Cerumol, 538Cervarix, 611Cetirizine, 153, 154Cetraben, 552, 554

BNFC 2011–2012 Cetrimide—Cocaine 817Cetrimidescalp, 584skin, 557, 593, 594, 595benzalkonium with, 557chlorhexidine with, 595dimeticone with, 557CFCs, 147Charcoal, activated, 25, 26Charcodote, 26Cheilitis, angular, 545, 559Chenodeoxycholic acid, 68, 69Chenofalk, 70Chickenpox, 322, 625corticosteroids, 371Chilblains, 110, 597Children, prescribing for, 1Chirocaine, 651Chlamydiaeye, 251, 518genital, 250Chloractil (chlorpromazine), 174Chloral betaine see Cloral betaine,170Chloral hydrate, 170clinical procedures, 637Chlorambucil, 420Chloramphenicol, 284ear, 534, 536eye, 518, 519systemic, 284ChloraPrep, 595Chlorhexidinebladder infections, 412mouth, 543, 545, 546, 547chlorobutanol with, 547nose, neomycin with, 542, 543skinbenzalkonium with, 554emollient with, 554hydrocortisone and nystatinwith, 561skin disinfection, 594, 595cetrimide with, 595dusting powder, 595Chlorine poisoning, 33Chlorobutanol, 547Chlorofluorocarbon propellants,147Chlorohex—discontinuedChloromycetin, 519Chloroquine, 335malariaprophylaxis, 331, 332, 333,334, 335treatment, 331, 335proguanil with, 335Chlorothiazidechronic hypoglycaemia, 361diabetes insipidus, 385hypertension, 77Chloroxylenol, 597Chlorphenamine, 153, 156allergic emergencies, 159Chlorpheniramine see ChlorphenamineChlorpromazinenausea and vomiting, 192, 194psychosis, 174Chlortalidone, 78Cholecalciferol see ColecalciferolCholera vaccine, 604travel, 626Cholestasis, 68, 70Cholestatic conditions, 68Cholesterol, 70Smith-Lemli-Opitz syndrome,70Cholestyramine see ColestyramineCholic acid, 69Choline, 479Choline salicylatedental gel, 543, 544Cholinergic crises, 512Cholinesterase inhibitors, 512,646Choragon, 383Choreas, 237Chorionic gonadotrophin, 379,383Chronic myeloid leukaemia, 428Churg-Strauss syndrome, 152Cicafem (co-cyprindiol), 578Ciclesonide, 150Ciclosporinaplastic anaemia, 448eczema, 572immunosuppression, 431, 433,434nephrotic syndrome, 434psoriasis, 572rheumatic disease, 508ulcerative colitis, 48, 54Cidofovir, 324Cidomycin, 278Cigarette smoking, 238Cilastatin, 272imipenem with, 272Cilest, 401Ciloxan, 519Cinchocainerectal, 66[ingredient], 67Cinnarizine, 193Cipramil, 187Ciprofloxacin, 297, 298Crohn’s disease, 49ear, 535, 537eye, 518, 519meningococcal meningitisprophylaxis, 254Ciproxin, 298Circadin, 171Cisatracurium, 643, 644Cisplatin, 429, 430Citalopram, 186, 187Citanest preparations, 6534%—discontinuedCitramag, 64Citrulline, 493, 494Clairette, 578Clarithromycin, 280, 281, 282Helicobacter pylori eradication,42pertussis prophylaxis, 254Classification changes, xviiiClasteon, 390Clavulanic acid, 260amoxicillin with, 260, 263ticarcillin with, 264, 265Cleanlet Fine, 357Cleansers, skin, 594Clenil Modulite, 148Clexane preparations, 117ClikSTAR, 357Clindamycin, 283, 284acne, 575, 576bacterial vaginosis, 395benzoyl peroxide with, 575malaria, 330oral infections, 283pneumocystis pneumonia, 342vaginal infections, 395Clinipak syringe, 357Clinistix, 363Clinitas, 531Clinitek Microalbumin, 363Clinitest, 363ClinOleic, 467Clinutren preparationsenteral feed, 752nutritional supplement, 759Clioquinolbetamethasone with, 562ear, 534, 536fluocinolone with, 564Clobazam, 230epilepsy, 217, 230Clobetasol propionate, 562, 563neomycin and nystatin with,563Clobetasone butyrate, 563tetracycline with, 563Clodronate sodium see Sodiumclodronate, 390Clofarabine, 423, 424Clonazepamepilepsy, 217, 230, 231, 232status epilepticus, 231, 232neonatal seizures, 217Clonidine, 98Cloral betaine, 170Clostridium botulinum, 604Clostridium difficile, 49antibacterial therapy, 245metronidazole in, 295vancomycin in, 285Clotrimazoleanogenital, 394ear, 536skin, 588, 589betamethasone with, 562hydrocortisone with, 560vulvovaginal candidiasis,recurrent, 394Clozapine, 173, 177, 178, 179hypersalivation, 177Clozaril, 179Cluster headache, 214CMV see CytomegalovirusCoal tar, 566, 567, 569, 570dithranol and salicylic acid with,570hydrocortisone with, 570scalp, 569, 584, 585zinc with, 569Co-amilofruse, 81Co-amilozide, 81Co-amoxiclav, 260, 263, 264Cobalin-H (hydroxocobalamin),447COC see Contraception, oral,combined, 396Cocaine, poisoning by, 31Index

818 Co-careldopa—Cough BNFC 2011–2012IndexCo-careldopa, 235, 236Co-codamol preparations, 201Cocois, 569Co-cyprindiol, 578Cod liver oilzinc oxide with, 557Codalax preparations, 59Co-danthramer preparations, 59Co-danthrusate preparations, 60Codeinecough suppressant, 167diarrhoea, 47pain, 203, 204, 205buclizine and paracetamolwith, 202palliative care, 17paracetamol with, 201Co-dydramol, 201, 202Coeliac disease, 468ACBS, 777Co-enzyme Q10 see Ubidecarenone,497Co-fluampicil, 261, 263Colazide, 50Cold sores, 591Colecalciferol, 482, 484calcium with, 484Colestid, 129Colestipol, 128, 129Colestyraminediarrhoea, 47, 70familial hypercholesterolaemia,70hypercholesterolaemia, 128pruritus, 70palliative care, 19Colic, bowelpalliative care, 20Colief, 777Colifoam, 53Colistimethate sodium, 288eye drops, 529Colistin see Colistimethate sodiumColistin sulphomethate sodium seeColistimethate sodiumColitisClostridium difficile infection,49ulcerative, 48Collodiondefinition, 551flexible, 593Colloidal oatmeal, 552, 554Colofac preparations, 41Colomycin, 288Colophony, 580, 593Colpermin, 41Comahyperglycaemic, 360hyperosmolar nonketotic, 360hypoglycaemic, 361hypothyroid, 366insulin, 360ketoacidotic, 360Co-magaldrox, 37Combined hormonalcontraceptives, 399see also ContraceptionCombivir, 315Combur-3 Test, 363Comfort Point, 357Compact, 364Companies, specialist-importing,809Complan Shake, 760Complementary medicine, 2Compliance, 1Concerta XL, 190Concordance, 1Condyline, 581Condylomata acuminata, 581Confusion, palliative care, 19Congenital agammaglobulinaemia,replacement therapy, 622Conjunctivitis, 251, 518allergic, 522Conotrane, 556Constipation, 57palliative care, 18Contact lenses, 533Contiflo XL (tamsulosin), 410Continuous infusion devices, 19Contour products, 364Contraception, 396devices, 406, 407, 408contraceptive caps, 408contraceptive diaphragms,408implants, 404intra-uterine system, 405, 406oral, 396combined hormonal, 396emergency, 408, 409missed pill, 397, 403progestogen-only, 403starting routines, 399, 403surgery, 398, 403travel, 397parenteral, 404, 405spermicidal, 406transdermal, 396, 400detached patch, 397starting routines, 399Controlled drugs, 9travel abroad, 11Conversion tables, inside backcoverConvulex, 229Convulsionsfebrile, 235palliative care, 18poisoning and, 25see also EpilepsyConvulsive status epilepticus, 231Co-phenotrope, 47Coracten preparations, 108Cordarone X, 85Cordilox preparations, 109, 110Corn flour, ACBS, 781Corn starch, ACBS, 781Corneal ulcers, 518, 521Coronary heart diseasepreventionantiplatelet therapy, 120diabetes, 92dyslipidaemia, 126hypertension, 92non-drug treatment, 92obesity, 92risk assessment, 126Corsodyl preparations, 547Corticorelin, 382, 383Corticosteroids, 369administration, 371adrenal suppression, 371allergic emergencies, 159allergy, 371nasal, 538, 539anaesthesia, 371, 628anaphylaxis, 371angioedema, 371aphthous ulcers, 543, 544asthma, 146acute, severe, 134chronic, 135blood disorders, 448breast-feeding, 373cancer, 433chickenpox, 371croup, 137ear, 534equivalent doses, 370eye, 519, 521haemorrhoids, 66hepatic impairment, 373hypercalcaemia, 473immunosuppression, 433infantile spasms, 217infections, 371inflammatory bowel disease,48, 53inhaled, 146measles, 371mouth, 544myasthenia gravis, 512, 513nasal polyps, 538neuropathic pain, 212pregnancy, 373proctitis, 53proctosigmoiditis, 53psychiatric reactions, 372renal impairment, 373replacement therapy, 369rheumatic disease, 506septic shock, 370side-effects, 373skinchoice, 558eczema, 558, 565nappy rash, 556potency, 559psoriasis, 559, 567steroid treatment card, 373surgery, 371, 628tuberculosis, 291ulcerative colitis, 53, 54withdrawal of, 372Corticotrophin see Corticotropin,382Corticotrophin-releasing hormonesee Corticorelin, 382, 383Corticotropin, 382Cortisol, 369Co-simalcite [ingredient], 37Cosmegen Lyovac, 422CosmoFer, 445Cosopt, 528Cosuric (allopurinol), 417Co-trimoxazole, 289, 290pneumocystis pneumonia, 289,342Coughpalliative care, 19suppressants, 167

BNFC 2011–2012 Coumarins—Dermatophyte 819Coumarins, 118Covering creams, 583Covermark preparations, 583Cow & Gate Pepti preparations,764Cozaar preparations, 104Crab lice, 592Cradle cap, 566, 584Creamsdefinition, 551suitable quantities, 551Creatinine clearance see Glomerularfiltration rate, 14Creeping eruption see Cutaneouslarva migrans, 346Creon preparations, 71, 72Crestor, 127Cretinism see Hypothyroidism,neonatal, 365CRH Ferring, 383CRH see Corticorelin, 382, 383Crisantaspase, 427, 428Crixivan, xixCrohn’s disease, 48fistulating, 49Cromoglicate (or cromoglycate) seeSodium cromoglicateCrotamiton, 557hydrocortisone with, 560scabies, 592Croup, 137Cryptococcosis, 301Crystacide, 596Crystapen, 258CS gas see CS spray, 33CS spray, 33Cuplex, 580Curatoderm, 569Curosurf, 163Cu-Safe T300, 407Cushing’s syndrome, 377, 391corticosteroid-induced, 374Cutaneous larva migrans, 346Cutivate, 565CX Antiseptic Dusting Powder,595Cyanides, poisoning by, 32Cyanocobalamin, 446Cyanokit, 32Cyclimorph, 209Cyclizine, 193, 194motion sickness, 193nausea and vomiting, 192, 193palliative care, 19, 20Cyclopentolate, 524Cyclophosphamide, 420, 431Cycloplegics, 524Cycloserine, 292, 293Cyclosporin see CiclosporinCyklokapron, 124Cymevene, 325Cyproteroneacne, 578precocious puberty, 380Cystadane, 496Cystagon, 493Cysteamine see Mercaptamine,492, 493Cysteine amino acid supplement,783Cystic fibrosisdelayed puberty, 377fat malabsorption, 70respiratory-tract infections,247, 255, 264Cysticide, 346Cystinosis, nephropathic, 492Cystitis, 412haemorrhagic, 419Cystrin, 411Cytarabine, 423, 424Cytochrome oxidase deficiency,480Cytokine modulatorsCrohn’s disease, 55juvenile idiopathic arthritis, 509Cytomegalovirusinfections, 322, 324, 521Cytotoxic drugs, 414alopecia, 416antibiotic, 421bone-marrow suppression, 416delayed toxicity, 416extravasation, 415handling guidelines, 414hyperuricaemia, 417nausea and vomiting, 415pregnancy, 416urothelial toxicity, 419Dd4T see Stavudine, 310, 313, 314Dacarbazine, 428Dactinomycin, 422Daktacort, 560Daktarinoral gel, 546skin, 590Dalacin, 284acne, 576bacterial vaginosis, 395Dalivit, 487Dalteparin, 116Danaparoid, 117, 118Dandrazol preparations, 584Dandruff, 583Danlax, 59Danthron see Dantron, 59Dantrium, 515Intravenous, 649Dantrolenemalignant hyperthermia, 648muscle spasm, 514, 515Dantron, 59Dapsonepneumocystis pneumonia, 342,343poisoning, elimination, 25Daraprim, 341Darbepoetin, 448, 449Darier’s disease, 567Darunavir, 310, 316Daunorubicin, 421, 422DaunoXome, 422DDAVP, 387DDI see Didanosine, 312Decan, 468Decapeptyl SR, 381Decongestantsnasal, 541systemic, 168DEET see Diethyltoluamide, 331Defective medicines, 13Defenac (diclofenac) preparations,502Deferasirox, 451, 452Deferiprone, 451, 452Deferoxamine see DesferrioxamineDeflazacort, 370, 374Deleted preparations, xixDelph, 582Deltacortril (prednisolone), 377Deltaprim, 333Demeclocycline, 275Demorem (ondansetron), 197Demulcent cough preparations,167Dendritic ulcer, 521Dental Practitioners’ Formulary,794Dental prescribingabscess, 252anaesthesiageneral, 629local, 649vasoconstrictors, 649angular cheilitis, 545endocarditis prophylaxis, 256fluoride, 476herpes labialis, 321herpetic gingivostomatitis, 321infectionsbacterial, 244, 251fungal, 545viral, 321, 545joint prosthesis prophylaxis,257oral hygiene, 546pain, 199, 204, 500postoperative, 199sedation, 637sinusitis, 541Dentinox, colic drops, 38Denzapine, 179Dependence see Drug dependenceDepoCyte, 424Depolarising muscle relaxants seeMuscle relaxantsDepo-Medrone, 376, 506with Lidocaine, 506Depo-Provera, 404, 405Depression, 183antipsychotics, 172manic, 181Derbac-M, 593Dermabond ProPen, 593Dermacolor preparations, 583Dermal, 584Dermalo, 554Dermamist, 552DermatitisACBS, 786herpetiformis, 777seborrhoeic, 566see also EczemaDermatological preparations,special-order, 550Dermatonics Heel Balm, 553Dermatophyte infections, 301,588Index

820 Dermol—Disfiguring BNFC 2011–2012IndexDermol preparations, 554, 556Dermovate preparations, 563Desferal, 453Desferrioxaminealuminium overload, 452eye, 529iron overload, 451, 452, 453iron poisoning, 30Desflurane, 633Desloratadine, 153, 154Desloughing agents, 596Desmomelt, 387Desmopressin, 387assessment tests, 385diabetes insipidus, 385fibrinolytic response, 385haemophilia, 123, 385nocturnal enuresis, 385, 411Desmospray, 387Desmotabs, 387Desogestrel, 404ethinylestradiol with, 401Destolit, 69Detemir, insulin see Insulin detemirDetrusitol preparations, 411Dexamethasone, 370, 374, 375anorexia, palliative care, 18bacterial meningitis, 375cerebral oedema, 375corticosteroid replacementtherapy, 375croup, 137dysphagia, palliative care, 18dyspnoea, palliative care, 19inflammatory and allergicdisorders, 375ear, 535, 536eye, 521, 522malignant disease, 433nausea and vomiting, 192palliative care, 19neuropathic pain, palliativecare, 18raised intracranial pressure,palliative care, 19suppression test, 370Dexamfetamine, 188, 189Dexamphetamine see Dexamfetamine,188, 189Dexedrine—discontinuedDeximune, 435Dexomon (diclofenac)preparations, 502Dexrazoxane, 416, 417Dexsol (dexamethasone), 375Dextrogel, 361Dextromethorphan, 167Dextropropoxyphenepoisoning by, 28Dextrose monohydrate see GlucoseDF 118 Forte, 206DHC Continus, 206Diabetes insipidus, 385Diabetes mellitus, 349diagnosis, 365genetic defects of beta-cellfunction, 348management with insulin, 349monitoring, 351glucose, 363ketone, 363meters, 364, 365test strips, 364, 365neonatal, 352surgery, 351Diabeticketoacidosis, 360, 462nephropathy, 362neuropathy, 363skin ulcers, 596Diabur Test-5000, 363Diacomit, 226DIAGLYK (gliclazide), 359Dialamine, 774Dialar (diazepam), 515Diamicron, 359Diamorphinepain, 203, 205chronic, 203palliative care, 17, 20morphine equivalence, 20Diamox preparations, 527Dianette, 578Diaphragms, contraceptive, 408Diarrhoea, 46oral rehydration, 459Diastix, 363Diazemuls (diazepam), 233Diazepamanxiety, palliative care, 18convulsions, 25palliative care, 18dyspnoea, palliative care, 18epilepsystatus epilepticus, 231,232, 233muscle spasm, 514, 515palliative care, 18tetanus, 515Diazepam Rectubes, 233Diazoxidechronic hypoglycaemia, 361hypertension, 93hypoglycaemia, 362Dibenyline, 100Dibucaine see CinchocaineDiclofenacactinic keratoses, 583eye, 533eye surgery, 532juvenile idiopathic arthritis, 501pain and inflammation, 501,502postoperative pain, 640rheumatic disease, 500, 501Diclofenac potassium, 501Diclofenac sodium, 501Dicloflex (diclofenac)preparations, 502Diclomax preparations, 502Diclozip (diclofenac), 502Dicobalt edetate, 32Dicyclomine see Dicycloverine, 39Dicycloverine, 39Didanosine, 312Dienogest, estradiol with, 402Dietary Specials products, 777,778, 779Diethylcarbamazine, 346Diethyltoluamide, 331Differin, 576Difflamoral rinse, 543spray, 544Diffundox XL (tamsulosin), 410Diflucan preparations, 302Diflucortolone valerate, 563Digibind, 75Digoxin, 73, 74, 75arrhythmias, 83poisoning, 74Digoxin-specific antibodyfragments, 74, 75Dihydrocodeine, 203, 205, 206Dihydropyridine calcium-channelblockers, 105Dihydrotachysterol, 482Dihydroxycholecalciferol, 482Diloxanide furoate, 339Diltiazem, 106anal fissure, 67poisoning by, 30see also Calcium-channelblockersDimercaprol, xix, 32Dimeticonehead lice, 592skinbenzalkonium with, 556cetrimide with, 557zinc oxide with, 557Dinoprostone, 131, 132Dioctyl, 60Dioctyl sodium sulphosuccinatesee Docusate sodiumDioderm, 560Dioralyte preparations, 459Diovan, 104Dip/Ser, 606Dipentum, 52Dipeptiven, 468Diphenoxylate, 47Diphenylbutylpiperidines, 173Diphosphonates see BisphosphonatesDiphtheriaantibacterialprophylaxis, 254treatment, 257antitoxin, 606immunisation, 604travel, 605vaccines, combined, 605, 606Dipotassium hydrogen phosphate,475Diprivan, 632Diprobase, 552Diprobath, 555Diprosalic, 562Diprosone, 562Dipyridamole, 121Disease-modifying antirheumaticdrugs, 507Disfiguring skin lesions, ACBS,787

BNFC 2011–2012 Disinfectants—Emergency 821Disinfectants, 594ACBS, 787DiskhalerBecodisks, 148Relenza, 327Serevent, 141Disodium clodronate see Sodiumclodronate, 390Disodium cromoglicate see SodiumcromoglicateDisodium folinate, 418Disodium hydrogen phosphate,475Disodium levofolinate, 419Disodium pamidronate, 389, 390Disprol (paracetamol)preparations, 201Distaclor preparations, 267Distal intestinal obstructionsyndromeacetylcysteine, 165amidotrizoates, 65Distamine, 489Dithranol, 566, 567, 570coal tar and salicylic acid with,570Dithrocream, 570Ditropan, 411elixir—discontinuedDiuretics, 76anaesthesia and, 629beta-blockers with, 87carbonic anhydrase inhibitors,82loop, 76, 78osmotic, 81potassium and, 457potassium with, 82potassium-sparing, 76, 80with other diuretics, 81thiazides, 76DMARDs see Disease-modifyingantirheumatic drugs, 507DMPS see Unithiol, 32DMSA see Succimer, 32Dobutamine, 110, 111infusion table (neonatal), 792DocOmega, 784Docusate sodiumear, 538laxative, 59, 60Docusol, 60Dolmatil, 176Domperidonegastro-intestinal stasis, 41gastro-oesophageal reflux,41migraine, 214nausea and vomiting, 192, 195,196, 416palliative care, 18Dopamine, 110, 111, 112infusion table (neonatal), 792Dopram, xixDornase alfa, 165, 166Dorzant (dorzolamide), 528Dorzolamide, 527, 528timolol with, 528Dose changes, xviiDOT (directly observed therapy),291Doublebase preparations, 553,555Dovobet preparations, 568Dovonex preparations, 568scalp solution—discontinuedDoxadura (doxazosin)preparations, 99Doxapram, xixDoxazosin, 99, 409cardiovascular, 99urinary tract, 409Doxepin, 185, 557topical, 557, 558Doxorubicin, 421, 422Doxycycline, 275, 276acne, 578aphthous ulcers, 544malaria prophylaxis, 331, 332,333, 334, 338malaria treatment, 330, 338mouth, 545oral infections, 274periodontitis, 252, 543, 544Doxylar (doxycycline), 276Dozic, 175Drapolene, 557Dressingspain on changing, 634Driclor, 597Dried prothrombin complex, 124Driving and skilled tasks, 2Droperidol, 192, 194, 195Drospirenonecontraceptionethinylestradiol with,401Drug dependence, 204management, 238prescribing in, 9Drug information services, insidefront coverDrug interactions, 655Dry mouth, 548palliative care, 18Duac, 575Dual block, 645Ductus arteriosus, 130, 131Dukoral, 604Dulcolax (bisacodyl), 59Dulcolax Pico (sodium picosulfate),61Duobar, 773Duocal preparations, 773Duofilm, 580Duphalac (lactulose), 62Duraphat preparations, 477Durogesic DTrans, 207Dusting powders, 551Dysenteryamoebic, 339bacillary see Shigellosis, 245Dysfunctional voiding, 409Dysmenorrhoea, 199Dyspepsia, 35Dysphagia, palliative care, 18Dyspnoea, palliative care, 18Dysport, 238Dystonias, 235drug-induced, 173, 237EE numbers, inside back coverE45 preparations, 553, 555Itch Relief, 554EAA supplement, 784Earinfections, 534wax removal, 537EarCalm, 535Easi-BreatheSalamol, 140Easiphen, 784Easyhalerbeclometasone, 148budesonide, 149formoterol, 138salbutamol, 140Ebufac (ibuprofen), 503Echinocandin antifungal drugs,300, 306Echinococcosis, 346Econac (diclofenac), 502Econazoleanogenital, 395skin, 588, 589vaginal, 395Ecopace (captopril), 102Ecstacy, liquid (sodium oxybate),31Ecstasycontrolled drug, 9poisoning by, 31Ectopic tachycardia, 82Eczema, 565ACBS, 786ear, 535scalp, 584Eczmol, 554Ednyt (enalapril), 102Edrophoniumanaesthesia, 646myasthenia gravis, 512, 513Efavirenz, 310, 319emtricitabine and tenofovirwith, 314Efcortesol, 376Eformoterol see FormoterolElaprase, 492Electrolade, 459Electrolyte and water replacementintravenous, 460oral, 457Electrolyte concentrations, 456intravenous fluids, 456Electrolytesintravenous nutrition, 467Elemental-028 Extra, 746Elidel, 573ellaOne, 409Elocon, 565Elspar, 428Eltroxin (levothyroxine), 366Eludril preparations, 547Emadine, 523Emedastine, 522, 523Emergencies in the community,medical, inside back coverEmergencycontraception, 408supply, medication, 8Index

822 Emeside—Extravasation BNFC 2011–2012IndexEmeside, 220EMLA, 652Emollients, 552eczema, 565pruritus, 557palliative care, 19psoriasis, 566Emollin, 553Emsogen, 752Emtricitabine, 310, 312, 313efavirenz and tenofovir with,314tenofovir with, 314Emtriva, 313Emulsiderm, 556Emulsifying ointment, 552Enalapril, 102, 103see also ACE inhibitorsEnbrel, 511Enbucrilate, 594Encephalopathy, hepatic, 61En-De-Kay preparations, 477Endocarditis, 246, 277antibacterial prophylaxis, 256Endophthalmitis, 518Ener-G productsgluten- and wheat-free, 780gluten-free, 777, 778, 779low-protein, 780Energivit, 773Energy, intravenous nutrition, 466Enfamil preparations, 765thickened, 767Enfuvirtide, 310, 320, 321Engerix B, 609Enoxaparin, 116, 117Enoximone, 75Enshake, 775Ensure Plus preparations, 757,758, 759Ensure preparations, 750, 756Entamoeba histolytica, 339Entecavir, 325Enteralfeeding tubesadministering drugs via, 68clearing blockages, 68nutrition, 469foods, ACBS, 743Enteric infections, 245Enterobiasis, 344Enterocolitis, necrotising, 245Entocort preparations, 53Entonox, 634Enuresis, nocturnal, 411Enzira, 612Enzyme induction, 655Enzymesfibrinolytic, 121Epaderm preparations, 553Epanutin preparations, 225Ready Mixed Parenteral, 235Epaxal, 607Ephedrinehypotension, 112nasal congestion, 541, 542Epiduo, 577Epiglottitis, 247Epiglu, 593Epilepsy, 215, 217breast-feeding and, 216driving, 216neonatal seizures, 217pregnancy and, 216status epilepticus, 231non-convulsive, 232syndromes, 217Epilim preparations, 228, 229Epimaz (carbamazepine), 218Epinastine, 522, 523Epinephrine see AdrenalineEpiPen preparations, 160, 161Epirubicin, 421, 422, 423Episenta preparations, 229Epival, 229Epivir, 313Epoetinalfa, 449beta, 449, 450zeta, 449, 450Epoprostenol, 95, 96, 118infusion table (neonatal), 792Eposin, 426Eprex, 449Eptacog alfa (activated), 124Eptadone (methadone), 207Equanox, 634Equasym XL, 190Ergocalciferol, 482, 483Ergot alkaloids, 212Ertapenem, 272Erwinase, 428Erymax, 283Erysipelas, 253Erythema, perianal, 66Erythrocin, 283Erythromycin, 280, 282, 283acne, 575, 576, 577, 578tretinoin with, 577diphtheria prophylaxis, 254eye infections, 519gastro-intestinal stasis, 41pneumococcal prophylaxis, 255rheumatic fever prophylaxis,254Erythroped preparations, 283Erythropoietins, 448Esmeron, 645Esmolol, 82, 88, 90see also Beta-adrenoceptorblocking drugsEsomeprazole, 45Essential amino acidssupplement, 784Estradiolcontraceptiondienogest with, 402Estriol, labial adhesions, 393Etanerceptjuvenile idiopathic arthritis,509, 510, 511psoriasis, 574Ethambutol, 290, 292, 293tuberculosis treatment, 291Ethanol, poisoning, use in, 32Ethinylestradiolacne see Co-cyprindiol, 578contraception, 396desogestrel with, 401drospirenone with, 401etonogestrel with, 400gestodene with, 401, 402levonorgestrel with, 401,402norelgestromin with, 400norethisterone with, 401,402norgestimate with, 401hormone therapy, 377, 378Ethinyloestradiol see EthinylestradiolEthosuximide, 217, 219, 220Ethyl-2-cyanoacrylate, 593Ethylene glycol, poisoning by, 32Ethynodiol see Etynodiol, 404Etomidate, 630Etomidate-Lipuro, 630Etonogestrelethinylestradiol with, 400implant, 404, 405Etopophos, 426Etoposide, 426Etoricoxib, 500, 502, 503Etravirine, 310, 319, 320Etretinate, 567Etynodiol, 404Eucalyptus oil, 166Eucardic, 90Eucerin, 554Eudeminehypertension, 93hypoglycaemia, 362Eumovate, 563Eurax preparations, 557, 560European viper venom antiserum,34EvohalerFlixotide, 150Seretide, 150Ventolin, 140Evoltra, 424Evotrox (levothyroxine), 366Evra, 400Excipientsdetails provided, 2skin preparations and, 551Exelderm—discontinuedExfoliative dermatitis, 370Exjade, 452Exocin, 520Exorex, 569Expectorants, 167Extemporaneous preparations, 6Exterol, 538Extrapyramidal symptomsantipsychotics and, 173treatment, 237Extravasation, 516

BNFC 2011–2012 Eye—Formaldehyde 823Eyeanaesthesia, local, 529antibacterials, 518frequency ofadministration, 519antifungals, 520antivirals, 521contact lenses, 533corticosteroids, 521cycloplegics, 524drops, administration, 517glaucoma, 525inflammation, 521lotions, administration, 517microbial contamination, 518miotics, 528mydriatics, 524ointments, administration, 517prostaglandins, 525, 526Ezetimibe, 129Ezetrol, 129FFabrazyme, 490Fabry’s disease, 490Factor VIIa (recombinant), 124Factor VIII fraction, 124inhibitor bypassing, 124Factor IX fraction, 124Factor XIII fraction, 125Faecal softeners, 61Falciparum malaria, 330Fallot’s tetralogy see Tetralogy ofFallot, 88Famciclovir, 322, 395Familial hypercholesterolaemia,125Fanhdi (factor VIII fraction), 124Fansidar, 338Fasigyn, 340Fastclix, 357Fasturtec, 418Fat emulsions, intravenous, 466Fate products, 780Faverin, 188Favism, 454Febrile convulsions, 235Fectrim (co-trimoxazole), 290Feed thickeners, 471, 777Feeds see FoodsFEIBA (factor VIII inhibitorbypassing fraction), 124Feldene preparations, 505Felypressin, 649prilocaine with, 653FemCap, 408Femidom, 396Femodene preparations, 401Femodette, 401Femulen, 404Fenactol (diclofenac)preparations, 502Fenbid, 504Fendrix, 610Fenofibrate, 129, 130Fentalis (fentanyl), 207Fentanyl, 641analgesia, 206, 207peri-operative, 640, 641palliative care, 17, 18morphine equivalence, 18Fentazin, 176Fenticonazole, 395Ferinject, 445Ferric carboxymaltose, 444, 445Ferriprox preparations, 452Ferrous fumarate, 443, 444Ferrous gluconate, 443, 444Ferrous sulphate, 443Fersaday, 443Fersamal, 444Feverfen (ibuprofen), 503Fexofenadine, 153, 154Fibrates, 129Fibrelief, 58Fibrinolytic drugs, 121Fibrogammin P (factor XIII fraction),125Filariasis, 346Filaricides, 346Filgrastim, 454, 455, 456Finacea, 575Finax products, 779Finepoint, 357Fingertip unit, 559Fits see EpilepsyFlagyl preparations, 297Flamatak (diclofenac)preparations, 502Flamazine, 587Flamrase (diclofenac)preparations, 502Flavour Mix, 777Flavouring preparations, 777FlavourPac, 777Flebogamma DIF, 624Flecainide, 82, 83, 85, 86FleetReady-to-use enema, 63Flexbumin preparations(albumin), 464Flexible collodion, 593Flexi-T intra-uterine devices, 407Flexotard MR (diclofenac), 502Flixonase preparations, 540Flixotide preparations, 150Diskhaler—discontinuedFlolan, 96Flomaxtra XL, 410Florinef, 370Flowfusor, 594Floxapen (flucloxacillin), 260Flu-Amp (co-fluampicil), 263Fluarix, 612Fluclomix (flucloxacillin), 260Flucloxacillin, 259, 260ampicillin with [co-fluampicil],261ear infection, 535Fluconazole, 300, 301, 302oropharyngeal candidiasis, 545palliative care, 18vulvovaginal candidiasis,recurrent, 394Flucytosine, 301, 308Fludara, 424Fludarabine, 423, 424Fludrocortisone, 369, 370Fludroxycortide, 563Fluid and electrolyte replacement,456neonate, 461oral, 457parenteral, 460Flumazenil, 30, 647, 648Flumetasone, 536Flumethasone see Flumetasone,536Flunisolide, 540Fluocinolone acetonide, 564clioquinol with, 564neomycin with, 564Fluocinonide, 564Fluocortolone, 564[ingredient], 67Fluor-a-day, 477Fluorescein, 532lidocaine with, 529proxymetacaine with, 529Fluoride, 476, 477FluoriGard preparations, 477Fluorometholone, 522Fluorouracil, 583Fluoxetine, 186, 187Flurandrenolone see Fludroxycortide,563Flurbiprofeneye, 533sore throat, 543, 544Fluticasone furoate, 540Fluticasone propionateasthma, 146, 150chronic, 135salmeterol with, 150nasal allergy, 540nasal polyps, 540skin, 564, 565Fluvastatin, 126, 127Fluvirin, 612Fluvoxamine, 186, 187, 188FML, 522Focal seizures, 217Folate deficiency, 446Folate rescue, 418Folic acid, 446, 447methotrexate, following, 508pregnancy, 446Folicare, 447Folinic acid, 418rescue, 418Folliculitis, 585Fomepizole, 32Food allergy, 56Foodlink preparations, 760FoodsACBS, 743enteral, 469, 470feed thickeners, 471gluten-free, 777intolerance, 470, 777low-protein, 780special diets, 468, 470, 777vitamin supplements, 487,488thickened, 777Foradil, 138Forceval, 487Formaldehyde, 580Index

824 Formoterol—Glyceryl BNFC 2011–2012IndexFormoterol, 138budesonide with, 149FormularyDental, 794Nurse, 796Forticare, 768Forticreme, 761Fortijuce, 757Fortimel Regular, 759Fortini preparations, 754Fortipine LA 40, 108Fortisip preparations, 758, 759,761Fortum, 270Fosamax preparations, 389Fosamprenavir, 310, 316Foscarnet, 324, 325Foscavir, 325Fosphenytoin, 224, 232, 233Fragmin, 116Framycetinear, 536, 537Frangula, sterculia with, 58Frebini preparations, 752, 755FreeStyle products, 357, 364Fresh frozen plasma, 125Fresubin preparationsenteral feed, 744, 747, 749soya formula, 745feed supplement, 772nutritional supplement, 759,761Friars’ Balsam, 166Frisium (clobazam), 230FructoseACBS, 777presence of, 2Fructose-based infant formula,767Frumil preparations (co-amilofruse),81Frusemide see FurosemideFrusol (furosemide), 80FTC see EmtricitabineFTU see Fingertip unit, 559Fucibet, 562Fucidin, 285skin, 587Fucidin H, 561Fucithalmic, 519Fulsovin, 309Fungal infections, 300anogenital, 394eye, 520oral, 300oropharyngeal, 545skin, 301, 588Fungizone, 306Furadantin, 300Furosemide, 78, 79, 80amiloride with, 81Fusidic acidangular cheilitis, 545eye, 518, 519skin, 587betamethasone with, 562hydrocortisone with, 561systemic, 284, 285Fuzeon, 321Fybogel, 58Fybogel Mebeverine, 41GG6PD deficiencydrugs to be avoided in, 454GA gel, 781GA1 Anamix, 781Gabapentin, 217, 220Gabitril, 226Galactomin preparations, 765,767Galenamox (amoxicillin), 261,262Galenphol, 167Galfer, 444Galpseud, 168Galsulfase, 491, 492Gammagard S/D, 624Gamma-hydroxybutyrate (sodiumoxybate), 10, 31Gammanorm, 623Gammaplex, 624Ganciclovir, 324, 325Gardasil, 611Gas-gangreneprophylaxis, 255treatment, 257Gastric emptying, poisoning and,25Gastrocote, 38Gastro-enteritis, 47, 245Gastrografin, 65Gastro-intestinal procedures,antibacterial prophylaxis, 255Gastro-intestinal secretionselectrolyte content, 456Gastro-oesophageal refluxdisease, 35Gaucher’s disease, 490Gaviscon preparations, 38G-CSF see Granulocyte-colony stimulatingfactor, 454, 455, 456Gedarel preparations, 401Gelatininfusion, 465succinylated, 465Gelofusine, 465Geloplasma, 465Gels, definition, 551GelTears, 530Generaid preparations, 768General anaesthesia see Anaesthesia,generalGenetic defects of beta-cellfunction, 348Genital warts, 581Genius products, 777Genotropin preparations, 384Gentamicin, 277, 278, 279ear, 536, 537eye, 518, 519, 529Genticin, 279ear, 537eye, 519Gentisone HC, 536German measles see RubellaGestodene, ethinylestradiol with,401, 402GHB (sodium oxybate), 10, 31Giardia lamblia, 340Giardiasis, 340Gilles de la Tourette syndrome seeTourette syndrome, 237Gingivitisantibacterial treatment, 252,296mouthwashes, 546Glamin, 467Glandosane, 548Glargine, insulin see Insulin glargineGlaucoma, 525steroid, 521Glebe Farm products, 779Glibenclamide, 358, 359Gliclazide, 359Glivec, 429Glomerular filtration rate, dosageand, 14GlucaGen HypoKit, 361Glucagon, 361beta-blocker poisoning, 30Glucocorticoidsequivalent doses, 370replacement therapy, 369GlucoGel, 361GlucoMen products, 364Glucophage, 360GlucoseACBS, 781cyanosis, 88hypoglycaemia, 361infusion, 462potassium and, 463sodium and, 462intravenous nutrition, 466oral rehydration, 459presence of, 2syrup, hydrogenated, presenceof, 2testsblood, 363tolerance, 365urine, 363Glucose 6-phosphate dehydrogenasedeficiencydrugs to be avoided in, 454Glue ear, 537Glulisine, insulin see Insulin glulisineGlutafin productsgluten- and wheat-free, 780gluten-free, 777, 778, 779Glutaraldehyde, 580Glutaricacidaemias, 480aciduria, 781Glutarol, 580Gluten, presence of, 3Gluten-free foods, ACBS, 777,778, 779, 780Gluten-sensitive enteropathies,777Glycerin suppositories, 60Glycerolconstipation, 59, 60glaucoma, 527Glyceryl trinitrateanal fissure, 67extravasation, 516infusion table (neonatal), 793shock, 111vasodilation, 104, 105

BNFC 2011–2012 Glycogen—Homatropine 825Glycogen storage diseasedietary supplement, 781granulocyte-colony stimulatingfactor, in, 455hypoglycaemia, 361Glycopeptide antibiotics, 285Glycophos, 468Glycopyrrolate see GlycopyrroniumbromideGlycopyrronium bromideairway secretions, 636hyperhidrosis, 597hypersalivation, 636neostigmine with, 647palliative care, 19, 20premedication, 635, 636Glycosade, 781Glypressin, 387GnRH see Gonadorelin, 385Goitre, lymphadenoid, 366Gold, 507Golden Eye Drops (propamidine),520Golden Eye Ointment (dibrompropamidine),520Gonadorelin, 385Gonadorelin analogues, 380Gonadotrophin deficiency, 377Gonadotrophin-releasing hormonesee Gonadorelin, 385Gonadotrophins, 383Gonapeptyl, 381Gonorrhoeaantibacterial treatmenteye, 251genital, 249pharyngeal, 249GoQuick, 384GORD see Gastro-oesophagealreflux disease, 35Goserelin, 380, 381Gout, 511Gramicidin [ingredient]ear drops, 536Granisetron, 192, 197Granocyte, 456Granulocyte-colony stimulatingfactor, 454, 455, 456Grass pollen extracts, 157, 158Graves’ disease, 367Grazax, 158Griseofulvin, 301, 308, 309Ground-nut oil see Arachis oilGrowth factor, platelet derived,596Growth hormone, 383Guillain-Barré syndrome, 622Gygel, 406Gynaecological surgery, antibacterialprophylaxis, 256GyneFix, 406, 407Gynest, 393Gyno-Daktarin Ovule, 395Gyno-Pevaryl preparations, 395Gynoxin preparations, 395HHaelan preparations, 563Haem arginate, 497Haemate P (factor VIII fraction),124Haemoctin (factor VIII fraction),124Haemodialysis, 25Haemolytic anaemia, 447, 448G6PD deficiency, 454Haemophilia, 385blood products, 124Haemophilus influenzae type b(Hib)immunisation, 606prophylaxis, 254vaccinesdiphtheria with, 605meningococcal with, 607Haemorrhage, 123gastro-intestinal, 43Haemorrhagic disease ofnewborn, 486Haemorrhoids, 66Haemostatics, 123HAES-steril, 465Haldol, 175Haleraid, 145Half-Beta-Prograne(propranolol), 89Half-Inderal LA, 89Half-Securon SR, 109Haloperidolmovement disorders, 237nausea and vomiting, 174, 192palliative care, 19, 20psychosis, 174, 175tics, 174Halothane, 633Harifen products, 780Harlequin ichthyosis, 571Hartmann’s solution see Sodiumlactate, intravenous infusion,compound, 461, 462Hashimoto’s thyroiditis, 365Havrix preparations, 607Hay fever, 153, 538Hay-Crom preparations (sodiumcromoglicate), 523HBIG see Hepatitis B immunoglobulinHBvaxPRO, 610HCG see Chorionic gonadotrophin,379, 383HCU preparations, 781, 782Head lice, 592Headachecluster, 214migraine, 212Heaf test, 603Healthy Start vitamins, 479Heart failure, 76ACE inhibitors, 76beta-blockers, 76, 88diuretics, 76, 78enoximone, 76spironolactone, 76Heart see also CardiacHedrin, 592Helicobacter pyloridyspepsia, 35eradication, 42test, 43Helixate NexGen (factor VIIIfraction), 124Helminth infections, 344Hemohes, 465Heparin, 114, 115flushes, 118infusion, 116infusion table (neonatal), 793injectioncalcium, 116sodium, 116Heparinoids, topical, 597, 598Heparon Junior, 768Hepatect, 625Hepaticencephalopathy, 61impairment, prescribing in, 14Hepatitis Aimmunisation, 607immunoglobulin, normal,622travel, 626vaccine, 607, 608hepatitis B with, 608typhoid with, 608Hepatitis Bauto immune, 371chronic, 313, 325chronic active, 439immunisation, 608immunoglobulin, 624, 625travel, 626vaccine, 608, 609, 610Hepatitis Cchronic, 325chronic active, 439Hepatolenticular degeneration seeWilson’s disease, 488Hepatyrix, 608Herbal medicines, 2Hereditary angiodema see AngiodemaHeroin see DiamorphineHeron productsgluten- and wheat-free, 780gluten-free, 779Herpes infections, 321eye, 521genital, 322, 395immunoglobulin, 626mouth, 545skin, 591Hewletts—discontinuedHexetidine, 547HFAs, 147HGH see Somatotrophin, 383Hib see Haemophilus influenzaetype bHibi liquid, 595Hibiscrub, 595Hibitane preparations, 595Hiccup, 174palliative care, 19High-energy supplements, 771Hirsutism, 578Hirudoid, 598Histamine H 1 -antagonists, 153Histamine H 2 -antagonists, 43Histoacryl, 594Histoplasmosis, 301HIV infection, 309pregnancy, 310HNIG see Immunoglobulins, normal,622, 623, 624Hodgkin’s disease, 428Homatropine, 524Index

826 Homocystinuria—Hypurin BNFC 2011–2012IndexHomocystinuria, 495, 781Hookworm infections, 346Hormone replacement, 377androgens, 379oestrogens, 377progestogens, 377How to use BNFC, xiHRF, 3855HT 1 -receptor agonists, 2125HT 3 -receptor antagonists, 192,197, 416HTIG see Immunoglobulins,tetanus, 625Humalog preparations, 353, 356Human chorionic gonadotrophinsee Chorionic gonadotrophin,379, 383Human coagulation factor VIII,124Human factor IX fraction, 124Human factor VIII fraction, 124Human factor XIII fraction, 125Human papilloma virus, vaccine,610, 611HumaPen Luxura products, 357Humatrope, 384Humira, 510Humulin I, 355Humulin M3, 356Humulin S, 352Hyabak, 531Hyaline membrane disease, 162Hydatid disease, 346Hydralazine, 93, 94Hydrex, 595Hydrochlorothiazideamiloride with, 81Hydrocortisone, 370, 371, 375,376asthma, acute, 134colitis, 53ear, 536eye, 522haemorrhoids, 66intra-articular, 506mouth, 543, 544pneumocystis pneumonia, 342rectal, 66, 67replacement therapy, 369rheumatic disease, 506septic shock, 111skin, 560, 561chlorhexidine and nystatinwith, 561clotrimazole with, 560coal tar with, 570crotamiton with, 560fusidic acid with, 561miconazole with, 560nystatin with, 561urea and lactic acid with,560urea with, 560Hydrocortistab, 506Hydrofluoroalkane propellants,147Hydrogen peroxidemouthwash, 546, 547skin, 596Hydromol preparations, 553, 555HC Intensive, 560Intensive, 554Hydromoor, 531Hydromorphone, 207morphine equivalence, 17Hydrotalcite, 37simeticone with, 37Hydrous ointment, 552Hydroxocobalaminanaemias, 446, 447cyanide posioning, 32Hydroxycarbamide, 451sickle-cell disease, 450Hydroxychloroquine, 507, 508Hydroxycholecalciferol, 482Hydroxyethyl starch see Starch,etherified, 465, 466Hydroxyethylcellulose, 530Hydroxypropyl guar, 530Hydroxyquinolinebenzoyl peroxide with, 575Hydroxyurea see HydroxycarbamideHydroxyzine, 156Hygroton, 78Hylo preparations, 531Hyoscine butylbromide, 39, 40palliative care, 20Hyoscine hydrobromide, 198excessive respiratorysecretions, 198hypersalivation, 198motion sickness, 193nausea and vomiting, 198palliative careexcessive respiratorysecretions, 19, 20gastro-intestinal pain, 18premedication, 635, 636, 637HYPER LYS preparations, 782Hyperactivity, attention deficit,188Hyperammonaemia, 493Hypercalcaemia, 388, 473Hypercalciuria, 473Hypercholesterolaemia, 125, 126,128, 129Hyperemesis gravidarum, 192Hyperglycaemia, 349coma, 360neonatal, 351HyperHAES, 466Hyperhidrosis, 597Hypericum perforatum, 184Hyperinsulinaemichypoglycaemia, 361Hyperinsulinism, 361Hyperkalaemia, 458see also SalbutamolHyperlipidaemia, 125Hyperlysinaemia, 782Hypermethioninaemia, 781Hypernatraemia, 461Hyperosmolar hyperglycaemicnonketotic coma see Hyperosmolarhyperglycaemic state, 360Hyperosmolar hyperglycaemicstate, 360Hyperphosphataemia, 475, 476Hyperprolactinaemia, 377Hypersalivation, 635Hypersecretion, airways, 635Hypersensitivity see Allergic disordersHypertension, 92ACE inhibitors, 101beta-blockers, 87crisis, 92diabetes, 92diuretics, 76, 78malignant, 92nephritis, 93poisoning and, 24portal, variceal bleeding in, 385pregnancy, 92pulmonary, 95, 118renal disease, 92thiazide diuretics, 76Hyperthermiamalignant, 648poisoning and, 25Hyperthyroidism see ThyrotoxicosisHypertonic sodium chloride, 166Hyperuricaemia, 417Hypnomidate, 630Hypnotics, 169Hypnovel, 639Hypocalcaemia, 471Hypodermic equipment, insulin,356Hypodermoclysis, 460Hypo-Fit, 361Hypogammaglobulinaemia, 622Hypoglycaemia, 351acute, 361chronic, 361hyperinsulinaemia, 361neonatal, 361Hypoglycaemic drugs, oral seeAntidiabetic drugs, oral, 357Hypogonadism, 377, 379, 383Hypokalaemiadiuretics and, 76intravenous potassium, 463potassium, oral, 457Hypolar Retard 20, 108Hypomagnesaemia, 473Hyponatraemianeonate, 461sodium replacementoral, 458parenteral, 461Hypophosphataemia, 474Hypopituitarism, 369, 379Hyposensitisation, 157Hypotension, poisoning and, 24Hypothalamic hormones, 385Hypothermiaantipsychotics and, 173poisoning and, 25Hypothyroidism, 365neonatal, 365Hypovase, 100Hypovolaemia, 464Hypoxaemia, 163Hypromellose, 530, 531Hypurin Isophane, 355biphasic, 356Hypurin Lente, 355Hypurin Neutral, 352Hypurin Protamine Zinc, 355

BNFC 2011–2012 Ibuprofen—Iodide 827IIbuprofen, 503, 504ductus arteriosus, 130juvenile idiopathic arthritis, 503migraine, 212pain, 500, 503postoperative, 640preparations, 503pyrexia, 503post-immunisation, 600rheumatic disease, 500, 503Ichthammol, 565, 566zinc with, 566Ichthyosis, 552, 567, 571Idiopathic thrombocytopenicpurpura see ThrombocytopenicpurpuraIdursulfase, 491, 492Ifosfamide, 421Il Pane di Anna products, 779Ilaris, 441Iloprostpulmonary hypertension, 95,96, 97Raynaud’s syndrome, 110Ilube, 530Imatinib, 428, 429Imidazole antifungal drugs, 305Imiglucerase, 490, 491Imigran preparations, 213Imipenem, 272, 273Imipramineattention deficit hyperactivitydisorder, 185nocturnal enuresis, 185, 186,412Imiquimod, 581Immukin, 440Immune interferon see Interferon,gamma-1b, 440Immunisationimmunityactive, 599passive, 602international travel, 626schedule, 601Immunodeficiency, 622, 626syndrome, acquired, 309Immunoglobulins, 602, 622aplastic anaemia, 447hepatitis B, 624, 625Kawasaki syndrome, 622myasthenia gravis, 512normal, 622, 623, 624passive immunity, 622rabies, 625tetanus, 625thrombocytopenic purpura, 453varicella–zoster, 625, 626Immunostimulants, 438Immunosuppressants, 431malignant disease, 433myasthenia gravis, 513skin disease, 572transplant rejection, 431Imodium preparations, 48Impetigo, 585systemic treatment, 253topical treatment, 253Implanon, 404Imuran, 432Imuvac, 612INCI synonyms, sunscreens, 582Increlex, 392Independent prescribing, 799Inderal preparations, 89Indian hemp see Cannabis, 10Indinavir, xix, 310Indolar SR (indometacin), 504Indometacinductus arteriosus, 130juvenile idiopathic arthritis, 504pain and inflammation, 504rheumatic disease, 500, 504Infacol, 38Infanrix-IPV, 605Infantileacne, 574, 579spasms, 217InfaSoy, 767Infatrini preparations, 753Infectionsamoebic, 339antisera, 602, 622ear, 534eye, 518fungal, 300helminth, 344immunoglobulins, 622nail, fungal, 301notifiable diseases, 243oropharyngeal, 545bacterial, 244, 251protozoal, 329skin, 585trichomonal, 340vaccines, 599vaginal, 394viral, 309vulval, 394Inflammatory bowel disease, 48InfliximabCrohn’s disease, 48, 55, 56inflammatory bowel disease, 49rheumatic diseases, 509Influenzaimmunisation, 611prophylaxis, 326treatment, 326vaccines, 611A(H1N1)v, 612seasonal, 612Influvac Sub-unit, 612Information servicesmedicines, inside front coverpoisons, 24Infusion devices, continuous, 19Infusions, intravenous (neonatal),791Inhalationsaromatic, 166Benzoin tincture, compound,166menthol and eucalyptus, 166steam, 541Inhaler devices, 144Innohep, 117Innovace, 103Inositol, 479Inotropic drugs, positive, 73, 110Inovelon, 225Insect stings, 34, 153Insecticides, poisoning by, 33Insomnia, 169antihistamines, 153palliative care, 19Instillagel, 652Insulatard preparations, 355Insulin, 349aspart, 352, 353biphasic, 354, 355detemir, 354glargine, 354glulisine, 352, 353human, 349infusionintravenous, 351subcutaneous, 350infusion table (neonatal), 793injection equipment, 356, 357isophane, 354, 355biphasic, 354, 356lispro, 352, 353biphasic, 354, 356protamine zinc, 354, 355soluble, 352zinc suspension, 354, 355crystalline, 354mixed, 354Insulin-like growth factor, 391InsumanBasal, 355Comb preparations, 356Rapid, 352Insupak, 357Intal, 151Intelence, 320Interactions, 655Interferonalfa, 439, 440chronic hepatitis B, 325chronic hepatitis C, 326peginterferon, 325, 326gamma-1b, 440Interferon gamma release assay,604International nomenclature, cosmeticingredients see INCI synonyms,582International travel, immunisationfor, 626Intracranial pressure, raisedcorticosteroids, 370osmotic diuretics, 81palliative care, 19Intralipid preparations, 467Intratect, 624Intra-uterine devicescopper-bearing, 406, 407, 408progestogen-releasing, 405,406Intravenousinfusion table (neonatal), 792infusions, 460nutrition, 466IntronA, 440Invanz, 272Invirase, 318Iocare, 531Iodide, 368Index

828 Iodine—Latin BNFC 2011–2012IndexIodineradioactive, 367skin disinfection, 596thyrotoxicosis, 367, 368Iopidine, 532Ipocol, 51Ipratropiumasthma, 141, 142acute, 134rhinorrhoea, 541, 542Steri-Neb, 142IPV see Poliomyelitis, immunisation,617Irondeficiency, 442neonatal, 443oral, 442, 443, 444overload, 451parenteral, 444, 445poisoning by, 30Iron dextran, 444, 445Iron sucrose, 444, 445Ironorm, 443Irriclens, 594Irripod, 594Irritable bowel syndrome, 39, 49Isentress, 321Isoflurane, 633, 634Isogel, 58Isoleucine Amino AcidSupplement, 782Isoniazid, 292, 293tuberculosis prophylaxis, 255tuberculosis treatment, 290,291Isophane protamine insulin seeInsulin, isophaneIsoplex, 465Isoprenaline, 110IsoptoAlkaline, 531Plain, 531Isosource preparations, 744, 747,750, 755Isotretinoin, 574acneerythromycin with, 577oral, 578, 579topical, 576, 577Isotrex, 577Isotrexin, 577Isovaleric acidaemia, 782Isovorin, 419Ispagel Orange, 58Ispaghulaconstipation, 57, 58diarrhoea, 47mebeverine with, 41Istin, 106Itraconazole, 300, 301, 303, 304oropharyngeal candidiasis, 545IUDs see Intra-uterine devicesIVA Anamix preparations, 782Ivermectinlarva migrans, 346onchocerciasis, 346scabies, 592strongyloidiasis, 347IZS see Insulin, zinc suspensionJJapanese encephalitis, 627Jet nebulisers, 146Jevity preparations, 744, 748, 749Jext preparations, 160, 161Joy-Rides, 198Juvela productsgluten-free, 778, 779low-protein, 780, 781KKala-azar, 340Kalcipos-D, 484Kaletra, 317Kaolin, 47Kaplon (captopril), 102Katya 30/75, 401Kawasaki syndromeaspirin, 120immunoglobulin, 120Kay-Cee-L, 457Kefadim, 270Keflex, 268Keftid (cefaclor), 267Kemadrin preparations, 237Kemicetine, 284Kenalog Intra-articular/Intramuscular,507Keppra, 223Keratitis, 518Keratoconjunctivitis, vernal, 522Keratolytics, warts and calluses,580Keratosis follicularis, 567Keromask preparations, 583Ketalar, 631Ketamine, 631abuse, 10anaesthesia, 630clinical procedures, 637palliative care, 18sedation, 630Ketoacidosis, diabetic, 360KetoCal preparations, 769Ketoconazole, 305anogenital, 395Cushing’s syndrome, 391scalp, 584skin, 588, 589Ketodiastix, 363Ketonesmonitoring, 365testsblood, 363urine, 363Ketorolaceye, 533pain, postoperative, 640Ketostix, 363Ketotifen, 157allergy, 156eye, 522, 523Ketovite, 488Ketur Test, 363KeyOmega, 784Kindergen, 769Kiovig, 624Kivexa, 312Klaricid preparations, 282Klean-Prep, 64Klinefelter’s syndrome, 377Kogenate Bayer (factor VIII fraction),124Kolanticon, 39Konakion preparations, 487Kuvan, 469Kwells, 198Kytril, 197LLabelling of medicines, 7Labelling, cautionary and advisorysee Cautionary and advisorylabelsLabetalol, 87, 90, 91see also Beta-adrenoceptorblocking drugsLabial adhesions, 393Labour, analgesia, 203Labyrinthine disorders, 193Lacosamide, 220, 221Lacri-Lube, 531Lactase, ACBS, 777Lactate see Sodium lactate, compoundLactic acidhydrocortisone and urea with,560salicylic acid with, 580urea with, 553Lactic acidosis, 311congenital, 480Lactose, presence of, 3Lactugal (lactulose), 62Lactulose, 61, 62Ladropen (flucloxacillin), 260Laevulose see FructoseLamictal, 222Lamisiloral, 309topical, 590Lamivudine, 313abacavir and zidovudine with,312abacavir with, 312chronic hepatitis B, 313, 325HIV infection, 310zidovudine with, 315Lamotrigine, 217, 221, 222Lancets, sterile, 357Landau-Kleffner syndrome, 217Lanolin, excipient, 553Lanoxin preparations, 75Lansoprazole, 45, 46Lantus preparations, 354Lanvis, 426Larapam SR, 211Largactil, 174Lariam, 336Laronidase, 491, 492LarvE, 596Laryngojet, 652Lasix, 80Lassa fever, 328Lassar’s paste, 571Latanoprost, 526Latin abbreviations, inside backcover

BNFC 2011–2012 Laxatives—Magnesium 829Laxatives, 57bulk-forming, 57faecal softeners, 61osmotic, 61palliative care, 18stimulant, 59palliative care, 18Laxido Orange, 62Ledclair, 33Ledermycin—discontinuedLegionnaires’ disease, 280Leishmaniasis, 340Lennox-Gastaut syndrome, 217Lenograstim, 454, 456Leptospirosis, 257, 274Lescol preparations, 127Leucine amino acid supplement,784Leukeran, 420Leukotriene receptor antagonists,152Leuprorelin, 381Levamisole, 345Levemir preparations, 354Levest, 401Levetiracetam, 217, 222, 223Levobunolol, 526Levobupivacaine, 651Levocetirizine, 153, 154, 155Levodopadopa-decarboxylase inhibitorwith, 235dystonias, 235metabolic disorders, 235Levofloxacineye, 518, 520Levofolinic acid, 419Levomepromazine, 175nausea and vomiting, 192palliative care, 19, 20Levonelle 1500, 409Levonelle One Step, 409Levonorgestrel, 405contraception, 404emergency, 408, 409ethinylestradiol with, 401,402intra-uterine, 406menstrual disorders, 378Levothyroxine, 366Lexpec (folic acid), 447LH-RH see Gonadorelin, 385Lice, 592Licensed medicines, 2, 6Lidocainearrhythmias, 84, 86, 87eye, 529fluorescein with, 529local anaesthesia, 649, 651,652catheterisation, 412dental, 649, 652phenylephrine with, 652prilocaine with, 651, 652urethral pain, 412neonatal seizures, 217rectal, 66, 67ventricular fibrillation, 83ventricular tachycardia, 83Life supportnewborn, 114paediatric, 114Lifestyle products, 778Lignocaine see LidocaineLignospan Special, 652Li-Liquid, 183Linezolid, 287, 288Linola Gamma—discontinuedLioresal, 514Liothyronine, 366, 367Lipantil, 130Lipid-regulating drugs, 125Lipitor, 127Lipobase, 553Lipodystrophy syndrome, 310Lipofundin preparations, 467Liposic, 530Lipostat, 127LiquiBand, 594Liquid and White Soft ParaffinOintment, 552Liquid paraffineye ointment, 531Liquifilm Tears, 531Liquigen, 772Lisinopril, 103see also ACE inhibitorsLiskonum, 183Lispro, insulin see Insulin lisproLithiumbipolar disorder, 181mania, 181poisoning by, 30recurrent depression, 181surgery, 629Lithium carbonate, 182, 183Lithium citrate, 183Liver see HepaticLivwell products, 778LMX 4, 652Loa loa, 346Load 375, 407Local anaesthetics see Anaesthesia,localLocasol, 767Loceryl, 589cream—discontinuedLocoid preparations, 561Locorten-Vioform, 536Lodoxamide, 522, 523Loestrin preparations, 401Logynon preparations, 402Lomotil (co-phenotrope), 47Loniten, 94Loperamidediarrhoea, 47, 48simeticone with, 48palliative care, 18Lophlex preparations, 784, 785Lopinavir, 310, 316ritonavir with, 317Lopresor preparations, 91Loprofin products, 780, 781PKU preparations, 784Loratadine, 153, 155Lorazepamanxiety, palliative care, 18convulsions, 25dyspnoea, palliative care, 19epilepsystatus epilepticus, 231, 233premedication, 638Loron, 390Losartan, 103, 104Losec, 46Lotionsdefinition, 551eye, 517suitable quantities, 551Lotriderm, 562Low calcium infant formula, 767Low-protein foods, ACBS, 780,781Lp-drink, 784LSD see Lysergide, 10Lugol’s solution see Aqueous iodineoral solution, 368Lumecare preparations, 530, 531Lumefantrineartemether with, 334, 335Lupus erythematosussystemic, 371, 508Lustral, 188Luvinsta c XL, 127Lyclear, 593Lyflex (baclofen), 514Lyme disease, 261Lymecycline, 276acne, 578Lymphogranuloma venereum,274Lyrinel XL, 411Lysergic acid diethylamide seeLysergide, 10Lysergide, regulations, 10Lysodren, 429Lysosomal storage disorder, 490,491MMaalox preparations, 37MabCampath, 439Mabron, 211MabThera, 439Macrobid, 300Macrodantin, 300Macrogols, 61bowel cleansing, 64constipation, 62faecal impaction, 62Macrolides, 280Magnapen, 263Magnaspartate, 474Magnesium citrate, 64sodium picosulfate with, 65Magnesium glycerophosphate,474Magnesium hydroxide, 63antacid, 37preparations, 63Magnesium saltsconstipation, 63Index

830 Magnesium—Methylene BNFC 2011–2012IndexMagnesium sulphatearrhythmias, 473asthma, 134hypocalcaemia neonatal, 473hypomagnesaemia, 473, 474pulmonary hypertension, 95,97torsade de pointes, 473Magnesium trisilicate, 37Magnesium-L-aspartate, 474Malabsorption syndromes, 49electrolytes, 457vitamin K, 486Malariafalciparum, 330prophylaxis, 331treatment, 329, 331Malarivon, 335Malarone, 337malaria prophylaxis, 331, 332,333, 334, 336malaria treatment, 330, 336Paediatric, 337Malathion, 592, 593Malignant disease, 414pain, 203bone, 199Malignant hyperthermia, 648Maltitol, 2Manevac, 60Mania, 172, 181Manic depression see Bipolar disorder,181Mannitol, 81diuresis, 81, 82glaucoma, 525presence of, 2Mantoux test, 603Manufacturersindex of, 800Manufacturers, special-order, 809Maple syrup urine disease, 480,782Maraviroc, 310, 321Marcain preparations, 651Marevan (warfarin), 119Marine stings, 34Marketing authorisation, 2Marol, 211Marvelon, 401Mastaflu, 612Matrifen (fentanyl), 207Maturity-onset diabetes of theyoung see Genetic defects of betacellfunction, 348Maxidex, 521Maxijul preparations, 771Maxitram SR, 211Maxitrol, 522Maxolon preparations, 196Maxtrex (methotrexate), 509McCune-Albright syndrome, 380MCT Oil, 773MCT Pepdite preparations, 766MDMA see MethylenedioxymethamfetamineMeaslescorticosteroids, 371immunisation, 612immunoglobulin, normal, 623vaccines, combined, 612, 613,614Measles, mumps and rubellavaccine, 613Mebendazole, 344, 345hookworm infections, 346roundworm infections, 345threadworm infections, 344whipworm infections, 344Mebeverine, 40, 41ispaghula with, 41Mecasermin, 391, 392Mecillinam, 265Meconiumaspiration syndrome, 163ileus, uncomplicatedamidotrizoates, 65Mecysteine, 166Medac, 428Medi, 144Medicaid, 557Medical emergencies in the community,inside back coverMedicated bandages, 566Medicines information services,inside front coverMedicines, unlicensed, 2, 6Medikinet preparations, 190Medinol (paracetamol)preparations, 201Medi-Test products, 363Medrone, 376Medroxyprogesterone, 404, 405Mefenamic acid, 504dysmenorrhoea, 504menorrhagia, 504pain, 500rheumatic disease, 500Mefloquine, 335, 336malaria prophylaxis, 331, 332,333, 334malaria treatment, 330Megaloblastic anaemia, 445Meglumine amidotrizoate, 65Melatonin, 171Meloxicam, 500, 504, 505Melphalan, 421Menadiol sodium phosphate, 486Mendelson’s syndrome, 43, 629Meningitec, 614Meningitisantibacterial therapy, initial, 248bacterialdexamethasone in, 375cryptococcal, 301fungal, 301haemophilus, 248listerial, 248meningococcal, 248prophylaxis, 254travel, 614, 626vaccine, 614, 615vaccine, Hib with, 607pneumococcal, 248streptococcal, 248Meningococcal see MeningitisMenitorix, 607Menjugate, 615Menorrhagia, 405, 406antifibrinolytics, 123Menstruationpostponement of, 378Menthol, eucalyptus with, 166Menveo, 615Mepacrine, 507Mepact, 441Mepivacaine, 649, 653Mepradec (omeprazole), 46Merbentyl preparations, 39Mercaptamine (cysteamine), 492,493MercaptopurineCrohn’s disease, 54, 55inflammatory bowel disease,48, 49malignant disease, 423, 424,425ulcerative colitis, 54, 556-Mercaptopurine see MercaptopurineMercilon, 401Meronem, 273Meropenem, 272, 273Mesalazine, 48, 49, 50, 51Mesnacystic fibrosis, 165urothelial toxicity, 419Mesren MR, 51Mestinon, 513Mestranol, norethisterone with,401Metabolic acidosis, 463Metabolic Mineral Mixture, 776Metals, poisoning by, 32Metanium, 557Metaraminol, 112, 113Meted, 584Metenix-5, 78Metformin, 359, 360Methadoneneonatal abstinence syndrome,238oral solution (1 mg/mL), 207pain, 203, 207poisoning by, 28Methaemoglobinaemia, treatmentof, 653Methanol, poisoning by, 32Metharose (methadone), 207Methicillin-resistant Staphylococcusaureus see MRSAMethionine, 27, 28MethotrexateCrohn’s disease, 48, 54, 55folic acid with, 508malignant disease, 423, 425psoriasis, 572, 573rheumatic disease, 507, 508,509Methotrimeprazine see LevomepromazineMethyl alcohol see Methanol, 32Methyl cysteine see Mecysteine,166Methyl salicylate, 594dithranol and salicylic acid with,571Methyl salicylate [ingredient], 570Methylated spirit, industrial, 594Methylcellulose, 58diarrhoea, 47Methylcysteine see Mecysteine,166Methyldopa, 98Methylene blue see Methylthioniniumchloride, 653

BNFC 2011–2012 Methylenedioxymethamfetamine—MPD 831Methylenedioxymethamfetaminecontrolled drug, 9poisoning by, 31Methylmalonic acidaemia, 783Methylphenidate, 188, 189, 190Methylprednisolone, 376intra-articular, 506lidocaine with, 506rheumatic disease, 506Methylthioninium chloride, 653Meticillin-resistant Staphylococcusaureus see MRSAMetoclopramidemigraine, 214paracetamol with, 202nausea and vomiting, 192, 196palliative care, 19Metoject, 509Metolazone, 77, 78Metopirone, 391Metoprolol, 87, 91see also Beta-adrenoceptorblocking drugsMetosyn, 564Metrogel, 587Metrolyl, 297Metronidazole, 295, 296, 297amoebiasis, 339bacterial vaginosis, 395Crohn’s disease, 49gas-gangrene prophylaxis, 255giardiasis, 340Helicobacter pylori eradication,42oral infections, 296protozoal infections, 339rosacea, 574skin infections, 585, 587, 588fungating tumours, 19trichomoniasis, 340vaginal, 395Metrosa, 587Metrotop—discontinuedMetsol (metformin), 360Metyrapone, 391Mezolar (fentanyl), 207Miacalcic, 388Micafungin, 301, 306, 307, 308Micanol, 570Micolette Micro-enema, 63Miconazolemouth, 545, 546palliative care, 18skin, 588, 589, 590hydrocortisone with, 560vaginal, 395Micralax Micro-enema, 63Micral-Test II, 363Microalbustik, 363Microgynon preparations, 401Microlance, 357Micronor, 404MicroPeak, 144Microphallus, 379Micropirin (aspirin), 121Midazolamanaesthesia, 638, 639clinical procedures, 637, 638convulsions, 25palliative care, 18dyspnoea, palliative care, 19infusion table (neonatal), 793neonatal seizures, 217palliative care, 18, 20premedication, 637, 638status epilepticus, 231, 234Mifamurtide, 441Miglustat, 491, 496Migraineacute attack, 212beta-blockers, 88prophylaxis, 214Migraleve, 202Mildison, 560Milex diaphragms, 408Millinette preparations, 401Milrinone, 75, 76MilupaLow Protein drink, 784PKU preparations, 784Milward Steri-Let, 357Mineralocorticoids, 369replacement therapy, 369Mini TT 380 Slimline, 407MinijetAdrenaline, 161Atropine Sulphate, 636Furosemide, 80Glucose , 462Lignocaine, 87Magnesium Sulphate, 474Morphine Sulphate, 209Naloxone, 29Sodium Bicarbonate,464MinimsArtificial Tears, 530Atropine Sulphate, 524Chloramphenicol, 519Cyclopentolate, 524Dexamethasone, 522Fluorescein Sodium, 532Lidocaine and Fluorescein, 529Oxybuprocaine, 529Phenylephrine, 525Pilocarpine Nitrate, 529Prednisolone, 522Proxymetacaine, 529Proxymetacaine and Fluorescein,529Saline, 531Tetracaine, 529Tropicamide, 525MiniQuick, 384Miniversol, 594Mini-Wright, 144Minocin MR, 276Minocycline, 274, 276acne, 578Minoxidil, 93, 94Miochol-E, 532Miphtel, 532Mirena, 405, 406Mission products, 363Mistabron, 165Misuse of drugsAct, 9Regulations 2001, 9Mitochondrial disorders, 495Mitotane, 429Mitoxantrone, 421, 423Mitozantrone see Mitoxantrone,421, 423Mivacron, 644Mivacurium, 643, 644Mixtard 30—discontinuedMizolastine, 153, 155Mizollen, 155MMA/PA Anamix preparations,783MMR vaccine, 612, 613, 614MMRvaxPRO, 614Mobic, 505Mobile, 364Modafinil, 188, 190, 191Modigraf, 437Modjul Flavour System, 777Modrasone, 561Modulen IBD, 769Moduret-25 (co-amilozide), 81MODY see Genetic defects of betacellfunction, 348Molaxole, 62Molcer, 538Mometasoneasthma, 146, 151chronic, 135nasal allergy, 540skin, 565Monoamine-oxidase inhibitors,186Monofluorophosphate, 476Monogen, 766Monoject products, 357Monolet, 357Mononine (factor IX fraction),125Montelukast, 152Morhulin, 557Moroctocog alfa, 124Morphine, 207, 208, 209cough, palliative care, 19cyclizine with, 209infusion table (neonatal),793neonatal abstinence syndrome,238oral solutions, 208pain, 203chronic, 203diamorphine equivalence,20fentanyl equivalence, 18palliative care, 17, 18postoperative, 203Motifene, 502Motilium, 196Motion sickness, 193Mouth ulceration, 543Mouthwash solution-tablets,548Mouthwashes, 546Movicol preparations, 62Moxifloxacin, eye, 518, 520Moxivig, 520MPD Ultra Thin, 357Index

832 MRSA—Nicam BNFC 2011–2012IndexMRSA, 259linezolid in, 287nasal, 542MST Continus, 209palliative care, 17MSUD preparations, 782, 783MucoClear preparations,166Mucodyne, 166Mucogel, 37Mucolytics, 165eye, 530Mucopolysaccharidosis, 491Mucosal bleedingpalliative care, 19Mucositismethotrexate-induced,418oral, 415Multiclix, 357Multiload IUDs, 407Multiple myeloma, 448Multi-Safe devices, 407Multivitamins, 487Mumpsvaccines, 615combined, 612, 613, 614Mupirocinnose, 542skin, 585, 586Muscle relaxantsanaesthesia, 642depolarising, 645non-depolarising, 642skeletal, 513Muscle spasm, 513Musculoskeletal disorders,rheumatic, 499MXL, 209palliative care, 17Myasthenia gravisanticholinesterases,512corticosteroids, 513diagnosis, 512diagnostic test, 513immunosuppressants,513Mycamine, 308Mycobacterium avium complexinfections, 291, 294Mycobutin, 294Mycophenolate mofetil, 431, 432eczema, 572Mycoplasma infections,274Mycota, 591Mydriacyl, 525Mydriatics, 524Mydrilate, 524Myleran, 420Myoclonic seizures, 217Myozyme, 493Mysoline, 224Myxoedema, juvenile, 365NNabilone, 192, 198Naglazyme, 492Nalcrom, 56Nalidixic acid, 297, 299Naloxoneopioid poisoning, 28, 29palliative care, 18postoperative, 647, 648Nappy rash, 556Naprosyn preparations, 505Naproxendysmenorrhoea, 505juvenile idiopathic arthritis,505pain and inflammation, 500,505rheumatic disease, 500, 505Narcolepsy, 188Narcotic analgesics see Analgesics,opioidNarcotic antagonists see OpioidantagonistsNaropin, 654Nasacort, 541Nasalallergy, 538congestion, 538decongestantssystemic, 168topical, 541MRSA, 542polyps, 538Naseptin, 543Nasobec preparations, 539Nasofan, 540Nasogastric feeding tubes see Enteralfeeding tubesNasonex, 540Natecal D3, 484Nateglinide, 360National Institute for Health andClinical Excellence, 3Nausea, 193cytotoxic drugs, 415motion sickness, 193opioid-induced, 192palliative care, 19postoperative, 192pregnancy, 192vomiting and, 192Nebulisers, 145Nebusal, 166Necatoriasis, 346Necrotising enterocolitis, 245Nedocromilasthma, 151, 152eye, 522, 523Needles, insulin, 357clipping device, 357Neimann-Pick type C disease,495NeisVac-C, 615Nelarabine, 423, 425Nelfinavir, 310, 317Neocate preparations, 763Neoclarityn, 154Neo-Cytamen (hydroxocobalamin),447Neokay, 487Neo-Mercazole, 368Neomycin, 277ear, 534, 536, 537betamethasone with, 535dexamethasone with, 535prednisolone with, 536eye, 518, 520, 522betamethasone with, 521prednisolone with, 522nose, 542chlorhexidine with, 542,543skin, 585, 586betamethasone valeratewith, 562clobetasol and nystatinwith, 563fluocinolone acetonidewith, 564Neo-NaClex preparations, 77Neonatalabstinence syndrome, 238apnoea see Apnoea, neonatalseizures, 217Neoral, 435NeoRecormon, 450Neo-Safe T380, 408Neosporin—discontinuedNeostigmineanaesthesia, 646, 647glycopyrronium bromide with,647myasthenia gravis, 512, 513Neotigason, 572Nephropathic cystinosis, 492Nephrotic syndromechlorambucil, 420chlortalidone, 78ciclosporin, 434corticosteroids, 371levamisole, 345spironolactone, 80Nepro, 769Nerisone preparations, 563Nerve agent, poisoning by, 33Nesidioblastosis, 361Neupogen, 455Neural tube defects, prevention,446Neuralgiapostherpetic, 212Neuroleptic malignant syndrome,173Neuroleptics see AntipsychoticsNeuromuscularblocking drugs, 642disorders, 512Neurontin, 220Neuropathic pain, 212Neuropathycompression, 506diabetic, 363Neutral insulin see Insulin, soluble,352Neutropenias, 448, 454Nevirapine, 310, 320New names, xviiiNew preparations, xixNexium, 45Nexplanon, 404, 405NHS Direct, inside back coverNicam, 577

BNFC 2011–2012 Nicardipine—Oftaquix 833Nicardipine, 105, 106, 107see also Calcium-channelblockersNicAssist preparations (nicotinereplacement therapy), 240, 241NICE see National Institute forHealth and Clinical Excellence, 3Nicef (cefradine), 269Niclosamide, 345Nicorette preparations, 240Nicotinamidetopical, 577Nicotinesmoking cessation products,240, 241Nicotine replacement therapy,239Nicotinell preparations, 241Nifedipine, 107, 108, 110angina, 105chronic hypoglycaemia, 362pulmonary hypertension, 95Raynaud’s syndrome, 105see also Calcium-channelblockersNifedipress MR, 108Niferex, 444Nimbex, 644Nimodipine, 106, 108, 109Nimotop, 109Niquitin preparations, 241Nitisinone, 496, 497Nitrates, 104Nitrazepam, 230, 231Nitric oxide, 95Nitrocine, 105Nitrofurantoin, 300urinary infectionsprophylaxis, 255treatment, 249Nitronal, 105Nitroprusside see Sodium nitroprusside,93, 94, 95Nitrous oxide, 634, 635clinical procedures, 637Nitrous oxide-oxygen, 634Nivaquine, 335Nivestim, 456Nizoral, 305anogenital, 395scalp, 584skin, 589Nocturnal enuresis, 411Nonacog alfa, 125Non-convulsive status epilepticus,232Non-depolarising muscle relaxantssee Muscle relaxantsNon-medical prescribing, 799Non-nucleoside reverse transcriptaseinhibitors, 310, 319Nonoxinol, 406Noonan syndrome, 383Noradrenaline, 113infusion table (neonatal), 793Norcuron, 645Norditropin, 384Norelgestromin, ethinylestradiolwith, 400Norepinephrine see NoradrenalineNorethisteronecontraception, 404ethinylestradiol with, 401,402mestranol with, 401parenteral, 405delayed puberty, 378menstrual disorders, 378, 379Norethisterone enantate, 404Norgalax Micro-enema, 60Norgestimate, ethinylestradiolwith, 401Norgeston, 404Norgestrel see LevonorgestrelNoriday, 404Norimin, 401Norimode (loperamide), 48Norinyl-1, 401Noristerat, 404, 405Normacol preparations, 58Normal immunoglobulin seeImmunoglobulins, normal, 622,623, 624Normal saline see Sodium chlorideNormasol, 594Normax, 60Normosang, 497Nortriptyline, 186depression, 186nocturnal enuresis, 186Norvir, 318capsules—discontinuedNorzol (metronidazole), 297Nose see NasalNotifiable diseases, 243Novasource preparations, 744,748Nova-T, 408Novgos, 381NovoFine products, 357NovoMix 30, 355NovoPen, 357NovoRapid, 353NovoSeven (factor VIIa fraction),124NovoTwist, 357Nozinan, 175NPH see Insulin, isophaneNSAIDs (non-steroidal antiinflammatorydrugs) see AnalgesicsNTBC see Nitisinone, 496, 497Nucleoside analogues see Nucleosidereverse transcriptase inhibitors,310, 311Nucleoside reverse transcriptaseinhibitors, 310, 311Nuelin SA, 143Nurofen (ibuprofen) preparations,503Nurse independent prescribing,797Nurse Prescribers’ Formulary, 796Nu-Seals Aspirin, 121Nutilis preparations, 761, 777Nutramigen preparations, 764,765Nutraplus, 554Nutrini preparations, 751, 753,754, 755Nutriprem preparations, 751Nutrison preparations, 745, 748,749, 750soya formula, 745NutritionACBS, foods, 743enteral, 468, 469, 743intravenous, 466oral, 468, 469total parenteral, 466Nutrizym preparations, 71, 72NutropinAq, 384NuvaRing, 400Nyogel, 526Nystaform, 590Nystaform-HC, 561Nystanmouth, 546Nystatin, 305mouth, 545, 546palliative care, 18skin, 588, 590chlorhexidine and hydrocortisonewith, 561clobetasol and neomycinwith, 563hydrocortisone with, 561OObesity, 191Obstetric surgery, antibacterialprophylaxis, 256Occlusal, 580Octagam—discontinuedOctalbin preparations (albumin),464Octanate (factor VIII fraction),124Octaplas (fresh frozen plasma),125Octaplex (dried prothrombincomplex), 124Octim, 387Octocog alfa, 124Octreotide, 362chronic hypoglycaemia, 362hyperinsulinaemichypoglycaemia, 362varices, bleeding from, 362, 385Octylcyanoacrylate, 593Ocufen, 533Ocusan, 531Oedemacerebral, 81, 375pulmonary, 76Oesophageal varices, 385Oesophagitis see Gastro-oesophagealreflux disease, 35Oestrogenshormone therapy, 377labial adhesions, 393oral contraceptives, 396Ofloxacinear, 537eye, 518, 520Oftaquix, 520Index

834 Oilatum—Paraldehyde BNFC 2011–2012IndexOilatumcream, 553Emollient, 555Junior bath additive, 555Plus, 556shower emollient, 555Oily cream, 552Ointmentsdefinition, 551eye, 517suitable quantities, 551Olanzapinepsychosis, 177, 179Oligospermia, 383Olive oil, ear, 538Olopatadine, 522, 523Olsalazine, 48, 50, 52Omalizumab, 158, 159Omeprazole, 45, 46Omnikan, 357Omnitrope, 384Oncaspar, 428Onchocerciasis, 346Oncovin, 427Ondansetron, 192, 197palliative care, 19Ondemet (ondansetron), 197One Touch products, 357, 364,365One-Alpha, 483Onkotrone, 423Onychomycosis see Fungal infections,skin, 301, 588Opatanol, 523Opioid analgesics see Analgesics,opioidOpioid antagonists, 647poisoning in, 28Optichamber, 145OptiClik, 357Opticrom preparations, 523OptiFlo preparations, 412Optil (diltiazem), 106Optilast, 523OptiPen Pro 1, 357Optium products, 365Optivate (factor VIII and vonWillebrand factor concentrate),124Optive, 530Optometrist independentprescribing, 799OPV see Poliomyelitis, immunisation,617Oral balance see Biotène OralbalanceOral contraceptives see Contraception,oralOral glucose tolerance test, 365Oral Impact, 760Oral rehydration salts, 459WHO formula, 459Oral rehydration therapy,459Oral syringes, 2Oraldene, 547Oramorph preparations,208Orap, 176Orbifen (ibuprofen), 503Orelox, 269Orencia, 510Orfadin, 497Organophosphorus insecticides,poisoning by, 33Orgaran, 118Orgran products, 779Orlept (sodium valproate), 228Orlistat, 191Oropharynxinfections, 545ulceration and inflammation,543ORS see Oral rehydration saltsORT see Oral rehydration therapy,459Ortho All-Flex diaphragm, 408,409Orthopaedic surgeryantibacterial prophylaxis,256Oseltamivir, 326, 327Osmanil (fentanyl), 207Osmolite preparations, 745, 748,750Osteoarthritis, 499Osteomyelitis, 251, 283, 285Osteonecrosis of the jaw, 389Osteoporosis, 388calcitriol, 482corticosteroid-induced,388Otex, 538Otitis externa, 534antibacterial choice, 252Otitis media, 537antibacterial choice, 252Otomize, 535Otosporin, 536Otradrops (xylometazoline),542Otrivine (xylometazoline), 542Otrivine-Antistin, 522Ovranette, 401Ovysmen, 401Oxactin (fluoxetine), 187Oxandrolone, 379, 381, 382Oxazolidinone antibacterials,287Oxcarbazepine, 217, 219Oxis, 138Oxyal, 531Oxybuprocaine, 529Oxybutynin, 410, 411Oxycodone, 209, 210morphine equivalence, 17palliative care, 17OxyContin, 210Oxygen, 163ambulatory therapy, 164arrangements for supply, 164asthma acute, 163cluster headache, 215nitrous oxide and, 634Oxymetazoline, 541Oxymetholone, 448Oxymycin (oxytetracycline), 276OxyNorm, 209Oxytetracycline, 276acne, 578oral infections, 274PPaediasure preparationsenteral feeds, 753, 756nutritional supplements, 757Paediatric Life Support algorithms,inside back coverPaediatric Seravit, 776Pain, 199bone, 199dental, 199, 204, 500dressing changes, 634ear, 535, 537musculoskeletal, 199neuropathic, 212orofacial, 199, 204, 212, 500palliative care, 17peri-operative, 639postoperative, 203rheumatic, 499sickle-cell disease, 199urethral, 412visceral, 202Palivizumab, 328Palladone preparations, 207Palliative carecontinuous infusion devices, 19prescribing in, 17Paludrine, 337Paludrine/Avloclor, 335Pamidronate disodium seeDisodium pamidronate, 389, 390Panadol (paracetamol)preparations, 201Panadol OA, 201Pancrease HL, 72Pancreatin, 70, 71, 72Pancreatitis, chronic, 70Pancrex preparations, 71Pancuronium, 643, 644Pandemrix, 612Panoxyl preparations, 575Panthenol, 479Pantothenic acid, 479Papaveretum, 210Paracetamolfebrile convulsions, 235migraine, 212buclizine and codeine with,202metoclopramide with, 202pain, 199, 200, 201codeine with, 201palliative care, 17postoperative, 640tramadol with, 202poisoning by, 26post-immunisation pyrexia, 600Paracetamol Seltzer (paracetamol),201Paracodol (co-codamol 8/500),201Paraffineye ointment, 531liquid and white soft, 552white soft, 552yellow soft, 552Parainfluenza virus, 328Paraldehydeconvulsions, palliative care, 18neonatal seizures, 217status epilepticus, 232, 234

BNFC 2011–2012 Paramax—Plaquenil 835Paramax, 202Paraproteinaemias, 448Parasiticidal preparations, 591,592Parasympathomimeticsanaesthesia, 646eye conditions, 528myasthenia gravis, 512Pardelprin (indometacin), 504Parenteral nutrition, 466supplements, 467, 468PARI Vortex Spacer, 145Parkinsonism, drug-induced, 173Paromomycin, 340Paronychia, 253, 588Partial seizures see Focal seizures,217Parvolex, 28Pastes, definition, 551Pasticely products, 778, 779Patient group direction, 3Patient information leaflets, 2Pavacol-D (pholcodine), 167Peak flow meters, 144Peanut oil see Arachis oilPedea, 130Pediacel, 605Pediculosis, 592Peditrace, 468Pelvic inflammatory disease, 250Pemphigus, 370Penbritin, 262Penciclovir, 322, 591Penfine, 357Penicillamine, 488, 489cystinuria, 489rheumatic disease, 507Wilson’s disease, 488Penicillin G see BenzylpenicillinsodiumPenicillin V see PhenoxymethylpenicillinPenicillin VK see PhenoxymethylpenicillinPenicillinases, 259Penicillins, 257antipseudomonal, 264broad spectrum, 260hypersensitivity, 257penicillinase-resistant, 259penicillinase-sensitive, 257Pentacarinat, 344Pentamidine isetionate, 343, 344leishmaniasis, 340, 343pneumocystis pneumonia, 342,343trypanosomiasis, 343Pentasa, 51Pentastarch, 465Pentostam, 340Pentrax, 584Pepdite preparations, 765, 766Peppermint oil, 40, 41Peptac, 38Peptamen preparations, 745, 750,754Peptisorb preparations, 746Perative, 750Perfalgan, 201Perfan, 75Periapical abscess, 252Periciazine see Pericyazine, 175,176Pericoronitis, 251Pericyazine, 175, 176Perinal, 66Periodontal abscess, 252Periodontitis, 543antibacterial treatment, 252Periogard, 547Periostat, 543, 544Peritonitis, 245Permethrin, 592, 593Permitabs, 596Peroxyl, 547Perphenazinenausea and vomiting, 192, 195psychosis, 176Persantin preparations, 121Personal Best, 144Pertussisimmunisation, 615prophylaxis, 254vaccines, combined, 605, 615Pethidine, 210analgesia, 203postoperative, 203Petroleum jelly, 552Pevaryl, 589PGD see Patient group direction, 3PGI 2 see EpoprostenolPhaeochromocytoma, 87, 100Pharmacist independentprescribing, 799Pharma-Ject Morphine Sulphate,204Pharmalgen, 157Pharmorubicin preparations, 423rapid dissolution injection—discontinuedPharyngitis see Throat infectionsPharynx see OropharynxPhenergan preparations, 157, 171Phenobarbitalepilepsy, 223, 224status epilepticus, 234, 235neonatal abstinence syndrome,238neonatal seizures, 217palliative care, 18poisoning, elimination, 25Phenobarbitone see PhenobarbitalPhenothiazinesclassification, 173nausea and vertigo, 193nausea and vomiting, 192poisoning by, 31psychosis, 173Phenoxybenzamine, 100Phenoxymethylpenicillin, 258, 259pneumococcal infectionprophylaxis, 255rheumatic fever prophylaxis,254Phenylalanine amino acidsupplement, 784Phenylephrineeye, 525hypotension, 113local anaesthesialidocaine with, 652Phenylketonuria, 468, 784Phenytoinepilepsy, 224, 225status epilepticus, 231, 235neonatal seizures, 217Phlexy-10, 784Phlexy-Vits preparations, 784Pholcodine, 167Phosex, 476Phosgene, poisoning by, 33Phosphate supplements, 474Phosphate-binding agents, 475Phosphatesconstipation, 61, 63hypophosphataemia, 474, 475Phosphate-Sandoz, 475Phosphodiesterase inhibitorstype-3cardiovascular, 75type-5pulmonary hypertension,95, 97Phosphorus, 474Photochemotherapy, psoriasis,567Photodamage, skin, 583Photodermatoses, 582ACBS, 787Phototherapy, psoriasis, 567Phyllocontin Continus, 144Physeptone (methadone), 207Physiological saline see SodiumchloridePhytex, 590Phytomenadione, 119, 486, 487Picolax, 65Picosulfate see Sodium picosulfatePiko-1, 144Pilocarpine, 528, 529Pimecrolimus, 572, 573Pimozidepsychosis, 174, 176Tourette syndrome, 176, 237Pinetarsol, 570Pinexel PR (tamsulosin), 410Pinnacle, 144Pinworm infections, 344Piperacillintazobactam with, 264, 265Piperazine, 345roundworm infections, 345threadworm infections, 344,345Piracetam, 231Piriton, 156Piroxicam, 500, 505Pitressin, 388Pituitaryfunction test, 382metyrapone, 391hormones, 382anterior, 382posterior, 385Pityriasis versicolor, 301, 588Pivmecillinam, 265, 266Pizotifen, 214PK Aid 4, 784PK Foods products, 780, 781PKU preparations, 784, 785Plaque, 546Plaquenil, 508Index

836 Plasma—Pro-Cal BNFC 2011–2012IndexPlasmaconcentrations, electrolytes,456substitutes, 464, 465Plasma, fresh frozen, 125Plasmapheresis, myastheniagravis, 512Plastipak, 357Pneumococcal infectionantibacterial prophylaxis, 255immunisation, 616vaccines, 616, 617vaccines, 616Pneumocystis pneumonia, 342prophylaxis, 342Pneumonia, 247hospital-acquired, 247pneumococcal, 616Pneumovax II, 616Pocket Chamber, 145Pocketpeak, 144PocketScan, 365Podophyllotoxin, 581Poisoning, 24active elimination, 25adsorbents, 25hospital admission, 24Poisons information services,inside back coverPoliomyelitisimmunisation, 617travel, 617vaccines, 617combined, 605, 606Pollen extracts, 157Pollinex, 158Polyacrylic acid see Carbomers,530Polyarteritis nodosa, 371Polycal, 771glucose tolerance test, 365Polyene antifungal drugs, 305Polyethoxylated castor oil seePolyoxyl castor oil, 3Polyethylene glycols, 62, 64Polyfax, 586eye, 520Polymethylmethacrylate, 593Polymyositis, 508Polymyxin Beye, 522Polymyxinsear, 536, 537eye, 518, 520inhalation, 288skin, 585, 586systemic, 288Polyoxyl castor oil, presence of, 3Polyps, nasal, 538Polysaccharide-iron complex, 444Polystyrene sulphonate resins,458PolytarAF—discontinued, xixEmollient, 570Liquid, 585Plus, 585Polyvinyl alcohol, 531Pompe disease, 493Ponstan preparations, 504POP see Progestogens, contraceptives,oral, 396, 403Poractant alfa, 163Porphyrias, acute, 497drugs to be avoided in, 497, 498Posalfilin—discontinuedPotassium acid phosphate, 475Potassium bicarbonate, 460tablets, effervescent, 460Potassium canrenoate, 80, 81Potassium chlorideinfusionglucose and, 463sodium chloride and, 463sodium chloride, glucoseand, 463oral, 457, 458parenteral, 463Potassium citrate, 412Potassium iodide, 368Potassium permanganate, 566,594, 596Potassium supplements, 457Povidone-iodineskin, 594, 596shampoo, 584Prader-Willi syndrome, 383Pralidoxime chloride, 33, 34Pramocaine [ingredient], 66, 67Pramoxine see Pramocaine, 66, 67Pravastatin, 126, 127Praziquantelschistosoma, 346tapeworm, 346Prazosin, 99, 100Precocious puberty, 380Pred Forte, 522Predenema, 54Predfoam, 54Prednisolone, 370, 376, 377asthma, acute, 134Crohn’s disease, 54ear, 536eye, 522haemorrhoids, 67hepatitis, 377infantile spasms, 217, 377inflammatory and allergicdisorders, 377malignant disease, 433nephrotic syndrome, 377palliative care, 18, 19pneumocystis pneumonia, 342rectal, 54, 67ulcerative colitis, 54withdrawal of, 372Predsolear, 536eye, 522rectal, 54Predsol-Near, 536eye, 522Pre-eclampsia, 92Pregestimil, 765Pregnancyanticoagulants, 119antihistamines, 153asthma, 133corticosteroids, 373cytotoxic drugs, 416epilepsy and, 216folate supplements, 446HIV infection, 310hypertension in, 92immunosuppressants, 431iron, 442malaria, 331prophylaxis, 332treatment, 330nausea and vomiting, 192prescribing in, 16tuberculosis and, 291urinary infections, 299Pregnyl, 383Premedication, 635, 637PrescribingACBS, 743breast-feeding, 16children, 1controlled drugs, 10hepatic impairment, 14independent, 799instalments, 10palliative care, 17pregnancy, 16renal impairment, 14repeat prescriptions, 10supplementary, 799Prescription formscontrolled drugs, 9European Economic Area(EEA), 3nurses, 796security, 3Switzerland, 3Prescription only medicines seepreparations identified by Athroughout BNF for ChildrenPrescription writing, 4Presinex (desmopressin), 387Prestige products, 365Pre-thickened infant feeds, 767Prevenar 13, 616, 617Prezista, 316Priadel, 183Prices, xviPrilocaine, 653dental, 653felypressin with, 649, 653lidocaine with, 651, 652Primacine (erythromycin), 283Primacor, 76Primaquinemalaria treatment, 331, 336pneumocystis pneumonia, 342Primaxin, 273Primene, 467Primidone, 223, 224Primolut N, 379Priorix, 614Pripsen, 345Privigen, 624Pro-Banthine, 40Procaine benzylpenicillin, 249,257Pro-Cal preparations, 775

BNFC 2011–2012 Procarbazine—Regulan 837Procarbazine, 430Proceli products, 778, 779, 780Prochlorperazine, 192, 193, 195Proctofoam HC, 67Proctosedyl, 67Procyclidine, 237Product licence, 2Pro-Epanutin, 233Proflavine cream, 593Progesteronehormone therapy, 378Progestogen-only pill see Progestogens,contraceptives, oral,396, 403Progestogenscontraceptivesemergency, 408, 409intra-uterine, 405, 406oral, 396, 403parenteral, 404, 405hormone therapy, 378Prograf, 437Proguanil, 336, 337atovaquone with, 337chloroquine with, 335malaria prophylaxis, 331, 332,333, 334, 336Promethazineallergic disorders, 153, 157hypnotic, 170, 171motion sickness, 193nausea and vomiting, 192, 194sedation, 170Promethazine teoclate, 194Promin products, 780, 781Promixin, 288Propamidine isetionate, eye, 518,520Propantheline, 39, 40Prophylaxis, antibacterial, 254Propionibacterium acnes, 576Propionic acidaemia, 783Propofol, 630, 631, 632Propofol-Lipuro, 632Propoven (propofol), 632Propranolol, 88, 89cardiovascular, 88hyperthyroidism, 369migraine prophylaxis, 88, 214see also Beta-adrenoceptorblocking drugstetralogy of Fallot, 88thyrotoxicosis, 367, 369tremor, 237Propylene glycolpresence of, 3Propylthiouracil, 367, 368, 369ProSource, 774Prostacyclin see EpoprostenolProstaglandinsanticoagulant, 118ductus arteriosus, 131eye, 525, 526Prostap preparations, 381Prostin E2, 132Prostin VR, 131ProSure, 769Protamine sulphate, 115, 120Protease inhibitors, 310, 315Proteinintravenous nutrition, 466urinalysis, 363Protein C concentrate, 125Prothionamide see Protionamide,292Prothrombin complex, dried, 124Protifar, 774Protionamide, 292Protirelin—discontinuedProton pump inhibitors, 45Protopam, 34Protopic, 574Protozoal infections, 329ProvideXtra, 757Provigil, 191Proxymetacaine, 529fluorescein with, 529Prozac, 187Prozep (fluoxetine), 187ProZero, 784Pruritus, 153ACBS, 786cholestasis, 70palliative care, 19perianal, 66skin, 557Pseudoephedrine, 168Pseudomembranous colitisantibacterial therapymetronidazole in, 295vancomycin in, 285Pseudomonas aeruginosainfections, 264, 266, 273, 276,288eye, 518Psittacosis, 274Psoralen, 567Psoriasis, 566corticosteroids, 559photochemotherapy, 567Psoriderm preparations, 569, 570scalp, 584Psorin preparations, 570Psychiatric reactionscorticosteroids, 372Psychoses, 171Pubertydelayed, 377, 378, 379, 383precocious, 380, 381Pubic lice, 592Pulmicort preparations, 149aerosol inhalation—discontinuedPulmonaryhypertension, 95, 118oedema, 76, 78, 80surfactants, 162Pulmozyme, 166Pulvinalbeclometasone, 148salbutamol, 140Pure products, 779Puri-Nethol, 425Purpura, thrombocytopenic, 453PUVA, 567Pyelonephritis, 299Pyralvex, 545Pyrazinamide, 293, 294tuberculosis treatment, 290,291, 292Pyrexiapost immunisation, 600Pyridostigmine, 512, 513Pyridoxineanaemias, 448isoniazid-induced neuropathy,480metabolic disorders, 479, 480,481seizures, 217, 480status epilepticus, 231Pyrimethaminemalaria, 338sulfadoxine with, 330, 338toxoplasmosis, 341Pyrithione zinc shampoos, 584Pyruvate dehydrogenase defects,495QQ-fever, 274Qlaira, 402QuantiFERON-TB Gold, 604Quaternary ammoniumcompounds, 39Questran preparations, 128Quetiapine, 177, 179, 180QuickCal, 775Quinine, 338malaria, 330, 338poisoning, elimination, 25Quinoderm, 575Quinolones, 297ear, 537eye, 518Quinoric (hydroxychloroquine),508QV preparations, 553, 555Qvar preparations, 148RRabiesimmunisation, 617immunoglobulin, 625travel, 626vaccine, 618Rabipur, 618Raltegravir, 310, 321Ranitic (ranitidine), 44Ranitidine, 43, 44Rapamune, 435Rapifen, 641Rapitil, 523Raporsin XL (doxazosin), 99Rasburicase, 417, 418Ratiograstim, 456Raynaud’s syndrome, 106, 110Rebetol, 329Red eye, 519, 521Redoxon, 482ReFacto AF (factor VIII fraction),124Reflexions diaphragm, 408Reflux oesophagitis see Gastrooesophagealreflux disease, 35Refolinon (calcium folinate), 418Regranex, 597Regulan, 58Index

838 Regulose—Scopolamine BNFC 2011–2012IndexRegulose (lactulose), 62Rehydrationoral, 459parenteral, 461Relaxit, 64Relenza, 327Relestat, 523Remedeine, 202Remicade, 56Remifentanil, 640, 641, 642Renagel, 476Renalexcretion, interactions affecting,655impairment, prescribing in, 14Renamil, 770Renapro, 770Renastart, 770Renilon, 761Repevax, 605Replagal, 490Replenine-VF (factor IX fraction),125Resonium A, 458Resource preparationsenteral feed, 748, 755feed thickener, 777fibre supplement, 776nutritional supplement, 757,760, 761Respiratorydepressionpoisoning, 24postoperative, 647distress syndrome, 76, 78pulmonary surfactants, 162failure, 162secretions, excessive (palliativecare), 19stimulants, 162syncytial virus infections, 327Respontin, 142Restandol, 379Restlessness, palliative care, 19Resuscitationcardiopulmonary, 114dental practice, 629Retacrit, 450Retapamulin, 585, 586Retin-A, 577Retinoidsacneoral, 578topical, 576leukaemia, 430psoriasis, 567, 571Retinol see Vitamin ARetrovir, 315Revatio, 98Revaxis, 606Rexocaine, 652Reyataz, 316Rheumatac Retard (diclofenac),502Rheumatic diseases, 499corticosteroid injections, 506Rheumatic feverprophylaxis, 254Rhinitis, allergic, 538Rhinocort Aqua, 540Rhinolast preparations, 539Rhumalgan CR (diclofenac), 502Riamet, 330, 335Ribavirin, 328, 329chronic hepatitis C, 326, 327Lassa fever, 328respiratory syncytial virus, 327Riboflavin, 479, 480Rickets, 482hypophosphataemic, 474, 482Rickettsia, 274Rifabutin, 292, 294Rifadin, 295Rifampicin, 294, 295Haemophilus influenzaeprophylaxis, 254isoniazid and pyrazinamidewith, 295isoniazid with, 295meningococcal meningitisprophylaxis, 254tuberculosis, 290, 291, 292prophylaxis, 255treatment, 291Rifamycins, 290, 291, 292, 294Rifater, 295Rifinah preparations, 295Rigevidon, 401Rimacid (indometacin), 504Rimacillin (ampicillin), 262Rimactane, 295Rimafen (ibuprofen), 503Rimapam (diazepam), 515Rimapurinol (allopurinol), 417Rimoxallin (amoxicillin), 261, 262Rinatec, 542Ringer’s solution, 462Ringer-Lactate solution, 462Ringworm infection see Dermatophyteinfection, 301, 588Risedronate sodium, 390Risperdal preparations, 181Risperidone, 177aggression, 180mania, 180psychosis, 180Ritalin, 190Ritonavir, 310, 317, 318lopinavir with, 317see also KaletraRituximab, 438, 439Rivotril, 231, 232Rizopia products, 779Roaccutane, 579Robinul powder, 597Rocaltrol, 484Rocephin, 271Rocuronium, 643, 644, 645Roferon-A, 440Ropivacaine, 653, 654Rosacea, 574Rosiced, 588Rosuvastatin, 126, 127Rotarix, 618Rotavirus vaccine, 618Roundworm infections, 345Rozex, 588rt-PA see Alteplase, 122Rubellaimmunisation, 619immunoglobulin, 623vaccines, combined, 612, 614Rufinamide, 217, 225Rupafin, 155Rupatadine, 153, 155Rusyde (furosemide), 80Rynacrom preparations, 541SSt John’s Wort, 184S.O.S. preparations, 771Sabril, 230Saizen preparations, 384Salactol, 580Salamol (salbutamol)preparations, 140Salapin (salbutamol), 139Salatac, 580Salazopyrin, 53Salbulin Novolizer, 140Salbumalin (salbutamol), 140Salbutamol, 137, 139, 140asthma, acute, 134hyperkalaemia, 139Salbutamol Cyclocaps—discontinuedSalcatonin see Calcitonin, 388, 473Salicylatesaphthous ulcers, 544, 545Salicylic acid, 571acne, 577, 578betamethasone with, 562fungal infections, 590hyperkeratoses, 580psoriasis, 567coal tar and dithranol with,570coal tar with, 584dithranol with, 570sulphur with, 584zinc with, 571scalp, 584warts and calluses, 580Saline see Sodium chlorideSalinum—discontinuedSaliva, artificial, 548Saliveze, 548Salivix, 549Salmeterol, 140fluticasone with, 150Salmonellosis, 245Salofalk preparations, 51Salpingitis, 274Salt substitutes, 457Sandimmun, 435Sandocal preparations, 472colecalciferol with, 484Sando-K, 458Sandostatin, 362Sanomigran, 214Sapropterin, 469Saquinavir, 310, 318Savlon Dry powder, 596Scabies, 592Scandishake, 775Scandonest preparations, 653Scheriproct, 67Schistosoma, 346Schistosomicides, 346Schizophrenia, 172School, managing medicines at, 2Scopoderm preparations, 199Scopolamine see Hyoscine

BNFC 2011–2012 Scottish—Sodium 839Scottish Medicines Consortium, 3Scurvy, 481Seasonal influenza vaccines, 612Sebco, 569Sebomin MR, 276Seborrhoeicdermatitis, 566eczema, 566Securon preparations, 109Sedation, clinical procedures, 637Sedatives, 169see also AnxiolyticsSegawa syndrome, 235Seizuresabsence, 217neonatal, 217see also EpilepsySelect-A-Jet Dopamine—discontinuedSelenium sulphide, 584, 588Selexid, 266Selsun, 584Semisodium valproate, 181Senna, 60, 61Senokot, 60, 61Septanest, 650Septic arthritis, 251Septic shock, 370Septic spots see Paronychia, 253,588Septicaemia, 250catheter-related, 250hospital-acquired, 250meningococcal, 250Septrin, 290Serenace, 175Seretide, 150Serevent, 140Seroquel preparations, 180Serotonin re-uptake inhibitor antidepressantssee Antidepressants,serotonin re-uptake inhibitors,183, 186Sertraline, 186, 188Sesame oil, presence of, 3Sevelamer hydrochloride, 475,476Sevoflurane, 633, 634Sevredol, 208Sex hormonesandrogens, 379oestrogens, 377progestogens, 378Shampoos, 583Shared care, 4Sharpsguard, 357Shigellosis, 245Shingles, 322Shock, 110anaphylactic, 159blood-volume expansion, 465cardiogenic, 111hypovolaemic, 111metabolic acidosis, 463septic, 110, 370neonatal, 111Short stature homeobox-containinggene deficiency, 383Shower preparationsantimicrobial with, 556emollient, 555SHOX deficiency see short staturehomeobox-containing gene deficiencySickle-cell disease, 450delayed puberty, 377pain, 199pneumococcal infectionprophylaxis, 255Significant changes, xviiSiklos, 451Sildenafil, 95, 97, 98Silk clothing, 565Silkis, 569Silver nitrate, 580, 581Silver sulfadiazine, 586, 587skin, 586Silver sulphadiazine see Silver sulfadiazineSimeticone, 37, 38aluminium hydroxide with, 37hydrotalcite with, 37Similac preparations, 753Simple eye ointment, 531Simple linctus, 168paediatric, 168SimpleXx, 384Simulect, 434Simvador (simvastatin), 128Simvastatin, 126, 128Sinemet preparations, 236Sinepin, 185Singulair, 152Sinusitis, 541antibacterial treatment, 252Siopel, 557Sirolimus, 433, 435Skin preparationsACBS, 786antibacterials, 585antiviral, 591barrier, 556camouflagers, 583cleansing, 594corticosteroids, 558dilution, 551emollient, 552excipients, 551ulcers, 596Skinoren, 575SLO Drinks, 777Slocinx XL (doxazosin), 99Slofenac SR (diclofenac)preparations, 502Slo-Phyllin, 143Slo-Pro (propranolol), 89Slow-K, 458Slow-Sodium, 459SMA preparations, 751low lactose, 766thickened, 767Smallpox vaccine, 619SMC see Scottish Medicines Consortium,3Smith-Lemli-Opitz syndrome, 69Smoking cessation, 238Snake bites, 34antivenom, 34Sno Tears, 531Sno-Pro, 785Soap substitutes, 552Sodiofolin, 418Sodium acid phosphate, 475Sodium alendronate see Alendronicacid, 389Sodium amidotrizoate, 65Sodium benzoate, 493, 494, 495Sodium bicarbonatecyanosis, 88ear wax removal, 538intravenous, 463, 464oral, 460Sodium calcium edetate, 32, 33Sodium calciumedetate see Sodiumcalcium edetate, 32, 33Sodium chloridebladder irrigation, 412, 594electrolyte replacementoral, 458, 459parenteral, 461, 462eye irrigation, 517, 531, 532hypercalcaemia, 473hypertonic inhalation, 165infusion, 462glucose and, 461, 462potassium chloride and,463potassium chloride, glucoseand, 463mouthwash, 546, 548compound, 548nasalcongestion, 541postoperative douche, 538nebuliser solution, 146hypertonic, 166skin cleansing, 594, 595Sodium citratebladder irrigation, 412rectal, 63, 64Sodium clodronate, 390Sodium content, antacids, 36Sodium cromoglicateasthma, 151eye, 522, 523food allergy, 56nose, 538, 541Sodium cromoglycate see SodiumcromoglicateSodium dichloroacetate, 497Sodium docusate see DocusatesodiumSodium feredetate, 443, 444Sodium fluoride, 476, 477Sodium fusidate, 285angular cheilitis, 545mouth, 545Sodium hyaluronate, 531, 532tear deficiency, 531Sodium iodine, radioactive, 367Sodium ironedetate see Sodiumferedetate, 443, 444Sodium lactateintravenous infusioncompound, 461, 462Sodium nitrite, 32Sodium nitroprusside, 93, 94, 95Sodium oxybate, 31Sodium phenylbutyrate, 493, 495Sodium picosulfate, 61magnesium citrate with, 65Sodium picosulphate see SodiumpicosulfateSodium pidolate, 553Index

840 Sodium—Syringe BNFC 2011–2012IndexSodium polystyrene sulphonate,458Sodium stibogluconate, 340Sodium thiosulphate, 32Sodium valproate see ValproateSofradexear, 536eye, 522Soft tissue disorders, 499Softclix products, 357Solaraze, 583Solian, 178Solivito N, 468Solu-Cortef, 376Solu-Medrone, 376Solvazinc, 478Solvents, ear wax removal, 538Somatomedins, 391Somatotrophin, 383Somatropin, 383, 384, 385Somnite (nitrazepam), 231Sorbitol, presence of, 2Sotacor, 92Sotalol, 82, 87, 88, 91, 92see also Beta-adrenoceptorblocking drugssupraventricular tachycardia,82Soya oil, 554Soya-based infant formula, 767Spacer devices, 145Spasmmuscle, 513vascular, 106, 108Spasmonal preparations, 40Spasticity, 513Specialist-importing companies,809Special-orderdermatological preparations,550manufacturers, 809SpectraBan—discontinuedSpermicides, 406SPF see Sun protection factor, 582Spiramycin, 280, 341Spiritindustrial methylated, 594surgical, 594Spironolactone, 80, 81heart failure, 76precocious puberty, 380Splenectomy see AspleniaSporanox, 304Sporanox-Pulse, 304Sport, drugs and, 23Sprilon, 557SSRIs see Antidepressants, serotoninre-uptake inhibitors, 183,186SST, 549Stamaril, 622Stannous fluoride, 477Staphylococcal scalded skinsyndrome, 253Starch, etherified, 465, 466Statins, 126Status epilepticus, 231Stavudine, 310, 313, 314Steam inhalations, 541Stefluvin c XL, 127Stelazine, 177Stemetil, 195Sterculiaconstipation, 58frangula with, 58diarrhoea, 47Stericlens (sodium chloride), 594Steri-Nebipratropium, 142Salamol (salbutamol), 140sodium chloride, 146Steripod (sodium chloride), 595Steripoule (sodium chloride), 146Steroid treatment card, 373suppliers, 372Steroids see Anabolic steroids;Corticosteroids; Glucocorticoids;or MineralocorticosteroidsStesolid (diazepam), 233Stiemycin, 576Still’s disease see Arthritis, juvenileidiopathic, 507Stimulantscentral nervous system, 188respiratory, 162Stings, 34Stiripentol, 217, 226Stoma, drugs and, 68Stomatitisangular, 545herpetic, 545Strattera, 189Strefen, 544Streptase, 123Streptococcal infectionantibacterial prophylaxis, 254Streptokinase, 122, 123Streptomycinbrucellosis, 295endocarditis, 277tuberculosis, 291, 292, 295Stronazon MR (tamsulosin), 410Strongyloidiasis, 347Stugeron, 193Subcuvia, 623Subgam, 624Sublimaze, 641Succimer, 32Succinylcholine see Suxamethonium,645, 646Sucralfate, 44Sucrose, presence of, 2Sudafed, 168Sudocrem, 557Sugammadex, 647Sugar-free liquid medicines seepreparations identified by ‘sugarfree’throughout BNF for ChildrenSugar-free, definition, 2Sulazine EC (sulfasalazine), 53Sulconazole—discontinuedSulfadiazinetoxoplasmosis, 341, 342Sulfadiazine, silver, 586Sulfadoxinemalaria, 338pyrimethamine with, 330,338Sulfamethoxazole, trimethoprimwith, see Co-trimoxazoleSulfasalazineinflammatory bowel disease,48, 49, 52, 53rheumatic disease, 507, 511Sulfonamides, 289Sulfonylureas, 358Sulpha... see also Sulfa...Sulphasalazine see SulfasalazineSulphites, presence of, 3Sulphonamides see Sulfonamides,289Sulphonylureas see Sulfonylureas,358Sulphur, 567salicylic acid with, 584Sulphur dioxide, poisoning, 33Sulpiridepsychosis, 174, 176Tourette syndrome, 176, 237Sulpor, 176Sumatriptancluster headache, 213, 214migraine, 213Sun protection factor, 582Sunnyvale products, 778Sunscreens, 582ACBS, 787Sunsense Ultra, 582Sunya 20/75, 401Superinfection, 244Suplena, 770Supplementary prescribing, 799Suprax, 268Suramin, 346Surfactants, pulmonary, 162Surgeryantibacterial prophylaxis, 255,256, 257diabetes and, 351long-term medication and, 628tetanus vaccine, 619wound infection, 253Surgical spirit, 594Survanta, 163Survimed preparations, 746Sustanon, 379Sustiva, 319Suxamethonium, 645, 646Swine influenza, 611, 612Symbicort, 146, 149Symbols and abbreviations, 3Sympathomimeticsasthma, 137eye, 525, 526inotropic, 110vasoconstrictor, 112Synacthen, 382Synacthen Depot, 382Synagis, 328Synalar preparations, 564Syner-KINASE, 123Synflex, 505Synflorix, 616, 617Synphase, 402Syntaris, 540Synthamin preparations, 467Syphilis, 249Syprol (propranolol), 89Syringe drivers, palliative care, 19mixing and compatibility, 20problems, 20

BNFC 2011–2012 Syringes—Tocopherols 841Syringesinsulin, 357blind patients, 357oral, 2Systane, 530Sytron, 444TTabphyn MR (tamsulosin), 410Tacalcitol, 567, 568, 569Tachycardias see ArrhythmiasTacrolimuseczema, 572, 573, 574immunosuppression, 431, 433,436, 437Taenicides, 345Tambocor, 86Tambocor XL, 86Tamiflu, 327Tamsulosin, 409, 410Tapeworm infections, 345Tar, 569, 570see also Coal tarTaranis products, 780, 781Tardive dyskinesia, 173Targocid, 287Tartrazine, presence of, 3Tazarotene, 566Tazobactampiperacillin with, 264, 265Tazocin, 2653TC see LamivudineTear deficiency, 529Tear gas, 33Tears Naturale, 531Tears, artificial, 529Tegretol preparations, 218, 219Teicoplanin, 285, 286, 287Telangiectasia, hereditaryhaemorrhagic, 378Telfast, 154Telzir, 316Temazepampalliative care, 18premedication, 637, 639Temgesic, 204Temomedac (temozolomide), 428Temodal, 428Temozolomide, 428Tendinitis, 506Tennis elbow, 506Tenofovirchronic hepatitis B, 325HIV infection, 310, 314efavirenz and emtricitabinewith, 314emtricitabine with, 314Tenormin preparations, 89TENS see Transcutaneous electricalnerve stimulation, 18Tensipine MR, 108Tensium (diazepam), 515Tentrini preparations, 753, 754,756Teoptic, 526Teratology information service,inside back coverTerbinafine, 590dermatophyte infections, 301,308systemic treatment, 309topical treatment, 588, 590Terbutaline, 141asthma, 137acute, 134Terlipressin, 385, 387Terminal care see Palliative careTestolactone, 380Testosterone, 379, 380enantate, 379esters, 379propionate, 379, 380undecanoate, 379Testotoxicosis see Puberty, precocious,380, 381Tetanusantibacterial treatment, 257,296immunisation, 619, 625immunoglobulin, 625travel, 626vaccines, combined, 605, 606,619wounds, 619Tetracaineeye, 529local anaesthetic, 654rectal, 66Tetracosactide, 217, 382Tetracosactrin see Tetracosactide,217, 382Tetracycline, 274, 275acne, 578oral infections, 274skin, clobetasone butyrate with,563Tetrahydrobiopterin, 469Tetrahydrofolate reductasedeficiency, 495Tetralogy of Fallot, 88Tetralysal-300, 276Tetraspan, 465Tetrastarch, 465, 466Tevagrastim, 456T-Gel, 585Thalassaemia, 451THAM see Trometamol, 463, 464Theophylline, 142, 143poisoning by, 31poisoning, elimination, 25see also AminophyllineThiabendazole see Tiabendazole,346Thiamine, 479, 480Thiazides, 76diabetes insipidus, 385see also DiureticsThick and Easy, 777Thickened foods, 777Thickened supplements, 759, 761Thioguanine see Tioguanine, 423,425, 426Thiopentalanaesthesia, 630, 632status epilepticus, 231, 632Thiopentone see ThiopentalThiopurine methyltransferase,431Thioxanthenes, 173Thixo-D, 777Threadworm infections, 344Throat infectionsantibacterial treatment, 252fungal, 545gonorrhoea, 249viral, 545Thrombocytopenias, 448Thrombocytopenic purpura, 453immunoglobulins, 622prednisolone, 377Thrombo-embolism, 118Thrombolytics, 121Thrombosisantiplatelet drugs, 120deep-vein, 114, 118prophylaxis, 115Thrush see CandidiasisThymoglobuline, 434Thymol, 548Thyroidantagonists, 367hormones, 365storm, 367Thyroidectomy, 367Thyroiditis, Hashimoto’s, 365Thyrotoxic crisis, 367Thyrotoxicosis, 367beta-blockers, 88, 367Thyrotoxicosis, neonatal, 367Thyroxine see Levothyroxine, 366Tiabendazole, 346Tiagabine, 217, 226Ticarcillin, 264clavulanic acid with, 264, 265Tick-borne encephalitisimmunisation, 619travel, 627vaccine, 620TicoVac, 620Tics, 237Tilade, 152Tildiem preparations, 106Tilofyl (fentanyl), 207Tiloryth (erythromycin), 283Timentin, 265Timodine, 561Timolol, eye, 526dorzolamide with, 528Timoptol preparations, 526Tinea infections, 301, 588Tinidazole, 340amoebiasis, 339, 340giardiasis, 340protozoal infections, 340trichomoniasis, 340Tinzaparin, 116, 117Tioconazole, 588, 590Tioguanine, 423, 425, 426Tipranavir, 310, 318Tisept, 595Tissue adhesive, 593Tissue-type plasminogen activatorsee Alteplase, 122Titanium dioxide, 557, 582Tobi, 280Tobia products, 779Tobramycin, 277, 279, 280eye, 518, 520Tobravisc, 520Tocopherols, 485Index

842 Tocopheryl—Ursodeoxycholic BNFC 2011–2012IndexTocopheryl, 485Toilet preparations, ACBS, 786Tolazoline, 95, 98Tolbutamide, 358, 359Tolterodine, 410, 411Tonic seizures, 217Tonic-clonic seizures, 217Tonsillitis see Throat infectionsTopal, 39Topamax, 227Topiramateepilepsy, 217, 226, 227migraine, 214, 226Toradol, 640Torsade de pointes, 83magnesium sulphate, 473Total parenteral nutrition, 466Tourette syndrome, 237TOXBASE, 24Toxoplasma choroidoretinitis, 341Toxoplasmosis, 341TPN see Total parenteral nutrition,466Trachoma, 274, 518Tracleer, 96Tracrium, 643Tradorec XL, 212Tramacet, 202Tramadolpain, 203, 210, 211, 212paracetamol with, 202Tramake preparations, 211Tramquel SR, 211Trandate, 91Tranexamic acid, 123, 124palliative care, 18, 19Tranquillisers, 169Transcutaneous electrical nervestimulation, 18Transfusion reactions, 448Transplant rejection, 431, 433Travasept-100, 595Travel, vaccination for, 626Travellers’ diarrhoea, 627Travoprost, 526Treatment cards, anticoagulant,119Tree pollen extracts, 157, 158Tremors, 237Tretinoinacne, 576, 577erythromycin with, 577leukaemia, 430Triadene, 402Triamcinoloneintra-articular, 506rheumatic disease, 507nose, 540, 541skin, 565Triazole antifungal drugs, 301Tribavirin see RibavirinTrichomonacides, 340Trichomonal infections, 340Triclofos—discontinuedTricyclic antidepressants see Antidepressants,tricyclicTrientine, 488, 489Trifluoperazineanxiety, 176, 177nausea and vomiting, 192, 195psychosis, 174, 176Trihexyphenidyl, 237Tri-iodothyronine see Liothyronine,366, 367Trileptal, 219Trimeprazine see AlimemazineTrimethoprim, 289, 290pneumocystis pneumonia, 342sulfamethoxazole with, see Cotrimoxazoleurinary infectionsprophylaxis, 255treatment, 249Trimopan (trimethoprim), 290Trimovate, 563TriNovum, 402Triptans see 5HT 1 -receptor agonists,212Triptorelin, 381TriRegol, 402Tris-hydroxymethyl aminomethanesee Trometamol, 463,464Tritamyl products, 779Trizivir, 312Trometamol, 463, 464Tropical diseases, advice, 329Tropicamide, 524, 525Trosyl, 590TRUEone, 365TRUEresult products, 365TRUEtrack products, 365Trusopt, 528Truvada, 314Trypanocides, 341Trypanosomiasis, 341T-Safe 380A devices, 408T-SPOT.TB, 604TT 380 Slimline, 408Tub/BCG, Dried, 603Tuberculin, 603, 604Tuberculosis, 290antibacterial prophylaxis, 291diagnosis, 603immunisationvaccines, 603prophylaxis, 255travel, 626Tubular bandages, 565Tumour lysis syndrome, 416Tumour, fungating, 19TurbohalerBricanyl, 141Oxis, 138Symbicort, 149Turner’s syndrome, 377, 381, 383Twinrix preparations, 608Typherix, 620Typhim Vi, 620Typhoidfever, treatment, 245immunisationvaccines, 620, 621travel, 626TYR preparations, 786Tyrosinaemia, 495, 786Tyrosineamino acid supplement, 785supplement in phenylketonuria,785UUbidecarenone, 497Ubiquinone see Ubidecarenone,497Ucerax, 156Ulcerative colitis, 48Ulcerative gingivitisantibacterial treatment, 252,296mouthwashes, 546Ulcer-healing drugs, 42Ulcersaphthous, 543corneal, 518, 521duodenal, 42, 43gastric, 42, 43mouth, 543neuropathic, diabetic, 596NSAID-associated, 43Ulipristal, 409Ultiva, 642Ultra productsgluten-free, 778, 779, 780low-protein, 780, 781Ultrabase, 553Ultralanum Plain, 564Ultraproct, 67Ultraviolet radiation, 582Umbilical granulomas, 581Undecenoates, 590, 591Unguentum M, 553Unifine products, 357Unilet products, 357Uniphyllin Continus, 143Uniroid-HC, 67Unisept, 595Unistik products, 357Unithiol, 32Univer, 110Universal, 357Unlicensed medicines, 2, 6Urdox, 69Urea, 552, 553, 554emollient with, 553hydrocortisone and lactic acidwith, 560hydrocortisone with, 560Urea cycle disorders, 493arginine supplement, 786essential amino acidssupplement, 784Urethritis, non-gonococcal, 250,274Uriflex preparations, 412Urinaryalkalinisation, 412frequency, 410incontinence, 410infections, 299genital, 395prophylaxis, 255treatment, 249retention, 409Urinary infectionsprophylaxis, 299Urine tests, 363Uristix, 363Urokinase, 123Uro-Tainer preparations, 412Ursodeoxycholic acid, 68, 69

BNFC 2011–2012 Ursofalk—Waxsol 843Ursofalk, 69Ursogal, 69Urticaria, 153UT 380 devices, 408Utovlan, 379UVB, psoriasis, 567Uvistat preparations, 583VVaccinationHIV-positive subjects, 600schedule, 601travel, 626Vaccinesactive immunity, 599allergen extract, 157breast-feeding, 600cautions, 599contra-indications, 599post-immunisation pyrexia, 600pregnancy, 600side-effects, 600storage and use, 602Vaginal infectionoral treatment, 394Vaginitiscandidal, 394Vaginosis, bacterial, 395Vaginyl (metronidazole), 297Valaciclovir, 322, 323, 324genito-urinary infection, 395herpetic stomatitis, 545Valine Amino Acid Supplement,783Valni XL, 108Valoid, 193Valproatebipolar disorder, 181epilepsy, 217, 227, 228, 229Valproic acid see ValproateValsartan, 103, 104Valtrex, 324Vamin preparations, 467Vaminolact, 467Vancocin, 286Vancomycin, 285, 286eye, 529Vancomycin-resistantenterococci, 287Vaqta, 608Variceal bleeding, 385Varicella-zoster, 322corticosteroids, 371immunisationvaccine, 621, 626immunoglobulin, 625, 626Varilrix, 621Variquel, 387Varivax, 621Vascular spasm, 106, 108Vasoconstrictorslocal anaesthesia, 649dental practice, 649sympathomimetic, 112Vasodilatorsantihypertensive, 93peripheral, 110Vasogen, 557Vasopressinshock, 111variceal bleeding, 385, 387,388Vectavir, 591Vecuronium, 643, 645infusion table (neonatal), 793Vedrop, 485Vegenat-med preparations, 762Veil preparations, 583Velaglucerase alfa, 490, 491Velbe, 427Venofer, 445Ventavis, 97Ventmax SR, 139Ventolin preparations, 139, 140Vepesid, 426Veracur, 580Verapamil, 109, 110arrhythmias, 82, 84, 105beta-blockers and, 109hypertension, 105poisoning by, 30see also Calcium-channelblockersVerapress MR, 110Vermox, 345Verrucas, 580Verrugon, 580Vertab SR 240, 110Vertigo, 193Vesanoid, 430Vestibular disorders, 193Vfend, 305Viagra, 97ViATIM, 608Vibramycin-D, 276Victanyl (fentanyl), 207Videne, 596Videx preparations, 312Vigabatrin, 217, 229, 230Vigam, 624Vigranon-B, 481Vimpat, 221Vinblastine, 426, 427Vinca alkaloids, 426Vincent’s infectionantibacterial treatment, 252,296mouthwashes, 546Vincristine, 426, 427Viper venom antiserum,European, 34Viracept, 317Viramune, 320Virazole, 329Viread, 314Viroflu, 612Virormone, 380Virovir (aciclovir), 323Virus infections, 309Visclair, 166Viscotears, 530Vismed preparations, 531Vistamethasoneear, 535eye, 521nose, 539Vita-Bite, 780Vitajoule, 772Vitalograph, 144Vitamin A, 478, 479vitamin D and, 479Vitamin B group, 479preparations, 481Vitamin B 12 , 445, 447Vitamin C see Ascorbic acidVitamin D, 482, 483psoriasis, 566, 567, 568Vitamin D 2 see Ergocalciferol, 482,483Vitamin D 3 see ColecalciferolVitamin deficiency, 478Vitamin E, 485Vitamin K, 486, 487deficiency bleeding, 486palliative care, 18Vitamins, 478children’s drops, 479multivitamins, 487, 488parenteral, 467Vitapro, 774Vitaquick, 777Vitasavoury, 775Vitiligo, 583ACBS, 787Vitlipid N, 468Vitrex products, 357Vivadex, 438Vivaglobin, 624Vividrin (sodium cromoglicate),523, 541Vivotif, 621Volplex, 465Volsaid (diclofenac) preparations,502Voltarol preparations, 502eye, 533Ophtha, 533Rapid, 501Volulyte, 465Volumatic, 145Volume expansion, 464Voluven, 466Vomitingcytotoxic drugs, 415motion sickness, 193nausea and, 192opioid-induced, 192palliative care, 19postoperative, 192pregnancy, 192von Willebrand’s disease, 385Voriconazole, 300, 301, 304, 305VPRIV, 491Vulvitis, candidal, 394Vulvovaginal candidiasis,recurrent, 394VZIG see Immunoglobulins, varicella–zoster,625, 626WWarfarin, 119Warticon preparations, 581Warts, 580anogenital, 581Wasp sting allergy preparations,157Water for injections, 464WaveSense products, 357, 365Waxsol, 538Index

844 Welldorm—Zyvox BNFC 2011–2012IndexWelldorm, 170Wellfoods products, 778, 779,780Wellvone, 343West’s syndrome, 229Whitfield’s ointment, 588Whooping cough see PertussisWilate (factor VIII fraction), 124Wilson’s disease, 488Wilzin, 489Withdrawalantipsychoticsatypical, 177nicotine, 238opioids, 204Wolff-Parkinson-White syndrome,82Wool fat, hydrous, 553Worm infestation, 344Wuchereria bancrofti, 346Wysoy, 767XXagrid, 453Xamiol, 568Xanthine bronchodilators seeTheophyllineXenical, 191Xepin, 558Xerostomia, 548Xerotin, 549XLEU preparations, 782XLYS Low TRY preparations,781XLYS preparations, 782XLYS TRY preparations, 781XMET preparations, 782XMTVI preparations, 783Xolair, 159Xomolix, 195XP preparations, 785, 786XPHEN TYR preparations, 786XPTM preparations, 786Xylitol, presence of, 2Xylocaine, 652Xylometazolineeye, 522nose, 541, 542Xyloproct, 67Xyzal, 155Y8Y (factor VIII fraction), 124Yasmin, 401Yeasts, 305Yellow cardsadverse drug reporting, 12reporting cards, inside backcoverYellow feverimmunisationvaccine, 621, 622travel, 626ZZaditen, 157, 523Zafirlukast, 152, 153Zamadol preparations, 211, 212Zanamivir, 326, 327Zantac, 44effervescent tablets—discontinuedZaponex, 179Zarontin, 220Zarzio, 456Zavesca, 496ZeaSORB, 597Zeffix, 313oral solution—discontinuedZenalb preparations (albumin),464Zeridame SR, 211Zerit, 314Zerobase, 553Zerocream, 553Zeroguent , 553Zerolatum preparations, 555, 556Zeroneum, 555Zerozole, 556Zestril, 103Ziagen, 312Zicron (gliclazide), 359Zidoval, 395Zidovudine, 310, 314, 315abacavir and lamivudine with,312lamivudine with, 315Zinacef, 271Zincbandages, 566deficiency, 478skincastor oil and, 556coal tar with, 569cod liver oil with, 557cream, 556dimeticone with, 557ichthammol with, 565, 566ointment, 556salicylic acid with, 571Wilson’s disease (zinc acetate),489Zindaclin, 576Zineryt, 576Zinnat, 271Zithromax, 281Zocor, 128Zofran, 197Zoladex preparations, 381Zollinger–Ellison syndrome, 45Zolmitriptancluster headache, 213, 215migraine, 213, 214Zolvera (verapamil), 109Zomacton, 385Zomig preparations, 214Zoster see Herpes infectionsZoton FasTab, 46Zovirax preparations, 323cold sore cream, 591cream, 591eye ointment, 521Zuvogen, 591Zydol preparations, 211, 212Zyloric, 417Zyomet, 588Zyprexa, 179Zyvox, 288

NEWBORN LIFE SUPPORTDry the babyRemove any wet towels and coverStart the clock or note the timeBirthATAssess (tone), breathing and heart rate30 sALLIf gasping or not breathing:Open the airwayGive 5 inflation breathsConsider SpO 2 monitoring60 sSTAGESRe-assessIf no increase in heart ratelook for chest movementASK :If chest not moving:Recheck head positionConsider 2-person airway controland other airway manoeuvresRepeat inflation breathsConsider SpO 2 monitoringLook for a responseAcceptablepre-ductal SpO 22 min 60%3 min 70%4 min 80%5 min 85%10 min 90%If no increase in heart ratelook for chest movementDOWhen the chest is moving:If heart rate is not detectableor slow (< 60 min -1 )Start chest compressions3 compressions to each breathReassess heart rate every 30 sIf heart rate is not detectableor slow (

PAEDIATRIC BASIC LIFE SUPPORT(Healthcare professionals with a duty to respond)UNRESPONSIVE?Shout for helpOpen airwayNOT BREATHING NORMALLY?5 rescue breathsNO SIGNS OF LIFE ?15 chest compressions2 rescue breaths15 compressionsCall resuscitation teamReproduced with the kind permission of the Resuscitation Council (UK) from Resuscitation Guidelines, October 2010

PAEDIATRIC ADVANCED LIFE SUPPORTUnresponsive?Not breathing or only occasional gaspsCPR(5 initial breaths then 15:2)Attach defibrillator/monitorMinimise interruptionsCallResuscitation Team(1 min CPR first,if alone)Assess rhythmShockable(VF/pulseless VT)Non-shockable(PEA/Asystole)1 Shock4J / kgReturn ofspontaneouscirculationImmediately resumeCPR for 2 minMinimise interruptionsImmediate post cardiacarrest treatment• Use ABCDE approach• Controlled oxygenationand ventilation• Investigations• Treat precipitating cause• Temperature control• Therapeutic hypothermia?Immediately resumeCPR for 2 minMinimise interruptionsDuring CPR• Ensure high-quality CPR: rate, depth, recoil• Plan actions before interrupting CPR• Give oxygen• Vascular access (intravenous, intraosseous)• Give adrenaline every 3-5 min• Consider advanced airway and capnography• Continuous chest compressions whenadvanced airway in place• Correct reversible causesReversible causes• Hypoxia• Hypovolaemia• Hypo- / hyperkalaemia / metabolic• Hypothermia• Tension pneumothorax• Toxins• Tamponade - cardiac• ThromboembolismReproduced with the kind permission of the Resuscitation Council (UK) from Resuscitation Guidelines, October 2010

BODY SURFACE AREA IN CHILDRENBody-weight under 40kgBody-weight Surface area(kg) (m 2 )1 0.101.5 0.132 0.162.5 0.193 0.213.5 0.244 0.264.5 0.285 0.305.5 0.326 0.346.5 0.367 0.387.5 0.408 0.428.5 0.449 0.469.5 0.4710 0.4911 0.5312 0.5613 0.5914 0.6215 0.6516 0.68Body-weight Surface area(kg) (m 2 )17 0.7118 0.7419 0.7720 0.7921 0.8222 0.8523 0.8724 0.9025 0.9226 0.9527 0.9728 1.029 1.030 1.131 1.132 1.133 1.134 1.135 1.236 1.237 1.238 1.239 1.340 1.3Values are calculated using the Boyd equationNote Height is not required to estimate body surface area using these tablesAdapted by permission from Macmillan Publishers Ltd: Sharkey I et al, British Journal of Cancer 2001; 85 (1): 23–28, © 2001

BODY SURFACE AREA IN CHILDRENBody-weight over 40kgBody-weight Surface area(kg) (m 2 )41 1.342 1.343 1.344 1.445 1.446 1.447 1.448 1.449 1.550 1.551 1.552 1.553 1.554 1.655 1.656 1.657 1.658 1.659 1.760 1.761 1.762 1.763 1.764 1.765 1.8Body-weight Surface area(kg) (m 2 )66 1.867 1.868 1.869 1.870 1.971 1.972 1.973 1.974 1.975 1.976 2.077 2.078 2.079 2.080 2.081 2.082 2.183 2.184 2.185 2.186 2.187 2.188 2.289 2.290 2.2Values are calculated using the Boyd equationNote Height is not required to estimate body surface area using these tablesAdapted by permission from Macmillan Publishers Ltd: Sharkey I et al, British Journal of Cancer 2001; 85 (1): 23–28, © 2001

Medical emergencies in thecommunityDrug treatment outlined below is intended for use bycommunity healthcare professionals. Only drugs thatare used for immediate relief are shown; advice onsupporting care is not given. Where the child’s conditionrequires investigation and further treatment, thechild should be transferred to hospital promptly.Anaphylaxis(section 3.4.3)Adrenaline injection (1 mg/mL (1 in 1000)). By intramuscular injectionChild under 6 years 150 micrograms (0.15 mL),repeated every 5 minutes if necessaryChild 6–12 years 300 micrograms (0.3 mL),repeated every 5 minutes if necessaryChild 12–18 years 500 micrograms (0.5 mL),repeated every 5 minutes if necessary; 300 micrograms(0.3 mL) should be given if child is small orprepubertalHigh-flow oxygen (section 3.6) and intravenousfluids should be given as soon as available.Chlorphenamine injection by intramuscular or intravenousinjection (section 3.4.1) may help counter histamine-mediatedvasodilation and bronchoconstriction.Hydrocortisone (preferably as sodium succinate) byintravenous injection (section 6.3.2) has delayed actionbut it should be given to severely affected children toprevent further deterioration.Asthma: acute(section 3.1)Regard each emergency consultation as being forsevere acute asthma until shown otherwise; failure torespond adequately at any time requires immediatetransfer to hospitalEither salbutamol aerosol inhaler (100 micrograms/metered inhalation). By aerosol inhalation via large-volume spacer (anda close-fitting face mask if child under 3 years)Child under 18 years 2–10 puffs each inhaledseparately, repeated at 10–20 minute intervals or asnecessaryor salbutamol nebuliser solution (1 mg/mL, 2 mg/mL). By inhalation of nebulised solution (via oxygendrivennebuliser if available)Child under 5 years 2.5 mg every 20–30 minutes oras necessaryChild 5–12 years 2.5–5 mg every 20–30 minutes oras necessaryChild 12–18 years 5 mg every 20–30 minutes or asnecessaryor terbutaline nebulised solution (2.5 mg/mL). By inhalation of nebulised solution (via oxygendrivennebuliser if available)Child under 5 years 5 mg every 20–30 minutes or asnecessaryChild 5–12 years 5–10 mg every 20–30 minutes oras necessaryChild 12–18 years 10 mg every 20–30 minutes or asnecessaryPlus (in all cases)Either prednisolone tablets (or prednisolone solubletablets) (5 mg). By mouthChild under 12 years 1–2 mg/kg (max. 40 mg) oncedaily for up to 3 days or longer if necessary; if thechild has been taking an oral corticosteroid for morethan a few days, give prednisolone 2 mg/kg (max.60 mg) once dailyChild 12–18 years 40–50 mg once daily for at least5 daysor hydrocortisone (preferably as sodium succinate). By intravenous injectionChild up to 18 years 4 mg/kg (max. 100 mg) every 6hours, until conversion to oral prednisolone is possible;alternative dose if weight unavailable, Childunder 2 years 25 mg, 2–5 years 50 mg, 5–18 years100 mgHigh-flow oxygen (section 3.6) should be given if availableMonitor response 15 to 30 minutes after nebulisation; ifany signs of acute asthma persist, arrange hospitaladmission. While awaiting ambulance, repeat nebulisedbeta 2 agonist (as above) and give withipratropium nebuliser solution (250 micrograms/mL). By inhalation of nebulised solution (via oxygendrivennebuliser if available)Child under 12 years 250 micrograms repeatedevery 20–30 minutes for the first 2 hours, then every4–6 hours as necessaryChild 12–18 years 500 micrograms every 4–6 hoursas necessaryConvulsive (including febrile) seizureslasting longer than 5 minutes(section 4.8.2 and section 4.8.3)Either midazolam buccal solution (5 mg/mL, 10 mg/mL) or injection solution given by buccal route. By buccal administration, repeated once after 10minutes if necessaryNeonate 300 micrograms/kgChild 1–6 months 300 micrograms/kg (max.2.5 mg)Child 6 months–1 year 2.5 mgChild 1–5 years 5 mgChild 5–10 years 7.5 mgChild 10–18 years 10 mgor diazepam rectal solution (2 mg/mL, 4 mg/mL). By rectum, repeated once after 10 minutes if necessaryNeonate 1.25–2.5 mgChild 1 month–2 years 5 mgChild 2–12 years 5–10 mgChild 12–18 years 10–20 mg

Croup(section 3.1)Dexamethasone oral solution (2 mg/5 mL). By mouthChild 1 month–2 years 150 micrograms/kg as asingle doseDiabetic hypoglycaemia(section 6.1.4)Glucose or sucrose. By mouthChild 2–18 years approx. 10–20 g (55–110 mLLucozade c Energy Original or 100–200 mL Coca-Cola c —both non-diet versions or 2–4 teaspoonfulsof sugar or 3–6 sugar lumps), repeated after 10–15minutes if necessaryor if hypoglycaemia unresponsive or if oral routecannot be usedGlucagon injection (1 mg/mL). By subcutaneous, intramuscular or intravenousinjectionChild body-weight under 25 kg 500 micrograms(0.5 mL)Child body-weight over 25 kg 1 mg (1 mL)or if hypoglycaemia prolonged or unresponsive toglucagon after 10 minutesGlucose intravenous infusion (10%). By intravenous injection into large veinChild 1 month–18 years 5 mL/kg (glucose 500 mg/kg)Meningococcal disease(Table 1, section 5.1)Benzylpenicillin sodium injection (600 mg, 1.2 g). By intravenous injection (or by intramuscular injectionif venous access not available)Neonate 300 mgChild 1 month–1 year 300 mgChild 1–10 years 600 mgChild 10–18 years 1.2 gNote A single dose can be given before urgent transfer tohospital, so long as this does not delay the transferor if history of allergy to penicillinCefotaxime injection (1 g). By intravenous injection (or by intramuscular injectionif venous access not available)Neonate 50 mg/kgChild 1 month–12 years 50 mg/kg (max. 1 g)Child 12–18 years 1gNote A single dose can be given before urgent transfer tohospital, so long as this does not delay the transferor if history of immediate hypersensitivity reaction(including anaphylaxis, angioedema or urticarialreaction) to penicillin or to cephalosporinsChloramphenicol injection (1 g). By intravenous injectionChild 1 month–18 years 12.5–25 mg/kgNote A single dose can be given before urgent transfer tohospital, so long as this does not delay the transfer

Approximate conversions and unitslb kg stones kg mL fl oz1 0.45 1 6.35 50 1.82 0.91 2 12.70 100 3.53 1.36 3 19.05 150 5.34 1.81 4 25.40 200 7.05 2.27 5 31.75 500 17.66 2.72 6 38.10 1000 35.27 3.18 7 44.458 3.63 8 50.809 4.08 9 57.1510 4.54 10 63.5011 4.99 11 69.8512 5.44 12 76.2013 5.90 13 82.5514 6.35 14 88.9015 95.25Length1 metre (m) = 1000 millimetres (mm)1 centimetre (cm) = 10 mm1 inch (in) = 25.4 mm1 foot (ft) = 12 inches12 inches = 304.8 mmMass1 kilogram (kg) = 1000 grams (g)1 gram (g) = 1000 milligrams (mg)1 milligram (mg) = 1000 micrograms1 microgram = 1000 nanograms1 nanogram = 1000 picogramsPrescribing for childrenWeight, height, and genderThe table below shows the mean values for weight,height and gender by age; these values have beenderived from the UK-WHO growth charts 2009 andUK1990 standard centile charts, by extrapolating the50th centile, and may be used to calculate doses in theabsence of actual measurements. However, the child’sactual weight and height might vary considerably fromthe values in the table and it is important to see the childto ensure that the value chosen is appropriate. In mostcases the child’s actual measurement should beobtained as soon as possible and the dose re-calculated.Age Weight HeightkgcmFull term neonate 3.5 511 month 4.3 552 months 5.4 583 months 6.1 614 months 6.7 636 months 7.6 671 year 9 753 years 14 965 years 18 1097 years 23 12210 years 32 13812 years 39 14914 year-old boy 49 16314 year-old girl 50 159Adult male 68 176Adult female 58 164Volume1 litre = 1000 millilitres (mL)1 millilitre (1 mL) = 1000 microlitres1 pint 568 mLOther units1 kilocalorie (kcal) = 4186.8 joules (J)1000 kilocalories (kcal) = 4.1868 megajoules (MJ)1 megajoule (MJ) = 238.8 kilocalories (kcal)1 millimetre of mercury (mmHg) = 133.3 pascals (Pa)1 kilopascal (kPa) = 7.5 mmHg (pressure)Plasma-drug concentrations in BNF for Childrenare expressed in mass units per litre (e.g. mg/litre).The approximate equivalent in terms of amount ofsubstance units (e.g. micromol/litre) is given inbrackets.

Recommended wording of cautionaryand advisory labelsFor details see Appendix 31. Warning: This medicine may make you sleepy2. Warning: This medicine may make you sleepy. Ifthis happens, do not drive or use tools ormachines. Do not drink alcohol3. Warning: This medicine may make you sleepy. Ifthis happens, do not drive or use tools ormachines4. Warning: Do not drink alcohol5. Do not take indigestion remedies 2 hours beforeor after you take this medicine6. Do not take indigestion remedies, or medicinescontaining iron or zinc, 2 hours before or afteryou take this medicine7. Do not take milk, indigestion remedies, or medicinescontaining iron or zinc, 2 hours before orafter you take this medicine8. Warning: Do not stop taking this medicine unlessyour doctor tells you to stop9. Space the doses evenly throughout the day. Keeptaking this medicine until the course is finished,unless you are told to stop10. Warning: Read the additional information givenwith this medicine11. Protect your skin from sunlight—even on a brightbut cloudy day. Do not use sunbeds12. Do not take anything containing aspirin whiletaking this medicine13. Dissolve or mix with water before taking14. This medicine may colour your urine. This isharmless15. Caution: flammable. Keep your body away fromfire or flames after you have put on the medicine16. Dissolve the tablet under your tongue—do notswallow. Store the tablets in this bottle with thecap tightly closed. Get a new supply 8 weeksafter opening17. Do not take more than... in 24 hours18. Do not take more than... in 24 hours. Also, do nottake more than... in any one week19. Warning: This medicine makes you sleepy. If youstill feel sleepy the next day, do not drive or usetools or machines. Do not drink alcohol21. Take with or just after food, or a meal22. Take 30 to 60 minutes before food23. Take this medicine when your stomach is empty.This means an hour before food or 2 hours afterfood24. Suck or chew this medicine25. Swallow this medicine whole. Do not chew orcrush26. Dissolve this medicine under your tongue27. Take with a full glass of water28. Spread thinly on the affected skin only29. Do not take more than 2 at any one time. Do nottake more than 8 in 24 hours30. Contains paracetamol. Do not take anything elsecontaining paracetamol while taking this medicine32. Contains aspirin. Do not take anything else containingaspirin while taking this medicine

Abbreviations and symbolsInternationally recognised units and symbols are used inthe BNF for Children where possible.ACBS Advisory Committee on Borderline Substances,see Appendix 2ACE Angiotensin-converting enzymeADHD attention deficit hyperactivity disorderAIDS Acquired immunodeficiency syndromeapprox. approximatelyAV atrioventricularBAN British Approved NameBMI body mass indexBP British Pharmacopoeia 2010, unless otherwisestatedBPC British Pharmaceutical Codex 1973 and Supplement1976, unless otherwise statedCAPD Continuous ambulatory peritoneal dialysis2 preparation in Schedule 2 of the Misuse of DrugsRegulations 2001 (and subsequent amendments).For regulations see Prescribing Controlled Drugs3 preparation in Schedule 3 of the Misuse of DrugsRegulations 2001 (and subsequent amendments).For regulations see Prescribing Controlled DrugsK preparation in Schedule 4 (Part I) of the Misuse ofDrugs Regulations 2001 (and subsequentamendments). For regulations see PrescribingControlled DrugsL preparation in Schedule 4 (Part II) of the Misuse ofDrugs Regulations 2001 (and subsequentamendments). For regulations see PrescribingControlled DrugsCHM Commission on Human MedicinesCHMP Committee for Medicinal Products for Human UseCNS central nervous systemCSM Committee on Safety of Medicines (now subsumedunder Commission on Human Medicines)d. c. direct currentDMARD Disease-modifying antirheumatic drugDPF Dental Practitioners’ Formularye/c enteric-coated (termed gastro-resistant in BP)ECG electrocardiogramEEG electro-encephalogramf/c film-coatedG6PD glucose 6-phosphate dehydrogenaseHIV Human immunodeficiency virusHRT Hormone replacement therapyi/m intramusculari/v intravenousINR international normalised ratioMAOI Monoamine-oxidase inhibitorsmax. maximumMHRA Medicines and Healthcare products RegulatoryAgencym/r modified-releaseNCL no cautionary labels, see Appendix 3NHS National Health ServiceD not prescribable under National Health Service(NHS)NICE National Institute for Health and Clinical ExcellenceNPF Nurse Prescribers’ FormularyNSAID non-steroidal anti-inflammatory drugPGD patient group directionA prescription-only medicinectrade markrINN Recommended International Non-proprietaryNameRSV respiratory syncytial viruss/c sugar-coatedSLS Selected List SchemeSMC Scottish Medicines ConsortiumSPC Summary of Product Characteristicsspp. speciesSSRI Selective serotonin reuptake inhibitorsUK United KingdomUnits for SI units see Prescription WritingWHO World Health OrganizationT limited experience of the use of this product andthe CHM requests that all suspected adversereactions should be reported, see Adverse Reactionsto DrugsU considered by the Paediatric Formulary Committeeto be less suitable for prescribing, see How to Usethe BNF for ChildrenLatin abbreviationsDirections should be in English without abbreviation.However, Latin abbreviations have been used whenprescribing. The following is a list of appropriate abbreviations.It should be noted that the English version isnot always an exact translation.a. c. = ante cibum (before food)b. d. = bis die (twice daily)o. d. = omni die (every day)o. m. = omni mane (every morning)o. n. = omni nocte (every night)p. c. = post cibum (after food)p. r. n. = pro re nata (when required)q. d. s. = quater die sumendum (to be taken four timesdaily)q. q. h. = quarta quaque hora (every four hours)stat = immediatelyt. d. s. = ter die sumendum (to be taken three times daily)t.i.d. = ter in die (three times daily)E numbersThe following is a list of common E numbers and theinactive ingredients to which they correspond.E102E104E110E123E124E127E132E142E171E172E200E211TartrazineQuinoline YellowSunset Yellow FCFAmaranthPonceau 4RErythrosine BSIndigo CarmineGreen STitanium DioxideIron oxides, ironhydroxidesSorbic AcidSodium BenzoateE223 Sodium MetabisulphiteE320 Butylated HydroxyanisoleE321 Butylated HydroxytolueneE322 LecithinsE420 SorbitolE421 MannitolE422 GlycerolE901 Beeswax (white andyellow)E1520 Propylene Glycol