WHO Drug Information Vol. 25, No. 2, 2011

WHO Drug Information Vol. 25, No. 2, 2011World Health OrganizationWHO Drug InformationWHO Prequalification ofMedicines ProgrammeFacts and figures for 2010 101Safety and Efficacy IssuesSafety trials for long acting beta-agonists104Rotavirus vaccination: risk of intussusception104Tumour necrosis factor blockers: hepatosplenicT-cell lymphoma 106Dipeptidyl peptidase-4 inhibitors:possible glycaemic complications 106Lenalidomide: risk of new malignancies 106Pneumovax 23®: injection site reactions 107Dabigatran etexilate mesylate capsules:storage and handling 107Proton pump inhibitors: low magnesiumlevels 108Seasonal influenza vaccines 108Ipilimumab: severe immune-mediatedreactions 108Fluticasone propionate: risk ofosteonecrosis 109Varenicline: hyperglycaemia in patientswith diabetes 109Quinine sulfate: serious adversereactions 110Risk of oral clefts in children born tomothers taking topiramate 110WHO training course on pharmacovigilance111Quality Assurance IssuesWHO Certification Scheme: questionsand answers 113Regulatory Action and NewsBuflomedil: marketing authorizationsuspended 122Dolasetron mesylate intravenousinjection: withdrawal 122ContentsAbiraterone acetate approved forlate-stage prostate cancer 122Rituximab approved for Wegenergranulomatosis and microscopicpolyangiitis 122Human normal immuno-globulin: liftingof suspension 123Everolimus approved for pancreaticcancer 123Boceprevir approved for hepatitis C 124Linagliptin approved for type 2 diabetes 124Naproxcinod: withdrawal of marketingauthorization application 124Lumiracoxib: withdrawal of marketingauthorization application 125Erythropoietin: withdrawal of marketingauthorization application 125ATC/DDD ClassificationATC/DDD Classification (temporary) 126ATC/DDD Classification (final) 128Recent Publications,Information and EventsSelection and use of medicines 131Policy guidelines on controlledsubstances 132List of medicines to save mothers andchildren 133World medicines situation 133Artesunate instead of quinine saves lives134Consultation DocumentsThe International PharmacopoeiaRevision of monograph on capsules 135Revision of monograph on tablets 139Paediatric retinol oral solution 147Proposed InternationalNonproprietary NamesList 10515199

World Health OrganizationWHO Drug Information Vol. 25, No. 2, 2011WHO Drug InformationDigital Library,e-mail table of contentsand subscriptionsavailable at:http://www.who.int/druginformation100

WHO Drug Information Vol. 25, No. 2, 2011WHO Prequalification ofMedicines ProgrammeFacts and figures for 2010Evaluation of medicines by the WHOPrequalification of Medicines Programme(PQP) includes assessment of data andinformation on safety, efficacy and quality.Inspections are performed to assesscompliance with good manufacturingpractices (GMP) and include manufacturersof selected active pharmaceuticalingredients (API) and clinical sites.Clinical sites, including contract researchorganizations (CROs), are also inspectedto verify bio-equivalence with goodlaboratory practices and good clinicalpractices.Thirty-six products were prequalified in2010, of which 30 were generics. At theend of 2010, the WHO list of prequalifiedmedicines totalled 252 products manufacturedin 20 countries. WHO prequalification“firsts” included artesunate powderfor injection (which was the first prequalifiedsterile product made in China); thefirst combination tenofovir disoproxilfumarate/lamivudine and the first genericemtricitabine.Six medicines quality control laboratories(QCLs) were also prequalified: one inBolivia, one in Canada, one in Peru, twoin Ukraine and one in Uruguay. At the endof 2010, a total of 17 QCLs had beenprequalified and a further 30 were workingtowards becoming prequalified.Invitations to manufacturers to submit anexpression of interest (EOI) for productevaluation were issued for anti-TB medicines,HIV/AIDS-related care and treatmentproducts, and reproductive healthproducts. The new invitations incorporateadditional products and/or take intoaccount revisions made to WHO treatmentguidelines. Additionally, the firstinvitation to manufacturers of activepharmaceutical ingredients (APIs) wasissued in October 2010, marking thelaunch of WHO prequalification of APIs.(A second, expanded invitation to APImanufacturers to submit an EOI wasissued in March 2011.) It is expected thattime taken to reach prequalification will beshorter for finished pharmaceuticalproducts (FPPs) that are manufacturedusing WHO-prequalified APIs, than forFPPs that are manufactured using APIsthat have not previously been evaluatedby WHO PQP.Assessment activitiesIn 2010, 51 dossiers were submitted and53 dossiers (two of which were receivedin late 2009) were accepted for evaluation.Nearly 1000 assessment reportswere produced. PQP also assessednearly 600 variations submitted bymanufacturers of prequalified products.The assessment sessions held in Copenhagen,Denmark, include a trainingcomponent which is enabling a growingnumber of developing country assessorsto acquire stringent regulatory expertise.The Copenhagen sessions also incorporatetechnical consultations so thatapplicants can discuss technical issuesrelating to their dossiers with assessors.The consultations benefit from the presenceof a range of assessors with considerableassessment experience.A new collaborative procedure for facilitatingregistration of prequalified medicinesin the East African Community (EAC) waspiloted. The overall aim was to identify aframework, for WHO-EAC, for jointevaluation and approval of dossiers and101

WHO Prequalification of Medicines ProgrammeWHO Drug Information Vol. 25, No. 2, 2011inspections of medicine manufacturingsites, and to ensure that these assessmentsare integrated into national regulatorydecision-making. Two assessorseach from three EAC countries (Kenya,Tanzania and Uganda) and six WHOassessors jointly assessed two productdossiers submitted by a single manufacturer.The dossiers were submitted inparallel, and with identical content, toeach participating EAC country and toPQP. The products were both prequalified:HA488 (abacavir, dispersible tablets60 mg) in August 2010 and TB217(amikacin, injection 500 mg/2 ml) inJanuary 2011. For the manufacturer, theprincipal benefit of this joint assessmentwas that once the products had beenjointly assessed and approved by WHO-EAC, they were granted immediateaccess to the markets of each of thecountries that had participated in the jointassessment. For the regulators involved,such joint assessment contributes toharmonization of regulatory requirementsat regional level. PQP is hoping to usethe same model for assessing selected,technically complex, high-priority products.Several partners and stakeholderssee joint assessment as an effectivemeans of speeding up access to muchneeded products.InspectionsPQP inspectors carried out 59 inspectionsin 18 countries: 38 of finishedpharmaceutical product manufacturingsites; five of API manufacturing sites;seven of CROs and nine of pharmaceuticalQCLs. (Inspections were carried outmostly in India and in China, but also inAlgeria, Belgium, Bolivia, Egypt, France,Iran, Kenya, Morocco, the Netherlands,Peru, Russia, South Africa, Tanzania,Uganda, Uruguay, the United States andZimbabwe.)A new collaborative procedure for jointinspections was initiated at the beginningof 2010. A secure web site has beenestablished for the sharing of inspectionplans, arranging of joint inspections, andsharing of information and inspectionreports, with recognition by participatingEAC parties and PQP. This will be furtherexplored and possibly expanded. Jointinspections are planned for 2011 in anattempt to prevent duplication of inspections.Inspection reports will be shared bythe parties following the inspection. It ishoped that the outcome of the inspectionwill be accepted by all participatinginspectorates. PQP continues to invitelocal medicines regulatory authority staffor observers to participate in inspections.The risk assessment procedure foridentifying which API manufacturing sitesshould be inspected has been completedfor substances used to manufactureproducts for the treatment of malaria andTB. It is planned to expand this riskassessment to APIs used in products forthe treatment of HIV/AIDS.Advice and assistancePQP continues to respond to manufacturers’request for assistance concerningissues relating to, for example, bioequivalencestudy protocols and choice ofcomparator products.PQP continues to provide technicalassistance to manufacturers and nationalQCLs that aims at resolving specificpractical problems related to GMP, goodpractices for QCLs and/or meetingmedicines regulatory requirements.Assistance is given in the form of anaudit, advice on development of animprovement plan, and training in technicalor regulatory areas. Follow-up missionsare also organized to supportimplementation of improvement plans. In2010, PQP organized 22 technical assistancemissions to pharmaceutical manufacturersin four countries (Argentina,China, India and Indonesia) and 10technical assistance missions to nationalQCLs (in Argentina, Brazil, Burkina Faso,China, Egypt, Jamaica, Panama, Peruand Yemen).102

WHO Drug Information Vol. 25, No. 2, 2011WHO Prequalification of Medicines ProgrammeTraining and hands-on practice remaincrucial to capacity building. PQP organized,co-organized or supported 23training courses. Training on general orspecific technical issues was given tomanufacturers, and to MRA and QCLstaff, as well as an introduction and/orupdate on PQP requirements and services.Training included group sessions aswell as discussion sessions with membersof assessment or inspection teamsworking with PQP. In 2010, these workshopsinvolved more than 1200 participantsrepresenting regulatory authorities,pharmaceutical manufacturers and QCLstaff.Testing of medicines qualityWhen implementing sampling and testingprojects PQP evaluates specifically thequality of WHO-prequalified products. Ina study of the quality of antimalarials,concluded in 2010, the quality of WHOprequalifiedproducts far exceeded that ofnon-WHO-prequalified products. (Lessthan 4% of WHO-prequalified artemetherlumefantrineand artesunate-amodiaquinesamples failed to comply with internationalquality standards, whereas thefailure rate reached 60% for non-WHOprequalifiedsamples of the same composition.)Similarly, a survey of the quality ofanti-TB medicines conducted in 2009/2010 in Armenia, Azerbaijan, Belarus,Kazakhstan, Ukraine and Uzbekistanshowed that all prequalified productssampled and containing isoniazid/rifampicincomplied with internationalquality standards.Norms and standards underpinning orrelevant to WHO prequalificationactivitiesThe Forty-fifth meeting of the WHOExpert Committee on Specifications forPharmaceutical Preparations adoptedfive monographs for HIV and relatedconditions, four monographs for antimalarialmedicines, six monographs forantituberculosis medicines, two monographsfor influenza-specific antiviralmedicines and one for a reproductivehealth product. The Committee alsoadopted a number of new or revisedguidelines and procedures of directrelevance to PQP’s activities.Improving PQP servicesThe results of a survey of manufacturersprovided further information for developinggreater “client” focus. Based on thesurvey results, PQP staff worked onimprovements to the Programme, someof which have already been implemented.For example, raising awareness of theopportunity for manufacturers to meetand consult with PQP assessors, clarifyingprocedure for resolving disagreementssurrounding questions raisedduring the assessment of product dossiers— and some of which (e.g., reducingthe time taken to review and reply toapplicants during the dossier assessmentprocess, providing the same assessorsthroughout the assessment process for aproduct dossier) depend upon completionof other activities (e.g., finalization ofPQP’s new information managementsystem). Others — for example, theperceived greater stringency of WHOGMP requirements — will require furtherdiscussion with manufacturers.Benefits to manufacturersIn 2010, PQP initiated a study to help itdescribe and quantify the potentialbenefits to manufacturers of having aproduct or products prequalified by WHO.PQP will use the results to develop a“business case for participation in WHOmedicines prequalification” for presentationto manufacturers.Further information on the WHO Prequalificationof Medicines Programme, includingthe full list of medicines prequalifiedby WHO can be found at: http://www.who.int/prequal.103

WHO Drug Information Vol. 25, No. 2, 2011Safety and Efficacy IssuesSafety trials for long actingbeta-agonistsUnited States of America — To furtherevaluate the safety of long acting betaagonists(LABAs) when used in combinationwith inhaled corticosteroids for thetreatment of asthma, the Food and DrugAdministration (FDA) is requiring manufacturersto conduct five randomized,double-blind, controlled clinical trialscomparing the addition of LABAs toinhaled corticosteroids versus inhaledcorticosteroids alone.Four clinical trials will be conducted inadult and adolescent patients 12 yearsof age and older to evaluate:• Budesonide and formoterol.• Fluticasone and salmeterol.• Mometasone and formoterol.• Formoterol.One clinical trial will be conducted inpaediatric patients aged 4 to 11 years andwill include 6200 patients. Patients in alltrials will be treated for six months, andthe primary endpoint will be a compositeof serious asthma outcomes: asthmarelateddeath, intubation, or hospitalization.The paediatric trial will also assessother relevant quality of life endpointssuch as days of school missed andemergency room visits because ofasthma related illness.The clinical trials will begin in 2011 andFDA expects to receive results in 2017.Reference: FDA Drug Safety Communication,15 April 2011 at http://www.fda.gov/Drugs/DrugSafetyRotavirus vaccination: riskof intussusceptionAustralia — The Therapeutic GoodsAdministration (TGA) has undertaken aninvestigation of a possible associationbetween the use of the rotavirus vaccinesRotarix® and RotaTeq® and the occurrenceof a rare form of bowel obstructionknown as intussusception (IS). This is acondition caused by the telescoping ofone segment of the bowel into another. Itis estimated to occur each year in around80 per 100 000 children under 12 monthsof age, which represents approximately200 cases per year in Australia. The peakincidence is in infants 5–10 months ofage, with 80% of cases occurring before24 months of age. It is much more commonin males than females.IS was found to be a side effect of thefirst generation rotavirus vaccine,RotaShield®, that was available in theUnited States in 1998–1999 and wasestimated to cause IS in 10–20 of every100 000 doses given to infants. It wasvoluntarily withdrawn from the US marketin October 1999 (1, 2).RotaShield® was not used outside theUSA, however, as the historical incidenceof IS is 2.5 to 3 times higher in infants inAustralia than in the US, this would havetranslated to 25–60 cases of IS for every100 000 doses of RotaShield®.Subsequently, two new rotavirus vaccines,Rotarix® and RotaTeq® weredeveloped and both were tested in largestudies designed to explore whether therewas a risk of IS (3, 4). In Australia, twopost-marketing studies have been conductedto investigate whether the new104

WHO Drug Information Vol. 25, No. 2, 2011Safety and Efficacy Issuesrotavirus vaccines are associated with anincreased risk of IS. The first study wasconducted using two surveillance systems,the Paediatric Enhanced DiseaseSurveillance (PAEDS) and the AustralianPaediatric Surveillance Unit (APSU). Thisstudy found an apparent four-fold increasedrisk of IS in babies within oneweek of being given the first dose ofeither vaccine, compared with historicaldata on hospitalizations coded as IS, butno overall increase in overall rates of ISup to the age of nine months.Following this, a large self-controlled caseseries (SCCS) study using data on allhospitalized cases coded as IS wascommissioned by the TGA. This studyfound a statistically significant four-foldincrease in the occurrence of IS in thefirst 1–7 days following the first dose ofeither Rotarix® or RotaTeq® comparedwith other time periods after vaccinereceipt. This increase in risk translates toapproximately two additional cases of ISoccurring in every 100 000 first doses ofvaccine administered, or six additionalcases each year in children under 12months of age in Australia.The World Health Organization (WHO)and the Australian Technical AdvisoryGroup on Immunization (ATAGI) haverecommended the continued use ofrotavirus vaccine for infants.References1. Withdrawal of Rotavirus Vaccine Recommendation.MMWR 1999;48(3):1107.2. Murphy T, Gargiullo P, Massoudi M, NelsonD et al. Intussusception among infants givenan oral rotavirus vaccine. New EnglandJournal of Medicine 2001; 344(8):564–723. Ruiz-Palacios G, P rez-Schael I, VelazqueaF, H HA, Breuer T et al. Safety and efficacy ofan attenuated vaccine against severe rotavirusgastroenteritis. New England Journal ofMedicine 2006;354(1):11–22.4. Vesikari T, Matson D, Dennehy P, DammePV et al. Safety and efficacy of a pentavalenthuman-bovine (WC3) reassortant rotavirusvaccine. New England Journal of Medicine2006;354(1):23–33.5. Macartney KK, Porwal M, Dalton D, CrippsT et al. Decline in rotavirus hospitalisationsfollowing introduction of Australia’s nationalrotavirus immunisation programme. J PaediatrChild Health 2011; published online: 18 Jan2011 DOI: 10.1111/j.1440-1754.2010.01953.6. Lambert SB, Faux CE, Hall L, Birrell FA etal. Early evidence for direct and indirect effectsof the infant rotavirus vaccine program inQueensland. Med J Aust 2009; 191: 157–160.7. Haber P, Patel M, Izurieta H, Baggs J et al.Postlicensure monitoring of intussusceptionafter RotaTeq® vaccination in the UnitedStates, February 1, 2006, to September 25,2007. Pediatrics 2008;121(6):1206–12.8. Velazquez FR, Colindres R, Grajales C,Hernandez MT, Mercadillo MG, Torres FJ,Yolanda M Apolinar C, DeAntonio-Suarez R,Ortega E, Blum M, Breuer T, Verstraeten T.Postmarketing surveillance of intussusceptionfollowing mass introduction of the humanrotavirus vaccine in Mexico: an interimanalysis. Excellence in Paediatrics, London,December 2–4, 20109. World Health Organization, Global AdvisoryCommittee on Vaccine Safety. Statement onRotarix® and Rotateq® vaccines and intussusception.22 September 2010.10. Buttery JP, Danchin MH, Lee KJ, CarlinJB, McIntyre PB, Elliott EJ, Booy R, Bines JEfor the PAEDS/APSU Study Group. Intussusceptionfollowing rotavirus vaccine administration:post marketing surveillance in theNational Immunization Program in Australia.Vaccine, 2011. In Press.11. Tapiainen T, Bonhoeffer J, Heininger U.Evaluation of the Brighton Collaboration casedefinition of acute intussusception during activesurveillance. Vaccine 2006;24(9):1483–7.12. Galati JC, Harsley S, Richmond P, CarlinJB. The burden of rotavirus-related illnessamong young children on the Australian healthcare system. ANZ Journal of Public Health2006;30:416-421.105

Safety and Efficacy IssuesWHO Drug Information Vol. 25, No. 2, 2011Tumour necrosis factorblockers: hepatosplenicT-cell lymphomaUnited States of America — The Foodand Drug Administration (FDA) continuesto receive reports of hepatosplenic T-Celllymphoma (HSTCL), primarily in adolescentsand young adults being treated forCrohn disease and ulcerative colitis withmedicines known as tumour necrosisfactor (TNF) blockers, as well as withazathioprine, and/or mercaptopurine.Crohn disease and ulcerative colitiscause inflammation of the digestivesystem. Common symptoms are pain inthe abdomen, cramps, and diarrhoea.Bleeding from the rectum, weight loss,joint pain, skin problems and fever alsomay occur. Children with the disease mayhave growth problems, develop intestinalblockage and experience malnutrition.FDA believes the risks and benefits ofusing TNF blockers, azathioprine, and/ormercaptopurine should be carefullyweighed when prescribing these drugs tochildren and young adults, especially forthe treatment of Crohn disease andulcerative colitis.The product labels for infliximab(Remicade®) and adalimumab (Humira®)have been updated and the productlabels for azathioprine and mercaptopurineare being updated to include warningsabout HSTCL that have been reportedin patients treated with theseproducts.Reference: FDA Drug Safety Communication,14 April 2011 at http://www.fda.gov/Drugs/DrugSafetyDipeptidyl peptidase-4inhibitors: possible glycaemiccomplicationsJapan — The Ministry of Health, Labourand Welfare (MHLW) has warned aboutthe risk of hypoglycaemia associatedwith concomitant use of dipeptidyl peptidase-4(DPP-4) inhibitors and sulfonylureas,and the risk of diabetic ketoacidosisand hyperglycaemia afterswitching from insulin to glucagon-likepeptide-1 (GLP-1) receptor agonists.DPP-4 inhibitors and GLP-1 receptoragonists are antidiabetic drugs whichinactivate incretin. Incretin is a gastrointestinalhormone which stimulatesinsulin secretion. DPP-4 inhibitors areused to treat type 2 diabetes mellitus byincreasing the endogenous active incretinlevel and thereby controlling bloodglucose. As of December 2010, sitagliptinphosphate hydrate, vildagliptin, andalogliptin benzoate have been approvedin Japan.GLP-1 receptor agonists are used to treattype 2 diabetes mellitus by binding to theGLP-1 receptor to promote insulin secretionin response to the increase in bloodglucose. As of December 2010, liraglutide(genetic recombination) and exenatidehave been approved.Reference: Pharmaceuticals and MedicalDevices Safety Information, No.275. December2010 at http://www.pmda.go.jp/englishLenalidomide: risk ofnew malignanciesUnited States of America — The Foodand Drug Administration (FDA) hasprovided information on clinical trials thatfound that patients treated with lenalidomide(Revlimid®) may be at increasedrisk of developing new types of cancercompared to patients who did not take thedrug.FDA is currently reviewing all availableinformation on this potential risk andrecommends that patients continuelenalidomide treatment as prescribed bytheir physician. The benefits and the risks106

WHO Drug Information Vol. 25, No. 2, 2011Safety and Efficacy Issuesshould be carefully weighed when prescribingthis drug. Lenalidomide is usedto treat myelodysplastic syndrome and isused along with other drugs to treatpeople with multiple myeloma.Preliminary data derived from evaluationof outcomes after longer-term exposureto lenalidomide and from controlledclinical trials conducted inside and outsidethe Unites States shows an increasedincidence of some secondprimary malignancies, particularly acutemyelogenous leukemia (AMaL) and B-celllymphoma malignancies when comparedto controls. Since lenalidomide is ananalogue of thalidomide, FDA is alsocurrently reviewing all available informationon this potential risk for thalidomide.Reference: FDA Drug Safety Communication,8 April 2011 at http://www.fda.gov/Drugs/DrugSafetyPneumovax 23®:injection site reactionsAustralia — The Therapeutic GoodsAdministration (TGA) is advising healthprofessionals not to administer a secondor subsequent dose of Pneumovax 23®vaccine pending the outcome of a reviewof an apparent increased rate of injectionsite reactions following administration ofthe second dose.Pneumovax 23® vaccination is used toprevent life threatening bacterial infectionsfor anyone who is at high risk ofpneumococcal infections.Pneumovax 23® vaccine is known to beassociated with a high rate of localinjection site reactions which can includesevere injection site reactions such ascellulitis and abscess. There is varyingevidence from published trials as towhether injection site reactions are morecommon following revaccination.The Australian Technical Advisory Groupon Immunization (ATAGI) is currentlyreviewing the place of Pneumovax 23®in the National Immunization Programme.This alert is not applicable to use of the7-valent pneumococcal conjugate vaccinePrevenar® or the 10-valent pneumococcalconjugate vaccine, Synflorix®, whichare given to babies.Reference: Therapeutic Goods AdministrationSafety Alert. 18 April 2011. http://www.tga.gov.au/safety/alerts-medicine-pneumovax-110416.htmDabigatran etexilate mesylatecapsules: storage and handlingUnited States of America — The Foodand Drug Administration (FDA) is alertingthe public to important storage andhandling requirements for dabigatranetexilate mesylate (Pradaxa®) capsules.Due to the potential for product breakdownfrom moisture and loss of potency,Pradaxa® capsules should only bedispensed and stored in the original bottleor blister package. However, manyconsumers use pill boxes or pill organizersto aid them in remembering to taketheir medications.Although the current Pradaxa® labelstates that the product should be discarded30 days after the original bottle isopened, data currently under review bythe FDA indicate that the product maintainsits potency up to 60 days after bottleopening as long as it is stored in theoriginal bottle and the handling requirementsare met — including that the cap isclosed tightly after use and the bottle iskept away from excessive moisture, heatand cold. Pradaxa® capsules will hydrolyseover time when exposed to humidity,causing a breakdown of active ingredientand rendering the medication less effective.Reference: FDA Drug Safety Communication,29 March 2011 at http://www.fda.gov/Drugs/DrugSafety107

Safety and Efficacy IssuesWHO Drug Information Vol. 25, No. 2, 2011Proton pump inhibitors:low magnesium levelsUnited States of America — The Foodand Drug Administration (FDA) is informingthe public that prescription protonpump inhibitor (PPI) drugs may causehypomagnesaemia if taken for prolongedperiods of time (in most cases, longerthan one year). In approximately onequarterof the cases reviewed, magnesiumsupplementation alone did notimprove low serum magnesium levelsand the PPI had to be discontinued.PPIs are used to treat gastroesophagealreflux disease (GERD), stomach andsmall intestine ulcers, and inflammation ofthe esophagus.Prescription PPIs include esomeprazolemagnesium, dexlansoprazole, omeprazole,lansoprazole, pantoprazolesodium, and abeprazole sodium.Reference: FDA Drug Safety Communication,2 March 2011 at http://www.fda.gov/Drugs/DrugSafetySeasonal influenza vaccinesAustralia — During the 2010 influenzaseason, an excess number of cases offebrile reactions and febrile convulsionswere observed in paediatric populationsfollowing immunization with one of theregistered seasonal trivalent influenzavaccines. Consequently, the TherapeuticGoods Administration (TGA) has imposeda condition on the registration of all 2011seasonal influenza vaccines with apaediatric indication which were notsupplied in Australia in 2010. Sponsorsare required to undertake active surveillanceof children from six months to nineyears of age to ensure effective monitoringof paediatric populations in Australiapreviously unexposed to these vaccines.Two sponsors were unable to meet thiscondition of registration. Although thesafety of Agrippal® and Fluarix ®hasbeen demonstrated in the northernhemisphere 2010/2011 influenza season,the TGA does not have any safety dataon the use of these vaccines in Australianchildren. Hence, the TGA recommendsthat these vaccines are not used in anychild under the age of nine years.For children under the age of nine years itis recommended that they be vaccinatedwith either Influvac® or Vaxigrip®. Thesetwo vaccines were not associated withincreased rates of fever or febrile reactionsin 2010.Reference: Therapeutic Goods AdministrationSafety Advisory, 11 March 2011. http://www.tga.gov.au/safetyIpilimumab: severe immunemediatedreactionsUnited States of America — The Foodand Drug Administration (FDA) hasposted information from the manufacturerof Ipilimumab (Yervoy®) about the riskevaluation and mitigation strategy(REMS) developed to ensure that thebenefits of ipilimumab outweigh the risksof severe and fatal immune-mediatedadverse reactions.Ipilimumab was approved in March 2011with a boxed warning stating that use ofthe product can result in severe and fatalimmune-mediated adverse reactions dueto T-cell activation and proliferation.These immune-mediated reactions mayinvolve any organ system. However, themost common severe immune-mediatedadverse reactions are enterocolitis,hepatitis, dermatitis (including toxicepidermal necrolysis), neuropathy, andendocrinopathy. The majority of theseimmune-mediated reactions initiallymanifested during treatment. However, aminority occurred weeks to months afterdiscontinuation.Reference: FDA Medwatch Communication,Dear Healthcare Professional Letter, 6 April2011 at http://www.fda.gov/Drugs/DrugSafety108

WHO Drug Information Vol. 25, No. 2, 2011Safety and Efficacy IssuesFluticasone propionate:risk of osteonecrosisCanada — Health Canada has receivedfive reports of osteonecrosis suspectedof being associated with fluticasonepropionate.The potential for osteonecrosis with highdoses of inhaled corticosteroids has beensuggested in the literature. Becausecorticosteroid-induced osteonecrosistends to occur in younger patients andtreatment options for advanced diseaseare limited, early identification is important.Fluticasone propionate is a highly potentglucocorticoid anti-inflammatory steroid.In Canada, it is available as an aqueousnasal spray, an inhalation aerosol, apowder for inhalation and a topical cream(1–3). Steroid-induced osteonecrosis, oravascular necrosis, is characterized bybone cell death resulting from compromizedblood supply. Corticosteroids,administered orally or parenterally, havebeen associated with osteonecrosis (4).Osteonecrosis related to inhaled ortopical use of steroids has also beenreported but the oral or parenteral use ofsteroids was a confounding factor (4).The potential for osteonecrosis with highdoses of inhaled corticosteroids, such asin the treatment of severe persistentasthma or eosinophilic oesophagitis, hasbeen suggested (4).Systemic adverse reactions may occurwith intranasal and inhaled use of corticosteroids(1, 2). The long-term effects offluticasone propionate are still unknown.The relative determinants of systemicadverse reactions to inhaled and intranasalcorticosteroids have been assessedand fluticasone propionate was determinedto have a high systemic potency(5). Because corticosteroid-inducedosteonecrosis tends to occur in youngerpatients (the average age at onset is 33)and treatment options for advanceddisease are limited, early identification isimportant (4).Extracted from the Canadian AdverseReaction Newsletter, Volume 21(2), April2011 at http://www.healthcanada.gc.caReferences1. Flovent HFA, Flovent Diskus® (fluticasonepropionate) [product monograph]. Mississauga(ON): GlaxoSmithKline Inc.; 2010.2. Flonase® (fluticasone propionate) [productmonograph]. Mississauga (ON):GlaxoSmithKline Inc.; 2004.3. Advair Diskus (salmeterol xinafoate/fluticasone propionate) [product monograph].Mississauga (ON): GlaxoSmithKline Inc.;2008.4. Powell C, Chang C, Naguwa S, et al.Steroid induced osteonecrosis: an analysis ofsteroid dosing risk. Autoimmun Rev2010;9(11):721–43.5. Lipworth BJ, Jackson CM. Safety ofinhaled and intranasal corticosteroids. DrugSaf 2000;23(1):11–33.Varenicline: hyperglycaemiain patients with diabetesCanada — Health Canada has received18 reports of hyperglycaemia suspectedof being associated with varenicline(Champix®) in patients with type 1 andtype 2 diabetes.Varenicline is indicated for smokingcessationtreatment in adults in conjunctionwith smoking-cessation counselling.The current Canadian product monographlists diabetes mellitus and hypoglycaemiaunder “less common clinical trialadverse drug reactions” and describesthese adverse reactions (ARs) as infrequentand rare, respectively.Diabetes mellitus is a chronic metabolicdisorder characterized by the presence ofhyperglycaemia and consequently is a109

Safety and Efficacy IssuesWHO Drug Information Vol. 25, No. 2, 2011confounder. Other confounders identifiedin some of the reports included infection,medications (e.g., insulin, oral antidiabeticagents, diuretics), alcohol consumptionand smoking cessation. In some instances,the patient was still smokingwhile taking varenicline.Extracted from the Canadian AdverseReaction Newsletter, Volume 21(2), April2011 at http://www.healthcanada.gc.caReferences1. Champix® (varenicline) [product monograph].Kirkland (QC): Pfizer Canada Inc;2010.2. Kristensen PL, Pedersen-Bjergaard U,Thorsteinsson B. Varenicline may triggersevere hypoglycaemia in type 1 diabetes.Diabet Med 2008;25(5):625-6.Quinine sulfate: seriousadverse reactionsCanada — Quinine sulfate, in combinationwith a second antimalarial drug, isrecommended for the treatment of uncomplicatedPlasmodium falciparummalaria. Quinine sulfate is not indicated inCanada for the prevention or treatment ofnocturnal leg cramps. However, quininesulfate is used for the prevention andtreatment of leg cramps, at a dose of 200to 300 mg at bedtime. The use of quininesulfate to prevent leg cramps has been asubject of recent concern. Several internationalregulators have taken action toeither withdraw this indication for use orhave added conditions for its use for legcramps.Adverse reactions to quinine sulfateinclude life-threatening blood-relatedreactions, such as sudden, severethrombocytopenia.Extracted from the Canadian AdverseReaction Newsletter, Volume 21(2), April2011 at http://www.healthcanada.gc.caReferences1. CATMAT. Canadian recommendations forthe prevention and treatment of malariaamong international travellers 2009. CanCommun Dis Rep 2009;35(Suppl 1):1–82.2. Quinine sulfate [Canadian PharmacistsAssociation monograph]. In: e-CPS. Ottawa(ON): Canadian Pharmacists Association;2010.3. Adverse Drug Reactions Advisory Committee(ADRAC) Quinine indications – crampsdeleted. Aust Adv Drug Reactions Bull2004;23(5):20.4. Medsafe. Quinine – not for leg crampsanymore. Prescriber Update 2007;28(1):2–3.5. US Food and Drug Administration. Quininesulfate (marketed as Qualaquin®): off-label(not approved by FDA) use of quinine. FDADrug Safety Newsletter 2009;2(2):11–3.6. Medicines and Healthcare products RegulatoryAgency. Quinine: not to be used routinelyfor nocturnal leg cramps. Drug Safety Update2010;3(11):3–4.7. US Food and Drug Administration. FDADrug Safety Communication: New riskmanagement plan and patient MedicationGuide for Qualaquin® (quinine sulfate). 7August 2010.8. Aster RH, Bougie DW. Drug-inducedimmune thrombocytopenia. N Engl J Med2007;357(6):580–7.9. Brinker AD, Beitz J. Spontaneous reports ofthrombocytopenia in association with quinine:clinical attributes and timing related to regulatoryaction. Am J Hematol 2002;70(4):313–7.Risk of oral clefts in childrenborn to mothers takingtopiramateUnited States of America — The Foodand Drug Administration (FDA) is informingthe public of new data that show thatthere is an increased risk for the develop-110

WHO Drug Information Vol. 25, No. 2, 2011Safety and Efficacy Issuesment of oral clefts in infants of womentreated with topiramate (Topamax® andgeneric products) during pregnancy.Topiramate is an anticonvulsant used totreat epilepsy. It is approved for use toprevent migraine headaches. Topiramateis being placed in Pregnancy Category Dindicating positive evidence of humanfetal risk but with potential benefits thatmay be acceptable in certain situationsdespite its risks.Reference: FDA Drug Safety Communication,4 March 2011 at http://www.fda.gov/Drugs/DrugSafetyWHO training course onpharmacovigilanceA recent survey by the WHO Programmefor International Drug Monitoring identifiedserious gaps in technical capacity forpharmacovigilance (PV) in resourcelimited settings. The Inter-regionalPharmacovigilance Training Course, heldin February 2011 in New Delhi, India, waspart of the WHO strategy to help establishminimum standards for PV as identifiedby WHO and the Global Fund during aconsensus meeting in 2010.The course identified leveraging opportunitiesoffered by liaison and sharingresources with lymphatic filariasis publichealth programmes. By introducing PVwithin mass preventive treatment campaigns,the quality of care and patientsafety within such programmes could besignificantly improved.The specific objectives of the trainingcourse were to:• Raise awareness about public healthissues and patient safety in relation tothe use of medicines.• Demonstrate the importance of PVactivities in improving patient safety andtreatment outcomes.• Provide training on the latest tools inbasic adverse drug reaction (ADR)reporting, to enhance reporting withincountries and to the WHO Programmefor International Drug Monitoring.• Build or reinforce capacity of nationalPV centres.• Share experiences and challengesfaced in establishing or strengtheningPV programmes.• Establish networking among regulatoryagencies, PV centres, national neglectedtropical diseases (NTD) controlprogrammes and WHO for informationsharing and providing assistance indetecting signals and making judgmentsbased on sound science.Two participants per country attendedfrom Cambodia, Lao PDR, Maldives,Nepal and Viet Nam, with six participantsfrom India. Others represented thenational PV centre or the NTD controlprogramme.The five-day course covered the followingtopics:• WHO Programme for International DrugMonitoring.• Establishing a PV centre; how to promotereporting.• Vigibase (a WHO global database ofindividual case reports), VigiFlow (aweb-based case report managementsystem), WHO Adverse ReactionTerminology and WHO Drug Dictionary.• Causality assessment.• Collaboration with public health programmesand NTD control programmesin particular.• Risk management and the prevention ofADRs.111

Safety and Efficacy IssuesWHO Drug Information Vol. 25, No. 2, 2011• Rational use of medicines.• Communication in pharmacovigilance.• Development of country-specific actionplans for next year.At the end of the course participantspresented draft plans of priority activitiesfor the next ten months for PV in theirsettings, with key deliverables, timelinesand expected outcomes.Countries that are not yet members of theWHO Programme (Lao PDR, Maldives)described their plans to establish a PVcentre and join the Programme in thefuture. Participants from Cambodia, anassociate member of the WHO Programme,expressed their intention tobecome a full member by sending arequired number of ADR reports to theWHO Programme. Three countries thatare members of the WHO Programme —India, Nepal, and Viet Nam — presentedplans to strengthen or expand theircurrent PV work by holding workshops onPV for stakeholders, improving collaborationbetween PV and public health programmesand other actions. Participantsfrom Nepal and Viet Nam confirmed thatthe course was useful in establishingcollaboration for the first time between thenational PV and the NTD control programmes.Reference: World Health Organization.Pharmaceutical Newsletter, April 2011 athttp://www.who.int/medicinesSpontaneous monitoring systems are useful in detecting signals of relatively rare, serious orunexpected adverse drug reactions. A signal is defined as “reported information on a possiblecausal relationship between an adverse event and a drug, the relationship being unknown orincompletely documented previously. Usually, more than a single report is required to generatea signal, depending upon the seriousness of the event and the quality of the information”.All signals must be validated before any regulatory decision can be made.112

WHO Drug Information Vol. 25, No. 2, 2011Quality Assurance IssuesWHO Certification SchemeThe WHO Certification Scheme on the Quality of Pharmaceutical Products Movingin International Commerce is an international voluntary agreement mechanism whichprovides information to participating countries on the quality status of finished pharmaceuticalproducts moving in international commerce. The primary focus of theScheme is the Certificate of a Pharmaceutical Product (CPP).The WHO Expert Committee on Specifications for Pharmaceutical Preparations(ECSPP) recommended that the WHO Certification Scheme on the Quality of PharmaceuticalProducts Moving in International Commerce should be reviewed in linewith changing practices and rapid globalization of the pharmaceutical manufacturingsector, regulatory environment and procurement systems. However, the Schemecan only be opened for revision by decision of the World Health Assembly (1). As aninterim measure, the ECSPP requested that a question and answer document onthe functions of the Scheme should be prepared (2). Version one of the documenthas been developed with the aim of improving understanding of the objectives of theScheme and its implications for quality improvement and provision of effective, safemedicines by participating countries. Comments and suggestions on this documentmay be sent to Dr Samvel Azatyan, Medicines Regulatory Support Programme, WorldHealth Organization, 1211 Geneva 27, Switzerland, or e-mail: azatyans@who.int.WHO Certification Scheme:questions and answersQ1 What is the WHO CertificationScheme on the Quality of PharmaceuticalProducts Moving in International Commerce?A1 It is a Scheme developed by theWorld Health Organization (WHO) inresponse to the request of WHO MemberStates to facilitate international trade inpharmaceutical products between MemberStates.Q2 When was the Scheme developed?A2 It was first developed in 1975. Sincethen it has been revised in 1988, 1992and in 1997.Q3 How can it facilitate trade in pharmaceuticalproducts?A3 The Scheme is an administrativeinstrument that requires a participatingMember State (a certifying country), uponapplication by a commercially interestedparty (the applicant company), to certify/attest to the competent authority ofanother participating Member State (therecipient country) that:• A specific pharmaceutical product isauthorized for marketing in the certifyingcountry, or if not, the reason why authorizationhas not been accorded.• The manufacturing facilities and operationsconform to good manufacturingpractices (GMP) as recommended byWHO.113

Quality Assurance IssuesWHO Drug Information Vol. 25, No. 2, 2011Q4 Why is it called the WHO CertificationScheme?A4 It is called the WHO CertificationScheme because it was developed byWHO in response to the request ofMember States.Q5 How does the Scheme operate?A5 The Scheme operates as follows:The certificate recipient authority has inits national medicine legislation or guidelinesa requirement for the submission ofa Certificate for a Pharmaceutical Product(CPP) for products being imported intothe country as a support to ensure thequality of the product being imported. (Insome countries the CPP forms part of thedossiers to be submitted to the medicinesregulatory authority (MRA) to have aproduct registered by the authority).The applicant/importing company requestsa CPP from the certifying authoritythrough the exporting company.The certifying authority issues a CPP tothe importing/applicant company via theexporting company. At the time of thedevelopment of the Scheme the understandingwas that a CPP would be sentdirectly to the recipient authority by theissuing authority.Q6 Is the Scheme mandatory?A6 No. The Scheme is not mandatory. Itis a voluntary agreement devised toenable countries with limited regulatorycapacity to obtain partial assurance fromexporting countries concerning thequality, safety and efficacy of the pharmaceuticalproduct they plan to import.Q7 Can anyone issue a CPP?A7 No. Only countries and regionalorganizations such as the EuropeanMedicines Agency (EMA) that are party tothe Scheme can issue a CPP.Q8 How can a WHO Member State orregional organization be eligible forparticipation in the Scheme?A8 Any WHO Member State or regionalorganization intending to participate in theScheme may do so by notifying theDirector-General of WHO in writing:• Of its willingness to participate in theScheme.• Of any significant reservations it intendsto observe relating to its participation.• By providing the names and address ofits MRA or other competent authority.Q9 Where can one find the list of organizationsand countries party to theScheme?A9 WHO publishes the names andaddresses of Member States party to theScheme. The list is available at http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/en/index.html. A hard copy ofthe list is also published and distributed toMember States. The list is regularlyupdated.Q10 Does the list of Member States andorganizations party to the Schemeprovide the names and addresses ofthose government organizations authorizedto sign and issue a CPP?A10 Yes. The list provides the namesand full addresses of those governmentorganizations authorized to sign andissue a CPP. MRAs receiving a CPP canuse this list to check and verify if thecertificate they are receiving has beenissued by the authorized organization.Q11 Is there any written document thatprovides detailed information on the WHOCertification Scheme?114

WHO Drug Information Vol. 25, No. 2, 2011Quality Assurance IssuesA11 Yes. Guidelines for implementationof the WHO Certification Scheme on theQuality of Pharmaceutical ProductsMoving in International Commerce areavailable at http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/guidelines/en/index.html”http://www.who.int/medicines/areas/quality_safety/regulation_legislation/certification/guidelines/en/index.html.Q12 What should Member States andregional organizations possess in order toissue a CPP to support the export pharmaceuticalproducts?A12 In order to issue a CPP, MemberStates and regional organizations shouldhave the following infrastructure andsystems in place:• An effective national licensing systemfor pharmaceutical products, manufacturersand distributors.• GMP requirements consonant withthose recommended by WHO to whichall manufacturers of finished pharmaceuticalproducts (FPPs) are required toconform.• Effective controls to monitor the qualityof pharmaceutical products registeredor manufactured within the country,including access to an independentquality control laboratory.• A national pharmaceutical inspectoratehaving the technical competence,experience and resources to assesswhether GMP and other controls areeffectively implemented and the legalpower to conduct appropriate investigations.• The administrative capacity to issue therequired certificates, to institute inquiriesin the case of a complaint associatedwith a potentially serious quality defector other hazard and to notify WHO andother concerned parties.Q13 Does WHO issue CPPs?A13 No. WHO does not issue CPPs orany of the certificates described under theScheme.Q14 Should a CPP issued by MemberStates bear the WHO emblem or refer tothe WHO acronym?A14 No. Certificates should not bear theWHO emblem or the acronym. Use of theemblem or acronym creates the impressionthat the certificate is issued or endorsedby WHO. This is an illegal act andcountries receiving such CPPs shouldreject them and report such practices toWHO.Q15 What products are covered underthe WHO Certification Scheme?A15 Pharmaceutical products are coveredunder the Scheme and include:• FPPs intended for administration tohuman beings.• Pharmaceutical products intended foradministration to food-producing animals.• Active pharmaceutical ingredients(APIs). There is now a separate schemecalled the WHO pharmaceutical startingmaterials certification scheme (SMACS)which has guidelines on importation ofAPIs.Q16 What are the different types ofCertificate that can be requested withinthe scope of the Scheme?A16 Three types of certificate can berequested within the scope of theScheme:• A Certificate for a PharmaceuticalProduct (CPP) or Product Certificate(PC);115

Quality Assurance IssuesWHO Drug Information Vol. 25, No. 2, 2011• A Statement of Licensing Status ofPharmaceutical Product(s) (SLSPP);• Batch Certificate of a PharmaceuticalProduct (BCPP).Q17 By whom and when is a Certificatefor a Pharmaceutical Product (CPP)issued?A17 A CPP is issued by the competentauthority of the exporting country and isintended for use by the competent authorityof the importing country:• When a pharmaceutical product isunder consideration for a productlicence/marketing authorization forimportation and sale in the importingcountry.• When administrative action is requiredto renew, extend, vary or review suchlicence.Q18 When and by whom is a Statementof Licensing Status of PharmaceuticalProduct(s) (SLSPP) issued?A18 An SLSPP is issued by the competentauthority of the exporting country andis intended for use by importing agentswhen considering bids in an internationaltender. It is requested by the importingagent as a condition for bidding.Q19 What is a Batch Certificate?A19 A Batch Certificate accompanies andattests to the quality and expiry date of aspecific batch or consignment that hasalready been licensed/approved formarketing in the importing country.A batch certificate is usually issued by themanufacturer.In case of biological products, a lotcertificate is issued by the competentauthority of the exporting country.Q20 Is there a standard format forCPPs?A20 Yes, there is a standard format. TheWHO standard format was last agreed bythe World Health Assembly in 1997 (1).The standard WHO format for CPPsfacilitates understanding and review bythe recipient authority. It obliges certifyingauthorities to disclose important informationto the importing country.Recipient authorities should refrain fromobtaining data other than in the WHOstandard format or in addition to thestandard CPP format.Certifying authorities should not issue afree-sale certificate. This has beenreplaced by the WHO format CPP.Q21 Is the CPP evidence of quality,safety, efficacy review and approval?A21 Yes, the CPP is based on theassumption that the authorities issuing aCPP have the capacity to assess thequality, safety, and efficacy (QSE) of theproduct they have approved for marketing.Based on the intention of the Schemeand when evidence of approval in anothercountry is required, a recipientauthority may request a CPP if it isunable to undertake a full review of QSEdata.Q22 Does the CPP provide evidence ofgood manufacturing practices (GMP)status?A22 Yes. The GMP declaration in theCPP refers to assurance of GMP for theproduct approved in the certifying countryat the stated manufacturing site.In addition, certificates from medicinesregulatory authorities (MRAs) party to thePharmaceutical Inspection Cooperation116

WHO Drug Information Vol. 25, No. 2, 2011Quality Assurance IssuesScheme (PIC/S) and International Conferenceon Harmonisation (ICH) (USA,Japan, and EU) provide evidence of GMPstatus.Q23 What is the difference betweenapproval of the quality data in the submissionand evidence of GMP?A23 Approval of the quality information ina submission is a determination of howthe applicant proposes to manufactureand control the quality of the product atthe time of manufacture and throughoutthe life of the product.Evidence of GMP compliance confirmsthat the applicant company has been ableto demonstrate that the manufacturingfacilities and operations conform to goodmanufacturing practices (GMP) asrecommended by WHO.Q24 When would a CPP be required?A24 When the CPP replaces either a fullor partial quality, safety and efficacy(QSE) review. The CPP would be acondition of approval but it would not berequired at the time of submission.If local legislation stipulates provision of aCPP at the time of submission, theauthority review should comprise averification procedure with published,communicated timelines that should beshort and avoid delaying patient access.Q25 Are there any alternatives to a CPPas evidence of approval by an MRA?A25 In addition to the WHO CertificationScheme other forms of evidence include:• Product approval letters (or copies oflicences) from well-established MRAs,e.g., Australia, Canada, China, Denmark,Finland, Germany, India, Japan,Norway, Republic of Korea, Spain,United Kingdom, United States ofAmerica.• Positive scientific opinion from theEuropean Medicines Agency (EMA).• Decisions of the European Commission.• Licensing/approval information onregulatory authority web sites.• Evidence of approval on the UnitedStates Food and Drug Administrationweb site.Q26 Is it necessary for a pharmaceuticalproduct to be exported from the samecountry as the certifying authority?A26 No. It is not necessary for theproduct to be exported from the certifyingcountry as long as a declaration of GMPassurance appears on the CPP.The Scheme was established on thebasis that the certifying country was alsothe country where finished productmanufacture took place and was, therefore,the exporting country. Subsequentrevisions to the Scheme allow scope forCPPs to be issued by other referenceauthorities. Most certifying authoritiescurrently provide CPPs when the finishedproduct is not manufactured in the certifyingcountry on the basis of GMP assurance.Many authorities assume that certifyingauthorities issue CPPs even whenfinished product manufacture does notoccur in the certifying country. Strictadherence to the above assumptionpotentially limits licensing and registrationoptions and can delay the introduction oraffect the continued supply of neededmedicines.Q27 Is it possible to obtain a CPP from acertifying authority that is not of thecountry where the manufacture of thefinished product takes place?A27 Yes. The GMP declaration on theCPP will refer to assurance of GMP for117

Quality Assurance IssuesWHO Drug Information Vol. 25, No. 2, 2011the product approved in the certifyingcountry at the stated site, even if themanufacturing site is in a different countrythan the issuing authority.The Scheme has a provision that whenmanufacture takes place in a countryother than that where the product certificateis issued, an attestation that suchmanufacture complies with GMP may stillbe provided as an attachment to theproduct certificate on the basis of inspectionsundertaken for registration purposes.Q28 Is it necessary for the CPP to comefrom the country where finished productmanufacture takes place?A28 No. Although the Scheme was setup assuming that the certifying countrywas also the country where finishedproduct manufacture takes place, there isscope within the Scheme for CPPs to beissued by other authorities that canprovide independent assurance of theGMP compliance status.There needs to be an appreciation of thecomplexity of manufacturing and sourcingroutes currently employed by companiesoperating internationally. WHO MemberStates may define the source differently:• Country of finished product manufacture.• Country of final packing.• Country of final release.• Country of headquarters of the pharmaceuticalcompany, etc.A critical element is confirmation that allproduction/manufacturing/quality operationsare carried out according to GMP.Due to complex modern sourcing routes,together with varying local regulatoryprocesses, approval in the country wherefinished product manufacture takes placemay be subsequent to that in othercountries. In this case it is a matter ofjudgment whether it is necessary for theCPP to be issued from the country wherefinished product manufacture takes place.Preferred action, in order to speed uppatient access, would be to accept theCPP from the earlier approving country.In order to approve the product thecertifying authority must be assured ofGMP.GMP implementation and complianceensures product quality. Any requirementfor an additional CPP for the release site,if it is different from the product manufacturesite, will delay patient access becausemultiple CPPs provide no additionalvalue.Q29 What is the significance of thedeclaration of marketing status (i.e.,whether the product is actually on themarket in the exporting country)?A29 A declaration of marketing authorizationapproval is the aim of the CPP. It istrue that the WHO format CPP includesinformation on marketing status (if theproduct is actually on the market of theexporting country) but the Scheme alsohas a provision whereby the issuingauthority can indicate why the productmay not be marketed. In circumstanceswhere the product is not actually on themarket, the issuing authority can indicatethis on the certificate.The actual presence on the market of theproduct depends on many other factors.The recipient authority should not requirethat a product be marketed in the certifyingcountry.Q30 Should recipient authorities requirea CPP from more than one certifyingauthority?118

WHO Drug Information Vol. 25, No. 2, 2011Quality Assurance IssuesA30 No. They should not require a CPPfrom more than one certifying authority. AWHO-format CPP from a single certifyingauthority should provide appropriateevidence of approval and GMP status.Q31 Is it necessary for recipient authoritiesto require GMP certificates in additionto a CPP?A31 No. Since the CPP includes a GMPdeclaration, additional GMP certificatesare not necessary.Following introduction of the WHO CPPsome authorities no longer issue GMPcertificates (e.g., US FDA).In the presence of a CPP, separate GMPcertificates are redundant and are thereforediscouraged. CPPs should beaccepted (in particular from PIC/S andICH countries) as evidence of GMPstatus.However, outside of the Scheme, thereare occasions when it is appropriate torequire a GMP certificate.Q32 When a CPP forms part of a regulatoryreview, is it necessary to conduct asite inspection as well?A32 An inspection should not be necessarywhen the GMP declaration on theCPP covers the product to be approved inthe recipient country.Inspections outside of this condition are adecision which should be made by therecipient country. Mechanisms andsystems for recognizing inspectionscarried out by other authorities is encouragedto reduce duplication of inspections.CPPs should be accepted (in particularfrom PIC/S and ICH countries) as evidenceof GMP status. The decision toinspect should be made after a risk-basedassessment of the facility, taking intoaccount GMP and inspection statusprovided by other authorities.Q33 Imagine a situation in which companyA in one European country called Mproduces a pharmaceutical product calledX and the product is authorized formarketing in that country. Company Aalso produces X under contract manufacturingin country Z in Asia and wants toexport it to country Y in Africa. Theauthority in the importing country Yrequires a CPP to approve importation.(See figure 1 overleaf.)The questions are:Q33a Is contract manufacturing accepted?A33a Yes. Contract manufacturing isaccepted under GMP.Q33b In the case of a contract-manufacturedproduct, from which country shouldthe authority in the importing country(receiving authority) accept the CPP?A33b Country Z can issue a CPP if theproduct is registered by the authority ofcountry Z. If the product is not registeredin Z then the authority in Z cannot issuethe CPP.If the contract-manufactured product isalso authorized for marketing in theEuropean country, then the Europeancountry can issue the certificate.If the product is not registered in bothcountries, then the only country that canissue a certificate will be the Europeancountry, M. The authority of the Europeancountry will issue the CPP after it hassatisfied itself that the product undercontract manufacture is the same in allaspects as the one produced in its owncountry and that the product is producedin compliance with GMP.Q34 Can a CPP also be used to provideevidence of an administrative review andapproval, e.g., as certification of acceptabilityof a company name change?119

▼Quality Assurance IssuesWHO Drug Information Vol. 25, No. 2, 2011Figure 1. Question 33: contract manufacturingCompany Aproduces X in aEuropean country MProduct X isregistered in thatcountry▼Company A also contractmanufactures X incountry Z in AsiaCPP PRODUCTCountry Y in Africa▼▼ImportingA34 Yes. The CPP can also provideevidence of an administrative review andapproval (e.g., as certification of acceptabilityof a company name change, or fora name change of the owner of a manufacturingor production site) which oftenhappens in the context of companymergers and acquisitions.For administrative approvals that nowinvolve a QSE review, recipient authoritiesshould use alternatives to a CPP as apreferred and quicker option (see Question9).Issues related to manufacturing companyname change (administrative review) mayindeed create various practical difficultiesfor exporters–importers but are notassociated directly with safety/qualityconcerns and should be given lessprominence.Q35 Imagine a situation in which aproduct is authorized for marketing in thecountry of manufacture but is not actuallyavailable on the market. Can the competentauthority of the exporting countryissue a CPP to support export?A35 Yes, it can issue a CPP. What itshould do is explain why it is not on themarket. One reason for not being on themarket could be that the disease/healthproblem for which the product is indicatedmay not be prevalent in the country.Q36 Sometimes a country may wish toimport a special dosage form, strength orformulation of a certain known productand this particular product may not beregistered in the manufacturing country.Under such circumstances can theauthority of the exporting country issue aCPP?A36 Yes. It can issue a CPP but it shouldexplain on the certificate that the particularproduct is not authorized for marketingin the exporting country, that it has beenproduced based on the request of theimporting country and that manufacturingis in compliance with GMP.120

WHO Drug Information Vol. 25, No. 2, 2011Quality Assurance IssuesQ37 Is it necessary to legalize the CPP?A37 No. Legalization is not part of theWHO Scheme and it is not considered toprovide additional assurance of authenticity.Approval status in key referencecountries is currently available as publicinformation.Legalization should not be necessarysince an official governmental authority ofthe certifying country signs the CPP.Legalization delays availability of the CPPand thereby delays access to medicinesfor patients. If a recipient authority hasany doubts about the validity of a CPP itshould contact the certifying authoritydirectly.Q38 What should receiving countries doin case of any doubt about a CPP?A38 In case of any doubt, the competentauthorities of receiving countries shouldcommunicate directly with the authorizedbody that has issued the certificate orcontact WHO to clarify the matter.Q39 Are certifying authorities penalized ifthey issue CPPs, but do not meet WHOrequirements for self-certification andsubsequent issue of CPPs?A39 No. There is no penal system. WHOdoes not have the power to certify,inspect or penalize certifying authorities.Q40 What are the main problems encounteredin the application of theScheme?A40 A number of problems have beenreported during use of the Scheme, whichinclude:• Countries not party to the Scheme issuecertificates.• Authorities that do not meet the requirementsstated in the guidelines for theScheme issue certificates.• Some issuing authorities put the WHOemblem, logo or acronym on the certificate,thereby creating the impressionthat the certificate is authenticated byWHO.References1. WHO Certification Scheme on the Quality ofPharmaceutical Products Moving in InternationalCommerce. World Health Assemblyresolution WHA22.50 (1969), World HealthAssembly resolution WHA28.65 (1975), WorldHealth Assembly resolution WHA41.18 (1988),World Health Assembly resolution WHA45.29(1992), and World Health Assembly resolutionWHA50.3 (1997) available at: http://www.who.int/governance2. World Health Organization. Expert Committeeon Specifications for PharmaceuticalPreparations. Technical Report Series,2009;953:47-48 at http://www.who.int/medicines/publications.121

WHO Drug Information Vol. 25, No. 2, 2011Regulatory Action and NewsBuflomedil: marketingauthorization suspendedFrance — On 11 February 2011, theHealth Products Safety Agency(AFSSPS) suspended the marketingauthorization for buflomedil-containingproducts. This action was taken followingnotification of serious nervous and cardiacevents especially during accidentalor voluntary overdose.Reference: Spécialités à base de Buflomédil– Retrait de produits. 17 February 2011 athttp://www.afssaps.frDolasetron mesylateintravenous injection:withdrawalCanada — The manufacturer of dolasetronmesylate (Anzemet®) has announcedwithdrawal of the injectableform. New data show that intravenousadministration of the injectable form ofdolasetron mesylate is associated withQTc prolongation to an extent which maypotentially result in serious arrhythmias atthe doses recommended for the preventionof nausea and vomiting associatedwith chemotherapy. Dolasetron mesylateinjectable is no longer indicated to preventnausea and vomiting in adultsundergoing chemotherapy.However, tablets for oral use may still beused as the risk of developing an abnormalheart rhythm with the oral form of thisdrug is considered less than that seenwith the injectable form.Reference: Health Canada, Medeffect. 26April 2011. http://www.healthcanada.gc.ca/medeffect and http://www.hc-sc.gc.ca/dhpmps/medeff/advisories-avis/new-neufadvisories-avis-eng.phpAbiraterone acetate approvedfor late-stage prostate cancerUnited States of America — The Foodand Drug Administration (FDA) hasapproved abiraterone acetate (Zytiga®) incombination with prednisone to treatpatients with metastatic castrationresistantprostate cancer who havereceived prior docetaxel.Patients who received the Zytiga® andprednisone combination had a medianoverall survival of 14.8 months comparedto 10.9 months for patients receiving theplacebo and prednisone combination.The most commonly reported side effectsincluded joint swelling or discomfort, lowlevels of potassium in the blood, fluidretention (usually of the legs and feet),muscle discomfort, hot flashes, diarrhoea,urinary tract infection, cough, high bloodpressure, heartbeat disorders, urinaryfrequency, increased night-time urination,upset stomach or indigestion and upperrespiratory tract infection.Reference: FDA News Release, 28 April 2011at http://www.fda.govRituximab approved forWegener granulomatosis andmicroscopic polyangiitisUnited States of America — The Foodand Drug Administration (FDA) hasapproved rituximab (Rituxan®) in combinationwith glucocorticoids to treat patientswith Wegener granulomatosis (WG)and microscopic polyangiitis (MPA), tworare disorders that cause vasculitis.Rituximab is an antibody that is manufacturedthrough biotechnology methods.122

WHO Drug Information Vol. 25, No. 2, 2011Regulatory Action and NewsSafety and effectiveness was demonstratedin a single controlled trial in which197 patients with WG or MPA wereassigned at random to receive eitherRituxan® plus glucocorticoids once aweek for four weeks or oral cyclophosphamideplus glucocorticoids daily toinduce remission. After six months, 64%of patients treated with Rituxan® hadcomplete remission compared to 53% ofpatients treated with cyclosphosphamide.Rituximab carries a boxed warning forinfusion reactions. Other boxed warningsinclude severe mucocutaneous reactionsand progressive multifocal leukoencephalopathy.Rituximab is not recommendedfor use in patients with severe,active infections.The most common side effects in studyparticipants with WG and MPA includedinfection, nausea, diarrhoea, headache,muscle spasms, and anaemia.Rituximab, which has been marketedsince 1997, is also indicated for thetreatment of patients with non-Hodgkinlymphoma, chronic lymphocytic leukaemia,and rheumatoid arthritis.Reference: FDA News Release, 19 April 2011at http://www.fda.govHuman normal immunoglobulin:lifting of suspensionEuropean Union — The EuropeanMedicines Agency Committee for MedicinalProducts for Human Use (CHMP) hasrecommended the lifting of the suspensionof the marketing authorizations forhuman normal immunoglobulin 5% and10% (Octagam®) and associated names,and the re-introduction of the medicineonto the market in the European Union.The lifting of the suspension is subject toa change in the manufacturing process.Human normal immunoglobulin is anintravenous solution used to strengthenthe body’s immune system.The CHMP recommended the suspensionof the marketing authorizationsfollowing an unexpected increase inreports of thromboembolic reactions,including stroke, myocardial infarctionand pulmonary embolism in patientsreceiving the medicine.An in-depth review of all available data onthe safety and quality issues identifiedpreviously has now been finalized. TheCHMP has concluded that the unexpectedpresence of a pro-coagulant,factor XIa, was the main cause of thethromboembolic events and that anumber of critical steps in the manufacturingprocess could explain the presenceof substances that triggered the thromboembolicevents.The Committee’s opinion has now beenforwarded to the European Commissionfor the adoption of a legally bindingdecision. It is expected that supply ofOctagam® will resume shortly after theadoption of the Commission decision.Reference: EMA Press Release, EMA/297816/2011, 14 April 2011 at http://www.ema.euEverolimus approved forpancreatic cancerUnited States of America — The Foodand Drug Administration (FDA) hasapproved everolimus (Afinitor®) to treatpatients with progressive neuro-endocrinetumours located in the pancreas (PNET)that cannot be removed by surgery orhave become metastatic.Neuro-endocrine tumours found in thepancreas are slow-growing and rare. It isestimated that there are fewer than 1000new cases in the United States eachyear.123

Regulatory Action and NewsWHO Drug Information Vol. 25, No. 2, 2011The most commonly reported side effectsincluded stomatitis, rash, diarrhoea,fatigue, edema, abdominal pain, nausea,fever and headache.Afinitor® is also approved to treat patientswith advanced renal cell carcinomaafter they fail treatment with sunitinib orsorafenib, and patients with subependymalgiant cell astrocytoma associatedwith tuberous sclerosis who cannot betreated with surgery.Reference: FDA News Release, 6 May 2011at http://www.fda.govBoceprevir approvedfor hepatitis CUnited States of America — The Foodand Drug Administration (FDA) hasapproved boceprevir (Victrelis®) to treatcertain adults with chronic hepatitis C.Boceprevir is used for patients who stillhave some liver function and who eitherhave not been previously treated withdrug therapy for hepatitis C or who havefailed such treatment. Boceprevir isapproved for use in combination withpeginterferon alfa and ribavirin.Safety and effectiveness of boceprevirwas evaluated in two phase III clinicaltrials with 1500 adult patients. In bothtrials, two-thirds of patients receivingboceprevir in combination with pegylatedinterferon and ribavirin experienced asignificantly increased sustained virologicresponse.According to the US Centers for DiseaseControl and Prevention, about 3.2 millionpeople in the United States have chronichepatitis C. Most liver transplants performedin the United States are due toprogressive liver disease caused byhepatitis C virus infection.Reference: FDA News Release, 13 May 2011at http://www.fda.govLinagliptin approvedfor type 2 diabetesUnited States of America — The Foodand Drug Administration (FDA) hasapproved linagliptin (Tradjenta®) tabletsfor use with diet and exercise, to improveblood glucose control in adults with Type2 diabetes which is the most commonform of the disease, affecting between 90and 95% of the 24 million diabetics in theUnited States.Linagliptin was demonstrated to be safeand effective in eight double-blind, placebo-controlledclinical studies involvingabout 3800 patients with Type 2 diabetes.Linagliptin has been studied as a standalonetherapy and in combination withother type 2 diabetes therapies includingmetformin, glimepiride, and pioglitazone.Linagliptin has not been studied in combinationwith insulin, and should not beused to treat people with type 1 diabetesor in those who have diabetic ketoacidosis.Reference: FDA News Release, 2 May 2011at http://www.fda.govNaproxcinod: withdrawal ofmarketing authorizationapplicationEuropean Union — The EuropeanMedicines Agency (EMA) has beennotified by the manufacturer of its decisionto withdraw its application for acentralized marketing authorization forthe medicine naproxcinod (Beprana®),375 mg hard capsules.Naproxcinod was intended to be used forthe relief of the signs and symptoms ofosteoarthritis of the knee and hip inadults.In its official letter, the company statedthat their decision to withdraw the appli-124

WHO Drug Information Vol. 25, No. 2, 2011Regulatory Action and Newscation was based on the fact that theCommittee for Medicinal Products forHuman Use (CHMP) considers that thedata provided do not allow it to concludeon a positive benefit-risk balance.Reference: EMA Press Release, EMA/322628/2011, 20 April 2011 at http://www.ema.euLumiracoxib: withdrawal ofmarketing authorizationapplicationEuropean Union — The EuropeanMedicines Agency (EMA) has beennotified by the manufacturer of its decisionto withdraw its application for acentralized marketing authorization forthe medicine lumiracoxib (Joicela®) 100mg film-coated tablets. Lumiracoxib wasintended to be used for symptomatic reliefin the treatment of osteoarthritis of theknee and hip in patients who are noncarriersof the DQA1*0102 allele.In its official letter, the company statedthat its decision to withdraw the applicationwas based on its inability to addressthe CHMP request to provide additionaldata within the timeframe allowed in thecentralized procedure.Reference: EMA Press Release, EMA/309990/2011, 18 April 2011 at http://www.ema.euErythropoietin: withdrawal ofmarketing authorizationapplicationEuropean Union — The EuropeanMedicines Agency (EMA) has beennotified by the manufacturer of its decisionto withdraw its application for acentralized marketing authorization forthe medicine erythropoietin (Epostim®),2000 IU/ 0.5 ml, 4000 IU/0.4 ml, and10 000IU/ml solution for injection in prefilledsyringes.This medicine was intended to be usedfor the following indications:• Treatment of anaemia associated withchronic renal failure in paediatric andadult patients on haemodialysis andadult patients on peritoneal dialysis.• Treatment of severe anaemia of renalorigin accompanied by clinical symptomsin adult patients with renal insufficiencynot yet undergoing dialysis.• Treatment of anaemia and reduction oftransfusion requirements in adultpatients receiving chemotherapy forsolid tumours, malignant lymphoma ormultiple myeloma.• To increase the yield of autologousblood from patients in a predonationprogramme.• To reduce exposure to allogenic bloodtransfusions in adult non-iron deficientpatients prior to major elective orthopaedicsurgery.In its official letter, the company statedthat its decision to withdraw the applicationwas based on its inability to addressthe CHMP’s request to provide additionaldata within the timeframe allowed in thecentralized procedure.Reference: EMA Press Release, EMA/271900/2011, 6 April 2011 at http://www.ema.eu125

WHO Drug Information Vol. 25, No. 2, 2011ATC/DDD ClassificationATC/DDD Classification (temporary)The following anatomical therapeutic chemical (ATC) classifications and defined dailydoses (DDDs) were agreed by the WHO International Working Group for Drug StatisticsMethodology March 2011. Comments or objections to the decisions should beforwarded to the WHO Collaborating Centre for Drug Statistics Methodology atwhocc@fhi.no. The new ATC codes and DDDs will be considered final and be includedin the January 2012 issue of the ATC index. The inclusion of a substance inthe lists does not imply any recommendation of use in medicine or pharmacy. TheWHO Collaborating Centre for Drug Statistics Methodology can be contacted throughe-mail at: whocc@fhi.no.ATC level INN/Common name ATC codeNew ATC 5th level codes:ATC name changesabirateroneafliberceptaxitinibbosutinibbrentuximab vedotincatridecacogcrizotinibdapagliflozindexlansoprazolelevomethadonelosartan and amlodipinemeloxicam, combinationsmipomersennaproxen and misoprostolpasireotideperampanelruxolitinibsipuleucel-TtafamidistelaprevirtesamorelinvemurafenibL02BX03S01LA05L01XE17L01XE14L01XC12B02BD11L01XE16A10BX09A02BC06N07BC05C09DB06M01AC56C10AX11M01AE56H01CB05N03AX22L01XE18L03AX17N07XX08J05AE11H01AC06L01XE15Previous New ATC codeAntigrowth hormones Somatostatin and analogues H01CBCalcium, combinations with Calcium, combinations withother drugs vitamin D and/or other drugs A12AXEnzyme inhibitors Aromatase inhibitors L02BG126

WHO Drug Information Vol. 25, No. 2, 2011ATC/DDD ClassificationNew DDDs:INN/common name DDD Unit Adm.R ATC codeaspoxicillin 4 g P J01CA19aztreonam 0.225 g Inhal. solution J01DF01bekanamycin 0.6 g P J01GB13carumonam 2 g P J01DF02cefbuperazone 2 g P J01DC13cefminox 4 g P J01DC12conestat alfa 3.5 TU P B06AC04desvenlafaxine 50 mg O N06AX23fingolimod 0.5 mg O L04AA27flomoxef 2 g P J01DC14histrelin 0.137 mg 1 implant H01CA03isepamicin 0.4 g P J01GB11ribostamycin 1 g P J01GB10tapentadol 0.4 g O N02AX06ticagrelor 0.18 g O B01AC24vernakalant 0.2 g P C01BG111.DDD assigned according to the total content of the implant.Herbal medicinal products*New ATC 5th level codes::NameSt. John’s WortATC codeN06AX252.Assessed and approved by regulatory authorities based on dossiers including efficacy, safety,and quality data (e.g., well-established use procedure in EU)..../...127

WHO Drug Information Vol. 25, No. 2, 2011ATC/DDD ClassificationATC/DDD Classification (final)The following anatomical therapeutic chemical (ATC) classifications and defined dailydoses (DDDs) were agreed by the WHO International Working Group for Drug StatisticsMethodology in October 2010. They will be included in the January 2012 issueof the ATC index. The inclusion of a substance in the lists does not imply any recommendationof use in medicine or pharmacy. The WHO Collaborating Centre for DrugStatistics Methodology can be contacted at whocc@fhi.no.ATC level INN/Common name ATC codeNew ATC level codes (other than 5th level):Drugs used in hereditary angioedemaB06ACNew ATC 5th level codes:aspoxicillinazilsartan medoxomilbekanamycincabazitaxelcarumonamcefbuperazonecefminoxcinchocaineconestat alfadienogestdimeticonedonepezil and memantinedoxylamine,combinationsecallantideemtricitabine, tenofovirdisoproxil and rilpivirineflomoxeffluindioneiloperidoneipilimumabmeningococcus B,multi-component vaccinemetformin and linagliptinmetformin and saxagliptinmotavizumabpanobinostatpentosan polysulfate sodiumJ01CA19C09CA09J01GB13L01CD04J01DF02J01DC13J01DC12S02DA04B06AC04G03DB08P03AX05N06DA52R06AA59B06AC03J05AR08J01DC14B01AA12N05AX14L01XC11J07AH09A10BD11A10BD10J06BB17L01XX42G04BX15.../...128

WHO Drug Information Vol. 25, No. 2, 2011ATC/DDD ClassificationATC level INN/Common name ATC codepirfenidoneramipril and amlodipinerilpivirinesecukinumabsinecatechinsteduglutidetetrachlorodecaoxidevilazodonevon Willebrand factorL04AX05C09BB07J05AG05L04AC10D06BB12A16AX08D03AX11N06AX24B02BD10ATC code changes:INN/common name Previous ATC New ATCalitretinoin D11AX19 D11AH04C1-inhibitor, plasma derived B02AB03 B06AC01icatibant C01EB19 B06AC02ATC name changesPrevious New ATC codeAgents for atopic dermatitis, excluding Agents for dermatitis,corticosteroids excluding corticosteroids D11AHOther cold combination preparations Other cold preparations R05XNew DDDs:INN/common name DDD Unit Adm.R ATC codeasenapine 20 mg O N05AH05corifollitropin alfa 0.15 mg P G03GA09dienogest 2 mg O G03DB08eltrombopag 50 mg O B02BX05fampridine 20 mg O N07XX07flupirtine 0.4 g O N02BG07indacaterol 0.15 mg Inhal. powder R03AC18indometacin, combinations 0.1 g 1 O,R M01AB51mifamurtide 0.7 mg P L03AX15prucalopride 2 mg O A03AE04roflumilast 0.5 mg O R03DX07velaglucerase alfa 300 U P A16AB101.refers to indometacin129

ATC/DDD ClassificationWHO Drug Information Vol. 25, No. 2, 2011Herbal medicinal products*New ATC 5th level codes::NameHorse chestnut, seedsATC codeC05CX03*Assessed and approved by regulatory authorities based on dossiers includingefficacy, safety, and quality data (e.g., well-established use procedure in EU).130

WHO Drug Information Vol. 25, No. 2, 2011Recent Publications,Information and EventsSelection and use of medicinesWorld Health Organization — The 18thmeeting of the WHO Expert Committeeon the Selection and Use of EssentialMedicines took place in Accra, Ghana on21–25 March 2011. The purpose of themeeting was to review and update theWHO Model List of Essential Medicines(EML) as well as the WHO Model List ofEssential Medicines for Children (EMLc).In accordance with its approved procedures,the Committee evaluated thescientific evidence on the comparativeeffectiveness, safety and cost effectivenessof medicines and updated the WHOModel List of Essential Medicines and theModel List of Essential Medicines forChildren. The Committee:• Approved the addition of 16 new medicinesto the EML.• Approved the deletion of 13 medicinesfrom the EML.• Approved new indications for 4 medicinesalready listed on the EML.• Approved the addition of a new dosageform or strength for 4 medicines alreadyon the EML.• Rejected 9 applications for the additionof a medicine to EML.• Approved the addition of 16 new medicinesto the EMLc.• Approved the deletion of 15 medicinesfrom the EMLc,• Rejected 3 applications for the additionof a new medicine to the EMLc.Some of the main recommendationsmade, in order of their appearance on theEML, were:• Section 6: addition of artesunate +amodiaquine combination tablet for thetreatment of malaria in adults andchildren, in line with current WHOtreatment guidelines. In making itsdecision, the 2011 Committee reviewedthe latest clinical evidence and theinformation about licensing in severalcountries of the fixed dose combinationtablet. The Committee noted thatappropriate doses of both medicinescan also be achieved using combinationsof the mono-component products,including as co-blistered presentations.• Section 10: addition of tranexamic acidinjection for the treatment of adultpatients with trauma and significant riskof ongoing haemorrhage. On the basisof the results of a very large trial of theuse of tranexamic acid specifically fortrauma patients — including those whohave been in road traffic accidents, theCommittee concluded that there issufficient evidence to support theproposal that listing tranexamic acidmay contribute to a reduction in thiscause of death.• Section 18.5 : addition of glucagoninjection, 1 mg/ml to treat acute severehypoglycaemia in patients with diabetes,to support efforts in many countriesto ensure appropriate treatment of theincreasing number of patients withdiabetes. The Committee also recommendedthat careful attention be paid tothe cost of procuring glucagon andnoted that based on experience withother high cost medicines, such as131

Recent Publications, Information and EventsWHO Drug Information Vol. 25, No. 2, 2011antiretrovirals, inclusion in the EML mayhelp to contribute to a reduction inprices.• Section 22.1: addition of misoprostoltablet, 200 micrograms for the preventionof post-partum haemorrhage, whereoxytocin is not available or cannot besafely used. WHO guidelines currentlyrecommend that in situations wereoxytocin is not available, misoprostolcan be used to prevent and treat postpartum haemorrhage due to uterineatony.Based on the evidence provided, theCommittee considered that misoprostolcan be safely administered to women toprevent post-partum haemorrhage byhealth workers trained in its use in thethird stage of labour. The addition ofmisoprostol for the treatment of postpartumhaemorrhage was not approved.The clinical trials that compare misoprostolto oxytocin in women who needtreatment for post-partum haemorrhageshow that misoprostol is not as effectiveas oxytocin. In addition, there is noevidence to support the safety andefficacy of the 800-microgram dose fortreatment of post partum haemorrhagewhen given to women who have alreadyreceived prophylactic misoprostol 600micrograms orally. Countries need towork to make oxytocin available fortreatment of women who are bleedingafter delivery and misoprostol shouldonly be used if there is no other option.Other medicines that were added to theEML are: isoflurane, propofol, midazolam,clarithromycin, miltefosine, paclitaxel anddocetaxel, bisoprolol, terbinafine cream/ointment, mupirocin cream/ointment, andatracurium.A summary of reasons for all changes tothe EML is in Section 1 of the report. Allapplications and documents consideredby the Committee will remain availableon the web site for the meeting at http://www.who.int/selection_medicines/committees/expert/18/en/index.html.The next update of the WHO Model Listof Essential Medicines will take place in2013.Reference: Unedited report of the 18thmeeting of the WHO Expert Committee on theSelection and Use of Essential Medicines athttp://www.who.int/medicines/publications/unedited_trs/en/index.htmlPolicy guidelines oncontrolled substancesWorld Health Organization — The WHOAccess to Controlled Medicines Team haspublished “Ensuring balance in nationalpolicies on controlled substances: guidancefor availability and accessibility forcontrolled medicines”. This book providesguidance on policies and legislation withregards to availability, accessibility,affordability and regulation of controlledmedicines.It includes 21 guidelines on varioustopics: content of drug control legislationand policy; authorities and their role in thesystem; policy planning for availabilityand accessibility; healthcare professionals;estimates and statistics; procurement,and nationally listed drugs. Eachguideline is followed by an explanationand a description of the legal context. TheCountry Assessment Checklist enablesthe user to determine which guidelinesstill need to be worked on. A CD-ROMprovides additional information.The guidelines are currently available inEnglish. Other on-line language versionswill follow, some of them very soon(Armenian, Bulgarian, French, Georgian,Greek, Hungarian, Khmer, Polish, Russian,Serbian, Slovakian, Slovenian andTurkish). The publication will also becomeavailable in print in English and French.132

WHO Drug Information Vol. 25, No. 2, 2011Recent Publications, Information and EventsReference: Ensuring Balance in NationalPolicies on Controlled Substances, Guidancefor Availability and Accessibility of ControlledMedicines at: http://www.who.int/medicines/areas/quality_safety/guide_nocp_sanend/en/index.List of medicines to savemothers and childrenWorld Health Organization — The newdocument, “Priority medicines for mothersand children” contains a list of 30 medicinesdeveloped to advocate for bettersupply and use of the most importantessential medicines. The vast majority ofmaternal and child deaths can be preventedwhen these 30 medicines areavailable in the right formulations andprescribed and used correctly.Medicines on this new priority list wereselected based on burden of diseasedata and their potential for impact onmaternal and child mortality and morbidity.All medicines on the list are already inthe WHO Model List of Essential Medicinesand the latest WHO treatmentguidelines. The list was developed by theDepartment of Essential Medicines andPharmaceutical Policies (EMP) in collaborationwith the Departments of Child andAdolescent Health and Development(CAH) and Making Pregnancy Safer(MPS), UNICEF and UNFPA.Reference: Priority medicines for mothers andchildren, WHO/EMP/MAR/2011.1 at http://www.who.int/mediacentre/news/notes/2011/mother_child_ medicine_20110321. The listcan be downloaded at http://www.who.int/medicines/publications/emp_mar2011.1/en/index.htmlWorld medicines situationWorld Health Organization — The thirdedition of the “World Medicines SituationReport 2011” brings together new data on24 key topics relating to pharmaceuticalproduction and consumption, innovation,regulation and safety.Topics include selection, procurement,supply management, rational use,financing and pricing. Cross-cuttingchapters cover household medicines use,access and human rights, good governance,human resources and nationalmedicines policies.The chapters released in April 2011 are:• Background on past and present effortsto document and improve sharing ofinformation.• Medicines prices, availability andaffordability featuring data and informationfrom surveys using WHO standardmethodology.• Rational use of medicines describes theproblem of bad practices in medicinesprescribing and the harmful consequencesin terms of morbidity, mortalityand impact to health cost. This chapterlooks at global data, and draws attentionto trends in developing and transitionalcountries, in both public andprivate sectors.• Traditional medicines: global situationissues and challenges describes use oftraditional and herbal medicines aroundthe world.• Access to controlled medicines. Internationaldrug treaties stress that psychotropicand narcotic substances must beavailable for medical and scientific use,even if they are classified as controlledmedicines.• Good governance reviews the findingsof country studies, highlighting weaknessesand strengths in pharmaceuticalsystems that can help policy-makersbetter understand problems and identifysolutions.133

Recent Publications, Information and EventsWHO Drug Information Vol. 25, No. 2, 2011Reference: The World Medicines SituationReport 2011, available at http://www.who.int/medicines/areas/policy/world_medicines_situation/en/index.htmlArtesunate instead of quininesaves livesMédecins sans Frontières (MSF) havereleased a report calling for a change insevere malaria treatment protocols fromcenturies old quinine use to the newer,more effective drug artesunate (1).In its report “Making the Switch”, MSFcalls on African governments to followWorld Health Organization (WHO)guidelines, and switch from the far lesseffective quinine to artesunate whichcould avert nearly 200 000 deaths eachyear.For decades, quinine has been used insevere malaria but it can be both difficultto administer and dangerous. Artesunateis safer, easier and more effective thanquinine. Quinine has to be given threetimes a day in a slow intravenous dripthat takes four hours: a treatment that isburdensome for both patients andhealth staff. Artesunate, in contrast, canbe given in just four minutes as anintravenous or intramuscular injection.A landmark clinical trial in late 2010concluded that the use of artesunateto treat children with severe malariareduces the risk of death by nearly aquarter. The study, carried out in nineAfrican countries, found that for every 41children given artesunate over quinine,one extra life was saved. Because of thecomplexities of administering quinine,children in the trial who were assigned toreceive quinine were almost four timesmore likely to die before even receivingtreatment.MSF participated in the trial through itsresearch affiliate Epicentre, with a researchsite in Uganda. MSF has sincechanged its own treatment protocols andnow plans to work with national healthauthorities to roll out artesunate in itsprojects over the coming months.Reference: Médecins sans Frontières.Making the Switch at http://www.msf.org/msf/articles/2011/04/malaria-making-theswitch.cfm134

WHO Drug Information Vol. 25, No. 2, 2011Consultation DocumentsThe International PharmacopoeiaRevision of monograph on capsulesThis monograph was adopted by the Forty-fourth WHO Expert Committee on Specificationsfor Pharmaceutical Preparations in October 2009 for addition to The InternationalPharmacopoeia.CapsulesThe requirements of this monograph do not necessarily apply to preparations that areintended for use other than by oral administration, such as vaginal or rectal capsulesetc. Such preparations may require a special formulation, method of manufacture, orform of presentation appropriate to their particular use. Starch capsules (often knownas cachets) are not included in this monograph.DefinitionCapsules are solid dosage forms with hard or soft shells. They are of various shapesand sizes and contain a single dose of one or more active ingredients. They areintended for oral administration.Capsule surfaces may bear symbols or other markings.Capsule shells are made of gelatin or other substances, the consistency of which maybe modified by the addition of substances such as glycerol or sorbitol. The shellshould disintegrate in the presence of digestive fluids so that the contents are released.The contents of capsules may be solid, liquid, or of a paste-like consistency.Capsule shells and contents may contain excipients such as diluents, solvents, surface-activesubstances, opaque fillers, antimicrobial agents, sweeteners, colouringmatter authorized by the appropriate national or regional authority, flavouring substances,disintegrating agents, glidants, lubricants, and substances capable of modifyingthe behaviour of the active ingredient(s) in the gastrointestinal tract. The contentsshould not cause deterioration of the shell.When excipients are used, it is necessary to ensure that they do not adversely affectthe stability, dissolution rate, bioavailability, safety, or efficacy of the active ingredient(s);there must be no incompatibility between any of the components of thedosage form.The different categories of capsule include hard capsules, soft capsules, and modifiedreleasecapsules [including delayed-release capsules (gastro-resistant/enteric capsules)and sustained-release capsules (extended-/prolonged-release capsules)].135

Consultation DocumentsWHO Drug Information Vol. 25, No. 2, 2011ManufactureThe manufacturing and filling processes for capsules should meet the requirements ofgood manufacturing practices (GMP).Very broad guidelines concerning the main critical steps to be followed during productionof capsules, indicating those that are the most important, are provided below.Additional guidelines specific for hard or soft capsules are provided in the respectivesubsections below.In the manufacture of capsules, measures are taken to:• ensure that the active ingredient(s) when present in solid state form have appropriatesolid-state properties such as particle-size distribution and polymorphic form;• ensure that mixing with excipients is carried out in a manner that ensures homogeneity;• minimize the degradation of the active ingredient(s);• minimize the risk of microbial contamination, and• minimize the risk of cross contamination.The particle size of the active ingredient(s) may be of primary significance in determiningthe rate and extent of dissolution and the bioavailability of the drug product, especiallyfor substances of low solubility in aqueous media. The uniformity of the final drugproduct is affected by the particle size of the active ingredient(s) as well as the excipients.Throughout manufacturing, certain procedures should be validated and monitored bycarrying out appropriate in-process controls. These should be designed to guaranteethe effectiveness of each stage of production.Packaging is required to be adequate to protect capsules from light when required,and from moisture and damage during transportation.Visual inspectionUnpack and inspect at least 20 capsules. They should be smooth and undamaged.Evidence of physical instability is demonstrated by gross changes in physical appearance,including hardening or softening, cracking, swelling, mottling, or discoloration ofthe shell.Uniformity of massCapsules comply with the test for 5.2 Uniformity of mass for single-dose preparations,unless otherwise specified in the individual monograph.Uniformity of contentWhere a requirement for compliance with the test for 5.1 Uniformity of content forsingle-dose preparations is specified in an individual capsule monograph, the test for5.2 Uniformity of mass for single-dose preparations is not required.136

WHO Drug Information Vol. 25, No. 2, 2011Consultation DocumentsDissolution/disintegrationWhere a choice of test is given (either test A or test B may be applied), follow theinstructions in the monograph. Where a requirement for compliance with a dissolutiontest is specified in the individual monograph, the requirement for disintegration statedin the sections below do not apply.LabellingEvery pharmaceutical preparation must comply with the labelling requirements establishedunder GMP.The label should include:1. The name of the pharmaceutical product.2. The name(s) of the active ingredient(s); International Nonproprietary Names (INNs)should be used wherever possible.3. The amount of the active ingredient(s) in each capsule and the number of capsulesin the container.4. The batch (lot) number assigned by the manufacturer.5. The expiry date and, when required, the date of manufacture.6. Any special storage conditions or handling precautions that may be necessary.7. Directions for use, warnings, and precautions that may be necessary.8. The name and address of the manufacturer or the person responsible for placingthe product on the market.StorageCapsules should be kept in well-closed containers. They should be protected fromlight when required, and from excessive moisture, or dryness, and should not besubjected to temperatures above 30 °C. Additional special packaging, storage, andtransportation recommendations are provided, where necessary, in the individualmonograph.Requirements for specific types of capsulesHard capsulesDefinitionHard capsules have shells consisting of two prefabricated cylindrical sections that fittogether. One end of each section is rounded and closed, and the other is open. Thecontents of hard capsules are usually in solid form (powder or granules).ManufactureSometimes, the physical characteristics of the mixture of the active ingredient(s) andexcipients allow it to be directly filled into the shell, but it may occasionally be necessaryto granulate before filling. Normally the granulate needs to be mixed with lubricantsand/or disintegrating agents. The use of excessive amounts of lubricants shouldbe avoided since these may deleteriously affect the capsules.In-process controls during hard capsule production should include the moisture contentof the mixture and/or granulate (as well as of the shells), the size of granules, theflow of the final mixture, and the uniformity of mass, capsule size, integrity of the seals,and disintegration or dissolution rate (e.g., for modified-release capsules) of thefinished dosage form.137

Consultation DocumentsWHO Drug Information Vol. 25, No. 2, 2011Disintegration testHard capsules comply with 5.3 Disintegration test for tablets and capsules.Use water as the immersion fluid unless hydrochloric acid (0.1 mol/l) VS or othermedium is specified in the individual monograph. Operate the apparatus for 30 minutes,unless otherwise justified and authorized and examine the state of the capsules.If capsules float, use a disc as described under 5.3 Disintegration test for suppositories.Soft capsulesDefinitionSoft capsules have thicker shells than hard capsules, and antimicrobial preservativesare usually added. The shells are of one piece and various shapes. The contents ofsoft capsules are usually solutions or suspensions of the active ingredient(s) in nonaqueousliquids. Partial migration of the contents into the shell may occur (and viceversa) depending on the nature of the materials used and the product in question.ManufactureSoft capsules are usually formed, filled, and sealed in one operation. However, shellsfor extemporaneous use are sometimes prefabricated. Liquids may be incorporateddirectly. Solids are usually dissolved or dispersed in a suitable excipient(s) to give asolution, suspension or dispersion of paste-like consistency.In-process controls during soft capsule production should include the viscosity of thecontents, and the uniformity of mass, capsule size, integrity of the seals, and disintegrationor dissolution rate (e.g., for modified-release capsules) of the finished dosageform.Disintegration testSoft capsules comply with 5.3 Disintegration test for tablets and capsules, using wateras the immersion fluid unless hydrochloric acid (0.1 mol/l) VS or other medium isspecified in the individual monograph. Add a disc to each tube. Liquid active substancesdispensed in soft capsules may attack the disc; in such circumstances andwhere authorized, the disc may be omitted. Operate the apparatus for 30 minutes andexamine the state of the capsules. If the capsules fail to comply because of adherenceto the discs, the results are invalid. Repeat the test on a further 6 capsules omittingthe discs.Modified-release capsulesDefinitionModified-release capsules are hard or soft capsules in which the contents or the shellor both contain excipients or are prepared by special procedures such as microencapsulationwhich, separately or together, are designed to modify the rate, place ortime of release of the active ingredient(s) in the gastrointestinal tract.Sustained-release capsules (extended- or prolonged-release capsules)DefinitionSustained-release capsules are designed to slow the rate of release of the activeingredient(s) in the gastrointestinal tract.138

WHO Drug Information Vol. 25, No. 2, 2011Consultation DocumentsAll requirements for these specialized dosage forms are given in the individual monographs.Delayed-release capsules (gastro-resistant/enteric capsules)DefinitionDelayed-release capsules are hard or soft capsules prepared in such a manner thateither the shell or the contents resist the action of gastric fluid but release the activeingredient(s) in the presence of intestinal fluid.ManufactureThe additional statements given under either hard or soft capsules apply, as appropriateto delayed-release capsules.Disintegration testDelayed-release capsules with a gastro-resistant shell comply with 5.3 Disintegrationtest for tablets and capsules, using hydrochloric acid (0.1 mol/l) VS as the immersionfluid. Operate the apparatus without the discs for 2 hours, unless otherwise specified inthe individual monograph (but in any case for not less than 1 hour), and examine thestate of the capsules. No capsule should show signs of disintegration or rupturepermitting the contents to escape. Replace the acid by phosphate buffer solution, pH6.8, TS with added pancreatin R where specified in the individual monograph. Add adisc to each tube. Operate the apparatus for 60 minutes and examine the state of thecapsules. If the capsules fail to comply because of adherence to the discs, the resultsare invalid. Repeat the test on a further 6 capsules omitting the discs.For capsules in which the contents, rather than the shell, resist the action of gastricfluid, carry out a suitable dissolution test to demonstrate the appropriate release of theactive substance(s).Revision of monograph on tabletsThis monograph was adopted by the Forty-fourth WHO Expert Committee on Specificationsfor Pharmaceutical Preparations in October 2009 for addition to The InternationalPharmacopoeia.TabletsThe requirements of this monograph do not necessarily apply to preparations that areintended for use other than by oral administration, such as implants, solution-tabletsfor injections and irrigations, tablets for external use, vaginal tablets, etc. Such preparationsmay require a special formulation, method of manufacture, or form of presentation,appropriate to their particular use.DefinitionTablets are solid dosage forms usually obtained by single or multiple compression ofpowders or granules. In certain cases tablets may be obtained by moulding or extrusiontechniques. They are uncoated or coated.139

Consultation DocumentsWHO Drug Information Vol. 25, No. 2, 2011Tablets are normally right circular solid cylinders, the end surfaces of which are flat orconvex and the edges of which may be bevelled. They may have lines or break-marks(scoring), symbols, or other markings.If the break-mark(s) is/are intended to facilitate breaking the tablet for ease of swallowinga dose consisting of one or more whole tablets, the scoring is not critical. However,if the break-mark(s) is/are intended to permit accurate subdivision of the tablet in orderto provide doses of less than one tablet, the scoring is critical. Tablets containingactive ingredients having a narrow therapeutic window should generally not be presentedwith break-marks for subdivision. Non-functional break-marks should beavoided.Tablets contain one or more active ingredients. They may contain excipients such asdiluents, binders, disintegrating agents, glidants, lubricants, substances capable ofmodifying the behaviour of the dosage forms and the active ingredient(s) in the gastrointestinaltract, colouring matter authorised by the appropriate national or regionalauthority, and flavouring substances. When such excipients are used, it is necessaryto ensure that they do not adversely affect the stability, dissolution rate, bioavailability,safety, or efficacy of the active ingredient(s); there must be no incompatibility betweenany of the components of the dosage form.Tablets are single-dose preparations intended for oral administration. Some areintended to be swallowed whole, some after being chewed and some after beingcrushed, some are intended to be dissolved or dispersed in water before being takenand some are intended to be retained in the mouth where the active ingredient(s) is/are liberated.The different categories of tablet include:• uncoated tablets• coated tablets (including film-coated and sugar-coated tablets)• soluble tablets• dispersible tablets• effervescent tablets• chewable tablets• tablets for use in the mouth (including sublingual and buccal tablets)• modified-release tablets (including delayed-release tablets (gastro-resistant/entericcoatedtablets) and sustained-release tablets (extended-/prolonged-release tablets)).ManufactureThe manufacturing processes for tablets should meet the requirements of goodmanufacturing practices (GMP).The following information is intended to provide broad guidelines concerning thecritical steps to be followed during production of tablets.140

WHO Drug Information Vol. 25, No. 2, 2011Consultation DocumentsIn the manufacture of tablets, measures are taken to:• Ensure that the active ingredient(s) have appropriate solid-state properties such asparticle size distribution and polymorphic form.• Ensure that mixing with excipients is carried out in a manner that ensures homogeneity.• Ensure that the tablets possess a suitable mechanical strength to avoid crumbling orbreaking on subsequent processing, e.g. coating, storage and distribution.• Minimize the degradation of the active ingredient(s).• Minimize the risk of microbial contamination.• Minimize the risk of cross-contamination.In addition, in the manufacture of those scored tablets (tablets bearing a break-mark ormarks) for which subdivision is intended in order to provide doses of less than onetablet measures are taken to:• Ensure the effectiveness of break-marks with respect to the uniformity of mass of thesubdivided parts so that the patient receives the intended dose.A suitable test to assess this aspect of product quality during development is asfollows:Take 30 tablets at random. Break each tablet by hand and take one part for the testand reject the other part(s). Weigh each of the 30 parts thus obtained and calculate theaverage mass. No individual mass is outside the limits of 75% to 125% and not morethan one individual mass is outside the limits of 85% to 115% of the average mass.The particle size of the active ingredient(s) may be of primary significance in determiningthe rate and extent of dissolution, the bioavailability, and the uniformity of a drugproduct, especially for substances of low solubility in aqueous media.Sometimes, the physical characteristics of the mixture allow it to be directly compressed.In this case, the particle size distribution and flowability of the ingredientsbecomes particularly important because of the risk for segregation during handling ofthe mix. However, it is usually necessary to granulate before compression, preferablyby wet-granulation but in certain cases dry-granulation or slugging may be preferred.Generally, wet-granulation of the mix before compression reduces the risk for segregation.When a wet-granulation technique is employed, control of the residual moistureafter the drying step is important for smooth tablet compression. Too low or too highmoisture contents may influence the chemical and physical stability of the final tablet.The granulate and powders normally need to be mixed with glidants and lubricantsbefore the compression stage to improve the powder flow and to reduce sticking andadhesion to die walls and punches during compression. The use of excessive amountsof glidants and lubricants should be avoided since these will deleteriously affect thetablets. Some lubricants like magnesium stearate may in excessive amounts or bylong mixing times reduce the mechanical resistance of tablets and prolong disintegrationand dissolution time.141

Consultation DocumentsWHO Drug Information Vol. 25, No. 2, 2011Throughout manufacturing, certain procedures should be validated and monitored bycarrying out appropriate in-process controls. These should be designed to guaranteethe effectiveness of each stage of production. In-process controls during tablet productionshould include the moisture content of the mixture and/or granulate, the sizeof granules, the flow of the final mixture and, where relevant, the uniformity of mass oftablet cores before coating. In-process controls during tablet production should alsoinclude the dimensions (thickness, diameter), uniformity of mass, hardness and/orcrushing force, friability, disintegration, or dissolution rate (for example, for modifiedreleasetablets) of the finished dosage form.In the manufacture, packaging, storage and distribution of tablets, suitable measuresare taken to ensure their microbiological quality.Packaging is required to be adequate to protect the tablets from light, moisture, anddamage during transportation.The validation of the manufacturing process and the in-process controls are documented.Visual inspectionUnpack and inspect at least 20 tablets. They should be undamaged, smooth, andusually of uniform colour.Evidence of physical instability is demonstrated by:• Presence of excessive powder and/or pieces of tablets at the bottom of the container(from abraded, crushed, or broken tablets).• Cracks or capping, chipping in the tablet surfaces or coating, swelling, mottling,discoloration, fusion between tablets.• The appearance of crystals on the container walls or on the tablets.Uniformity of massTablets comply with the test for 5.2 Uniformity of mass for single-dose preparations,unless otherwise specified below or in the individual monograph.Uniformity of contentWhere a requirement for compliance with the test for 5.1 Uniformity of content forsingle-dose preparations is specified in an individual tablet monograph the test for 5.2Uniformity of mass for single-dose preparations is not required.Dissolution/disintegrationWhere a choice of test is given (either test A or test B may be applied), follow theinstructions in the monograph. Where a requirement for compliance with a dissolutiontest is specified in the individual monograph, the requirements for disintegration statedin the sections below do not apply.142

WHO Drug Information Vol. 25, No. 2, 2011Consultation DocumentsLabellingEvery pharmaceutical preparation must comply with the labelling requirements establishedunder GMP.The label should include:1. The name of the pharmaceutical product.2. The name(s) of the active ingredient(s); International Nonproprietary Names (INN)should be used wherever possible.3. The amount of the active ingredient(s) in each tablet and the number of tablets inthe container.4. The batch (lot) number assigned by the manufacturer.5. The expiry date and, when required, the date of manufacture.6. Any special storage conditions or handling precautions that may be necessary.7. Directions for use, warnings, and precautions that may be necessary.8. The name and address of the manufacturer or the person responsible for placingthe product on the market.For scored tablets where the directions for use include subdivision to provide doses ofless than one tablet, the label should also include:9. The storage conditions for and period of use of those subdivided part(s) not immediately taken or administered.StorageTablets should be kept in well-closed containers and protected from light, moisture,crushing, and mechanical shock. Tablets should be able to withstand handling, includingpackaging and transportation, without losing their integrity. Moisture-sensitiveforms, such as effervescent tablets, should be stored in tightly closed containers ormoisture-proof packs and may require the use of separate packages containing wateradsorbentagents, such as silica gel. Moisture-sensitive forms, such as effervescenttablets, should be stored in tightly closed containers or moisture-proof packs and mayrequire the use of separate packages containing water-adsorbent agents, such assilica gel, or in unit dose packaging (blister cards).Additional special packaging, storage, and transportation recommendations areprovided, where necessary, in the individual monograph.Requirements for specific types of tabletsUncoated tabletsDefinitionThe majority of uncoated tablets are made in such a way that the release of activeingredients is unmodified. A broken section, when examined under a lens, showseither a relatively uniform texture (single-layer tablets) or a stratified texture (multilayertablets), but no signs of coating.143

Consultation DocumentsWHO Drug Information Vol. 25, No. 2, 2011Disintegration testUncoated tablets, except soluble tablets, dispersible tablets, effervescent tablets andtablets for use in the mouth comply with 5.3 Disintegration test for tablets and capsules.Operate the apparatus for 15 minutes, unless otherwise specified in the individualmonograph, and examine the state of the tablets.Soluble tabletsDefinitionSoluble tablets are uncoated or film-coated tablets that are intended to be dissolved inwater giving a clear or slightly opalescent solution.Disintegration testSoluble tablets disintegrate within 3 minutes when examined by 5.3 Disintegration testfor tablets and capsules, but using water R at 15–25 °C.Dispersible tabletsDefinitionDispersible tablets are uncoated tablets or film-coated tablets intended to be dispersedin water before administration giving a homogeneous dispersion.Disintegration testDispersible tablets disintegrate within 3 minutes when examined by 5.3 Disintegrationtest for tablets and capsules, but using water R at 15–25 °C.Fineness of dispersionPlace 2 tablets in 100 ml of water R and stir until completely dispersed. A smoothdispersion is produced, which passes through a sieve screen with a nominal meshaperture of 710 µm.Effervescent tabletsDefinitionEffervescent tablets are uncoated tablets generally containing acid substances andcarbonates or hydrogen carbonates that react rapidly in the presence of water torelease carbon dioxide. They are intended to be dissolved or dispersed in waterbefore administration.ManufactureThe manufacture of effervescent tablets is carried out in low-humidity conditions sothat the reaction between acidic and basic components of the formulation does nottake place.LabellingThe label should state: “Not to be swallowed directly”.Disintegration testPlace one tablet in a 250 ml beaker containing 200 ml of water R at 15–25 °C. Numerousbubbles of gas are evolved. When the evolution of gas around the tablet or itsfragments ceases, the tablet should have disintegrated, being either dissolved ordispersed in the water so that no agglomerates remain. Repeat the operation on five144

WHO Drug Information Vol. 25, No. 2, 2011Consultation Documentsadditional tablets. The tablets comply with the test if each of the six tablets used in thetest disintegrates within 5 minutes, unless otherwise specified in the individual monograph.Chewable tabletsDefinitionChewable tablets are usually uncoated. They are intended to be chewed before beingswallowed.In the manufacture of chewable tablets, measures are taken to:• Ensure that the tablets are easily crushed by chewing.• Ensure that the tablets are palatable.Tablets for use in the mouth (sublingual, buccal)DefinitionTablets for use in the mouth are usually uncoated. They are usually formulated toeffect a slow release and local action of the active ingredient(s) (for example, compressedlozenges) or the release and absorption of the active ingredient(s) under thetongue (sublingual tablets) or in other parts of the mouth (buccal) for systemic action.ManufactureIn the manufacture of tablets for use in the mouth, measures are taken to:• Ensure the release characteristics are appropriate to the intended useCoated tabletsDefinitionCoated tablets are tablets covered with one or more layers of mixtures of substancessuch as natural or synthetic resins, polymers, gums, fillers, sugars, plasticizers,polyols, waxes, colouring matters authorized by the appropriate national or regionalauthority, flavouring substances, and sometimes also active ingredients. A brokensection, when examined under a lens, shows a core which is surrounded by a continuouslayer of a different texture.The tablets may be coated for a variety of reasons such as protection of the activeingredients from air, moisture, or light, masking of unpleasant tastes and odours, orimprovement of appearance. The substance used for coating is usually applied as asolution or suspension.Three main categories of coated tablet may be distinguished: sugar-coated, filmcoated,and certain modified-release tablets.Sugar-coated tabletsUniformity of massThe test for 5.2 Uniformity of mass for single-dose preparations, does not apply tosugar-coated tablets (see in-process controls under “Manufacture”).145

Consultation DocumentsWHO Drug Information Vol. 25, No. 2, 2011Disintegration testSugar-coated tablets comply with 5.3 Disintegration test for tablets and capsules.Operate the apparatus for 60 minutes, unless otherwise specified in the individualmonograph, using water, and examine the state of the tablets. If any of the tabletshas not disintegrated, repeat the test on an additional six tablets, using hydrochloricacid (0.1 mol/l) VS.All six tablets must disintegrate.Film-coated tabletsDefinitionA film-coated tablet is covered with a thin layer of resins, polymers, and/or plasticizerscapable of forming a film.Disintegration testFilm-coated tablets comply with 5.3 Disintegration test for tablets and capsules.Operate the apparatus for 30 minutes, and examine the state of the tablets.Modified-release tabletsDefinitionModified-release tablets are coated, uncoated, or matrix tablets containing excipientsor prepared by procedures which, separately or together, are designed tomodify the rate, the place or the time of release of the active ingredient(s) in thegastrointestinal tract.Sustained-release tablets (Extended-/prolonged-release tablets)DefinitionSustained-release tablets are designed to slow the rate of release of the activeingredient(s) in the gastrointestinal tract.All requirements for these specialized dosage forms are given in the individual monographs.Delayed-release tablets (gastro-resistant/enteric-coated tablets)DefinitionDelayed-release tablets are intended to resist gastric fluid but disintegrate in intestinalfluid. This is achieved by using coating substances such as cellacefate (celluloseacetate phthalate) and anionic copolymers of methacrylic acid and its esters. It issometimes necessary to apply more than one layer.Uniformity of massThe test for 5.2 Uniformity of mass for single-dose preparations does not apply todelayed-release tablets.Disintegration testDelayed-release tablets comply with 5.3 Disintegration test for tablets and capsules,using hydrochloric acid (0.1 mol/l) VS as the immersion fluid. Operate the apparatusfor 2 hours, unless otherwise specified in the individual monograph (but in any case146

WHO Drug Information Vol. 25, No. 2, 2011Consultation Documentsfor not less than 1 hour), and examine the state of the tablets. No tablet should showsigns of either disintegration (apart from fragments of coating) or cracks that wouldallow the contents to escape. Replace the acid by phosphate buffer solution, pH 6.8,TS. Operate the apparatus for 60 minutes and examine the state of the tablets.Paediatric retinol oral solutionDraft proposal for The International Pharmacopoeia (February2011). Please address any comments to Quality Assurance andSafety: Medicines, World Health Organization, 1211 Geneva 27,Switzerland. Fax +41227914730 or e-mail to mendyc@who.int. Asubscriber mailing list is now available to speed up consultation.For more information please contact bonnyw@who.int.[Note from the secretariat: Paediatric retinol soft gel capsules in doses of 100 000 IUand 200 000 IU have a unique mode of delivery for use in public health programmesworldwide: unlike other capsules, these preparations are equipped with a nipple to besnipped before use. The dosage form is then squeezed and its content is delivereddirectly into the patient’s mouth.WHO has developed a public standard which could be applicable to oral oily solutionsin multidose dispensers as well as to single doses, each encapsulated in a soft gelatinshell.Feedback is sought in particular about the proposed determination of the retinolcontent per delivered dose for single-dose containers. An alternative would be todetermine the retinol content per single-dose container (capsule). The different approacheswill influence the assay results as investigations have shown that about 10%of the material filled into soft capsules remain inside and is not actually deliveredunder the typical condition of use.]Other name. Paediatric vitamin A oral solution.Category. Vitamin.Storage. Paediatric retinol oral solution should be kept in a tight, light-resistant,container.Labelling. The labelling should state the name of the retinol ester or esters present,the proportion of vitamin A expressed in International Units (IU), and the names andproportions of any stabilizing agents added.Additional information. Strength in the current WHO Model List of Essential Medicinesfor Children:Oral oily solution in multidose dispenser: 100 000 IU/ml.Oral oily solution as single-doses (capsules): 100 000 IU; 200 000 IU.147

Consultation DocumentsWHO Drug Information Vol. 25, No. 2, 2011REQUIREMENTSComplies with the monograph for “Liquid preparations for oral use”.Definition. Paediatric retinol oral solution contains Retinol concentrate, oily formdiluted in a suitable vegetable oil. It may contain suitable antimicrobial agents andstabilizing agents such as antioxidants. The oral solution contains not less than 90%and not more than 120% of the amount of vitamin A stated on the label.Paediatric retinol oral solution may be presented either in a multidose container with asuitable administration device or as single doses, each encapsulated in a soft gelatinshell. The capsule shell is designed so that it may be broached (for example, with anipple which may be cut) and so that the oral solution may be administered easily bymouth when the broached shell is squeezed gently.Manufacture. For an oral solution presented as single doses, each encapsulated in asoft gelatin shell, the composition and method of manufacture of the soft gelatin shelland the packaging of the final product is chosen and/or validated to ensure that thecontents can be adequately expressed with use of only gentle pressure.Carry out the analytical procedures as rapidly as possible, avoiding exposure to actiniclight and oxidizing agents, and maintaining whenever possible an atmosphere ofnitrogen above the solutions.Identity testsEither tests A and B, or tests A and C, or tests A and D may be applied.A. Carry out test A.1 or, where UV detection is not available, test A.2.A.1 Carry out the test as described under 1.14.1 Thin-layer chromatography, usingsilica gel R6 as the coating substance and a mixture of 12 volumes of cyclohexane Rand 1 volumes of ether R as the mobile phase. Apply separately to the plate 2 µl ofeach of the following 4 solutions in cyclohexane R. For solution (A) dissolve a quantityof the oral solution containing the equivalent of 50 000 IU of vitamin A in 10 ml. Forsolution (B) prepare a solution of retinol acetate RS equivalent to 5000 IU of vitamin Aper ml. For solution (C) prepare a solution of retinol propionate RS equivalent to 5000IU of vitamin A per ml. For solution (D) prepare a solution of retinol palmitate RSequivalent to 5000 IU of vitamin A per ml. After removing the plate from the chromatographicchamber, allow it to dry in air, and examine the chromatogram in ultravioletlight (254 nm).The principal spot obtained with solution (A) corresponds in position and appearanceto one or more of the spots obtained with solutions (B), (C) and (D).A.2 Carry out the test as described under 1.14.1 Thin-layer chromatography, using theconditions described above under test A.1 but using silica gel R5 as the coatingsubstance. After removing the plate from the chromatographic chamber, allow it to dryin air and spray with antimony trichloride TS. Examine the chromatogram in daylight.The principal spot obtained with solution (A) corresponds in position and appearanceto one or more of the spots obtained with solutions (B), (C), and (D).148

WHO Drug Information Vol. 25, No. 2, 2011Consultation DocumentsB. Dissolve a drop of the oral solution in about 1 ml of dichloromethane R and add 5 mlof antimony trichloride TS; a blue colour is immediately produced which turns graduallyto violet-red.C. See the test described below under Assay method B. The retention time of theprincipal peak in the chromatogram obtained with solution (1) corresponds to that ofthe principal peak in the chromatogram obtained with solution (2).D. To a quantity of the oral solution containing the equivalent of 50 000 IU of vitamin A,add 100 ml of ethanol (~750 g/l) TS. Dilute 1 ml of the resulting solution to 50 ml with amixture of 100 volumes of ethanol (~750 g/l) TS and 1 volume of hydrochloric acid(~420 g/l) TS. Immediately after preparation measure the absorbance (1.6) in therange 300 to 400 nm. The solution exhibits a single maximum at 326 nm. Heat thesolution in a water bath for 30 seconds and cool rapidly. The absorption spectrum ofthe resulting solution, when observed between 300 and 400 nm, exhibits a shoulder at332 nm and maxima at 348, 367 and 389 nmUniformity of deliverable dose (single-dose containers). For an oral solutionpresented in single-dose containers the individual mass of the expressed contents ofat least 18 of the single-dose containers as weighed under Assay is within ± 10% ofthe average mass and no individual mass is outside ± 20%.[Note from the secretariat: feedback is sought on the proposed determination of theretinol content per delivered dose for singe-dose containers. An alternative would be todetermine the retinol content per capsule.]Assay. For an oral solution presented in single-dose containers express the contentsof 20 single-dose containers, following the directions for use as stated on the label.Weigh directly the individual contents delivered from each single-dose container andcalculate the average mass. [Do not weigh the contents delivered by difference betweenfull and empty containers.] Carry out the assay using the mixed oral solutionfrom the 20 containers.Either method A, where valid, or method B may be applied.A. Immediately dissolve a quantity of the oral solution containing the equivalent ofabout 200 000 IU of vitamin A, accurately weighed, in 5 ml of n-pentane R and dilutewith 2-propanol R to a presumed concentration of 10-15 IU per ml. Verify that theabsorption maximum of the solution to be examined, against 2-propanol as blank, liesbetween 325 nm and 327 nm. Measure the absorbances at 300 nm, 326 nm, 350 nmand 370 nm. Calculate the ratio Α λ/Α 326for each wavelength. If the ratios do not exceed0.60 at 300 nm, 0.54 at 350 nm and 0.14 at 370 nm, calculate the content of vitamin Ain IU.For an oral solution presented in a multidose container calculate the content of vitaminA in IU per ml from the expression: Α 326x V x d x 1900/ (100 x m), where A 326is theabsorbance at 326 nm, V is the total volume used for the dilution to give 10–15 IU perml, m is the mass of sample used in g, d is the weight per ml (1.3.1) of the oral solutionand 1900 is the factor to convert the specific absorbances of esters of retinol intoIU per g.149

Consultation DocumentsWHO Drug Information Vol. 25, No. 2, 2011For an oral solution presented as single doses calculate the deliverable content ofvitamin A in IU per capsule from the expression: Α 326x V x d x 1900/ (100 x m), whereA 326is the absorbance at 326 nm, V is the total volume used for the dilution to give 10-15 IU per ml, m is the mass of sample used in g, AM is the average mass of theexpressed contents in g per capsule and 1900 is the factor to convert the specificabsorbances of esters of retinol into IU per g.If one or more of the ratios Α λ/Α 326exceeds the values given, or if the wavelength ofthe absorption maximum does not lie between 325 nm and 327 nm, use Method B.B. Carry out the test as described under 1.14.4 High-performance liquid chromatography,using a stainless steel column (15 cm x 4.6 mm) packed with particles of silicagel, the surface of which has been modified with octadecysilyl groups (5 µm). As themobile phase, use a mixture of 95 volumes of methanol R and 5 volumes of water R.Prepare the following solutions. For solution (1) transfer a quantity of the oral solutioncontaining the equivalent of about 100 000 IU of vitamin A, accurately weighed, into a100 ml volumetric flask. Dissolve immediately in 5 ml of n-pentane R. Add 40 ml of 0.1M tetrabutylammonium hydroxide TS in 2-propanol R. Swirl gently and allow themixture to stand for 10 minutes at a temperature between 60 ° and 65 °C, swirlingoccasionally. Allow to cool to room temperature, dilute to volume with 2-propanol Rcontaining 1 g/l butylated hydroxytoluene R, and homogenise carefully to avoid airbubbles. Dilute 5 ml of the resulting solution to 50 ml with 2-propanol R. For solution(2) transfer an amount of retinol acetate RS or retinol palmitate RS containing about100 000 IU of vitamin A, accurately weighed, into a 100 ml volumetric flask. Proceedas described for solution (1).Operate with a flow rate of 1 ml per minute. As a detector use an ultraviolet spectrophotometerset at a wavelength of about 325 nm.Inject alternately 10 µl each of solutions (1) and (2) and record the chromatograms for1.5 times the retention time of retinol.Measure the areas of the peak responses obtained in the chromatograms fromsolutions (1) and (2). Determine the weight per ml (1.3.1) and calculate the content ofvitamin A in IU per ml of the oral solution or, where appropriate, in IU delivered percapsule.150

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105International Nonproprietary Names forPharmaceutical Substances (INN)Notice is hereby given that, in accordance with article 3 of the Procedure for the Selection of Recommended InternationalNonproprietary Names for Pharmaceutical Substances, the names given in the list on the following pages are underconsideration by the World Health Organization as Proposed International Nonproprietary Names. The inclusion of a namein the lists of Proposed International Nonproprietary Names does not imply any recommendation of the use of the substancein medicine or pharmacy.Lists of Proposed (1–101) and Recommended (1–62) International Nonproprietary Names can be found in Cumulative ListNo. 13, 2009 (available in CD-ROM only). The statements indicating action and use are based largely on informationsupplied by the manufacturer. This information is merely meant to provide an indication of the potential use of newsubstances at the time they are accorded Proposed International Nonproprietary Names. WHO is not in a positioneither to uphold these statements or to comment on the efficacy of the action claimed. Because of their provisional nature,these descriptors will neither be revised nor included in the Cumulative Lists of INNs.Dénominations communes internationales desSubstances pharmaceutiques (DCI)Il est notifié que, conformément aux dispositions de l'article 3 de la Procédure à suivre en vue du choix de Dénominationscommunes internationales recommandées pour les Substances pharmaceutiques les dénominations ci-dessous sont misesà l'étude par l'Organisation mondiale de la Santé en tant que dénominations communes internationales proposées.L'inclusion d'une dénomination dans les listes de DCI proposées n'implique aucune recommandation en vue de l'utilisationde la substance correspondante en médecine ou en pharmacie.On trouvera d'autres listes de Dénominations communes internationales proposées (1–101) et recommandées (1–62) dansla Liste récapitulative No. 13, 2009 (disponible sur CD-ROM seulement). Les mentions indiquant les propriétés et lesindications des substances sont fondées sur les renseignements communiqués par le fabricant. Elles ne visent qu'àdonner une idée de l'utilisation potentielle des nouvelles substances au moment où elles sont l'objet depropositions de DCI. L'OMS n'est pas en mesure de confirmer ces déclarations ni de faire de commentaires sur l'efficacitédu mode d'action ainsi décrit. En raison de leur caractère provisoire, ces informations ne figureront pas dans les listesrécapitulatives de DCI.Denominaciones Comunes Internacionales paralas Sustancias Farmacéuticas (DCI)De conformidad con lo que dispone el párrafo 3 del "Procedimiento de Selección de Denominaciones ComunesInternacionales Recomendadas para las Sustancias Farmacéuticas", se comunica por el presente anuncio que lasdenominaciones detalladas en las páginas siguientes están sometidas a estudio por la Organización Mundial de La Saludcomo Denominaciones Comunes Internacionales Propuestas. La inclusión de una denominación en las listas de las DCIPropuestas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia.Las listas de Denominaciones Comunes Internacionales Propuestas (1–101) y Recomendadas (1–62) se encuentranreunidas en Cumulative List No. 13, 2009 (disponible sólo en CD-ROM). Las indicaciones sobre acción y uso que aparecense basan principalmente en la información facilitada por los fabricantes. Esta información tiene por objeto dar una ideaúnicamente de las posibilidades de aplicación de las nuevas sustancias a las que se asigna una DCI Propuesta. LaOMS no está facultada para respaldar esas indicaciones ni para formular comentarios sobre la eficacia de la acción que seatribuye al producto. Debido a su carácter provisional, esos datos descriptivos no deben incluirse en las listasrecapitulativas de DCI.151

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011Proposed International Nonproprietary Names: List 105Comments on, or formal objections to, the proposed names may be forwarded by any person to the INN Programme of theWorld Health Organization within four months of the date of their publication in WHO Drug Information, i.e., for List 105 ofProposed INN not later than 31 October 2011Publication date: 30 June 2011Dénominations communes internationales proposées: Liste 105Des observations ou des objections formelles à l'égard des dénominations proposées peuvent être adressées par toutepersonne au Programme des Dénominations communes internationales de l'Organisation mondiale de la Santé dans undélai de quatre mois à compter de la date de leur publication dans WHO Drug Information, c'est à dire pour la Liste 105 deDCI Proposées le 31 octobre 2011 au plus tard.Date de publication: 30 juin 2011Denominaciones Comunes Internacionales Propuestas: Lista 105Cualquier persona puede dirigir observaciones u objeciones respecto de las denominaciones propuestas, al Programa deDenominaciones Comunes Internacionales de la Organización Mundial de la Salud, en un plazo de cuatro meses, contadosdesde la fecha de su publicación en WHO Drug Information, es decir, para la Lista 105 de DCI Propuestas el 31 deoctubre de 2011 a más tardar.Fecha de publicación: 30 de junio de 2011Proposed INN(Latin, English, French, Spanish)DCI ProposéeDCI PropuestaChemical name or description: Action and use: Molecular formulaChemical Abstracts Service (CAS) registry number: Graphic formulaNom chimique ou description: Propriétés et indications: Formule bruteNuméro dans le registre du CAS: Formule développéeNombre químico o descripción: Acción y uso: Fórmula molecularNúmero de registro del CAS: Fórmula desarrolladaabexinostatumabexinostatabexinostatabexinostat3-[(dimethylamino)methyl]-N-{2-[4-(hydroxycarbamoyl)phenoxy]ethyl}-1-benzofuran-2-carboxamideantineoplastic3-[(diméthylamino)méthyl]-N-{2-[4-(hydroxycarbamoyl)phénoxy]éthyl}-1-benzofurane-2-carboxamideantinéoplasique3-[(dimetilamino)metil]-N-{2-[4-(hidroxicarbamoil)fenoxi]etil}-1-benzofuran-2-carboxamidaantineoplásicoC 21 H 23 N 3 O 5 783355-60-2OH 3 CNOOHNONHOHH 3 C152

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105amilomotidum #amilomotideamilomotideamilomotidavirus like particle of bacteriophage Q-beta coat protein that iscoupled to multiple copies of human beta-amyloid1-6 peptidefragment;reaction products of bacteriophage Q-beta coat protein with humanbeta-amyloid protein-(1-6)-peptidylglycylglycyl-L-cysteine and3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-N-{6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexyl}propanamideimmunological agent for active immunizationpseudo-particule virale de la capside du phage Q-bêta couplée àplusieurs copies du fragment 1-6 de la protéine bêta-amyloïdehumaine;produit obtenu par réaction de la protéine de capside du phageQ-bêta avec la protéine bêta-amyloïde humaine-(1-6)peptidylglycylglycyl-L-cystéine et le 3-(2,5-dioxo-2,5-dihydro-1H-pyrrole-1-yl)-N-{6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexyl}propanamideagent immunologique d'immunisation activepseudo-particula viral de cápsida del fago Q-beta acoplada amúltiples copias del fragmento 1-6 de la proteína beta-amiloidehumana;producto obtenido por reacción de la proteína de cápsida del fagoQ-beta con la proteína beta-amiloide humana-(1-6)peptidilglicilglicil-L-cisteína y el 3-(2,5-dioxo-2,5-dihidro-1H-pirrol-1-il)-N-{6-[(2,5-dioxopirrolidin-1-il)oxi]-6-oxohexil}propanamidaagente inmunológico para inmuzación activaOHH Asp Ala Glu Phe Arg His Gly Gly NHCO 2 HHSN1238372-23-0Heavy chain / Chaîne lourde / Cadena pesadaAKLETVTLGN IGKDGKQTLV LNPRGVNPTN GVASLSQAGA VPALEKRVTV 50SVSQPSRNRK NYKVQVKIQN PTACTANGSC DPSVTRQAYA DVTFSFTQYS 100TDEERAFVRT ELAALLASPL LIDAIDQLNP AY 132Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro74-80Modified residues / Résidus modifiés / Residuos modificadosA1H CH 3K2-13-16-46-60-63-67HR NHCO 2 HR NHH 2 N CO 2 HOR = H or / ou / ó or / ou / óOOO*NONHNHCOCOand epimer at C*et l'épimère en C*y el epímero al C*153

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011anivamersenumanivamersenanivamersenanivamersén2'-O-methylcytidylyl-(3'→5')-2'-O-methylguanylyl-(3'→5')-2'-Omethylcytidylyl-(3'→5')-2'-O-methylguanylyl-(3'→5')-2'-Omethylguanylyl-(3'→5')-2'-O-methyluridylyl-(3'→5')-2'-Omethyladenylyl-(3'→5')-2'-O-methyluridylyl-(3'→5')-2'-Omethyladenylyl-(3'→5')-2'-O-methylguanylyl-(3'→5')-2'-Omethyluridylyl-(3'→5')-2'-O-methylcytidylyl-(3'→5')-2'-Omethylcytidylyl-(3'→5')-2'-O-methyladenylyl-(3'→5')-2'-Omethylcytidineanticoagulant inhibitor2'-O-méthylcytidylyl-(3'→5')-2'-O-méthylguanylyl-(3'→5')-2'-Ométhylcytidylyl-(3'→5')-2'-O-méthylguanylyl-(3'→5')-2'-Ométhylguanylyl-(3'→5')-2'-O-méthyluridylyl-(3'→5')-2'-Ométhyladénylyl-(3'→5')-2'-O-méthyluridylyl-(3'→5')-2'-Ométhyladénylyl-(3'→5')-2'-O-méthylguanylyl-(3'→5')-2'-Ométhyluridylyl-(3'→5')-2'-O-méthylcytidylyl-(3'→5')-2'-Ométhylcytidylyl-(3'→5')-2'-O-méthyladénylyl-(3'→5')-2'-Ométhylcytidineinhibiteur d'anticoagulant2'-O-metilcitidilil-(3'→5')-2'-O-metilguanilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'-O-metilguanilil-(3'→5')-2'-O-metilguanilil-(3'→5')-2'-O-metiluridilil-(3'→5')-2'-O-metiladenilil-(3'→5')-2'-O-metiluridilil-(3'→5')-2'-O-metiladenilil-(3'→5')-2'-O-metilguanilil-(3'→5')-2'-O-metiluridilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'-Ometiladenilil-(3'→5')-2'-O-metilctidinainhibidor de anticoagulanteC 157 H 208 N 56 O 103 P 14 959716-29-1(3'-5')-mC-mG-mC-mG-mG-mU-mA-mU-mA-mG-mU-mC-mC-mA-mCasunaprevirumasunaprevirasunaprévirasunaprevirtert-butyl {(2S)-1-[(2S,4R)-4-({7-chloro-4-methoxyisoquinolin-1-yl}oxy)-2-({(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-ethenylcyclopropyl}carbamoyl)pyrrolidin-1-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamateantiviral(2S)-1-[(2S,4R)-4-({7-chloro-4-méthoxyisoquinolin-1-yl}oxy)-2-({(1R,2S)-1-[(cyclopropanesulfonyl)carbamoyl]-2-éthènylcyclopropyl}carbamoyl)pyrrolidin-1-yl]-3,3-diméthyl-1-oxobutan-2-yl}carbamate de tert-butyleantiviral{(2S)-1-[(2S,4R)-4-({7-cloro-4-metoxiisoquinolin-1-il}oxi)-2-({(1R,2S)-1-[(ciclopropanosulfonil)carbamoil]-2-etenilciclopropil}carbamoil)pirrolidin-1-il]-3,3-dimetil-1-oxobutan-2-il}carbamato de terc-butiloantiviral154

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105C 35 H 46 ClN 5 O 9 S 630420-16-5OO SH 2 CH 3 CH 3 CONHONHH OCH 3OONHHHNCH 3CH 3CH 3HONClOCH 3besifovirumbesifovirbésifovirbesifovir[({1-[(2-amino-9H-purin-9-yl)methyl]cyclopropyl}oxy)methyl]phosphonic acidantiviralacide [({1-[(2-amino-9H-purin-9-yl)méthyl]cyclopropyl}oxy)méthyl]phosphoniqueantiviralácido [({1-[(2-amino-9H-purin-9-il)metil]ciclopropil}oxi)metil]fosfónicoantiviralC 10 H 14 N 5 O 4 P 441785-25-7H 2 NNNNNOOPOHOHblosozumabum #blosozumabblosozumabimmunoglobulin G4-kappa, anti-[Homo sapiens SOST (sclerostin)],humanized monoclonal antibody;gamma4 heavy chain (1-444) [humanized VH (Homo sapiensIGHV1-24*01 (85.70%) -(IGHD)-IGHJ4*01 L123>T (113)) [8.8.11] (1-118) -Homo sapiens IGHG4*01 hinge S10>P (226), CH3 K120>del(119-444)], (132-214')-disulfide with kappa light chain (1'-214')[humanized V-KAPPA (Homo sapiens IGKV1-13*02 (84.00%) -IGKJ1*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiens IGKC*01(108'-214')]; (224-224":227-227")-bisdisulfide dimerimmunomodulatorimmunoglobuline G4-kappa, anti-[Homo sapiens SOST(sclérostine)], anticorps monoclonal humanisé;chaîne lourde gamma4 (1-444) [VH humanisé (Homo sapiensIGHV1-24*01 (85.70%) -(IGHD)-IGHJ4*01 L123>T (113)) [8.8.11](1-118) -Homo sapiens IGHG4*01 charnière S10>P (226), CH3K120>del (119-444)], (132-214')-disulfure avec la chaîne légèrekappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1-13*02(84.00%) -IGKJ1*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiensIGKC*01 (108'-214')]; dimère (224-224":227-227")-bisdisulfureimmunomodulateur155

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011blosozumabinmunoglobulina G4-kappa, anti-[Homo sapiens SOST(esclerostina)], anticuerpo monoclonal humanizado;cadena pesada gamma4 (1-444) [VH humanizada (Homo sapiensIGHV1-24*01 (85.70%) -(IGHD)-IGHJ4*01 L123>T (113)) [8.8.11](1-118) -Homo sapiens IGHG4*01 bisagra S10>P (226), CH3K120>del (119-444)], (132-214')-disulfuro con la cadena ligerakappa (1'-214') [V-KAPPA humanizada (Homo sapiens IGKV1-13*02(84.00%) -IGKJ1*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiensIGKC*01 (108'-214')]; dímero (224-224":227-227")-bisdisulfuroinmunomodulador1132758-87-2Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VKKPGASVKV SCKVSGFPIK DTFQHWVRQA PGKGLEWMGW 50SDPEIGDTEY ASKFQGRVTM TEDTSTDTAY MELSSLRSED TAVYYCATGD 100TTYKFDFWGQ GTTVTVSSAS TKGPSVFPLA PCSRSTSEST AALGCLVKDY 150FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTKTYT 200CNVDHKPSNT KVDKRVESKY GPPCPPCPAP EFLGGPSVFL FPPKPKDTLM 250ISRTPEVTCV VVDVSQEDPE VQFNWYVDGV EVHNAKTKPR EEQFNSTYRV 300VSVLTVLHQD WLNGKEYKCK VSNKGLPSSI EKTISKAKGQ PREPQVYTLP 350PSQEEMTKNQ VSLTCLVKGF YPSDIAVEWE SNGQPENNYK TTPPVLDSDG 400SFFLYSRLTV DKSRWQEGNV FSCSVMHEAL HNHYTQKSLS LSLG 444Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCKASQDVH TAVAWYQQKP GKAPKLLIYW 50ASTRWTGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSDYPWTFGG 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 145-201 259-319 365-42322''-96'' 145''-201'' 259''-319'' 365''-423''Intra-L 23'-88' 134'-194'23'''-88''' 134'''-194'''Inter-H-L 132-214' 132''-214'''Inter-H-H 224-224'' 227-227''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación295, 295''brodalumabum #brodalumabbrodalumabimmunoglobulin G2-kappa, anti-[Homo sapiens IL17RA (interleukin17 receptor A, CD217)], Homo sapiens monoclonal antibody;gamma2 heavy chain (1-442) [Homo sapiens VH (IGHV1-18*01(96.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -Homo sapiensIGHG2*01 (117-442)], (130-214')-disulfide with kappa light chain(1'-214') [Homo sapiens V-KAPPA (IGKV1-15*01 (93.70%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')];(218-218":219-219":222-222":225-225")-tetrakisdisulfide dimerimmunomodulatorimmunoglobuline G2-kappa, anti-[Homo sapiens IL17RA (récepteurA de l'interleukine 17, CD217)], Homo sapiens anticorps monoclonal;chaîne lourde gamma2 (1-442) [Homo sapiens VH (IGHV1-18*01(96.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -Homo sapiensIGHG2*01 (117-442)], (130-214')-disulfure avec la chaîne légèrekappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-15*01 (93.70%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')];dimère (218-218":219-219":222-222":225-225")-tétrakisdisulfureimmunomodulateur156

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105brodalumabinmunoglobulina G2-kappa, anti-[IL17RA (receptor A de lainterleukina 17 de Homo sapiens, CD217)], anticuerpo monoclonalde Homo sapiens;cadena pesada gamma2 (1-442) [Homo sapiens VH (IGHV1-18*01(96.90%) -(IGHD)-IGHJ4*01) [8.8.9] (1-116) -Homo sapiensIGHG2*01 (117-442)], (130-214')-disulfuro con la cadena ligerakappa (1'-214') [Homo sapiens V-KAPPA (IGKV1-15*01 (93.70%) -IGKJ4*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')];dímero (218-218":219-219":222-222":225-225")-tetrakisdisulfuroinmunomodulador1174395-19-7Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VKKPGASVKV SCKASGYTFT RYGISWVRQA PGQGLEWMGW 50ISTYSGNTNY AQKLQGRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARRQ 100LYFDYWGQGT LVTVSSASTK GPSVFPLAPC SRSTSESTAA LGCLVKDYFP 150EPVTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS NFGTQTYTCN 200VDHKPSNTKV DKTVERKCCV ECPPCPAPPV AGPSVFLFPP KPKDTLMISR 250TPEVTCVVVD VSHEDPEVQF NWYVDGVEVH NAKTKPREEQ FNSTFRVVSV 300LTVVHQDWLN GKEYKCKVSN KGLPAPIEKT ISKTKGQPRE PQVYTLPPSR 350EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PMLDSDGSFF 400LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP GK 442Light chain / Chaîne légère / Cadena ligeraEIVMTQSPAT LSVSPGERAT LSCRASQSVS SNLAWFQQKP GQAPRPLIYD 50ASTRATGVPA RFSGSGSGTD FTLTISSLQS EDFAVYYCQQ YDNWPLTFGG 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 143-199 256-316 362-42022''-96'' 143''-199'' 256''-316'' 362''-420''Intra-L 23'-88' 134'-194'23'''-88''' 134'''-194'''Inter-H-L 130-214' 130''-214'''Inter-H-H 218-218'' 219-219'' 222-222'' 225-225''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación292, 292''cabozantinibumcabozantinibcabozantinibcabozantinibN-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideantineoplasticN-{4-[(6,7-diméthoxyquinoléin-4-yl)oxy]phényl}-N'-(4-fluorophényl)cyclopropane-1,1-dicarboxamideantinéoplasiqueN-{4-[(6,7-dimetoxiquinolin-4-il)oxi]fenil}-N'-(4-fluorofenil)ciclopropano-1,1-dicarboxamidaantineoplásicoC 28 H 24 FN 3 O 5 849217-68-1H 3 CONH 3 COOOOFNHNH157

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011calaspargasum pegolum #calaspargase pegolcalaspargase pégolcalaspargasa pegolpegylated Escherichia coli asparaginase;[27-alanine,64-aspartic acid,252-threonine,263-asparagine]-L-asparaginase 2 (EC 3.5.1.1, L-asparagine amidohydrolase II)Escherichia coli (strain K12) tetramer α 4 , carbamates withα-carboxy-ω-methoxypoly(oxyethylene)antineoplasticasparaginase d'Escherichia coli pégylée;carbamates entre le tétramère α 4 de [27-alanine,64-acideaspartique,252-thréonine,263-asparagine]-L-asparaginase 2(EC 3.5.1.1, L-asparagine amidohydrolase II) d’Escherichia coli(souche K12) et le α-carboxy-ω-méthoxypoly(oxyéthylène)antinéoplasiqueasparaginasa de Escherichia coli pegilada;carbamatos entre el tetrámero α 4 de [27-alanina,64-ácidoaspártico,252-treonina,263-asparagina]-L-asparaginasa 2(EC 3.5.1.1, L-asparagina amidohidrolasa II) de Escherichia coli(cepa K12) y el α-carboxi-ω-metoxipoli(oxietileno)antineoplásicoC 1516 H 2423 N 415 O 492 S 8 (peptide monomer) 941577-06-6Monomer / Monomère / MonómeroLPNITILATG GTIAGGGDSA TKSNYTAGKV GVENLVNAVP QLKDIANVKG 50EQVVNIGSQD MNDDVWLTLA KKINTDCDKT DGFVITHGTD TMEETAYFLD 100LTVKCDKPVV MVGAMRPSTS MSADGPFNLY NAVVTAADKA SANRGVLVVM 150NDTVLDGRDV TKTNTTDVAT FKSVNYGPLG YIHNGKIDYQ RTPARKHTSD 200TPFDVSKLNE LPKVGIVYNY ANASDLPAKA LVDAGYDGIV SAGVGNGNLY 250KTVFDTLATA AKNGTAVVRS SRVPTGATTQ DAEVDDAKYG FVASGTLNPQ 300KARVLLQLAL TQTKDPQQIQ QIFNQY 326approximately 9 residues are pegylated out of 23 (1 L and 22 K)environ 9 résidus sur 23 (1 L et 22 K) sont pegylésaproximadamente están pegilados 9 restos de 23 ( 1L y 22K)L1K22-29-43-49-71-72-79-104-107-139-162-172-186-196-207-213-229-251-262-288-301-314H 3 COOH 3 CO Hnn # 112NHCH 3CO 2 HH 3 COOOnNHn # 112H 2 NHCO 2 HDisulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro77-105 77'-105' 77'''-105''' 77''''-105''''158

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105cantuzumabum ravtansinum #cantuzumab ravtansinecantuzumab ravtansinecantuzumab ravtansinaimmunoglobulin G1-kappa, anti-[Homo sapiens MUC1 sialylatedcarbohydrate, tumour-associated (CA242, cancer antigen 242)],humanized monoclonal antibody conjugated to maytansinoid DM4;gamma1 heavy chain (1-449) [humanized VH (Homo sapiensIGHV7-4-1*02 (76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T(114)) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfide with kappa light chain (1’-219’) [humanized V-KAPPA(Homo sapiens IGKV2-28*01 (82.00%) -IGKJ3*01 V124>L (109),D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homo sapiensIGKC*01 (113'-219')]; (228-228":231-231")-bisdisulfide dimer;conjugated, on an average of 3 to 4 lysyl, to maytansinoid DM4 [N 2’ -deacetyl-N 2’ -(4-mercapto-4-methyl-1-oxopentyl)-maytansine] via thereducible SPDB linker [N-succinimidyl 4-(2-pyridyldithio)butanoate]For the ravtansine part, please refer to the document "INN forpharmaceutical substances: Names for radicals, groups and others"*antineoplasticimmunoglobuline G1-kappa, anti-[Homo sapiens glycane sialylé deMUC1, associé à des tumeurs (CA242, antigène du cancer 242)],anticorps monoclonal humanisé conjugué au maytansinoïde DM4;chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiensIGHV7-4-1*02 (76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T(114)) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfure avec la chaîne légère kappa (1'-219') [V-KAPPAhumanisé (Homo sapiens IGKV2-28*01 (82.00%) -IGKJ3*01 V124>L(109), D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homo sapiensIGKC*01 (113'-219')]; dimère (228-228":231-231")-bisdisulfure;conjugué, sur 3 à 4 lysyl en moyenne, au maytansinoïde DM4 [N 2' -déacétyl-N 2' -(4-mercapto-4-méthyl-1-oxopentyl)-maytansine] via lelinker SPDB réductible [4-(2-pyridyldithio)butanoate deN-succinimidyle]Pour la partie ravtansine, veuillez vous référer au document "INN forpharmaceutical substances: Names for radicals, groups andothers"*.antinéoplasiqueinmunoglobulina G1-kappa, anti-[Homo sapiens glicano sialilo deMUC1, asociado al tumor (CA242, antígeno del cancer 242)]anticuerpo monoclonal humanizado conjugado con el maitansinoideDM4;cadena pesada gamma1 (1-449) [VH humanizada (Homo sapiensIGHV7-4-1*02 (76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T(114)) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfuro con la cadena ligera kappa (1'-219') [V-KAPPAhumanizada (Homo sapiens IGKV2-28*01 (82.00%) -IGKJ3*01V124>L (109), D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homosapiens IGKC*01 (113'-219')]; dímero (228-228":231-231")-bisdisulfuro; conjugado, en 3-4 grupos lisil por término medio, con elmaitansinoide DM4 [N 2' -desacetil-N 2' -(4-mercapto-4-metil-1-oxopentil)-maitansina] mediante el conector SPDB reducible[4-(2-piridilditio)butanoato de N-succinimidilo]Para la fracción ravtansina, se ruega referirse al documento "INN forpharmaceutical substances: Names for radicals, groups andothers"*.antineoplásico159

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011868747-45-9Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VKKPGETVKI SCKASDYTFT YYGMNWVKQA PGQGLKWMGW 50IDTTTGEPTY AQKFQGRIAF SLETSASTAY LQIKSLKSED TATYFCARRG 100PYNWYFDVWG QGTTVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449Light chain / Chaîne légère / Cadena ligeraDIVMTQSPLS VPVTPGEPVS ISCRSSKSLL HSNGNTYLYW FLQRPGQSPQ 50LLIYRMSNLV SGVPDRFSGS GSGTAFTLRI SRVEAEDVGV YYCLQHLEYP 100FTFGPGTKLE LKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200VTHQGLSSPV TKSFNRGEC 219Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 146-202 263-323 369-42722''-96'' 146''-202'' 263''-323'' 369''-427''Intra-L 23'-93' 139'-199'23'''-93''' 139'''-199'''Inter-H-L 222-219' 222''-219'''Inter-H-H 228-228'' 231-231''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación299, 299''ceftolozanumceftolozaneceftolozaneceftolozano(6R,7R)-3-[(5-amino-4-{[(2-aminoethyl)carbamoyl]amino}-1-methyl-1H-pyrazol-2-ium-2-yl)methyl]-7-[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateantibiotic(6R,7R)-3-[(5-amino-4-{[(2-aminoéthyl)carbamoyl]amino}-1-méthyl-1H-pyrazol-2-ium-2-yl)méthyl]-7-[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acétamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ène-2-carboxylateantibiotique(6R,7R)-3-[(5-amino-4-{[(2-aminoetil)carbamoil]amino}-1-metil-1H-pirazol-2-io-2-il)metil]-7-[(2Z)-2-(5-amino-1,2,4-tiadiazol-3-il)-2-{[(2-carboxipropan-2-il)oxo]imino}acetamido]-8-oxo-5-tia-1-azabiciclo[4.2.0]oct-2-eno-2-carboxilatoantibióticoC 23 H 30 N 12 O 8 S 2 689293-68-3NSH 3 CCO 2 HH 3 CON OHNHN ONHCO 2SH 3 CNNONH 2NHNHNH 2H 2 N160

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105cenderitidumcenderitidenatriuretic peptide receptor type B (NPR-B) agonist;human C-type natriuretic peptide-(32-53)-peptide (CNP-22) fusionprotein with eastern green mamba (Dendroaspis angusticeps)natriuretic peptide-(24-38)-peptideatrial natriuretic factor type substancecendéritide agoniste du récepteur du peptide natriurétique de type B;peptide natriurétique de type-C humain-(32-53)-peptide (CNP-22)protéine de fusion avec le peptide natriurétique de Dendroaspisangusticeps (mamba vert)-(24-38)-peptidesubstance type facteur natriurétique auriculairecenderitida agonista del receptor del péptido natriurético de tipo B;péptido natriurético de tipo-C humano-(32-53)-péptido (CNP-22)proteína de fusión con el péptido natriurético de Dendroaspisangusticeps (mamba vert)-(24-38)-péptidosustancia de tipo péptido natriurético atrialC 158 H 263 N 49 O 50 S 3 507289-11-4GLSKGCFGLK LDRIGSMSGL GCPSLRDPRP NAPSTSA 37Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro6-22cepeginterferonum alfa-2b #cepeginterferon alfa-2bcépeginterféron alfa-2bcepeginterferón alfa-2bpegylated human interferon alpha-2b;N 2.1 -{4-[ω-methoxypoly(oxyethylene)]butyl}-human interferonalpha-2bimmunomodulatorinterféron alpha-2b humain pégylé;N 2.1 -{4-[ω-méthoxypoly(oxyéthylène)]butyl}interféron alpha-2bhumainimmunomodulateurinterferón alfa-2b humano pegilado;N 2.1 -{4-[ω-metoxipoli(oxietileno)]butil}interferón alfa-2b humanoinmunomoduladorC 865 H 1359 N 229 O 256 S 9 [C 2 H 4 O] n 1192706-52-7CDLPQTHSLG SRRTLMLLAQ MRRISLFSCL KDRHDFGFPQ EEFGNQFQKA 50ETIPVLHEMI QQIFNLFSTK DSSAAWDETL LDKFYTELYQ QLNDLEACVI 100QGVGVTETPL MKEDSILAVR KYFQRITLYL KEKKYSPCAW EVVRAEIMRS 150FSLSTNLQES LRSKE 165Disulfide bridges location / Positions des ponts disulfure / Posiciones de los puentes disulfuro1-98 29-138Modified residue / Résidu modifié / Residuo modificadoC1OH 3 COnn # 450HSHNHCO 2 H161

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011conberceptum #conberceptconberceptconberceptfusion protein for immune applications (FPIA) comprising Homosapiens FLT1 (fms-related tyrosine kinase 1, vascular endothelialgrowth factor receptor 1, VEGFR1, vascular permeability factorreceptor, tyrosine-protein kinase FRT) fragment, fused with Homosapiens KDR (kinase insert domain receptor, vascular endothelialgrowth factor receptor 2, VEGFR2, protein-tyrosine kinase receptorFLK1, CD309) fragment, fused with Homo sapiens immunoglobulinG1 Fc fragment;FLT1, 132-232 precursor fragment (1-101) -KDR, 227-421 precursorfragment (102-296) -glycyl-prolyl-glycyl (297-299) -gamma1 chain H-CH2-CH3 fragment (300-526) [Homo sapiens IGHG1*03 hinge 6-15P13>L (307) (300-309), CH2 (310-419), CH3-CH-S (420-526)]; (305-305':308-308')-bisdisulfide dimerangiogenesis inhibitorprotéine de fusion pour applications immunitaires (FPIA) comprenantun fragment d'Homo sapiens FLT1 (tyrosine kinase 1 apparentée aufms, récepteur 1 du facteur de croissance de l'endothéliumvasculaire, VEGFR1, récepteur du facteur de perméabilitévasculaire, tyrosine-protéine kinase FRT), fusionné à un fragmentd'Homo sapiens KDR (récepteur à domaine kinase, récepteur 2 dufacteur de croissance de l'endothélium vasculaire, VEGFR2,récepteur tyrosine-protéine kinase FLK1, CD309), fusionné aufragment Fc de l'Homo sapiens immunoglobuline G1;FLT1, fragment 132-232 du précurseur (1-101) -KDR, fragment 227-421 du précurseur (102-296) - glycyl-prolyl-glycyl (297-299) -fragment H-CH2-CH3 de la chaîne gamma1 (300-526) [Homosapiens IGHG1*03 charnière 6-15 P13>L (307) (300-309), CH2(310-419), CH3-CH-S (420-526)]; dimère (305-305':308-308')-bisdisulfureinhibiteur de l'angiogénèseproteína de fusión para aplicaciones inmunitarias (FPIA) quecomprende un fragmento de FLT1 de Homo sapiens (tirosina kinasa1 relacionada con fms, receptor 1 del factor de crecimiento delendotelio vascular, VEGFR1, receptor del factor de permeabilidadvascular, tirosina-protein kinasa FRT), fusionada a un fragmento deKDR de Homo sapiens (receptor con dominio kinasa, receptor 2 delfactor de crecimiento del endotelio vascular, VEGFR2, receptortirosina-protein kinasa FLK1, CD309), fusionado al fragmento Fc dela inmunoglobulina G1 de Homo sapiens;FLT1, fragmento 132-232 de precursor (1-101) -KDR, fragmento227-421 del precursor (102-296) - glicil-prolil-glicil (297-299) -fragmento H-CH2-CH3 de la cadena gamma1 (300-526) [Homosapiens IGHG1*03 bisagra 6-15 P13>L (307) (300-309), CH2 (310-419), CH3-CH-S (420-526)]; dímero (305-305':308-308')-bisdisulfuroinhibidor de la angiogénesis162

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 1051227158-72-6Fused chain / chaine fusionnée / cadena fusionadaGRPFVEMYSE IPEIIHMTEG RELVIPCRVT SPNITVTLKK FPLDTLIPDG 50KRIIWDSRKG FIISNATYKE IGLLTCEATV NGHLYKTNYL THRQTNTIID 100VVLSPSHGIE LSVGEKLVLN CTARTELNVG IDFNWEYPSS KHQHKKLVNR 150DLKTQSGSEM KKFLSTLTID GVTRSDQGLY TCAASSGLMT KKNSTFVRVH 200EKPFVAFGSG MESLVEATVG ERVRIPAKYL GYPPPEIKWY KNGIPLESNH 250TIKAGHVLTI MEVSERDTGN YTVILTNPIS KEKQSHVVSL VVYVPPGPGD 300KTHTCPLCPA PELLGGPSVF LFPPKPKDTL MISRTPEVTC VVVDVSHEDP 350EVKFNWYVDG VEVHNAKTKP REEQYNSTYR VVSVLTVLHQ DWLNGKEYKC 400KVSNKALPAP IEKTISKAKG QPREPQVYTL PPSRDELTKN QVSLTCLVKG 450FYPSDIAVEW ESNGQPENNY KATPPVLDSD GSFFLYSKLT VDKSRWQQGN 500VFSCSVMHEA LHNHYTQKSL SLSPGK 526Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-chain 27-76 121-182 340-400 446-50427'-76' 121'-182' 340'-400' 446'-504'Inter-chains 305-305' 308-308'N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación376, 376'crenezumabum #crenezumabcrénezumabcrenezumabimmunoglobulin G4-kappa, anti-[Homo sapiens amyloid beta (Abeta)peptides Aβ42 and Aβ40]], humanized monoclonal antibody;gamma4 heavy chain (1-438) [humanized VH (Homo sapiensIGHV3-23*04 (89.70%) -(IGHD)-IGHJ4*01 L123>T (107) [8.8.5](1-112) -Homo sapiens IGHG4*01 hinge S10>P (220) (113-438)],(126-219')-disulfide with kappa light chain (1'-219') [humanizedV-KAPPA (Homo sapiens IGKV2D-29*02 (86.00%) -IGKJ1*01)[11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (218-218":221-221")-bisdisulfide dimerimmunomodulatorimmunoglobuline G4-kappa, anti-[Homo sapiens peptides bêtaamyloïdes(Abêta) Aβ42 et Aβ40]], anticorps monoclonal humanisé;chaîne lourde gamma4 (1-438) [VH humanisé (Homo sapiensIGHV3-23*04 (89.70%) -(IGHD)-IGHJ4*01 L123>T (107) [8.8.5](1-112) -Homo sapiens IGHG4*01 charnière S10>P (220) (113-438)], (126-219')-disulfure avec la chaîne légère kappa (1'-219')[V-KAPPA humanisé (Homo sapiens IGKV2D-29*02 (86.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')];dimère (218-218":221-221")-bisdisulfureimmunomodulateurinmunoglobulina G4-kappa, anti-[péptidos beta-amiloides (Abeta)Aβ42 y Aβ40 de Homo sapiens]], anticuerpo monoclonalhumanizado;cadena pesada gamma4 (1-438) [VH humanizada (Homo sapiensIGHV3-23*04 (89.70%) -(IGHD)-IGHJ4*01 L123>T (107) [8.8.5](1-112) -Homo sapiens IGHG4*01 bisagra S10>P (220) (113-438)],(126-219')-disulfuro con la cadena ligera kappa (1'-219')[V-KAPPA humanizada (Homo sapiens IGKV2D-29*02 (86.00%) -IGKJ1*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')];dímero (218-218":221-221")-bisdisulfuroinmunomodulador163

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 20111095207-05-8Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG LVQPGGSLRL SCAASGFTFS SYGMSWVRQA PGKGLELVAS 50INSNGGSTYY PDSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCASGD 100YWGQGTTVTV SSASTKGPSV FPLAPCSRST SESTAALGCL VKDYFPEPVT 150VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT KTYTCNVDHK 200PSNTKVDKRV ESKYGPPCPP CPAPEFLGGP SVFLFPPKPK DTLMISRTPE 250VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS TYRVVSVLTV 300LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV YTLPPSQEEM 350TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL DSDGSFFLYS 400RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLG 438Light chain / Chaîne légère / Cadena ligeraDIVMTQSPLS LPVTPGEPAS ISCRSSQSLV YSNGDTYLHW YLQKPGQSPQ 50LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHVP 100WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200VTHQGLSSPV TKSFNRGEC 219Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 139-195 253-313 359-41722''-96'' 139''-195'' 253''-313'' 359''-417''Intra-L 23'-93' 139'-199'23'''-93''' 139'''-199'''Inter-H-L 126-219' 126''-219'''Inter-H-H 218-218'' 221-221''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación289, 289''crenolanibumcrenolanibcrénolanibcrenolanib1-(2-{5-[(3-methyloxetan-3-yl)methoxy]-1H-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amineantineoplastic1-(2-{5-[(3-méthyloxétan-3-yl)méthoxy]-1H-benzimidazol-1-yl}quinoléin-8-yl)pipéridin-4-amineantinéoplasique1-(2-{5-[(3-metiloxetan-3-il)metoxi]-1H-benzoimidazol-1-il}quinolin-8-il)piperidin-4-aminaantineoplásicoC 26 H 29 N 5 O 2 670220-88-9OOCH 3NH 2NNNNdabrafenibumdabrafenibdabrafénibN-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamideantineoplasticN-{3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophényl}-2,6-difluorobenzènesulfonamideantinéoplasique164

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105dabrafenibN-{3-[5-(2-aminopirimidin-4-il)-2-terc-butil-1,3-tiazol-4-il]-2-fluorofenil}-2,6-difluorobencenosulfonamidoantineoplásicoC 23 H 20 F 3 N 5 O 2 S 2 1195765-45-7NH 2FNNFF SHCHN3SNO O H 3 C CH 3daclatasvirumdaclatasvirdaclatasvirdaclatasvirdimethyl N,N'-([1,1'-biphenyl]-4,4'-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1-diyl][(1S)-3-methyl-1-oxobutane-1,2-diyl]})dicarbamateantiviralN,N'-([1,1'-biphényl]-4,4'-diylbis{1H-imidazole-5,2-diyl-[(2S)-pyrrolidine-2,1-diyl][(1S)-3-méthyl-1-oxobutane-1,2-diyl]})dicarbamate de diméthyleantiviralN,N'-([1,1'-bifenil]-4,4'-diilbis{1H-imidazol-5,2-diil-[(2S)-pirrolidina-2,1-diil][(1S)-3-metil-1-oxobutano-1,2-diil]})dicarbamato de dimetiloantiviralC 40 H 50 N 8 O 6 1099119-64-5CH 3H 3 COCH 3HONHHNONNHHNNNHHNOOOHCH 3CH 3CH 3dalanterceptum #dalanterceptfusion protein for immune applications (FPIA) comprising Homosapiens ACVRL1 (activin A receptor type II-like 1, activin receptorlikekinase 1, ALK1, ALK-1, serine/threonine-protein kinase receptorR3, SKR3, transforming growth factor-beta superfamily receptor typeI, TGF-B superfamily receptor type I, TSR-I, HHT2, ORW2)fragment, fused with Homo sapiens immunoglobulin G1 Fc fragment;ACVR2L1, 22-120 precursor fragment (1-99) -threonyl-triglycyl (100-103) -gamma1 chain H-CH2-CH3 fragment (104-328) [Homosapiens IGHG1*03 hinge 8-15 (104-111), CH2 L1.3>A (115), G1>A(118), A115>V (211) (112-221), CH3 S85.3>P (284) (222-328)];(107-107':110-110')-bisdisulfide dimerantineoplastic165

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011dalanterceptdalanterceptprotéine de fusion pour applications immunitaires (FPIA) comprenantun fragment d'Homo sapiens ACVRL1 (récepteur 1 de type II-like del'activine A, kinase 1 apparentée au récepteur de l'activine, ALK1,ALK-1, récepteur R3 de type sérine/thréonine-protéine kinase,SKR3, récepteur de type I de la superfamille du facteur decroissance transformant bêta, récepteur de type I de la superfamilledu TGF-B, TSR-I, HHT2, ORW2), fusionné au fragment Fc del'Homo sapiens immunoglobuline G1;ACVR2L1, fragment 22-120 du précurseur (1-99) -thréonyl-triglycyl(100-103) -fragment H-CH2-CH3 de la chaîne gamma1 (104-328)[Homo sapiens IGHG1*03 charnière 8-15 (104-111), CH2 L1.3>A(115), G1>A (118), A115>V (211) (112-221), CH3 S85.3>P (284)(222-328)]; dimère (107-107':110-110')-bisdisulfureantinéoplasiqueproteína de fusión para aplicaciones inmunitarias (FPIA) quecomprende un fragmento de ACVRL1 de Homo sapiens (receptor 1de tipo II-like de la activina A, kinasa 1 relacionada con el receptorde la activina, ALK1, ALK-1, receptor R3 de tipo serina/treoninaproteinkinasa,SKR3, receptor de tipo I de la superfamilia del factorde crecimiento transformador beta, receptor de tipo I de lasuperfamilia del TGF-B, TSR-I, HHT2, ORW2), fusionada con elfragmento Fc de la inmunoglobulina G1 de Homo sapiens;ACVR2L1, fragmento 22-120 del precursor (1-99) -treonil-triglicil(100-103) -fragmento H-CH2-CH3 de la cadena gamma1 (104-328)[Homo sapiens IGHG1*03 bisagra 8-15 (104-111), CH2 L1.3>A(115), G1>A (118), A115>V (211) (112-221), CH3 S85.3>P (284)(222-328)]; dímero (107-107':110-110')-bisdisulfuroantineoplásico1186210-24-1Fused chain / chaine fusionnée / cadena fusionadaDPVKPSRGPL VTCTCESPHC KGPTCRGAWC TVVLVREEGR HPQEHRGCGN 50LHRELCRGRP TEFVNHYCCD SHLCNHNVSL VLEATQPPSE QPGTDGQLAT 100GGGTHTCPPC PAPEALGAPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE 150DPEVKFNWYV DGVEVHNAKT KPREEQYNST YRVVSVLTVL HQDWLNGKEY 200KCKVSNKALP VPIEKTISKA KGQPREPQVY TLPPSREEMT KNQVSLTCLV 250KGFYPSDIAV EWESNGQPEN NYKTTPPVLD SDGPFFLYSK LTVDKSRWQQ 300GNVFSCSVMH EALHNHYTQK SLSLSPGK 328Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-chain 13-30 15-20 25-48 56-68 69-74 142-202 248-30613'-30' 15'-20' 25'-48' 56'-68' 69'-74' 142'-202' 248'-306'Inter-chains 107-107' 110-110'N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación77, 178, 77', 178'dasolampanelumdasolampaneldasolampaneldasolampanel(3S,4aS,6S,8aR)-6-[3-chloro-2-(1H-tetrazol-5-yl)phenoxy]-decahydroisoquinoline-3-carboxylic acidAMPA receptor antagonistacide (3S,4aS,6S,8aR)-6-[3-chloro-2-(1H-tétrazol-5-yl)phénoxy]décahydroisoquinoléine-3-carboxyliqueantagoniste des récepteurs de l'AMPAácido (3S,4aS,6S,8aR)-6-[3-cloro-2-(1H-tetrazol-5-il)fenoxi]-decahidroisoquinolina-3-carboxilicoantagonista de los receptores del AMPA166

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105C 17 H 20 ClN 5 O 3 503294-13-1HNHClOHHHCO 2 HNNNHNdelanzomibumdelanzomibdélanzomibdelanzomib{(1R)-1-[(2S,3R)-3-hydroxy-2-(6-phenylpyridine-2-carboxamido)butanamido]-3-methylbutyl}boronic acidantineoplasticacide {(1R)-1-[(2S,3R)-3-hydroxy-2-(6-phénylpyridine-2-carboxamido)butanamido]-3-méthylbutyl}boroniqueantinéoplasiqueácido {(1R)-1-[(2S,3R)-3-hidroxi-2-(6-fenilpiridina-2-carboxamido)butanamido]-3-metilbutil}borónicoantineoplásicoC 21 H 28 BN 3 O 5 847499-27-8NHOO HNHCH 3OHH HN BOHHOCH3CH 3delcasertibumdelcasertibdelcasertibdelcasertibhuman immunodeficiency virus 1 protein Tat-(46-57)-peptide (1→1')-disulfide with L-cysteinyl-[mouse protein kinase C delta type-(8-17)-peptide]protein kinase C inhibitorprotéine Tat du virus 1 de l’immunodéficience humaine-(46-57)-peptide (1→1')-disulfure avec le L-cystéinyl-(protéine kinase Ctype delta de souris-(8-17)-peptideinhibiteur de la protéine kinase Cproteína Tat del virus 1 de la inmunodeficiencia humana-(46-57)-péptido (1→1')-disulfuro con la L-cisteinil-[proteína kinasa Ctipo delta de ratón-(8-17)-péptido]inhibidor de la proteína kinasa CC 120 H 199 N 45 O 34 S 2 949100-39-4A chain / Chaîne A / Cadena ACYGRKKRRQR RR 12Light chain / Chaîne légère / Cadena ligeraCSFNSYELGS L 11'Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro1-1'167

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011dolutegravirumdolutegravirdolutégravirdolutegravir(4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamideantiviral(4R,12aS)-N-[(2,4-difluorophényl)méthyl]-7-hydroxy-4-méthyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamideantiviral(4R,12aS)-N-[(2,4-difluorofenil)metil]-7-hidroxi-4-metil-6,8-dioxo-3,4,6,8,12,12ª-hexahidro-2H-pirido[1',2':4,5]pirazino[2,1-b][1,3]oxazina-9-carboxamidaantiviralC 20 H 19 F 2 N 3 O 5 1051375-16-6H CH 3O OHONHNOOHNFFencaleretumencaleretencaléretencaleret2'-[(1R)-1-({[1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-yl]amino}-(2R)-2-hydroxypropoxy)ethyl]-3-methyl[1,1'-biphenyl]-4-carboxylicacidantagonist of the G-protein coupled calcium sensing receptoracide 2'-[(1R)-1-({[1-(4-chloro-3-fluorophényl)-2-méthylpropan-2-yl]amino}-(2R)-2-hydroxypropoxy)éthyl]-3-méthyl[1,1'-biphényl]-4-carboxyliqueantagoniste du récepteur sensible au calcium couplé à la protéine Gácido 2'-[(1R)-1-({[1-(4-cloro-3-fluorofenil)-2-metilpropan-2-il]amino}-(2R)-2-hidroxipropoxi)etil]-3-metil[1,1'-bifenil]-4-carboxílicoantagonista del receptor sensible al calcio acoplado a proteína GC 29 H 33 ClFNO 4 787583-71-5ClFH 3 CCH 3HNOH CH 3H OHCH 3CO 2 Hepelsibanumepelsiban(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1-(2,6-dimethylpyridin-3-yl)-2-(morpholin-4-yl)-2-oxoethyl]-6-[(2S)-butan-2-yl]piperazine-2,5-dioneoxytocin antagonist168

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105épelsibanepelsibán(3R,6R)-3-(2,3-dihydro-1H-indén-2-yl)-1-[(1R)-1-(2,6-diméthylpyridin-3-yl)-2-(morpholin-4-yl)-2-oxoéthyl]-6-[(2S)-butan-2-yl]pipérazine-2,5-dioneantagoniste de l'oxytocine(3R,6R)-3-(2,3-dihidro-1H-inden-2-il)-1-[(1R)-1-(2,6-dimetilpiridin-3-il)-2-(morfolin-4-il)-2-oxoetil]-6-[(2S)-butan-2-il]piperazina-2,5-dionaantagonista de la oxitocinaC 30 H 38 N 4 O 4 872599-83-2O HCH 3CH 3HNH OHONHNOH 3 CNCH 3etoxybamidumetoxybamideétoxybamideetoxibamida4-hydroxy-N-(2-hydroxyethyl)butanamidesedative, hypnotic4-hydroxy-N-(2-hydroxyéthyl)butanamidesédatif, hypnotique4-hidroxi-N-(2-hidroxietil)butanamidasedativo, hipnóticoC 6 H 13 NO 3 66857-17-8HOONHOHevacetrapibumevacetrapibévacétrapibevacetrapib(1r,4r)-4-({(5S)-5-[{[3,5-bis(trifluoromethyl)phenyl]methyl}(2-methyl-2H-tetrazol-5-yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl}methyl)cyclohexane-1-carboxylic acidantihyperlipidaemicacide (1r,4r)-4-({(5S)-5-[{[3,5-bis(trifluorométhyl)phényl]méthyl}(2-méthyl-2H-tétrazol-5-yl)amino]-7,9-diméthyl-2,3,4,5-tétrahydro-1H-benzazépin-1-yl}méthyl)cyclohexane-1-carboxyliqueantihyperlipidémiantácido (1r,4r)-4-({(5S)-5-[{[3,5-bis(trifluorometil)fenil]metil}(2-metil-2H-tetrazol-5-il)amino]-7,9-dimetil-2,3,4,5-tetrahidro-1H-1-benzazepin-1-il}metil)ciclohexano-1-carboxílicoantihiperlipémico169

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011C 31 H 36 F 6 N 6 O 2 1186486-62-3H 3 CCH 3F 3 CCF 3NHH HNCO 2 HN NN NCH 3exeporfinii chloridumexeporfinium chloridechlorure d'exéporfiniumcloruro de exeporfinio3,3'-(21H,23H-porphyrin-5,15-diylbis{[(4,1-phenylene)oxy]-N,N,Ntrimethylpropan-1-aminium})dichlorideantibacterialdichlorure de 3,3'-[21H,23H-porphyrin-5,15-diylbis(4,1-phénylèneoxy)]bis[N,N,N-triméthylpropan-1-aminium]antibactériendicloruro de 3,3'-(21H,23H-porfirin-5,15-diilbis{[(4,1-fenileno)oxi]-N,N,N-trimetilpropan-1-aminium})antibacterianoC 44 H 50 Cl 2 N 6 O 2 718638-68-7OClCHH 3 C 3N CH 3NHNNHNH 3 C NH 3 CClCH3OfaciniclinumfaciniclinefaciniclinefaciniclinaN-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1H-indazole-3-carboxamidenicotinic acetylcholine receptor partial agonistN-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1H-indazole-3-carboxamideagoniste partiel du récepteur nicotinique à l'acétylcholineN-[(3S)-1-azabiciclo[2.2.2]octan-3-il]-1H-indazol-3-carboxamidaagonista parcial del receptor nicotínico de la acetilcolinaC 15 H 18 N 4 O 677306-35-3NOHNHNNH170

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105fiboflaponumfiboflaponfiboflaponfiboflapón3-{3-(tert-butylsulfanyl)-1-{[4-(6-ethoxypyridin-3-yl)phenyl]methyl}-5-[(5-methylpyridin-2-yl)methoxy]-1H-indol-2-yl}-2,2-dimethylpropanoic acid5-lipoxygenase activating protein (FLAP) antagonistacide 3-{3-(tert-butylsulfanyl)-1-{[4-(6-éthoxypyridin-3-yl)phényl]méthyl}-5-[(5-méthylpyridin-2-yl)méthoxy]-1H-indol-2-yl}-2,2-diméthylpropanoïqueinhibiteur de la protéine activant la 5-lipoxygénase (FLAP)ácido 3-{3-(terc-butilsulfanil)-1-{[4-(6-etoxipiridin-3-il)fenil]metil}-5-[(5-metilpiridin-2-il)metoxi]-1H-indol-2-yl}-2,2-dimetilpropanoicoantagonista de la proteína activadora de la 5-lipoxigenasa (FLAP)C 38 H 43 N 3 O 4 S 936350-00-4H 3 CONH 3 CNCH 3CO 2 HH 3 CNOH 3 CSCH 3CH 3ficlatuzumabum #ficlatuzumabficlatuzumabimmunoglobulin G1-kappa, anti-[Homo sapiens HGF (hepatocytegrowth factor, scatter factor, SF, hepatopoeitin A)], humanizedmonoclonal antibody;gamma1 heavy chain (1-448) [humanized VH(Homo sapiens IGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01 V124>L(114)) [8.8.11] (1-118) -Homo sapiens IGHG1*03 (119-448)], (221-214')-disulfide with kappa light chain (1'-214') [humanized V-KAPPA(Homo sapiens IGKV4-1*01 (73.30%) -IGKJ2*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (227-227":230-230")-bisdisulfide dimerimmunomodulator, antineoplasticimmunoglobuline G1-kappa, anti-[Homo sapiens HGF (facteur decroissance de l'hépatocyte, facteur dispersant, SF, hépatopoïétineA)], anticorps monoclonal humanisé;chaîne lourde gamma1 (1-448) [VH humanisé (Homo sapiensIGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01 V124>L (114)) [8.8.11](1-118) -Homo sapiens IGHG1*03 (119-448)], (221-214')-disulfureavec la chaîne légère kappa (1'-214') [V-KAPPA humanisé (Homosapiens IGKV4-1*01 (73.30%) -IGKJ2*01) [6.3.9] (1'-107') -Homosapiens IGKC*01 (108'-214')]; dimère (227-227":230-230")-bisdisulfureimmunomodulateur, antinéoplasique171

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011ficlatuzumabinmunoglobulina G1-kappa, anti-[HGF de Homo sapiens (factor decrecimiento del hepatocito, factor dispersante, SF, hepatopoyetinaA)], anticuerpo monoclonal humanizado;cadena pesada gamma1 (1-448) [VH humanizada (Homo sapiensIGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01 V124>L (114)) [8.8.11](1-118) -Homo sapiens IGHG1*03 (119-448)], (221-214')-disulfurocon la cadena ligera kappa (1'-214') [V-KAPPA humanizada (Homosapiens IGKV4-1*01 (73.30%) -IGKJ2*01) [6.3.9] (1'-107') -Homosapiens IGKC*01 (108'-214')]; dímero (227-227":230-230")-bisdisulfuroinmunomodulador, antineoplásico1174900-84-5Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQPGAE VKKPGTSVKL SCKASGYTFT TYWMHWVRQA PGQGLEWIGE 50INPTNGHTNY NQKFQGRATL TVDKSTSTAY MELSSLRSED TAVYYCARNY 100VGSIFDYWGQ GTLLTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200CNVNHKPSNT KVDKRVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448Light chain / Chaîne légère / Cadena ligeraDIVMTQSPDS LAMSLGERVT LNCKASENVV SYVSWYQQKP GQSPKLLIYG 50ASNRESGVPD RFSGSGSATD FTLTISSVQA EDVADYHCGQ SYNYPYTFGQ 100GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 145-201 262-322 368-42622''-96'' 145''-201'' 262''-322'' 368''-426''Intra-L 23'-88' 134'-194'23'''-88''' 134'''-194'''Inter-H-L 221-214' 221''-214'''Inter-H-H 227-227'' 230-230''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación298, 298''galeteronumgaleteronegalétéronegaleterona17-(1H-benzimidazol-1-yl)androsta-5,16-dien-3β-olantiandrogen17-(1H-benzimidazol-1-yl)androsta-5,16-dién-3β-olantiandrogène17-(1H-benzoimidazol-1-il)androsta-5,16-dien-3β-olantiandrógenoC 26 H 32 N 2 O 851983-85-2NCHN 3CH 3HHOHHH172

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105ganetespibumganetespibganétespibganetespib5-[2,4-dihydroxy-5-(propan-2-yl)phenyl]-4-(1-methyl-1H-indol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-oneantineoplastic5-[2,4-dihydroxy-5-(propan-2-yl)phényl]-4-(1-méthyl-1H-indol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-oneantinéoplasique5-[2,4-dihidroxi-5-(propan-2-il)fenil]-4-(1-metil-1H-indol-5-il)-2,4-dihidro-3H-1,2,4-triazol-3-onaantineoplásicoC 20 H 20 N 4 O 3 888216-25-9H 3 CNOH 3 CCH 3NNHNHOOHindatuximabum ravtansinum #indatuximab ravtansineindatuximab ravtansineimmunoglobulin G4-kappa, anti-[Homo sapiens SDC1 (syndecan-1,CD138)], chimeric monoclonal antibody conjugated to maytansinoidDM4;gamma4 heavy chain (1-449) [Mus musculus VH (IGHV1-9*01 -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG4*01 (123-449)], (136-214')-disulfide with kappa light chain (1'-214') [Musmusculus V-KAPPA (IGKV10-94*01 -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; (228-228'':231-231'')-bisdisulfide dimer; conjugated, on an average of 3 to 4 lysyl, tomaytansinoid DM4 [N 2' -deacetyl-N 2' -(4-mercapto-4-methyl-1-oxopentyl)-maytansine] via the reducible SPDB linker[N-succinimidyl 4-(2-pyridyldithio)butanoate]For the ravtansine part, please refer to the document "INN forpharmaceutical substances: Names for radicals, groups and others"*immunomodulator, antineoplasticimmunoglobuline G4-kappa, anti-[Homo sapiens SDC1 (syndecan-1,CD138)], anticorps monoclonal chimérique conjugué aumaytansinoïde DM4;chaîne lourde gamma4 (1-449) [Mus musculus VH (IGHV1-9*01 -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG4*01 (123-449)], (136-214')-disulfure avec la chaîne légère kappa (1'-214')[Mus musculus V-KAPPA (IGKV10-94*01 -IGKJ1*01) [6.3.9] (1'-107')-Homo sapiens IGKC*01 (108'-214')]; dimère (228-228":231-231")-bisdisulfure; conjugué, sur 3 à 4 lysyl en moyenne, aumaytansinoïde DM4 [N 2' -déacétyl-N 2' -(4-mercapto-4-méthyl-1-oxopentyl)-maytansine] via le linker SPDB réductible[4-(2-pyridyldithio)butanoate de N-succinimidyle]Pour la partie ravtansine, veuillez vous référer au document "INN forpharmaceutical substances: Names for radicals, groups andothers"*.immunomodulateur, antinéoplasique173

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011indatuximab ravtansinainmunoglobulina G4-kappa, anti-[SDC1 de Homo sapiens (sindecán-1, CD138)], anticuerpo monoclonal quimérico conjugado con elmaitansinoide DM4;cadena pesada gamma4 (1-449) [Mus musculus VH (IGHV1-9*01 -(IGHD)-IGHJ4*01) [8.8.15] (1-122) -Homo sapiens IGHG4*01 (123-449)], (136-214')-disulfuro con la cadena ligera kappa (1'-214') [Musmusculus V-KAPPA (IGKV10-94*01 -IGKJ1*01) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (228-228":231-231")-bisdisulfuro; conjugado, en 3-4 grupos lisil por término medio con elmaitansinoide DM4 [N 2' -desacetil-N 2' -(4-mercapto-4-metil-1-oxopentil)-maitansina] mediante el espaciador SPDB reducible[4-(2-piridilditio)butanoato de N-succinimidilo]Para la fracción ravtansina, se ruega referirse al documento "INN forpharmaceutical substances: Names for radicals, groups and others"*inmunomodulador, antineoplásico1238517-16-2Heavy chain / Chaîne lourde / Cadena pesadaQVQLQQSGSE LMMPGASVKI SCKATGYTFS NYWIEWVKQR PGHGLEWIGE 50ILPGTGRTIY NEKFKGKATF TADISSNTVQ MQLSSLTSED SAVYYCARRD 100YYGNFYYAMD YWGQGTSVTV SSASTKGPSV FPLAPCSRST SESTAALGCL 150VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT 200KTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKGL PSSIEKTISK AKGQPREPQV 350YTLPPSQEEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS RLTVDKSRWQ EGNVFSCSVM HEALHNHYTQ KSLSLSLGK 449Light chain / Chaîne légère / Cadena ligeraDIQMTQSTSS LSASLGDRVT ISCSASQGIN NYLNWYQQKP DGTVELLIYY 50TSTLQSGVPS RFSGSGSGTD YSLTISNLEP EDIGTYYCQQ YSKLPRTFGG 100GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 149-205 263-323 369-43722''-96'' 149''-205'' 263''-323'' 369''-437''Intra-L 23'-88' 134'-194'23'''-88''' 134'''-194'''Inter-H-L 136-214' 136''-214'''Inter-H-H 228-228'' 231-231''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación299, 299''iofolastatum ( 123 I)iofolastat ( 123 I)iofolastat ( 123 I)iofolastat ( 123 I)N-{[(1S)-1-carboxy-5-{[(4-( 123 I)iodophenyl)methyl]amino}pentyl]carbamoyl}-L-glutamic acidradiopharmaceuticalacide N-{[(1S)-1-carboxy-5-{[(4-( 123 I)iodophényl)méthyl]amino}pentyl]carbamoyl}-L-glutamiqueradiopharmaceutiqueácido N-{[(1S)-1-carboxi-5-{[(4-( 123 I)iodofenil)metil]amino}pentil]carbamoil}-L-glutámicopreparacion farmaceutica radiactiva174

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105C 19 H 26 123 IN 3 O 7 949575-24-0NHCO 2 HHOH123 IHO 2 C NHNHCO 2 Hirdabisantumirdabisantirdabisantirdabisant6-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyridazin-3(2H)-onehistamine H 3 receptor antagonist6-(4-{3-[(2R)-2-méthylpyrrolidin-1-yl]propoxy}phényl)pyridazin-3(2H)-oneantagoniste du récepteur H 3 de l'histamine6-(4-{3-[(2R)-2-metilpirrolidin-1-il]propoxi}fenil)piridazin-3(2H)-onaantagonista del receptor H 3 de histaminaC 18 H 23 N 3 O 2 1005402-19-6NHNONOCH 3Hixekizumabum #ixekizumabixékizumabimmunoglobulin G4-kappa, anti-[Homo sapiens IL17A (interleukin17A, IL-17A)], humanized monoclonal antibody;gamma4 heavy chain (1-445) [humanized VH (Homo sapiensIGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homosapiens IGHG4*01 hinge S10>P (227), CH3 K130>del (120-445)],(133-219')-disulfide with kappa light chain (1'-219') [humanizedV-KAPPA (Homo sapiens IGKV2D-29*02 (89.00%) -IGKJ2*01)[11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (225-225":228-228")-bisdisulfide dimerimmunomodulatorimmunoglobuline G4-kappa, anti-[Homo sapiens IL17A (interleukine17A, IL-17A)], anticorps monoclonal humanisé;chaîne lourde gamma4 (1-445) [VH humanisé (Homo sapiensIGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homosapiens IGHG4*01 charnière S10>P (227), CH3 K130>del (120-445)], (133-219')-disulfure avec la chaîne légère kappa (1'-219')[V-KAPPA humanisé (Homo sapiens IGKV2D-29*02 (89.00%) -IGKJ2*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')];dimère (225-225":228-228")-bisdisulfureimmunomodulateur175

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011ixekizumabinmunoglobulina G4-kappa, anti-[Homo sapiens IL17A (interleukina17A, IL-17A)], anticuerpo monoclonal humanizado;cadena pesada gamma4 (1-445) [VH humanizada (Homo sapiensIGHV1-46*01 (82.70%) -(IGHD)-IGHJ4*01) [8.8.12] (1-119) -Homosapiens IGHG4*01 bisagra S10>P (227), CH3 K130>del (120-445)],(133-219')-disulfuro con la cadena ligera kappa (1'-219')[V-KAPPA humanizada (Homo sapiens IGKV2D-29*02 (89.00%) -IGKJ2*01) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')];dímero (225-225":228-228")-bisdisulfuroinmunomodulador1143503-69-8Heavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VKKPGSSVKV SCKASGYSFT DYHIHWVRQA PGQGLEWMGV 50INPMYGTTDY NQRFKGRVTI TADESTSTAY MELSSLRSED TAVYYCARYD 100YFTGTGVYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY 200TCNVDHKPSN TKVDKRVESK YGPPCPPCPA PEFLGGPSVF LFPPKPKDTL 250MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR 300VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL 350PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD 400GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLG 445Light chain / Chaîne légère / Cadena ligeraDIVMTQTPLS LSVTPGQPAS ISCRSSRSLV HSRGNTYLHW YLQKPGQSPQ 50LLIYKVSNRF IGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHLP 100FTFGQGTKLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200VTHQGLSSPV TKSFNRGEC 219Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 146-202 260-320 366-42422''-96'' 146''-202'' 260''-320'' 366''-424''Intra-L 23'-93' 139'-199'23'''-93''' 139'''-199'''Inter-H-L 133-219' 133''-219'''Inter-H-H 225-225'' 228-228''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación296, 296''ladarixinumladarixinladarixineladarixina4-[(2R)-1-oxo-1-(methanesulfonamido)propan-2-yl]phenyltrifluoromethanesulfonateinterleukin 8 inhibitortrifluorométhanesulfonate de 4-[(2R)-1-oxo-1-(méthanesulfonamido)propan-2-yl]phényleinhibiteur de l'interleukine 8trifluoromethanesulfonato de 4-[(2R)-1-oxo-1-(metanosulfonamido)propan-2-il]fenilinhibidor de la interleukina 8C 11 H 12 F 3 NO 6 S 2 849776-05-2O OSF 3 C OHCH 3HN CH 3 SOOO176

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105lenomorelinumlenomorelinlénomorélinelenomorelinaO 3.26 -octanoylhuman appetite-regulating hormone precursor (growthhormone-releasing peptide, protein M46)-(24-51)-peptide (ghrelin-28-C8)growth hormone release-stimulating peptideO 3.26 -octanoylprécurseur de l’hormone humaine de régulation del’appétit (peptide de libération d’hormone de croissance,protéine M46)-(24-51)-peptide (ghréline-28-C8)peptide de libération de l'hormone de croissanceO 3.26 -octanoilprecursor de la hormona humana de regulación delapetito (péptido de liberación de hormona del crecimiento,proteína M46)-(24-51)-péptido (ghrelina-28-C8)péptido estimulante de la liberación de la hormona del crecimientoC 149 H 249 N 47 O 42 258279-04-8GSSFLSPEHQ RVQQRKESKK PPAKLQPR 28Modified residue / Résidu modifié / Residuo modificadoS3O-octadecanoyl-L-serylO-octadécanoyl-L-sérylO-octadecanoil-L-seriloHNHCOOOCH 3lesinuradumlesinuradlésinuradlesinurad2-{[5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acidurate transporter inhibitoracide 2-{[5-bromo-4-(4-cyclopropylnaphtalén-1-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acétiqueinhibiteur du transporteur de l'urateácido 2-{[5-bromo-4-(4-ciclopropilnaftalen-1-il)-4H-1,2,4-triazol-3-il]sulfanil}acéticoinhibidor del transportador de uratoC 17 H 14 BrN 3 O 2 S 878672-00-5BrNNNSCO 2 Hlexibulinumlexibulinlexibuline1-ethyl-3-[2-methoxy-4-(5-methyl-4-{[(1S)-1-(pyridin-3-yl)butyl]amino}pyrimidin-2-yl)phenyl]ureaantineoplastic1-éthyl-3-[2-méthoxy-4-(5-méthyl-4-{[(1S)-1-(pyridin-3-yl)butyl]amino}pyrimidin-2-yl)phényl]uréeantinéoplasique177

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011lexibulina1-etil-3-[2-metoxi-4-(5-metil-4-{[(1S)-1-(piridin-3-il)butil]amino}pirimidin-2-il)fenil]ureaantineoplásicoC 24 H 30 N 6 O 2 917111-44-5H 3 CH 3 CHNNNHNONHOCH 3NHCH 3lipegfilgrastimum #lipegfilgrastimlipegfilgrastimlipegfilgrastimpegylated granulocyte colony stimulating factor;O 3.133 -[N 5 -(N-{[ω-methoxypoly(oxyethylene)]carbonyl}glycyl)-α-neuraminyl-(2→6)-α-D-galactopyranosyl]-L-methionyl-des-1-L-alanine-des-37-L-valine-des-38-L-serine-des-39-L-glutamic acidhumangranulocyte colony-stimulating factor (G-CSF, pluripoietin)colony stimulating factorfacteur de stimulation de colonie de granulocytes humain pégylé;O 3.133 -[N 5 -(N-{[ω-méthoxypoly(oxyéthylène)]carbonyl}glycyl)-α-neuraminyl-(2→6)-α-D-galactopyranosyl]-L-méthionyl-dès-1-L-alanine-dès-37-L-valine-des-38-L-sérine-dès-39-L-acideglutamique-facteur de stimulation de colonie de granulocytes humain(G-CSF, pluripoïétine)facteur de stimulation de coloniesfactor de estimulación de colonias de granulocitos humano pegilado;O 3.133 -[N 5 -(N-{[ω-metoxipoli(oxietileno)]carbonil}glicil)-α-neuraminil-(2→6)-α-D-galactopiranosil]-L-metionil-des-1-L-alanina-des-37-L-valina-des-38-L-serine-des-39-L-ácidoglutámico-factor de estimulación de colonias de granulocitoshumanos (G-CSF, pluripoyetina)factor estímulador de coloniasC 864 H 1369 N 225 O 258 S 9 [C 2 H 4 O] n 1117844-87-7M 0TPLGPASSLP QSFLLKCLEQ VRKIQGDGAA LQEKLCATYK LCHPEELVLL 50GHSLGIPWAP LSSCPSQALQ LAGCLSQLHS GLFLYQGLLQ ALEGISPELG 100PTLDTLQLDV ADFATTIWQQ MEELGMAPAL QPTQGAMPAF ASAFQRRAGG 150VLVASHLQSF LEVSYRVLRH LAQP 174Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro36-42 64-74Modified residue / Résidu modifié / Residuo modificadoTHO OH133COPEG-Gly-Neu-Gal-ThrO 2 HHO HOH 3 COOnOHNHNOOHHOHOOOHONHCH 3HCO178

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105lorediplonumlorediplonlorédiplonlorediplónN-{2-fluoro-5-[3-(thiophene-2-carbonyl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl}-N-methylacetamideanxiolyticN-{2-fluoro-5-[3-(thiophéne-2-carbonyl)pryrazolo[1,5-a]pyrimidin-7-yl]phényl}-N-méthylacétamideanxiolytiqueN-{2-fluoro-5-[3-(tiofeno-2-carbonil)pirazolo[1,5-a]pirimidin-7-il]fenil}-N-metilacetamidaansiolíticoC 20 H 15 FN 4 O 2 S 917393-39-6OCH 3NNNSH 3 CNOFlumacaftorumlumacaftorlumacaftorlumacaftor3-{6-[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxamido]-3-methylpyridin-2-yl}benzoic acidCFTR (Cystic fibrosis Transmembrane Regulator) channel activatoracide 3-{6-[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxamido]-3-methylpyridin-2-yl}benzoïqueactivateur de la protéine régulatrice de la perméabilité (CFTR)transmembrainre impliquée dans la mucoviscidoseácido 3-{6-[1-(2,2-difluoro-1,3-benzodioxol-5-il)ciclopropano-1-carboxamido]-3-metilpiridin-2-il}benzoicoactivateur del canal CFTR (regulador de la conductanciatransmembrana de la fibrosis quística)C 24 H 18 F 2 N 2 O 5 936727-05-8FOHNNCO 2 HFOOCH 3lurbinectedinumlurbinectedin(1'R,6R,6aR,7R,13S,14S,16R)-8,14-dihydroxy-6',9-dimethoxy-4,10,23-trimethyl-19-oxo-2',3',4',6,7,9',12,13,14,16-decahydro-6aH-spiro[7,13-azano-6,16-(epithiopropanooxymethano)[1,3]dioxolo[7,8]isoquinolino[3,2-b][3]benzazocine-20,1'-pyrido[3,4-b]indol]-5-yl acetateantineoplastic179

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011lurbinectédinelurbinectedinaacétate de (1'R,6R,6aR,7R,13S,14S,16R)-8,14-dihydroxy-6',9-diméthoxy-4,10,23-triméthyl-19-oxo-2',3',4',6,7,9',12,13,14,16-décahydro-6aH-spiro[7,13-azano-6,16-(épithiopropanooxyméthano)[1,3]dioxolo[7,8]isoquinolino[3,2-b][3]benzazocine-20,1'-pyrido[3,4-b]indol]-5-ylantinéoplasiqueacetato de (1′R,6R,6aR,7R,13S,14S,16R)-8,14-dihidroxi-6′,9-dimetoxi-4,10,23-trimetil-19-oxo-2',3',4',6,7,9',12,13,14,16-decahidro-16H-spiro[7,13-azano-6,16-(epitiopropanooximetano)[1,3]dioxolo[7,8]isoquinolino[3,2-b][3]benzazocina-20,1′-pirido[3,4-b]indol]-5-iloantineoplásicoC 41 H 44 N 4 O 10 S 497871-47-3HHOHONHOOH 3 CNH 3 COHHOHNHHSONHOCH 3CH 3OCH 3H 3 COmelphalanum flufenamidummelphalan flufenamidemelphalan flufénamidemelfalán flufenamidaethyl (2S)-2-[(2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanamido]-3-(4-fluorophenyl)propanoatealkylating agent(2S)-2-[(2S)-2-amino-3-{4-[bis(2-chloroéthyl)amino]phényl}propanamido]-3-(4-fluorophényl)propanoate d'éthyleagent alkylant(2S)-2-[(2S)-2-amino-3-{4-[bis(2-cloroetil)amino]fenil}propanamido]-3-(4-fluorofenil)propanoato de etiloagente alquilizanteC 24 H 30 Cl 2 FN 3 O 3 380449-51-4ClClNHNH 2HNOHOO CH 3F180

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105milciclibummilciclibmilciclibmilciclibN,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamideantineoplasticN,1,4,4-tétraméthyl-8-{[4-(4-méthylpipérazin-1-yl)phényl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamideantinéoplasiqueN,1,4,4-tetrametil-8-{[4-(4-metilpiperazin-1-il)fenil]amino}-4,5-dihidro-1H-pirazolo[4,3-h]quinazolina-3-carboxamidaantineoplásicoC 25 H 32 N 8 O 802539-81-7HNNH 3 CN N HN CH3H 3 CNNNOCH 3CH 3naldemedinumnaldemedinenaldémédinenaldemedina17-(cyclopropylmethyl)-6,7-didehydro-4,5α-epoxy-3,6,14-trihydroxy-N-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)propan-2-yl]morphinan-7-carboxamideopioid receptor antagonist17-(cyclopropylméthyl)-6,7-didéhydro-4,5α-époxy-3,6,14-trihydroxy-N-[2-(3-phényl-1,2,4-oxadiazol-5-yl)propan-2-yl]morphinan-7-carboxamideantagoniste des récepteurs opioïdes17-(ciclopropilmetil)-6,7-didehidro-4,5α-epoxi-3,6,14-trihidroxi-N-[2-(3-fenil-1,2,4-oxadiazol-5-il)propan-2-il]morfinan-7-carboxamidaantagonista de los receptores de opiáceosC 32 H 34 N 4 O 6 916072-89-4HOHHOONHOHNOHNONCH 3CH 3naloxegolumnaloxegolnaloxégol4,5α-epoxy-6α-[(3,6,9,12,15,18,21-heptaoxadocosan-1-yl)oxy]-17-(prop-2-en-1-yl)morphinan-3,14-diolµ-opioid receptor antagonist4,5α-époxy-6α-[(3,6,9,12,15,18,21-heptaoxadocosan-1-yl)oxy]-17-(prop-2-én-1-yl)morphinane-3,14-diolantagoniste des récepteurs opioïdes µ181

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011naloxegol4,5α-epoxi-6α-[(3,6,9,12,15,18,21-heptaoxadocosa-1-il)oxi]-17-(prop-2-en-1-il)morfinan-3,14-diolantagonista de los receptores µ de opiáceosC 34 H 53 NO 11 854601-70-0HNCH 2HOHOOHO HOOH 3 COOOOOnarnatumabum #narnatumabnarnatumabimmunoglobulin G1-kappa, anti-[Homo sapiens MST1R(macrophage stimulating 1 receptor, macrophage stimulating proteinreceptor, MSP receptor, c-met-related tyrosine kinase, proteintyrosinekinase 8, PTK8, RON, p185-Ron, CD136)], Homo sapiensmonoclonal antibody;gamma1 heavy chain (1-452) [Homo sapiens VH (IGHV3-7*01(95.90%) -(IGHD)-IGHJ6*01 T127>I (119)) [8.8.15] (1-122) -IGHG1*03 (123-452)], (225-214')-disulfide with kappa light chain(1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; (231-231'':234-234'')-bisdisulfide dimerimmunomodulator, antineoplasticimmunoglobuline G1-kappa, anti-[Homo sapiens MST1R (récepteur1 stimulant le macrophage, récepteur de la protéine stimulant lemacrophage, récepteur de la MSP, tyrosine kinase apparentée àc-met, protéine-tyrosine kinase 8, PTK8, RON, p185-Ron, CD136)],Homo sapiens anticorps monoclonal;chaîne lourde gamma1 (1-452) [Homo sapiens VH (IGHV3-7*01(95.90%) -(IGHD)-IGHJ6*01 T127>I (119)) [8.8.15] (1-122) -IGHG1*03 (123-452)], (225-214')-disulfure avec la chaîne légèrekappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dimère (231-231'':234-234'')-bisdisulfureimmunomodulateur, antinéoplasiquenarnatumab inmunoglobulina G1-kappa, anti-[Homo sapiens MST1R (receptor 1estimulante el macrófago, receptor de la proteína estimulante elmacrófago, receptor de la MSP, tirosina kinasa relacionada conc-met, proteína-tirosina kinase 8, PTK8, RON, p185-Ron, CD136)],Homo sapiens anticuerpo monoclonal;cadena pesada gamma1 (1-452) [Homo sapiens VH (IGHV3-7*01(95.90%) -(IGHD)-IGHJ6*01 T127>I (119)) [8.8.15] (1-122) -IGHG1*03 (123-452)], (225-214')-disulfuro con la cadena ligerakappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (98.90%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*01 (108'-214')]; dímero (231-231'':234-234'')-bisdisulfuroinmunomodulador, antineoplásico182

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 1051188275-92-4Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG LVQPGGSLRL SCAASGFTFS SYLMTWVRQA PGKGLEWVAN 50IKQDGSEKYY VDSVKGRFTI SRDNAKNSLN LQMNSLRAED TAVYYCTRDG 100YSSGRHYGMD VWGQGTTVIV SSASTKGPSV FPLAPSSKST SGGTAALGCL 150VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT 200QTYICNVNHK PSNTKVDKRV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP 250KPKDTLMISR TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ 300YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE 350PQVYTLPPSR EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP 400PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP 450GK 452Light chain / Chaîne légère / Cadena ligeraEIVLTQSPAT LSLSPGERAT LSCRASQSVS RYLAWYQQKP GQAPRLLIYD 50ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RSNWPRTFGQ 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 149-2105 266-326 372-43022''-96'' 149''-205'' 266''-326'' 372''-430''Intra-L 23'-88' 134'-194'23'''-88''' 134'''-194'''Inter-H-L 225-214' 225''-214'''Inter-H-H 231-231'' 234-234''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación302, 302''navarixinumnavarixinnavarixinenavarixina2-hydroxy-N,N-dimethyl-3-[(2-{[(1R)-1-(5-methylfuran-2-yl)propyl]amino}-3,4-dioxocyclobut-1-en-1-yl)amino]benzamideanti-inflammatory action through the inhibition of cytokine (IL-8)2-hydroxy-N,N-diméthyl-3-[(2-{[(1R)-1-(5-méthylfuran-2-yl)propyl]amino}-3,4-dioxocyclobut-1-én-1-yl)amino]benzamideanti-inflammatoire (inhibiteur de l'interleukine 8)2-hidroxi-N,N-dimetil-3-[(2-{[(1R)-1-(5-metilfuran-2-il)propil]amino}-3,4-dioxociclobut-1-en-1-il)amino]benzamidainhibidor de citokina (interleukina-8) con acción antiinflamatoriaC 21 H 23 N 3 O 5 473727-83-2H 3 COH 3 CHONHONHOHOCH 3NCH3nelociguatumnelociguatnélociguatnelociguatmethyl (4,6-diamino-2-{1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-5-yl)carbamateguanylate cyclase activator(4,6-diamino-2-{1-[(2-fluorophényl)méthyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}pyrimidin-5-yl)carbamate de méthyleactivateur de la guanylate cyclase(4,6-diamino-2-{1-[(2-fluorofenil)metil]-1H-pirazolo[3,4-b]piridin-3-il}pirimidin-5-il)carbamato de metiloactivador de la guanilato ciclasa183

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011C 19 H 17 FN 8 O 2 625115-52-8NFNNNNH 2HN OCH 3NH 2ONnivocasanumnivocasannivocasannivocasán(5R)-N-[(2S,3S)-2-(fluoromethyl)-2-hydroxy-5-oxooxolan-3-yl]-3-(isoquinolin-1-yl)-5-(propan-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxamidecaspase inhibitor(5R)-N-[(2S,3S)-2-(fluorométhyl)-2-hydroxy-5-oxooxolan-3-yl]-3-(isoquinoléin-1-yl)-5-(propan-2-yl)-4,5-dihydro-1,2-oxazole-5-carboxamideinhibiteur de la caspase(5R)-N-[(2S,3S)-2-(fluorometil)-2-hidroxi-5-oxooxolan-3-il]-3-(isoquinolin-1-il)-5-(propan-2-il)-4,5-dihidro-1,2-oxazol-5-carboxamidainhibidor de la caspasaC 21 H 22 FN 3 O 5 908253-63-4ONO ONHN O CH3H OHH 3 CFoclacitinibumoclacitiniboclacitiniboclacitinibN-methyl{trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methanesulfonamideantineoplastic (veterinary drug)N-méthyl[trans-4-(méthyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclohexyl]méthanesulfonamideantinéoplasique (produit vétérinaire)N-metil{trans-4-[metil(7H-pirrolo[2,3-d]pirimidin-4-il)amino]ciclohexil}metanosulfonamidaantineoplásico (medicamento veterinario)C 15 H 23 N 5 O 2 S 1208319-26-9O OH 3 C SNHCH 3NHNNN184

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105olcorolimusumolcorolimusolcorolimusolcorolimús(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-3-{(1R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl)propan-2-yl}-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-3,4,5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-icosahydro-11H-23,27-epoxypyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,11,28,29(31H)-tetroneimmunosuppressant(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihydroxy-3-{(1R)-1-[(1S,3R,4R)-4-hydroxy-3-méthoxycyclohexyl)propan-2-yl}-10,21-diméthoxy-6,8,12,14,20,26-hexaméthyl-3,4,5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-icosahydro-11H-23,27-époxypyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,11,28,29(31H)-tétroneimmunosuppresseur(3S,6S,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,27-dihidroxi-3-{(1R)-1-[(1S,3R,4R)-4-hidroxi-3-metoxiciclohexil)propan-2-il}-10,21-dimetoxi-6,8,12,14,20,26-hexametil-3,4,5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-icosahidro-11H-23,27-epoxipirido[2,1-c][1,4]oxaazaciclohentriacontina-1,11,28,29(31H)-tetronainmunosupresorC 51 H 81 NO 12 186752-78-3OHHHH 3 COHHOHON OOHOOHH 3 CCH 3HH OHOHH 3 C H CH 3 OCH 3CH 3HH 3 C HHCH 3H OCH 3ozoralizumabum #ozoralizumabimmunoglobulin single chain VH-VH'-VH, trivalent bispecific anti-[Homo sapiens TNF (tumor necrosis factor, TNF superfamilymember 2, TNFSF2, TNFA, TNF-alpha)] VH and anti-[Homo sapiensALB (albumin, human serum albumin, HSA)] VH', humanized Lamaglama monoclonal antibody;scVH-VH'-VH (1-363) [humanized VH (Homo sapiens IGHV3-74*01(88.80%) -(IGHD)-IGHJ1*01 W118>R (105)) [8.8.8] (1-115) - 9-merlinker (tetraglycyl-seryl-triglycyl-seryl) (116-124) -humanized VH'(Homo sapiens IGHV3-23*04 (89.60%) -(IGHD)-IGHJ1*01 W118>S(229), G119>S (230) [8.8.8] (125-239) -9-mer linker (tetraglycylseryl-triglycyl-seryl)(240-248) -humanized VH (Homo sapiensIGHV3-74*01 (88.80%) -(IGHD)-IGHJ1*01 W118>R (353)(249-363)immunomodulator, anti-inflammatory185

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011ozoralizumabozoralizumabimmunoglobuline single chain VH-VH'-VH, trivalente bispécifiqueanti-[Homo sapiens TNF (facteur de nécrose tumorale, membre 2 dela superfamille du TNF, TNFSF2, TNFA, TNF-alpha)] VH et anti-[Homo sapiens ALB (albumine, sérum albumine humaine, SAH)]VH', anticorps monoclonal de Lama glama humanisé;scVH-VH'-VH (1-363) [VH humanisé (Homo sapiens IGHV3-74*01(88.80%) -(IGHD)-IGHJ1*01 W118>R (105)) [8.8.8] (1-115) -9-merlinker (tétraglycyl-séryl-triglycyl-séryl) (116-124) -VH' humanisé(Homo sapiens IGHV3-23*04 (89.60%) -(IGHD)-IGHJ1*01 W118>S(229), G119>S (230) [8.8.8] (125-239) -9-mer linker (tétraglycylséryl-triglycyl-séryl)(240-248) -VH humanisé (Homo sapiens IGHV3-74*01 (88.80%) -(IGHD)-IGHJ1*01 W118>R (353)(249-363)immunomodulateur, anti-inflammatoireinmunoglobulina de cadena sencilla VH-VH'-VH, trivalentebiespecífica anti-[TNF de Homo sapiens (factor de necrosis tumoral,miembro 2 de la superfamilia del TNF, TNFSF2, TNFA, TNF-alpha)]VH y anti-[Homo sapiens ALB (albumina, albumina sérica humanaSAH)] VH', anticuerpo monoclonal de Lama glama humanizado;scVH-VH'-VH (1-363) [VH humanizado (Homo sapiens IGHV3-74*01(88.80%) -(IGHD)-IGHJ1*01 W118>R (105)) [8.8.8] (1-115) –conector nonámero (tetraglicil-seril-triglicil-seril) (116-124) -VH'humanizado (Homo sapiens IGHV3-23*04 (89.60%) -(IGHD)-IGHJ1*01 W118>S (229), G119>S (230) [8.8.8] (125-239) –espaciador nonámero (tetraglicil-seril-triglicil-seril) (240-248) -VHhumanizado (Homo sapiens IGHV3-74*01 (88.80%) -(IGHD)-IGHJ1*01 W118>R (353)(249-363)inmunomodulador, antiinflamatorio1167985-17-2scVH-VH'-VH chain / Chaîne scVH-VH'-VH / Cadena scVH-VH'-VHEVQLVESGGG LVQPGGSLRL SCAASGFTFS DYWMYWVRQA PGKGLEWVSE 50INTNGLITKY PDSVKGRFTI SRDNAKNTLY LQMNSLRPED TAVYYCARSP 100SGFNRGQGTL VTVSSGGGGS GGGSEVQLVE SGGGLVQPGN SLRLSCAASG 150FTFSSFGMSW VRQAPGKGLE WVSSISGSGS DTLYADSVKG RFTISRDNAK 200TTLYLQMNSL RPEDTAVYYC TIGGSLSRSS QGTLVTVSSG GGGSGGGSEV 250QLVESGGGLV QPGGSLRLSC AASGFTFSDY WMYWVRQAPG KGLEWVSEIN 300TNGLITKYPD SVKGRFTISR DNAKNTLYLQ MNSLRPEDTA VYYCARSPSG 350FNRGQGTLVT VSS 363Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-chain 22-96 146-220 270-34pateclizumabum #pateclizumabimmunoglobulin G1-kappa, anti-[Homo sapiens LTA (lymphotoxinalpha, TNFSF1, tumor necrosis factor superfamily member 1, LT)],humanized monoclonal antibody;gamma1 heavy chain (1-447) [humanized VH (Homo sapiensIGHV3-74*01 (76.50%) -(IGHD)-IGHJ5*01) [8.9.11] (1-118) -Homosapiens IGHG1*03 CH1 R120>K (215), CH3 K130>del (119-447)],(221-214')-disulfide with kappa light chain (1'-214') [humanizedV-KAPPA (Homo sapiens IGKV1-39*01 (88.40%) -IGKJ1*01) [6.3.9](1'-107') -Homo sapiens IGKC*01 (108'-214')]; (227-227":230-230")-bisdisulfide dimerimmunomodulator186

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105patéclizumabpateclizumabimmunoglobuline G1-kappa, anti-[Homo sapiens LTA (lymphotoxinealpha, TNFSF1, membre 1 de la superfamille du facteur de nécrosetumorale, LT)], anticorps monoclonal humanisé;chaîne lourde gamma1 (1-447) [VH humanisé (Homo sapiensIGHV3-74*01 (76.50%) -(IGHD)-IGHJ5*01) [8.9.11] (1-118) -Homosapiens IGHG1*03 CH1 R120>K (215), CH3 K130>del (119-447)],(221-214')-disulfure avec la chaîne légère kappa (1'-214') [V-KAPPAhumanisé (Homo sapiens IGKV1-39*01 (88.40%) -IGKJ1*01) [6.3.9](1'-107') -Homo sapiens IGKC*01 (108'-214')]; dimère (227-227":230-230")-bisdisulfureimmunomodulateurinmunoglobulina G1-kappa, anti-[LTA de Homo sapiens (linfotoxinaalfa, TNFSF1, miembro 1 de la superfamilia del factor de necrosistumoral, LT)], anticuerpo monoclonal humanizado;cadena pesada gamma1 (1-447) [VH humanizada (Homo sapiensIGHV3-74*01 (76.50%) -(IGHD)-IGHJ5*01) [8.9.11] (1-118) -Homosapiens IGHG1*03 CH1 R120>K (215), CH3 K130>del (119-447)],(221-214')-disulfuro con la cadena ligera kappa (1'-214') [V-KAPPAhumanizada (Homo sapiens IGKV1-39*01 (88.40%) -IGKJ1*01)[6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')]; dímero (227-227":230-230")-bisdisulfuroinmunomodulador1202526-59-7Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG LVQPGGSLRL SCAASGYTFT SYVIHWVRQA PGKGLEWVGY 50NNPYNAGTNY NEKFKGRFTI SSDKSKNTAY LQMNSLRAED TAVYYCSRPT 100MLPWFAYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPELLGGPS VFLFPPKPKD 250TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPG 447Light chain / Chaîne légère / Cadena ligeraDIQMTQSPSS LSASVGDRVT ITCRASQAVS SAVAWYQQKP GKAPKLLIYS 50ASHRYTGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQE SYSTPWTFGQ 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 145-201 262-322 368-42622''-96'' 145''-201'' 262''-322'' 368''-426''Intra-L 23'-88' 134'-194'23'''-88''' 134'''-194'''Inter-H-L 221-214' 221''-214'''Inter-H-H 227-227'' 230-230''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación298, 298''peginterferonum lambda-1a #peginterferon lambda-1a pegylated interferon lambda-1; pegylated interleukin 29;N-{3-[α-methylpoly(oxyethylene)oxy]propyl}-L-methionyl{[171-serine]human interleukin-29 (IFN-λ-1)-(7-181)-peptide}antiviralpeginterféron lambda-1ainterféron lambda-1 pégylé; interleukine-29 pégylée;N-{3-[α-méthylpoly(oxyéthylène)oxy]propyl}-L-méthionyl{[171-sérine]interleukine-29 humaine (IFN-λ-1)-(7-181)-peptide}antiviral187

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011peginterferón lambda-1ainterferón lambda-1 pegilado; interleukina-29 pegilada;N-{3-[α-metilpoli(oxietileno)oxi]propil}-L-metionil{[171-serina]interleukina-29 humana (IFN-λ-1)-(7-181)-péptido}antiviralC 875 H 1408 N 254 O 251 S 5 (C 2 H 4 O) n 914617-98-4MKPTT TGKGCHIGRF KSLSPQELAS FKKARDALEE SLKLKNWSCS 50SPVFPGNWDL RLLQVRERPV ALEAELALTL KVLEAAAGPA LEDVLDQPLH 100TLHHILSQLQ ACIQPQPTAG PRPRGRLHHW LHRLQEAPKK ESAGCLEASV 150TFNLFRLLTR DLKYVADGNL SLRTSTHPES T 181Modified residue / Résidu modifié / Residuo modificadoCH 3SM1H 3 COHO NnHODisulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro15-112 49-145pegnivacoginumpegnivacoginpégnivacogina ribonucleic acid aptamer which binds Factor XIa;ester of 2'-O-methyl-5'-O-phosphonoguanylyl-(3'→5')-2'-Omethyluridylyl-(3'→5')-2'-O-methylguanylyl-(3'→5')-2'-O-methylguanylyl-(3'→5')-2'-O-methyladenylyl-(3'→5')-2'-deoxy-2'-fluorocytidylyl-(3'→5')-2'-deoxy-2'-fluorouridylyl-(3'→5')-2'-Omethyladenylyl-(3'→5')-2'-deoxy-2'-fluorouridylyl-(3'→5')-2'-Omethyladenylyl-(3'→5')-2'-deoxy-2'-fluorocytidylyl-(3'→5')-2'-deoxy-2'-fluorocytidylyl-(3'→5')-2'-O-methylguanylyl-(3'→5')-2'-deoxy-2'-fluorocytidylyl-(3'→5')-2'-O-methylguanylyl-(3'→5')-2'-deoxy-2'-fluorouridylyl-(3'→5')-2'-O-methyladenylyl-(3'→5')-2'-Omethyladenylyl-(3'→5')-2'-deoxy-2'-fluorouridylyl-(3'→5')-2'-Omethylguanylyl-(3'→5')-2'-deoxy-2'-fluorocytidylyl-(3'→5')-2'-Omethyluridylyl-(3'→5')-guanylyl-(3'→5')-2'-O-methylcytidylyl-(3'→5')-2'-deoxy-2'-fluorocytidylyl-(3'→5')-2'-deoxy-2'-fluorouridylyl-(3'→5')-2'-O-methylcytidylyl-(3'→5')-2'-O-methylcytidylyl-(3'→5')-2'-Omethyladenylyl-(3'→5')-2'-O-methylcytidylyl-(3'→3')-thimidinewith6-[(2,6-bis{N-[ω-methoxypoly(oxyethylene)carbonyl]}-L-lysyl)amino]hexan-1-olanticoagulantacide ribonucleique aptamère se liant au Factor XIa;ester de 2'-O-méthyl-5'-O-phosphonoguanylyl-(3'→5')-2'-Ométhyluridylyl-(3'→5')-2'-O-méthylguanylyl-(3'→5')-2'-Ométhylguanylyl-(3'→5')-2'-O-méthyladénylyl-(3'→5')-2'-déoxy-2'-fluorocytidylyl-(3'→5')-2'-déoxy-2'-fluorouridylyl-(3'→5')-2'-Ométhyladénylyl-(3'→5')-2'-déoxy-2'-fluorouridylyl-(3'→5')-2'-Ométhyladénylyl-(3'→5')-2'-déoxy-2'-fluorocytidylyl-(3'→5')-2'-déoxy-2'-fluorocytidylyl-(3'→5')-2'-O-méthylguanylyl-(3'→5')-2'-déoxy-2'-fluorocytidylyl-(3'→5')-2'-O-méthylguanylyl-(3'→5')-2'-déoxy-2'-fluorouridylyl-(3'→5')-2'-O-méthyladénylyl-(3'→5')-2'-Ométhyladénylyl-(3'→5')-2'-déoxy-2'-fluorouridylyl-(3'→5')-2'-Ométhylguanylyl-(3'→5')-2'-déoxy-2'-fluorocytidylyl-(3'→5')-2'-Ométhyluridylyl-(3'→5')-guanylyl-(3'→5')-2'-O-méthylcytidylyl-(3'→5')-2'-déoxy-2'-fluorocytidylyl-(3'→5')-2'-déoxy-2'-fluorouridylyl-(3'→5')-2'-O-méthylcytidylyl-(3'→5')-2'-O-méthylcytidylyl-(3'→5')-2'-Ométhyladénylyl-(3'→5')-2'-O-méthylcytidylyl-(3'→3')-thimidineavec6-[(2,6-bis{N-[ω-méthoxypoly(oxyéthylène)carbonyl]}-L-lysyl)amino]hexan-1-olanticoagulant188

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105pegnivacoginaaptámero de ácido ribomucléico que se une a Factor XIa;éster of 2'-O-metil-5'-O-fosfonoguanilil-(3'→5')-2'-O-metiluridilil-(3'→5')-2'-O-metilguanilil-(3'→5')-2'-O-metilguanilil-(3'→5')-2'-O-metiladenilil-(3'→5')-2'-desoxi-2'-fluorocitidilil-(3'→5')-2'-desoxi-2'-fluorouridilil-(3'→5')-2'-O-metiladenilil-(3'→5')-2'-desoxi-2'-fluorouridilil-(3'→5')-2'-O-metiladenilil-(3'→5')-2'-desoxi-2'-fluorocitidilil-(3'→5')-2'-desoxi-2'-fluorocitidilil-(3'→5')-2'-Ometilguanilil-(3'→5')-2'-desoxi-2'-fluorocitidilil-(3'→5')-2'-Ometilguanilil-(3'→5')-2'-desoxi-2'-fluorouridilil-(3'→5')-2'-Ometiladenilil-(3'→5')-2'-O-metiladenilil-(3'→5')-2'-desoxi-2'-fluorouridilil-(3'→5')-2'-O-metilguanilil-(3'→5')-2'-desoxi-2'-fluorocitidilil-(3'→5')-2'-O-metiluridilil-(3'→5')-guanilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'-desoxi-2'-fluorocitidilil-(3'→5')-2'-desoxi-2'-fluorouridilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'-O-metilcitidilil-(3'→5')-2'-O-metiladenilil-(3'→5')-2'-O-metilcitidilil-(3'→3')-timidina6-[(2,6-bis{N-[ω-metoxipoli(oxietileno)carbonil]}-L-lisil)amino]hexan-1-olanticoagulanteC 327 H 422 F 11 N 114 O 213 P 31 (C 2 H 4 O) n 959716-28-0(3'-5')-R-pmG-mU-mG-mG-mA-dflC-dflU-mA-dflU-mA-dflC-dflC-mGdflC-mG-dflU-mA-mA-dflU-mG-dflC-mU-G-mC-dflC-dflU-mC-mC-mA-mC3'-3'dTLegend:dfl = 2'-deoxy-2'-fluoro ; m = 2'-O-methyl ; p (as prefix) = 5'-phosphateR- =OON OCH3x + y = nHyOH 3 C O H HN CH2O Nx HOpictrelisibumpictrelisibpictrélisibpictrelisib2-{1H-indazol-4-yl}-6-{[4-(methanesulfonyl)piperazin-1-yl]methyl}-4-(morpholin-4-yl)thieno[3,2-d]pyrimidineantineoplastic2-(1H-indazol-4-yl)-6-{[4-(méthanesulfonyl)pipérazin-1-yl]méthyl}-4-(morpholin-4-yl)-thiéno[3,2-d]pyrimidineantinéoplasique2-{1H-indazol-4-il}-6-{[4-(metanosulfonil)piperazin-1-il]metil}-4-(morfolin-4-il)tieno[3,2-d]pirimidinaantineoplásicoC 23 H 27 N 7 O 3 S 2 957054-30-7OHNNNNOONSNN S CH 3189

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011pimasertibumpimasertibpimasertibpimasertibN-[(2S)-2,3-dihydroxypropyl]-3-[(2-fluoro-4-iodophenyl)amino]pyridine-4-carboxamideantineoplasticN-[(2S)-2,3-dihydroxypropyl]-3-[(2-fluoro-4-iodophényl)amino]pyridine-4-carboxamideantinéoplasiqueN-[(2S)-2,3-dihidroxipropil]-3-[(2-fluoro-4-iodofenil)amino]piridina-4-carboxamidaantineoplásicoC 15 H 15 FIN 3 O 3 1236699-92-5NFIHOH OHNHONHrecoflavonumrecoflavonerécoflavonerecoflavona{[2-(3,4-dimethoxyphenyl)-5-methoxy-4-oxo-4H-chromen-7-yl]oxy}acetic acidmucin production enhanceracide {[2-(3,4-diméthoxyphényl)-5-méthoxy-4-oxo-4H-chromen-7-yl]oxy}acétiqueamplificateur de production de mucineácido {[2-(3,4-dimetoxifenil)-5-metoxi-4-oxo-4H-cromen-7-il]oxi}acéticoestimulante de la secreción de mucinaC 20 H 18 O 8 203191-10-0OCH 3OCH 3HO 2 COOO OCH 3rucaparibumrucaparibrucaparib8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-pyrrolo[4,3,2-ef][2]benzazepin-6-oneantineoplastic8-fluoro-2-{4-[(méthylamino)méthyl]phényl}-1,3,4,5-tétrahydro-6H-pyrrolo[4,3,2-ef][2]benzazépin-6-oneantinéoplasique190

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105rucaparib8-fluoro-2-{4-[(metilamino)metil]fenil}-1,3,4,5-tetrahidro-6H-pirrolo[4,3,2-ef][2]benzazepin-6-onaantineoplásicoC 19 H 18 FN 3 O 283173-50-2FHNHN CH 3ONHsafotibantumsafotibantsafotibantsafotibantN-{[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methyl}-2-{2-[(4-methoxy-2,6-dimethylbenzenesulfonyl)(methyl)amino]ethoxy}-N-methylacetamidebradykinin receptor antagonistN-{[4-(4,5-dihydro-1H-imidazol-2-yl)phényl]méthyl}-2-{2-[(4-méthoxy-2,6-diméthylbenzènesulfonyl)(méthyl)amino]éthoxy}-N-méthylacétamideantagoniste des récepteurs de la bradykinineN-{[4-(4,5-dihidro-1H-imidazol-2-il)fenil]metil}-2-{2-[(4-metoxi-2,6-dimetilbencenosulfonil)(metil)amino]etoxi}-N-metilacetamidoantagonista de los receptores de bradiquininaC 25 H 34 N 4 O 5 S 633698-99-4NH 3 COCH 3CH 3NSCH 3 O OOOCH 3NNHselepressinumselepressinsélépressineselepresinavasopressin type 1a (V1a) receptor agonist;[2-L-phenylalanine,3-L-isoleucine,4-(6-oxo-L-lysine),8-[5-N-(propan-2-yl)-L-ornithine]]human vasopressinvasoconstrictoragoniste du récepteur de la vasopressine type 1a (V1a);[2-L-phénylalanine,3-L-isoleucine,4-(6-oxo-L-lysine),8-[5-N-(propan-2-yl)-L-ornithine]]vasopressine humainevasoconstricteuragonista del receptor de la vasopresina tipo 1a (V1a);[2-L-fenillalanina,3-L-isoleucina,4-(6-oxo-L-lisina),8-[5-N-(propan-2-il)-L-ornitina]]vasopresina humanavasoconstrictor191

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011C 46 H 73 N 13 O 11 S 2 876296-47-8H 2 NOHH 3 CHNCH 3Gly NH 2HH Cys Phe Ile N Asn Cys Pro NHHOOsepantronii bromidumsepantronium bromidebromure de sépantroniumbromuro de sepantronio1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-[(pyrazin-2-yl)methyl]-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromideantineoplasticbromure de 1-(2-méthoxyéthyl)-2-méthyl-4,9-dioxo-3-[(pyrazin-2-yl)méthyl]-4,9-dihydro-1H-naphto[2,3-d]imidazoliumantinéoplasiquebromuro de 2-metil-1-(2-metoxietil)-4,9-dioxo-3-[(pirazin-2-il)metil]-4,9-dihidro-1H-nafto[2,3-d]imidazolioantineoplásicoC 20 H 19 BrN 4 O 3 781661-94-7OONNO CH 3CH 3 BrNNserelaxinumserelaxin human relaxin 2 (relaxin H2)hormonesérélaxine rélaxine 2 humaine (rélaxine H2)hormoneserelaxina relaxina 2 humana (relaxina H2)hormonaC 256 H 408 N 74 O 74 S 8 99489-94-8B chain / Chaîne B / Cadena BDSWMEEVIKL CGRELVRAQI AICGMSTWS 29A chain / Chaîne A / Cadena AQLYSALANKC CHVGCTKRSL ARFC 24'Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro10'-15' 11-11' 23-24'Modified residue / Résidu modifié / Residuo modificadoQ1'L-pyroglutamic acidONHHCO 2 H192

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105simeprevirumsimeprevirsiméprévirsimeprevir(2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropanesulfonyl)-2-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-5-methyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxamideantiviral(2R,3aR,10Z,11aS,12aR,14aR)-N-(cyclopropanesulfonyl)-2-({7-méthoxy-8-méthyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinoléin-4-yl}oxy)-5-méthyl-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tétradécahydrocyclopenta[c]cyclopropa[g][1,6]diazacyclotétradécine-12a(1H)-carboxamideantiviral(2R,3aR,10Z,11aS,12aR,14aR)-N-(ciclopropanosulfonil)-2-({7-metoxi-8-metil-2-[4-(propan-2-il)-1,3-tiazol-2-il]quinolin-4-il}oxi)-5-metil-4,14-dioxo-2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahidrociclopenta[c]ciclopropa[g][1,6]diazaciclotetradecina-12a(1H)-carboxamidaantiviralC 38 H 47 N 5 O 7 S 2 923604-59-5OHOO SNHONHHHHOOCH 3CH 3NNCH 3S CH 3NOCH 3siponimodumsiponimodsiponimodsiponimod1-({4-[(1E)-1-({[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy}imino)ethyl]-2-ethylphenyl}methyl)azetidine-3-carboxylic acidimmunomodulatoracide 1-({4-[(1E)-1-({[4-cyclohexyl-3-(trifluorométhyl)phényl]méthoxy}imino)éthyl]-2-éthylphényl}méthyl)azétidine-3-carboxyliqueimmunomodulateurácido 1-({4-[(1E)-1-({[4-ciclohexil-3-(trifluorometil)fenil]metoxi}imino)etil]-2-etilfenil}metil)azetidina-3-carboxílicoinmunomoduladorC 29 H 35 F 3 N 2 O 3 1230487-85-0NONCO 2 HCF 3CH 3CH 3193

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011sirukumabum #sirukumab immunoglobulin G1-kappa, anti-[Homo sapiens IL6 (interleukin 6,IL-6)], Homo sapiens monoclonal antibody;gamma1 heavy chain (1-449) [Homo sapiens VH (IGHV3-7*01(87.80%) -(IGHD)-IGHJ6*01) [8.8.12] (1-119) -IGHG1*01 (120-449)],(222-213')-disulfide with kappa light chain (1'-213') [Homo sapiensV-KAPPA (IGKV3-11*01 (87.40%) -IGKJ4*01) [5.3.9] (1'-107') -IGKC*01 (107'-213')]; (228-231'':228-231'')-bisdisulfide dimerimmunomodulatorsirukumab immunoglobuline G1-kappa, anti-[Homo sapiens IL6 (interleukine 6,IL-6)], Homo sapiens anticorps monoclonal;chaîne lourde gamma1 (1-449) [Homo sapiens VH (IGHV3-7*01(87.80%) -(IGHD)-IGHJ6*01) [8.8.12] (1-119) -IGHG1*01 (120-449)],(222-213')-disulfure avec la chaîne légère kappa (1'-213') [Homosapiens V-KAPPA (IGKV3-11*01 (87.40%) -IGKJ4*01) [5.3.9](1'-107') -IGKC*01 (107'-213')]; dimère (228-228'':231-231'')-bisdisulfureimmunomodulateursirukumabinmunoglobulina G1-kappa, anti-[IL6 de Homo sapiens (interleukina6, IL-6)], anticuerpo monoclonal de Homo sapiens;cadena pesada gamma1 (1-449) [Homo sapiens VH (IGHV3-7*01(87.80%) -(IGHD)-IGHJ6*01) [8.8.12] (1-119) -IGHG1*01 (120-449)],(222-213')-disulfuro con la cadena ligera kappa (1'-213') [Homosapiens V-KAPPA (IGKV3-11*01 (87.40%) -IGKJ4*01) [5.3.9](1'-107') -IGKC*01 (107'-213')]; dímero (228-228'':231-231'')-bisdisulfuroinmunomodulador1194585-53-9Heavy chain / Chaîne lourde / Cadena pesadaEVQLVESGGG LVQPGGSLRL SCAASGFTFS PFAMSWVRQA PGKGLEWVAK 50ISPGGSWTYY SDTVTGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARQL 100WGYYALDIWG QGTTVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449Light chain / Chaîne légère / Cadena ligeraEIVLTQSPAT LSLSPGERAT LSCSASISVS YMYWYQQKPG QAPRLLIYDM 50SNLASGIPAR FSGSGSGTDF TLTISSLEPE DFAVYYCMQW SGYPYTFGGG 100TKVEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200SSPVTKSFNR GEC 213Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 146-202 263-323 369-42722''-96'' 146''-202'' 263''-323'' 369''-427''Intra-L 23'-87' 133'-193'23'''-87''' 133'''-193'''Inter-H-L 222-213' 222''-213'''Inter-H-H 228-228'' 231-231''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación299, 299''194

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105spriferminum #spriferminsprifermineespriferminaL-methionyl[human fibroblast growth factor 18 (FGF-18, zFGF5)-(1-169)-peptide]fibroblast growth factorL-méthionyl[facteur 18 de croissance du fibroblaste humain (FGF-18,zFGF5)-(1-169)-peptide]facteur de croissance des fibroblastesL-metionil[factor 18 de crecimiento de fibroblastos humanos(FGF-18, zFGF5)-(1-169)-péptido]factor de crecimiento de los fibrobastosC 876 H 1396 N 258 O 256 S 6 890058-52-3MEENVDFRIHV ENQTRARDDV SRKQLRLYQL YSRTSGKHIQ VLGRRISARG 50EDGDKYAQLL VETDTFGSQV RIKGKETEFY LCMNRKGKLV GKPDGTSKEC 100VFIEKVLENN YTALMSAKYS GWYVGFTKKG RPRKGPKTRE NQQDVHFMKR 150YPKGQPELQK PFKYTTVTK 169Disulfide bridge location / Position du pont disulfure / Posición del puente disulfuro82-100suvorexantumsuvorexantsuvorexantsuvorexant[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanoneorexin receptor antagonist[(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-méthyl-1,4-diazépan-1-yl][5-méthyl-2-(2H-1,2,3-triazol-2-yl)phényl]méthanoneantagoniste du récepteur de l'orexine[(7R)-4-(5-cloro-1,3-benzoxazol-2-il)-7-metil-1,4-diazepan-1-il][5-metil-2-(2H-1,2,3-triazol-2-il)fenil]metanonaantagonista del receptor de la orexinaC 23 H 23 ClN 6 O 2 1030377-33-3ClONNCH 3HN ONNNH 3 Ctabalumabum #tabalumabimmunoglobulin G4-kappa, anti-[Homo sapiens TNFSF13B (tumornecrosis factor superfamily member 13B, BAFF, THANK, TALL-1,TALL1, BLYS, BLyS, B cell activating factor, B lymphocytestimulator, CD257)], Homo sapiens monoclonal antibody;gamma4 heavy chain (1-450) [Homo sapiens VH (IGHV4-34*01(100.00%) -(IGHD)-IGHJ4*01) [8.7.17] (1-123) -IGHG4*01 hingeS10>P (231) (124-450)], (137-214')-disulfide with kappa light chain(1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (97.90%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*05 (108'-214')]; (229-229'':232-232'')-bisdisulfide dimerimmunomodulator195

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011tabalumabtabalumabimmunoglobuline G4-kappa, anti-[Homo sapiens TNFSF13B(membre 13B de la superfamille du facteur de nécrose tumorale,BAFF, THANK, TALL-1, TALL1, BLYS, BLyS, facteur d'activationdes cellules B, stimulateur des lymphocytes B, CD257)], Homosapiens anticorps monoclonal;chaîne lourde gamma4 (1-450) [Homo sapiens VH (IGHV4-34*01(100.00%) -(IGHD)-IGHJ4*01) [8.7.17] (1-123) -IGHG4*01 charnièreS10>P (231) (124-450)], (137-214')-disulfure avec la chaîne légèrekappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01 (97.90%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*05 (108'-214')]; dimère (229-229'':232-232'')-bisdisulfureimmunomodulateurinmunoglobulina G4-kappa, anti-[TNFSF13B de Homo sapiens(miembro 13B de la superfamilia del factor de necrosis tumoral,BAFF, THANK, TALL-1, TALL1, BLYS, BLyS, factor de activación decélulas B, estimulante de linfocitos B, CD257)], Homo sapiensanticuerpo monoclonal;cadena pesada gamma4 (1-450) [VH de Homo sapiens (IGHV4-34*01 (100.00%) -(IGHD)-IGHJ4*01) [8.7.17] (1-123) -IGHG4*01bisagra S10>P (231) (124-450)], (137-214')-disulfuro con la cadenaligera kappa (1'-214') [Homo sapiens V-KAPPA (IGKV3-11*01(97.90%) -IGKJ1*01) [6.3.9] (1'-107') -IGKC*05 (108'-214')]; dímero(229-229'':232-232'')-bisdisulfuroinmunomodulador1143503-67-6Heavy chain / Chaîne lourde / Cadena pesadaQVQLQQWGAG LLKPSETLSL TCAVYGGSFS GYYWSWIRQP PGKGLEWIGE 50INHSGSTNYN PSLKSRVTIS VDTSKNQFSL KLSSVTAADT AVYYCARGYY 100DILTGYYYYF DYWGQGTLVT VSSASTKGPS VFPLAPCSRS TSESTAALGC 150LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSSLG 200TKTYTCNVDH KPSNTKVDKR VESKYGPPCP PCPAPEFLGG PSVFLFPPKP 250KDTLMISRTP EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN 300STYRVVSVLT VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ 350VYTLPPSQEE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400LDSDGSFFLY SRLTVDKSRW QEGNVFSCSV MHEALHNHYT QKSLSLSLGK 450Light chain / Chaîne légère / Cadena ligeraEIVLTQSPAT LSLSPGERAT LSCRASQSVS RYLAWYQQKP GQAPRLLIYD 50ASNRATGIPA RFSGSGSGTD STLTISSLEP EDFAVYYCQQ RSNWPRTFGQ 100GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150DNALQSGNSQ ESVTEQDSKD STYSLSNTLT LSKADYEKHK VYACEVTHQG 200LSSPVTKSFN RGEC 214Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-95 150-206 264-324 370-42822''-95'' 150''-206'' 264''-324'' 370''-428''Intra-L 23'-88' 134'-194'23'''-88''' 134'''-194'''Inter-H-L 137-214' 137''-214'''Inter-H-H 229-229'' 232-232''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación300, 300''tefinostatumtefinostatcyclopentyl (2S)-2-[({4-[8-(hydroxyamino)-8-oxooctanamido]phenyl}methyl)amino]-2-phenylacetateantineoplastic196

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105téfinostattefinostat(2S)-2-[({4-[8-(hydroxyamino)-8-oxooctanamido]phényl}methyl)amino]-2-phénylacétate decyclopentyleantinéoplasique(2S)-2-[({4-[8-(hidroxiamino)-8-oxooctanamido]fenil}metil)amino]-2-fenilacetato de ciclopentiloantineoplásicoC 28 H 37 N 3 O 5 914382-60-8OOHNHNHOOHNOHtrametinibumtrametinibtramétinibtrametinibN-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamideantineoplasticN-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophényl)amino]-6,8-diméthyl-2,4,7-trioxo-3,4,6,7-tétrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phényl)acétamideantinéoplasiqueN-(3-{3-ciclopropil-5-[(2-fluoro-4-iodofenil)amino]-6,8-dimetil-2,4,7-trioxo-3,4,6,7-tetrahidropirido[4,3-d]pirimidin-1(2H)-il}fenil)acetamidaantineoplásicoC 26 H 23 FIN 5 O 4 871700-17-3H 3 CHNONNOHNFOH 3 CNCH 3IOupamostatumupamostatupamostatethyl 4-{(2S)-3-{3-[(E)- N'-hydroxycarbamimidoyl]phenyl}-2-[2,3,5-tri(propan-2-yl)benzenesulfonamido]propanoyl}piperazine-1-carboxylateantineoplastic4-{(2S)-3-{3-[(E)- N'-hydroxycarbamimidoyl]phényl}-2-[2,3,5-tri(propan-2-yl)benzènesulfonamido]propanoyl}pipérazine-1-carboxylate d'éthyleantinéoplasique197

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011upamostat4-{(2S)-3-{3-[(E)-N′-hidroxicarbamimidoil]fenil}-2-[2,3,5-tri(propan-2-il)bencenosulfonamido]propanoil}piperazina-1-carboxilato de etiloantineoplásicoC 32 H 47 N 5 O 6 S 1191101-18-4H 3 CCH 3OHNH 3 CCH 3OH 3 CO SCH 3NHO N O CHH3NNH 2Ovatelizumabum #vatelizumabvatélizumabvatelizumabimmunoglobulin G4-kappa, anti-[Homo sapiens ITGA2 (integrinalpha 2, CD49b, GPIa, subunit of the alpha2beta1 integrin (VLA-2,collagen receptor))], humanized monoclonal antibody;gamma4heavy chain (1-446) [humanized VH (Homo sapiens IGHV4-59*01(79.40%) -(IGHD)-IGHJ6*01) [8.7.13] (1-119) -Homo sapiensIGHG4*01 (120-446)], (133-213')-disulfide with kappa light chain(1'-213') [humanized V-KAPPA (Homo sapiens IGKV6D-41*01(77.90%) -IGKJ1*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01 (107'-213')]; (225-225":228-228")-bisdisulfide dimerimmunomodulatorimmunoglobuline G4-kappa, anti-[Homo sapiens ITGA2 (intégrinealpha 2, CD49b, GPIa, sous-unité de l'intégrine alpha2bêta1 (VLA-2,récepteur du collagène))], anticorps monoclonal humanisé;chaîne lourde gamma4 (1-446) [VH humanisé (Homo sapiensIGHV4-59*01 (79.40%) -(IGHD)-IGHJ6*01) [8.7.13] (1-119) -Homosapiens IGHG4*01 (120-446)], (133-213')-disulfure avec la chaînelégère kappa (1'-213') [V-KAPPA humanisé (Homo sapiens IGKV6D-41*01 (77.90%) -IGKJ1*01) [5.3.9] (1'-106') -Homo sapiens IGKC*01(107'-213')]; dimère (225-225":228-228")-bisdisulfureimmunomodulateurinmunoglobulina G4-kappa, anti-[Homo sapiens ITGA2 (integrinaalfa 2, CD49b, GPIa, subunidad de la integrina alfa2beta1 (VLA-2,receptor del colageno))], anticuerpo monoclonal humanizado;cadena pesada gamma4 (1-446) [VH humanizada (Homo sapiensIGHV4-59*01 (79.40%) -(IGHD)-IGHJ6*01) [8.7.13] (1-119) -Homosapiens IGHG4*01 (120-446)], (133-213')-disulfuro con la cadenaligera kappa (1'-213') [V-KAPPA humanizada (Homo sapiensIGKV6D-41*01 (77.90%) -IGKJ1*01) [5.3.9] (1'-106') -Homo sapiensIGKC*01 (107'-213')]; dímero (225-225":228-228")-bisdisulfuroinmunomodulador198

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 1051238217-55-4Heavy chain / Chaîne lourde / Cadena pesadaQVQLQESGPG LVKPSETLSL TCTVSGFSLT NYGIHWIRQP PGKGLEWLGV 50IWARGFTNYN SALMSRLTIS KDNSKNQVSL KLSSVTAADT AVYYCARAND 100GVYYAMDYWG QGTLVTVSSA STKGPSVFPL APCSRSTSES TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTKTY 200TCNVDHKPSN TKVDKRVESK YGPPCPSCPA PEFLGGPSVF LFPPKPKDTL 250MISRTPEVTC VVVDVSQEDP EVQFNWYVDG VEVHNAKTKP REEQFNSTYR 300VVSVLTVLHQ DWLNGKEYKC KVSNKGLPSS IEKTISKAKG QPREPQVYTL 350PPSQEEMTKN QVSLTCLVKG FYPSDIAVEW ESNGQPENNY KTTPPVLDSD 400GSFFLYSRLT VDKSRWQEGN VFSCSVMHEA LHNHYTQKSL SLSLGK 446Light chain / Chaîne légère / Cadena ligeraDFVMTQSPAF LSVTPGEKVT ITCSAQSSVN YIHWYQQKPD QAPKKLIYDT 50SKLASGVPSR FSGSGSGTDY TFTISSLEAE DAATYYCQQW TTNPLTFGQG 100TKVEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200SSPVTKSFNR GEC 213Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-95 146-202 260-320 366-42422''-95'' 146''-202'' 260''-320'' 366''-424''Intra-L 23'-87' 133'-193'23'''-87''' 133'''-193'''Inter-H-L 133-213' 133''-213'''Inter-H-H 225-225'' 228-228''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación296, 296''199

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011AMENDMENTS TO PREVIOUS LISTSMODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURESMODIFICACIONES A LAS LISTAS ANTERIORESProposed International Non Proprietary Names (Prop. INN): List 89Denominations communes internationales proposées (DCI Prop.): Liste 89Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 89(WHO Drug Information, Vol. 17, No. 3, 2003)p. 188 cantuzumabummertansinum #cantuzumab mertansinecantuzumab mertansinecantuzumab mertansinareplace the description, the mechanism of action and the structure by thefollowingremplacer la description, le mécanisme d'action et la structure par lessuivantssustitúyase el nombre químico, el mecanismo de acción y la estructura porlos siguientesimmunoglobulin G1-kappa, anti-[Homo sapiens MUC1 sialylatedcarbohydrate, tumour-associated (CA242, cancer antigen 242)], humanizedmonoclonal antibody conjugated to maytansinoid DM1;gamma1 heavy chain (1-449) [humanized VH (Homo sapiens IGHV7-4-1*02(76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T (114)) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfide with kappa lightchain (1’-219’) [humanized V-KAPPA (Homo sapiens IGKV2-28*01 (82.00%) -IGKJ3*01 V124>L (109), D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; (228-228":231-231")-bisdisulfide dimer;conjugated, on an average of 4 lysyl, to maytansinoid DM1 [N 2’ -deacetyl-N 2’ -(3-mercapto-1-oxopropyl)-maytansine] via the reductible SPP linker[N-succinimidyl 4-(2-pyridyldithio)pentanoate]For the mertansine part, please refer to the document "INN for pharmaceuticalsubstances: Names for radicals, groups and others"*treatment of tumors that express CA242 antigenimmunoglobuline G1-kappa, anti-[Homo sapiens glycane sialylé de MUC1,associé à des tumeurs (CA242, antigène du cancer 242)], anticorpsmonoclonal humanisé conjugué au maytansinoïde DM1;chaîne lourde gamma1 (1-449) [VH humanisé (Homo sapiens IGHV7-4-1*02(76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T (114)) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfure avec la chaînelégère kappa (1’-219’) [V-KAPPA humanisé (Homo sapiens IGKV2-28*01(82.00%) -IGKJ3*01 V124>L (109), D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dimère (228-228":231-231")-bisdisulfure; conjugué, sur 4 lysyl en moyenne, au maytansinoïde DM1[N 2’ -déacétyl-N 2’ -(3-mercapto-1-oxopropyl)-maytansine] via le linker SPPréductible [4-(2-pyridyldithio)pentanoate de N-succinimidyle]Pour la partie mertansine, veuillez vous référer au document "INN forpharmaceutical substances: Names for radicals, groups and others"*.antitumoral spécifique des cellules exprimant l'antigène CA242200

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105inmunoglobulina G1-kappa, anti-[glicano sialilado de MUC1 de Homosapiens, asociado a tumores (CA242, antígeno del cáncer 242)], anticuerpomonoclonal humanizado conjugado con el maitansinoide DM1; cadenapesada gamma1 (1-449) [VH humanizada (Homo sapiens IGHV7-4-1*02(76.50%) -(IGHD)-IGHJ2*01 R120>Q (111), L123>T (114)) [8.8.12] (1-119) -Homo sapiens IGHG1*01 (120-449)], (222-219')-disulfuro con la cadenaligera kappa (1’-219’) [V-KAPPA humanizada (Homo sapiens IGKV2-28*01(82.00%) -IGKJ3*01 V124>L (109), D125>E (110), I126>L (111)) [11.3.9] (1'-112') -Homo sapiens IGKC*01 (113'-219')]; dímero (228-228":231-231")-bisdisulfuro; conjugado, por término medio, en 4 grupos lisil, con elmaitansinoide DM1 [N 2 ’-desacetil-N 2 ’-(3-mercapto-1-oxopropil)-maitansina] mediante el espaciador SPP reducible[4-(2-piridilditio)pentanoato de N-succinimidilo]Para la mertansina, por favor, consulten el documento "INN forpharmaceutical substances: Names for radicals, groups and others"*.antitumoral específico de las células que expresan el antígeno CA242cantuzumab/ cantuzumab / cantuzumabHeavy chain / Chaîne lourde / Cadena pesadaQVQLVQSGAE VKKPGETVKI SCKASDYTFT YYGMNWVKQA PGQGLKWMGW 50IDTTTGEPTY AQKFQGRIAF SLETSASTAY LQIKSLKSED TATYFCARRG 100PYNWYFDVWG QGTTVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449Light chain / Chaîne légère / Cadena ligeraDIVMTQSPLS VPVTPGEPVS ISCRSSKSLL HSNGNTYLYW FLQRPGQSPQ 50LLIYRMSNLV SGVPDRFSGS GSGTAFTLRI SRVEAEDVGV YYCLQHLEYP 100FTFGPGTKLE LKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200VTHQGLSSPV TKSFNRGEC 219Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuroIntra-H 22-96 146-202 263-323 369-42722''-96'' 146''-202'' 263''-323'' 369''-427''Intra-L 23'-93' 139'-199'23'''-93''' 139'''-199'''Inter-H-L 222-219' 222''-219'''Inter-H-H 228-228'' 231-231''N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación299, 299''mertansine / mertansine / mertansinaIgNHOSCH 3SO H CH 3ONH 3 C CH 3 OCH 3 ClOHH 3 CNHH HOOOHO NHH OCH 3 CH 3OCH 34cantuzumab = Ig(NH 2 ) 4201

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011Proposed International Non Proprietary Names (Prop. INN): List 102Denominations communes internationales proposées (DCI Prop.): Liste 102Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 102(WHO Drug Information, Vol. 23, No. 4, 2009)p. 332 delete/supprimer/suprimáse insert/insérer/inserteseintedanibumintedanibintédanibintedanibnintedanibumnintedanibnintédanibnintedanibProposed International Non Proprietary Names (Prop. INN): List 103Denominations communes internationales proposées (DCI Prop.): Liste 103Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 103(WHO Drug Information Vol. 24, No. 2, 2010)p. 127-128 delete/supprimer/suprimáse insert/insérer/inserteseatecegatranum fexenetilumatecegatran fexenetilatécégatran fexénétilatecegatrán fexenetiloatecegatranum metoxilumatecegatran metoxilatécégatran métoxilatecegatrán metoxilop. 155 delete/supprimer/suprimáse insert/insérer/inserteseobenoxazinumobenoxazineobenoxazineobenoxazinafabomotizolumfabomotizolefabomotizolefabomotizolp.159 oxelumabumoxelumaboxélumaboxelumabreplace the CASRN by the followingremplacer le numéro de registre du CAS par le suivantsustitúyase el Número de registro del CAS por el siguiente1186098-83-8p. 159 delete/supprimer/suprimáse insert/insérer/insertesepaliflutinumpaliflutinepaliflutinepaliflutinabitopertinumbitopertinbitopertinebitopertinap. 162 delete/supprimer/suprimáse insert/insérer/insertesepegsiticasumpegsiticasepegsiticasepegsiticasapegadricasumpegadricasepégadricasepegadricasa202

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105p. 165-166 samalizumabumsamalizumabsamalizumabsamalizumabreplace the description by the followingremplacer la description par la suivantesustitúyase el nombre químico por el siguienteimmunoglobulin G2/4-kappa, anti-[Homo sapiens CD200 (OX-2)], humanizedmonoclonal antibody;gamma2/4 heavy chain (1-442) [humanized VH (Homo sapiens IGHV1-69*01(73.50%) -(IGHD)-IGHJ4*01 L123>T (112), V124>L (113)) [8.8.10] (1-117) -Homo sapiens IGHG2*01 CH1-hinge-CH2 1.6-1.1 (118-232)- IGHG4*01 CH21-125, CH3 1-129 K130>del (233-442)], (131-214')-disulfide with kappa lightchain (1'-214') [humanized V-KAPPA (Homo sapiens IGKV1-33*01 (81.10%) -IGKJ2*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiens IGKC*01 (108'-214')];(219-219":220-220":223-223":226-226")-tetrakisdisulfide dimerimmunoglobuline G2/4-kappa, anti-[Homo sapiens CD200 (OX-2)], anticorpsmonoclonal humanisé;chaîne lourde gamma2/4 (1-442) [VH humanisé (Homo sapiens IGHV1-69*01(73.50%) -(IGHD)-IGHJ4*01 L123>T (112), V124>L (113)) [8.8.10] (1-117) -Homo sapiens IGHG2*01 CH1-charnière-CH2 1.6-1.1 (118-232)- IGHG4*01CH2 1-125, CH3 1-129 K130>del (233-442)], (131-214')-disulfure avec lachaîne légère kappa (1'-214') [V-KAPPA humanisé (Homo sapiens IGKV1-33*01 (81.10%) -IGKJ2*01 Q120>G (100)) [6.3.9] (1'-107') -Homo sapiensIGKC*01 (108'-214')]; dimère (219-219":220-220":223-223":226-226")-tétrakisdisulfureinmunoglobulina G2/4-kappa, anti-[Homo sapiens CD200 (OX-2)], anticuerpomonoclonal humanizado;cadena pesada gamma2/4 (1-442) [humanizado VH (Homo sapiens IGHV1-69*01 (73.50%) - (IGHD)-IGHJ4*01 L123>T (112), V124>L (113)) [8.8.10] (1-117) -Homo sapiens IGHG2*01 CH1-bisagra-CH2 1.6-1.1 (118-232)-IGHG4*01 CH2 1-125, CH3 1-129 K130>del (233-442)], (131-214')-disulfurocon la cadena ligera kappa (1'-214') [V-KAPPA humanizada(Homo sapiensIGKV1-33*01 (81.10%) -IGKJ2*01 Q120>G (100)) [6.3.9] (1'-107') -Homosapiens IGKC*01 (108'-214')]; dímero (219-219":220-220":223-223":226-226")-tetrakisdisulfurop. 168 delete/supprimer/suprimáse insert/insérer/insertesetasocitinibumtasocitinibtasocitinibtasocitinibtofacitinibumtofacitinibtofacitinibtofacitinibp. 179 vorapaxarumvorapaxarreplace the chemical name by the followingethyl [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(1E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethen-1-yl}-1-methyl-3-oxododecahydronaphtho[2,3-c]furan-6-yl]carbamate203

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011Proposed International Non Proprietary Names (Prop. INN): List 104Denominations communes internationales proposées (DCI Prop.): Liste 104Denominaciones Comunes Internacionales Propuestas (DCI Prop.): Lista 104(WHO Drug Information, Vol. 24, No. 4, 2010)p. 366 empagliflozinumempagliflozinempagliflozineempagliflozinareplace the chemical name by the followingremplacer le nom chimique par le suivantsustitúyase el nombre químico por el siguiente(1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxy}phenyl)methyl]phenyl}-D-glucitol(1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-{[(3S)-oxolan-3-yl]oxy]}phényl)méthyl]phényl}-D-glucitol(1S)-1,5-anhidro-1-C-{4-cloro-3-[(4-{[(3S)-oxolan-3-il]oxi}fenil)metil]fenil}-D-glucitol* "INN for pharmaceutical substances: Names for radicals, groups & others" document available at /document disponible à / documento disponible en :http://www.who.int/medicines/services/inn/publication/en/index.html# Electronic structure available on Mednet: http://mednet.who.int/# Structure électronique disponible sur Mednet: http://mednet.who.int/# Estructura electrónica disponible en Mednet: http://mednet.who.int/204

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105ANNEX 1PROCEDURE FOR THE SELECTION OF RECOMMENDED INTERNATIONALNONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES 1The following procedure shall be followed by the World Health Organization (hereinafter also referred to as “WHO”)in the selection of recommended international nonproprietary names for pharmaceutical substances, in accordance withresolution WHA3.11 of the World Health Assembly, and in the substitution of such names.Article 1 - Proposals for recommended international nonproprietary names and proposals for substitution of such namesshall be submitted to WHO on the form provided therefore. The consideration of such proposals shall be subject to thepayment of an administrative fee designed only to cover the corresponding costs of the Secretariat of WHO (“theSecretariat”). The amount of this fee shall be determined by the Secretariat and may, from time to time, be adjusted.Article 2 - Such proposals shall be submitted by the Secretariat to the members of the Expert Advisory Panel on theInternational Pharmacopoeia and Pharmaceutical Preparations designated for this purpose, such designated membershereinafter referred to as “the INN Expert Group”, for consideration in accordance with the “General principles for guidancein devising International Nonproprietary Names for Pharmaceutical Substances”, annexed to this procedure 2 . The nameused by the person discovering or first developing and marketing a pharmaceutical substance shall be accepted, unlessthere are compelling reasons to the contrary.Article 3 - Subsequent to the examination provided for in article 2, the Secretariat shall give notice that a proposedinternational nonproprietary name is being considered.a) Such notice shall be given by publication in WHO Drug Information 3 and by letter to Member States and to national andregional pharmacopoeia commissions or other bodies designated by Member States.i) Notice shall also be sent to the person who submitted the proposal (“the original applicant”) and other personsknown to be concerned with a name under consideration.b) Such notice shall:i) set forth the name under consideration;ii) identify the person who submitted the proposal for naming the substance, if so requested by such person;iii) identify the substance for which a name is being considered;iv) set forth the time within which comments and objections will be received and the person and place to whomthey should be directed;v) state the authority under which WHO is acting and refer to these rules of procedure.c) In forwarding the notice, the Secretariat shall request that Member States take such steps as are necessary to preventthe acquisition of proprietary rights in the proposed name during the period it is under consideration by WHO.Article 4 - Comments on the proposed name may be forwarded by any person to WHO within four months of the date ofpublication, under article 3, of the name in WHO Drug Information.1See Annex 1 in WHO Technical Report Series, No. 581, 1975. The original text was adopted by the Executive Board in resolution EB15.R7 and amendedin resolutions EB43.R9 and EB115.R4.2See Annex 2.3Before 1987, lists of international nonproprietary names were published in the Chronicle of the World Health Organization.205

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011Article 5 - A formal objection to a proposed name may be filed by any interested person within four months of the date ofpublication, under article 3, of the name in WHO Drug Information.Such objection shall:i) identify the person objecting;ii) state his or her interest in the name;iii) set forth the reasons for his or her objection to the name proposed.Article 6 - Where there is a formal objection under article 5, WHO may either reconsider the proposed name or use its goodoffices to attempt to obtain withdrawal of the objection. Without prejudice to the consideration by WHO of a substitute nameor names, a name shall not be selected by WHO as a recommended international nonproprietary name while there exists aformal objection thereto filed under article 5 which has not been withdrawn.Article 7 - Where no objection has been filed under article 5, or all objections previously filed have been withdrawn, theSecretariat shall give notice in accordance with subsection (a) of article 3 that the name has been selected by WHO as arecommended international nonproprietary name.Article 8 - In forwarding a recommended international nonproprietary name to Member States under article 7, the Secretariatshall:a) request that it be recognized as the nonproprietary name for the substance; andb) request that Member States take such steps as are necessary to prevent the acquisition of proprietary rights in the nameand to prohibit registration of the name as a trademark or trade name.Article 9a) In the extraordinary circumstance that a previously recommended international nonproprietary name gives rise to errorsin medication, prescription or distribution, or a demonstrable risk thereof, because of similarity with another name inpharmaceutical and/or prescription practices, and it appears that such errors or potential errors cannot readily be resolvedthrough other interventions than a possible substitution of a previously recommended international nonproprietary name, orin the event that a previously recommended international nonproprietary name differs substantially from the nonproprietaryname approved in a significant number of Member States, or in other such extraordinary circumstances that justify asubstitution of a recommended international nonproprietary name, proposals to that effect may be filed by any interestedperson. Such proposals shall be submitted on the form provided therefore and shall:i) identify the person making the proposal;ii) state his or her interest in the proposed substitution; andiii) set forth the reasons for the proposal; andiv) describe, and provide documentary evidence regarding the other interventions undertaken in an effort toresolve the situation, and the reasons why these other interventions were inadequate.Such proposals may include a proposal for a new substitute international nonproprietary name, devised in accordance withthe General principles, which takes into account the pharmaceutical substance for which the new substitute internationalnonproprietary name is being proposed.The Secretariat shall forward a copy of the proposal, for consideration in accordance with the procedure described insubsection (b) below, to the INN Expert Group and the original applicant or its successor (if different from the personbringing the proposal for substitution and provided that the original applicant or its successor is known or can be foundthrough diligent effort, including contacts with industry associations).In addition, the Secretariat shall request comments on the proposal from:i) Member States and national and regional pharmacopoeia commissions or other bodies designated by MemberStates (by including a notice to that effect in the letter referred to in article 3(a), and206

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105ii) any other persons known to be concerned by the proposed substitution.The request for comments shall:i) state the recommended international nonproprietary name that is being proposed for substitution (and theproposed substitute name, if provided);ii) identify the person who submitted the proposal for substitution (if so requested by such person);iii) identify the substance to which the proposed substitution relates and reasons put forward for substitution;iv) set forth the time within which comments will be received and the person and place to whom they should bedirected; andv) state the authority under which WHO is acting and refer to these rules of procedure.Comments on the proposed substitution may be forwarded by any person to WHO within four months of the date of therequest for comments.b) After the time period for comments referred to above has elapsed, the Secretariat shall forward any comments receivedto the INN Expert Group, the original applicant or its successor and the person bringing the proposal for substitution. If, afterconsideration of the proposal for substitution and the comments received, the INN Expert Group, the person bringing theproposal for substitution and the original applicant or its successor all agree that there is a need to substitute the previouslyrecommended international nonproprietary name, the Secretariat shall submit the proposal for substitution to the INN ExpertGroup for further processing.Notwithstanding the foregoing, the original applicant or its successor shall not be entitled to withhold agreement to aproposal for substitution in the event the original applicant or its successor has no demonstrable continuing interest in therecommended international nonproprietary name proposed for substitution.In the event that a proposal for substitution shall be submitted to the INN Expert Group for further processing, theINN Expert Group will select a new international nonproprietary name in accordance with the General principles referred toin article 2 and the procedure set forth in articles 3 to 8 inclusive. The notices to be given by the Secretariat under article 3and article 7, respectively, including to the original applicant or its successor (if not the same as the person proposing thesubstitution, and provided that the original applicant or its successor is known or can be found through diligent effort,including contacts with industry associations), shall in such event indicate that the new name is a substitute for a previouslyrecommended international nonproprietary name and that Member States may wish to make transitional arrangements inorder to accommodate existing products that use the previously recommended international nonproprietary name on theirlabel in accordance with national legislation.If, after consideration of the proposal for substitution and the comments received in accordance with theprocedure described above, the INN Expert Group, the original applicant or its successor and the person bringing theproposal for substitution do not agree that there are compelling reasons for substitution of a previously recommendedinternational nonproprietary name, this name shall be retained (provided always that the original applicant or its successorshall not be entitled to withhold agreement to a proposal for substitution in the event that the original applicant or itssuccessor has no demonstrable continuing interest in the recommended international nonproprietary name proposed to besubstituted). In such an event, the Secretariat shall advise the person having proposed the substitution, as well as theoriginal applicant or its successor (if not the same as the person proposing the substitution, and provided that the originalapplicant or its successor is known or can be found through diligent effort, including contacts with industry associations),Member States, national and regional pharmacopoeia commissions, other bodies designated by Member States, and anyother persons known to be concerned by the proposed substitution that, despite a proposal for substitution, it has beendecided to retain the previously recommended international nonproprietary name (with a description of the reason(s) whythe proposal for substitution was not considered sufficiently compelling).207

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011ANNEX 2GENERAL PRINCIPLES FOR GUIDANCE IN DEVISING INTERNATIONALNONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES 11. International Nonproprietary Names (INN) should be distinctive in sound and spelling. They should not be inconvenientlylong and should not be liable to confusion with names in common use.2. The INN for a substance belonging to a group of pharmacologically related substances should, where appropriate, showthis relationship. Names that are likely to convey to a patient an anatomical, physiological, pathological or therapeuticsuggestion should be avoided.These primary principles are to be implemented by using the following secondary principles:3. In devising the INN of the first substance in a new pharmacological group, consideration should be given to the possibilityof devising suitable INN for related substances, belonging to the new group.4. In devising INN for acids, one-word names are preferred; their salts should be named without modifying the acid name,e.g. “oxacillin” and “oxacillin sodium”, “ibufenac” and “ibufenac sodium”.5. INN for substances which are used as salts should in general apply to the active base or the active acid. Names fordifferent salts or esters of the same active substance should differ only in respect of the name of the inactive acid or theinactive base.For quaternary ammonium substances, the cation and anion should be named appropriately as separate components of aquaternary substance and not in the amine-salt style.6. The use of an isolated letter or number should be avoided; hyphenated construction is also undesirable.7. To facilitate the translation and pronunciation of INN, “f” should be used instead of “ph”, “t” instead of “th”, “e” instead of“ae” or “oe”, and “i” instead of “y”; the use of the letters “h” and “k” should be avoided.8. Provided that the names suggested are in accordance with these principles, names proposed by the person discoveringor first developing and marketing a pharmaceutical preparation, or names already officially in use in any country, shouldreceive preferential consideration.9. Group relationship in INN (see General principle 2) should if possible be shown by using a common stem. The followinglist contains examples of stems for groups of substances, particularly for new groups. There are many other stems in activeuse. 2 Where a stem is shown without any hyphens it may be used anywhere in the name.LatinEnglish-acum -ac anti-inflammatory agents, ibufenac derivatives-adolum -adol } analgesics-adol--adol-}-astum -ast antiasthmatic, antiallergic substances not acting primarily as antihistaminics-astinum -astine antihistaminics-azepamum -azepam diazepam derivativesbol bol steroids, anabolic-cain- -cain- class I antiarrhythmics, procainamide and lidocaine derivatives-cainum -caine local anaesthetics1In its Twentieth report (WHO Technical Report Series, No. 581, 1975), the WHO Expert committee on Nonproprietary Names for Pharmaceutical Substancesreviewed the general principles for devising, and the procedures for selecting, INN in the light of developments in pharmaceutical compounds in recent years. Themost significant change has been the extension to the naming of synthetic chemical substances of the practice previously used for substances originating in orderived from natural products. This practice involves the use of a characteristic “stem” indicative of a common property of the members of a group. The reason for,and the implications of, the change are fully discussed.The guiding principles were updated during the 13 th consultation on nonproprietary names for pharmaceutical substances (Geneva, 27-29 April 1983) (PHARMS/NOM 928 13 May 1983, revised 18 August 1983).2 A more extensive listing of stems is contained in the working document WHO/EMP/QSM/2009.3 which is regularly updated and can be requested from the INNProgramme, WHO, Geneva.208

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105cef- cef- antibiotics, cefalosporanic acid derivatives-cillinum -cillin antibiotics, 6-aminopenicillanic acid derivatives-conazolum -conazole systemic antifungal agents, miconazole derivativescort cort corticosteroids, except prednisolone derivatives-coxibum -coxib selective cyclo-oxygenase inhibitors-entanum -entan endothelin receptor antagonistsgab gab gabamimetic agentsgado- gado- diagnostic agents, gadolinium derivatives-gatranum -gatran thrombin inhibitors, antithrombotic agentsgest gest steroids, progestogensgli gli antihyperglycaemicsio- io- iodine-containing contrast media-metacinum -metacin anti-inflammatory, indometacin derivatives-mycinum -mycin antibiotics, produced by Streptomyces strains-nidazolum -nidazole antiprotozoal substances, metronidazole derivatives-ololum -olol β-adrenoreceptor antagonists-oxacinum -oxacin antibacterial agents, nalidixic acid derivatives-platinum -platin antineoplastic agents, platinum derivatives-poetinum -poetin erythropoietin type blood factors-pril(at)um -pril(at) angiotensin-converting enzyme inhibitors-profenum -profen anti-inflammatory substances, ibuprofen derivativesprost prost prostaglandins-relinum -relin pituitary hormone release-stimulating peptides-sartanum -sartan angiotensin II receptor antagonists, antihypertensive (non-peptidic)-vaptanum -vaptan vasopressin receptor antagonistsvin- vin- } vinca-type alkaloids-vin--vin-}ANNEXE 1PROCEDURE A SUIVRE EN VUE DU CHOIX DE DENOMINATIONS COMMUNESINTERNATIONALES RECOMMANDEES POUR LES SUBSTANCESPHARMACEUTIQUES 1L’Organisation mondiale de la Santé (également désignée ci-après sous l’appellation « OMS ») observe la procédureexposée ci-dessous pour l’attribution de dénominations communes internationales recommandées pour les substancespharmaceutiques, conformément à la résolution WHA3.11 de l’Assemblée mondiale de la Santé, et pour le remplacementde telles dénominations.Article 1 - Les propositions de dénominations communes internationales recommandées et les propositions deremplacement de telles dénominations sont soumises à l’OMS sur la formule prévue à cet effet. L’examen de tellespropositions est soumis au paiement d’une taxe administrative destinée uniquement à couvrir les coûts correspondantsassumés par le Secrétariat de l’OMS (« le Secrétariat »). Le montant de cette taxe est déterminé par le Secrétariat et peutêtre modifié de temps à autre.Article 2 - Ces propositions sont soumises par le Secrétariat aux experts désignés à cette fin parmi les personnalitésinscrites au Tableau d’experts de la Pharmacopée internationale et des Préparations pharmaceutiques, ci-après désignéssous l’appellation « le Groupe d’experts des DCI » ; elles sont examinées par les experts conformément aux « Directivesgénérales pour la formation de dénominations communes internationales pour les substances pharmaceutiques »reproduites ci-après 2 . La dénomination acceptée est la dénomination employée par la personne qui découvre ou qui, lapremière, fabrique et lance sur le marché une substance pharmaceutique, à moins que des raisons majeures n’obligent às’écarter de cette règle.1Voir annexe 1 dans OMS, Série de Rapports techniques, N° 581, 1975. Le texte original a été adopté par le Conseil exécutif dans sa résolution EB15.R7et amendé dans ses résolutions EB43.R9 et EB115.R4.2Voir annexe 2.209

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011Article 3 - Après l’examen prévu à l’article 2, le Secrétariat notifie qu’un projet de dénomination commune internationale està l’étude.a) Cette notification est faite par une insertion dans WHO Drug Information 1 et par l’envoi d’une lettre aux Etats Membres etaux commissions nationales et régionales de pharmacopée ou autres organismes désignés par les Etats Membres.i) Notification est également faite à la personne qui a soumis la proposition (« le demandeur initial ») et à d’autrespersonnes portant à la dénomination mise à l’étude un intérêt notoire.b) Cette notification contient les indications suivantes :i) dénomination mise à l’étude;ii) nom de l’auteur de la proposition tendant à attribuer une dénomination à la substance, si cette personne ledemande ;iii) définition de la substance dont la dénomination est mise à l’étude ;iv) délai pendant lequel seront reçues les observations et les objections à l’égard de cette dénomination ; nom etadresse de la personne habilitée à recevoir ces observations et objections ;v) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement.c) En envoyant cette notification, le Secrétariat demande aux Etats Membres de prendre les mesures nécessaires pourprévenir l’acquisition de droits de propriété sur la dénomination proposée pendant la période au cours de laquelle cettedénomination est mise à l’étude par l’OMS.Article 4 - Des observations sur la dénomination proposée peuvent être adressées à l’OMS par toute personne, dans lesquatre mois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3).Article 5 - Toute personne intéressée peut formuler une objection formelle contre la dénomination proposée dans les quatremois qui suivent la date de publication de la dénomination dans WHO Drug Information (voir l’article 3).Cette objection doit s’accompagner des indications suivantes :i) nom de l’auteur de l’objection ;ii) intérêt qu’il ou elle porte à la dénomination en cause ;iii) raisons motivant l’objection contre la dénomination proposée.Article 6 - Lorsqu’une objection formelle est formulée en vertu de l’article 5, l’OMS peut soit soumettre la dénominationproposée à un nouvel examen, soit intervenir pour tenter d’obtenir le retrait de l’objection. Sans préjudice de l’examen parl’OMS d’une ou de plusieurs appellations de remplacement, l’OMS n’adopte pas d’appellation comme dénominationcommune internationale recommandée tant qu’une objection formelle présentée conformément à l’article 5 n’est pas levée.Article 7 - Lorsqu’il n’est formulé aucune objection en vertu de l’article 5, ou que toutes les objections présentées ont étélevées, le Secrétariat fait une notification conformément aux dispositions du paragraphe a) de l’article 3, en indiquant que ladénomination a été choisie par l’OMS en tant que dénomination commune internationale recommandée.Article 8 - En communiquant aux Etats Membres, conformément à l’article 7, une dénomination commune internationalerecommandée, le Secrétariat :a) demande que cette dénomination soit reconnue comme dénomination commune de la substance considérée ; etb) demande aux Etats Membres de prendre les mesures nécessaires pour prévenir l’acquisition de droits de propriété surcette dénomination et interdire le dépôt de cette dénomination comme marque ou appellation commerciale.1Avant 1987, les listes de dénominations communes internationales étaient publiées dans la Chronique de l’Organisation mondiale de la Santé.210

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105Article 9 -a) Dans le cas exceptionnel où une dénomination commune internationale déjà recommandée donne lieu à des erreurs demédication, de prescription ou de distribution ou en comporte un risque démontrable, en raison d’une similitude avec uneautre appellation dans la pratique pharmaceutique et/ou de prescription, et où il apparaît que ces erreurs ou ces risquesd’erreur ne peuvent être facilement évités par d’autres interventions que le remplacement éventuel d’une dénominationcommune internationale déjà recommandée, ou dans le cas où une dénomination commune internationale déjàrecommandée diffère sensiblement de la dénomination commune approuvée dans un nombre important d’Etats Membres,ou dans d’autres circonstances exceptionnelles qui justifient le remplacement d’une dénomination commune internationalerecommandée, toute personne intéressée peut formuler une proposition dans ce sens. Cette proposition est présentée surla formule prévue à cet effet et doit s’accompagner des indications suivantes :i) nom de l’auteur de la proposition ;ii) intérêt qu’il ou elle porte au remplacement proposé ;iii) raisons motivant la proposition ; etiv) description, faits à l’appui, des autres interventions entreprises pour tenter de régler le problème et exposé desraisons pour lesquelles ces interventions ont échoué.Les propositions peuvent comprendre une proposition de nouvelle dénomination commune internationale de remplacement,établie conformément aux Directives générales, compte tenu de la substance pharmaceutique pour laquelle la nouvelledénomination commune internationale de remplacement est proposée.Le Secrétariat transmet une copie de la proposition pour examen, conformément à la procédure exposée plus loin auparagraphe b), au Groupe d’experts des DCI et au demandeur initial ou à son successeur (s’il s’agit d’une personnedifférente de celle qui a formulé la proposition de remplacement et pour autant que le demandeur initial ou son successeursoit connu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associationsindustrielles).De plus, le Secrétariat demande aux entités et personnes ci-après de formuler des observations sur la proposition :i) les Etats Membres et les commissions nationales et régionales de pharmacopée ou d’autres organismesdésignés par les Etats Membres (en insérant une note à cet effet dans la lettre mentionnée à l’article 3.a), etii) toutes autres personnes portant au remplacement proposé un intérêt notoire.La demande d’observations contient les indications suivantes :i) dénomination commune internationale recommandée pour laquelle un remplacement est proposé (et ladénomination de remplacement proposée, si elle est fournie) ;ii) nom de l’auteur de la proposition de remplacement (si cette personne le demande) ;iii) définition de la substance faisant l’objet du remplacement proposé et raisons avancées pour le remplacement ;iv) délai pendant lequel seront reçus les commentaires et nom et adresse de la personne habilitée à recevoir cescommentaires ; etv) mention des pouvoirs en vertu desquels agit l’OMS et référence au présent règlement.Des observations sur la proposition de remplacement peuvent être communiquées par toute personne à l’OMS dans lesquatre mois qui suivent la date de la demande d’observations.b) Une fois échu le délai prévu ci-dessus pour la communication d’observations, le Secrétariat transmet les observationsreçues au Groupe d’experts des DCI, au demandeur initial ou à son successeur et à l’auteur de la proposition deremplacement. Si, après avoir examiné la proposition de remplacement et les observations reçues, le Groupe d’experts desDCI, l’auteur de la proposition de remplacement et le demandeur initial ou son successeur reconnaissent tous qu’il estnécessaire de remplacer la dénomination commune internationale déjà recommandée, le Secrétariat soumet la propositionde remplacement au Groupe d’experts des DCI pour qu’il y donne suite.211

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011Nonobstant ce qui précède, le demandeur initial ou son successeur n’est pas habilité à refuser son accord à uneproposition de remplacement au cas où il ne peut être démontré qu’il porte un intérêt durable à la dénomination communeinternationale recommandée qu’il est proposé de remplacer.Dans le cas où une proposition de remplacement est soumise au Groupe d’experts des DCI pour qu’il y donnesuite, le Groupe choisit une nouvelle dénomination commune internationale conformément aux Directives généralesmentionnées à l’article 2 et selon la procédure décrite dans les articles 3 à 8 inclus. La notification faite par le Secrétariat envertu de l’article 3 et de l’article 7, respectivement, y compris au demandeur initial ou à son successeur (si ce n’est pas lamême personne que celle qui a proposé le remplacement et pour autant que le demandeur initial ou son successeur soitconnu ou puisse être retrouvé moyennant des efforts diligents, notamment des contacts avec les associations industrielles),doit dans un tel cas indiquer que la nouvelle dénomination remplace une dénomination commune internationale déjàrecommandée et que les Etats Membres peuvent souhaiter prendre des mesures transitoires pour les produits existants quiutilisent la dénomination commune internationale déjà recommandée sur leur étiquette conformément à la législationnationale.Si, après examen de la proposition de remplacement et des observations communiquées conformément à laprocédure exposée plus haut, le Groupe d’experts des DCI, le demandeur initial ou son successeur et l’auteur de laproposition de remplacement ne s’accordent pas sur le fait qu’il y a des raisons impératives de remplacer unedénomination commune internationale déjà recommandée, cette dernière est conservée (étant entendu toujours que ledemandeur initial ou son successeur n’est pas habilité à refuser son accord à une proposition de remplacement au cas où ilne peut être démontré qu’il porte un intérêt durable à la dénomination commune internationale recommandée qu’il estproposé de remplacer). Dans un tel cas, le Secrétariat informe l’auteur de la proposition de remplacement, ainsi que ledemandeur initial ou son successeur (s’il s’agit d’une personne différente de celle qui a formulé la proposition deremplacement et pour autant que le demandeur initial ou son successeur soit connu ou puisse être retrouvé moyennant desefforts diligents, notamment des contacts avec les associations industrielles), les Etats Membres, les commissionsnationales et régionales de pharmacopée, les autres organismes désignés par les Etats Membres et toutes autrespersonnes portant un intérêt notoire au remplacement proposé que, malgré une proposition de remplacement, il a étédécidé de conserver la dénomination commune internationale déjà recommandée (avec une brève description de la ou desraisons pour lesquelles la proposition de remplacement n’a pas été jugée suffisamment impérative).ANNEXE 2DIRECTIVES GENERALES POUR LA FORMATION DE DENOMINATIONSCOMMUNES INTERNATIONALES APPLICABLES AUX SUBSTANCESPHARMACEUTIQUES 11. Les dénominations communes internationales (DCI) devront se distinguer les unes des autres par leur consonance etleur orthographe. Elles ne devront pas être d’une longueur excessive, ni prêter à confusion avec des appellations déjàcouramment employées.2. La DCI de chaque substance devra, si possible, indiquer sa parenté pharmacologique. Les dénominations susceptiblesd’évoquer pour les malades des considérations anatomiques, physiologiques, pathologiques ou thérapeutiques devront êtreévitées dans la mesure du possible.Outre ces deux principes fondamentaux, on respectera les principes secondaires suivants :Lorsqu’on formera la DCI de la première substance d’un nouveau groupe pharmacologique, on tiendra compte de lapossibilité de former ultérieurement d’autres DCI appropriées pour les substances apparentées du même groupe.1Dans son vingtième rapport (OMS, Série de Rapports techniques, N° 581, 1975), le Comité OMS d’experts des Dénominations communes pour les Substancespharmaceutiques a examiné les directives générales pour la formation des dénominations communes internationales et la procédure à suivre en vue de leur choix,compte tenu de l’évolution du secteur pharmaceutique au cours des dernières années. La modification la plus importante a été l’extension aux substances desynthèse de la pratique normalement suivie pour désigner les substances tirées ou dérivées de produits naturels. Cette pratique consiste à employer des syllabescommunes ou groupes de syllabes communes (segments-clés) qui sont caractéristiques et indiquent une propriété commune aux membres du groupe dessubstances pour lequel ces segments-clés ont été retenus. Les raisons et les conséquences de cette modification ont fait l’objet de discussions approfondies.Les directives ont été mises à jour lors de la treizième consultation sur les dénominations communes pour les substances pharmaceutiques (Genève, 27-29 avril1983) (PHARM S/NOM 928, 13 mai 1983, révision en date du 18 août 1983).212

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 1054. Pour former des DCI des acides, on utilisera de préférence un seul mot. Leurs sels devront être désignés par un termequi ne modifie pas le nom de l’acide d’origine : par exemple «oxacilline» et «oxacilline sodique», «ibufénac» et «ibufénacsodique».5. Les DCI pour les substances utilisées sous forme de sels devront en général s’appliquer à la base active (ou à l’acideactif). Les dénominations pour différents sels ou esters d’une même substance active ne différeront que par le nom del’acide inactif (ou de la base inactive).En ce qui concerne les substances à base d’ammonium quaternaire, la dénomination s’appliquera de façon appropriée aucation et à l’anion en tant qu’éléments distincts d’une substance quaternaire. On évitera de choisir une désignationévoquant un sel aminé.6. On évitera d’ajouter une lettre ou un chiffre isolé ; en outre, on renoncera de préférence au trait d’union.7. Pour simplifier la traduction et la prononciation des DCI, la lettre « f » sera utilisée à la place de « ph », « t » à la place de« th », « e » à la place de « ae » ou « oe », et « i » à la place de « y » ; l’usage des lettres « h » et « k » sera aussi évité.8. On retiendra de préférence, pour autant qu’elles respectent les principes énoncés ici, les dénominations proposées parles personnes qui ont découvert ou qui, les premières, ont fabriqué et lancé sur le marché les préparationspharmaceutiques considérées, ou les dénominations déjà officiellement adoptées par un pays.9. La parenté entre substances d’un même groupe (voir Directive générale 2) sera si possible indiquée dans les DCI parl’emploi de segments-clés communs. La liste ci-après contient des exemples de segments-clés pour des groupes desubstances, surtout pour des groupes récents. Il y a beaucoup d’autres segments-clés en utilisation active. 1 Les segmentsclésindiqués sans trait d’union pourront être insérés n’importe où dans une dénomination.LatinFrançais-acum -ac substances anti-inflammatoires du groupe de l’ibufénac-adolum -adol } analgésiques-adol- -adol- }-astum -ast antiasthmatiques, antiallergiques n’agissant pas principalement en tantqu’antihistaminiques-astinum -astine antihistaminiques-azepamum -azépam substances du groupe du diazépambol bol stéroïdes anabolisants-cain- -caïn- antiarythmiques de classe I, dérivés du procaïnamide et de la lidocaïne-cainum -caïne anesthésiques locauxcef- céf- antibiotiques, dérivés de l’acide céphalosporanique-cillinum -cilline antibiotiques, dérivés de l’acide 6-aminopénicillanique-conazolum -conazole agents antifongiques systémiques du groupe du miconazolecort cort corticostéroïdes, autres que les dérivés de la prednisolone-coxibum -coxib inhibiteurs sélectifs de la cyclo-oxygénase-entanum -entan antagonistes du récepteur de l’endothélinegab gab gabamimétiquesgado- gado- agents diagnostiques, dérivés du gadolinium-gatranum -gatran antithrombines, antithrombotiquesgest gest stéroïdes progestogènesgli gli antihyperglycémiantsio- io- produits de contraste iodés-metacinum -métacine substances anti-inflammatoires du groupe de l’indométacine-mycinum -mycine antibiotiques produits par des souches de Streptomyces-nidazolum -nidazole substances antiprotozoaires du groupe du métronidazole-ololum -olol antagonistes des récepteurs β-adrénergiques-oxacinum -oxacine substances antibactériennes du groupe de l’acide nalidixique-platinum -platine antinéoplasiques, dérivés du platine-poetinum -poétine facteurs sanguins de type érythropoïétine-pril(at)um -pril(ate) inhibiteurs de l’enzyme de conversion de l’angiotensine-profenum -profène substances anti-inflammatoires du groupe de l’ibuprofèneprost prost prostaglandines1Une liste plus complète de segments-clés est contenue dans le document de travail WHO/EMP/QSM/2009.3 qui est régulièrement mis à jour et qui peut êtredemandé auprès du programme des DCI, OMS, Genève.213

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011-relinum -réline peptides stimulant la libération d’hormones hypophysaires-sartanum -sartan antagonistes d’un récepteur de l’angiotensine II, antihypertenseurs (nonpeptidiques)-vaptanum -vaptan antagonistes du récepteur de la vasopressinevin- vin- } alcaloïdes du type vinca-vin- -vin- }ANEXO 1PROCEDIMIENTO DE SELECCIÓN DE DENOMINACIONES COMUNESINTERNACIONALES RECOMENDADAS PARA SUSTANCIAS FARMACÉUTICAS 1La Organización Mundial de la Salud (OMS) seguirá el procedimiento que se expone a continuación tanto para seleccionardenominaciones comunes internacionales recomendadas para las sustancias farmacéuticas, de conformidad con lodispuesto en la resolución WHA3.11, como para sustituir esas denominaciones.Artículo 1 - Las propuestas de denominaciones comunes internacionales recomendadas y las propuestas de sustitución deesas denominaciones se presentarán a la OMS en los formularios que se proporcionen a estos efectos. El estudio de estaspropuestas estará sujeto al pago de una tasa destinada a sufragar los costos de administración que ello suponga para laSecretaría de la OMS («la Secretaría»). La Secretaría establecerá la cuantía de esa tasa y podrá ajustarla periódicamente.Artículo 2 - Estas propuestas serán sometidas por la Secretaría a los miembros del Cuadro de Expertos en FarmacopeaInternacional y Preparaciones Farmacéuticas encargados de su estudio, en adelante designados como «el Grupo deExpertos en DCI», para que las examinen de conformidad con los «Principios generales de orientación para formardenominaciones comunes internacionales para sustancias farmacéuticas», anexos a este procedimiento. 2A menos quehaya poderosas razones en contra, la denominación aceptada será la empleada por la persona que haya descubierto ofabricado y comercializado por primera vez esa sustancia farmacéutica.Artículo 3 - Tras el examen al que se refiere el artículo 2, la Secretaría notificará que está en estudio un proyecto dedenominación internacional.a) Esa notificación se hará mediante una publicación en Información Farmacéutica OMS 3 y el envío de una carta a losEstados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismos designados por losEstados Miembros.i) La notificación será enviada también a la persona que haya presentado la propuesta («el solicitante inicial») y aotras personas que tengan un interés especial en una denominación objeto de estudio.b) En esa notificación se incluirán los siguientes datos:i) la denominación sometida a estudio;ii) la identidad de la persona que ha presentado la propuesta de denominación de lasustancia, si lo pide esa persona;iii) la identidad de la sustancia cuya denominación está en estudio;iv) el plazo fijado para recibir observaciones y objeciones, así como el nombre y la dirección de la persona aquien deban dirigirse; yv) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento.1Véase el anexo 1 en OMS, Serie de Informes Técnicos, Nº 581, 1975. El texto vigente fue adoptado por el Consejo Ejecutivo en su resolución EB15.R7 ymodificado en las resoluciónes EB43.R9 y EB115.R4..2Véase el anexo 2.3Hasta 1987 las listas de DCI se publicaban en la Crónica de la Organización Mundial de la Salud.214

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105c) Al enviar esa notificación, la Secretaría solicitará de los Estados Miembros la adopción de todas las medidas necesariaspara impedir la adquisición de derechos de patente sobre la denominación propuesta, durante el periodo en que la OMS latenga en estudio.Artículo 4 - Toda persona puede formular a la OMS observaciones sobre la denominación propuesta dentro de los cuatromeses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3.Artículo 5 - Toda persona interesada puede presentar una objeción formal a una denominación propuesta dentro de loscuatro meses siguientes a su publicación en Información Farmacéutica OMS, conforme a lo dispuesto en el artículo 3.Esa objeción deberá acompañarse de los siguientes datos:i) la identidad de la persona que formula la objeción;ii) las causas que motivan su interés por la denominación; yiii) las causas que motivan su objeción a la denominación propuesta.Artículo 6 - Cuando se haya presentado una objeción formal en la forma prevista en el artículo 5, la OMS podráreconsiderar el nombre propuesto o utilizar sus buenos oficios para intentar lograr que se retire la objeción. La OMS noseleccionará como denominación común internacional una denominación a la que se haya hecho una objeción formal,presentada según lo previsto en el artículo 5, que no haya sido retirada, todo ello sin perjuicio de que la Organizaciónexamine otra denominación o denominaciones sustitutivas.Artículo 7 - Cuando no se haya formulado ninguna objeción en la forma prevista en el artículo 5, o cuando todas lasobjeciones presentadas hayan sido retiradas, la Secretaría notificará, conforme a lo dispuesto en el párrafo a) del artículo 3,que la denominación ha sido seleccionada por la OMS como denominación común internacional recomendada.Artículo 8 - Al comunicar a los Estados Miembros una denominación común internacional, conforme a lo previsto en elartículo 7, la Secretaría:a) solicitará que esta denominación sea reconocida como denominación común para la sustancia de que se trate; yb) solicitará a los Estados Miembros que adopten todas las medidas necesarias para impedir la adquisición de derechos depatente sobre la denominación, y prohíban que sea registrada como marca de fábrica o como nombre comercial.Artículo 9a) En el caso excepcional de que, debido a su semejanza con otra denominación utilizada en las prácticas farmacéuticasy/o de prescripción, una denominación común internacional recomendada anteriormente ocasione errores de medicación,prescripción o distribución, o suponga un riesgo manifiesto de que esto ocurra, y parezca que tales errores o potencialeserrores no sean fácilmente subsanables con otras medidas que no sean la posible sustitución de esa denominación comúninternacional recomendada anteriormente; en el caso de que una denominación común internacional recomendadaanteriormente difiera considerablemente de la denominación común aprobada en un número importante de EstadosMiembros, o en otras circunstancias excepcionales que justifiquen el cambio de una denominación común internacionalrecomendada, cualquier persona interesada puede presentar propuestas en este sentido. Esas propuestas se presentaránen los formularios que se proporcionen a estos efectos e incluirán los siguientes datos:i) la identidad de la persona que presenta la propuesta;ii) las causas que motivan su interés en la sustitución propuesta;iii) las causas que motivan la propuesta; yiv) una descripción, acompañada de pruebas documentales, de las otras medidas que se hayan adoptado con elfin de resolver la situación y de los motivos por los cuales dichas medidas no han sido suficientes.Entre esas propuestas podrá figurar una relativa a una nueva denominación común internacional sustitutiva,formulada con arreglo a los Principios generales y que tenga en cuenta la sustancia farmacéutica para la que se propongala nueva denominación común internacional sustitutiva.La Secretaría enviará al Grupo de Expertos en DCI y al solicitante inicial o a su sucesor (en el caso de que seauna persona diferente de la que ha presentado la propuesta de sustitución y siempre que el solicitante inicial o su sucesorsean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociaciones215

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011industriales) una copia de la propuesta, para que sea examinada de conformidad con el procedimiento descrito en elpárrafo b) infra.Además, la Secretaría solicitará observaciones sobre la propuesta:i) a los Estados Miembros y a las comisiones nacionales y regionales de las farmacopeas u otros organismosdesignados por los Estados Miembros (ello se hará incluyendo una notificación a tal efecto en la carta a la que serefiere el párrafo a) del artículo 3), yii) a cualquier persona que tenga un interés especial en la sustitución propuesta.Al solicitar que se formulen estas observaciones se facilitarán los siguientes datos:i) la denominación común internacional recomendada que se propone sustituir (y la denominación sustitutivapropuesta, si se ha facilitado);ii) la identidad de la persona que ha presentado la propuesta de sustitución (si lo pide esa persona);iii) la identidad de la sustancia a la que se refiere la sustitución propuesta y las razones para presentar lapropuesta de sustitución;iv) el plazo fijado para recibir observaciones, así como el nombre y la dirección de la persona a quien debandirigirse; yv) los poderes conferidos para el caso a la OMS y una referencia al presente procedimiento.Toda persona puede formular a la OMS observaciones sobre la sustitución propuesta dentro de los cuatro mesessiguientes a la fecha en que se realizó la solicitud de observaciones.b) Una vez agotado el mencionado plazo para la formulación de observaciones, la Secretaría enviará todos los comentariosrecibidos al Grupo de Expertos en DCI, al solicitante inicial o a su sucesor, y a la persona que haya presentado lapropuesta de sustitución. Si después de examinar la propuesta de sustitución y las observaciones recibidas, el Grupo deExpertos en DCI, la persona que haya presentado la propuesta de sustitución y el solicitante inicial, o su sucesor, están deacuerdo en la necesidad de sustituir la denominación común internacional recomendada anteriormente, la Secretaríaremitirá la propuesta de sustitución al Grupo de Expertos en DCI para que la tramite.No obstante lo anterior, el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta desustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuyasustitución se propone.En caso de que la propuesta de sustitución sea presentada al Grupo de Expertos en DCI para que la tramite, estegrupo seleccionará una nueva denominación común internacional de conformidad con los Principios generales a los que serefiere el artículo 2 y al procedimiento establecido en los artículos 3 a 8 inclusive. En ese caso, en las notificaciones que laSecretaría ha de enviar con arreglo a los artículos 3 y 7, respectivamente, incluida la notificación al solicitante inicial o a susucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que el solicitante inicial o susucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contacto con las asociacionesindustriales), se indicará que la nueva denominación sustituye a una denominación común internacional recomendadaanteriormente y que los Estados Miembros podrán, si lo estiman oportuno, adoptar disposiciones transitorias aplicables alos productos existentes en cuya etiqueta se utilice, con arreglo a la legislación nacional, la denominación comúninternacional recomendada anteriormente que se haya sustituido.En caso de que, después de haber estudiado la propuesta de sustitución y los comentarios recibidos de conformidadcon el procedimiento descrito anteriormente, el Grupo de Expertos en DCI, el solicitante inicial o su sucesor y la personaque haya presentado la propuesta de sustitución no lleguen a un acuerdo sobre la existencia de razones poderosas parasustituir una denominación común internacional recomendada anteriormente, esta denominación se mantendrá (siempre enel entendimiento de que el solicitante inicial o su sucesor no tendrán derecho a impedir el acuerdo sobre una propuesta desustitución en el caso de que hayan dejado de tener un interés demostrable en la denominación común internacional cuyasustitución se propone). En ese caso, la Secretaría comunicará a la persona que haya propuesto la sustitución, así comoal solicitante inicial o a su sucesor (en el caso de que no sea la misma persona que propuso la sustitución y siempre que elsolicitante inicial o su sucesor sean conocidos o puedan ser encontrados mediante esfuerzos diligentes, como el contactocon las asociaciones industriales), a los Estados Miembros, a las comisiones nacionales y regionales de las farmacopeas oa otros organismos designados por los Estados Miembros y a cualquier otra persona que tenga interés en la sustitución216

WHO Drug Information Vol. 25, No. 2, 2011 Proposed INN: List 105propuesta, que, pese a la presentación de una propuesta de sustitución, se ha decidido mantener la denominación comúninternacional recomendada anteriormente (con una descripción de la o las razones por las que se ha considerado que lapropuesta de sustitución no estaba respaldada por razones suficientemente poderosas).ANEXO 2PRINCIPIOS GENERALES DE ORIENTACIÓN PARA FORMAR DENOMINACIONESCOMUNES INTERNACIONALES PARA SUSTANCIAS FARMACÉUTICAS 11. Las denominaciones comunes internacionales (DCI) deberán diferenciarse tanto fonética como ortográficamente. Nodeberán ser incómodamente largas, ni dar lugar a confusión con denominaciones de uso común.2. La DCI de una sustancia que pertenezca a un grupo de sustancias farmacológicamente emparentadas deberá mostrarapropiadamente este parentesco. Deberán evitarse las denominaciones que puedan tener connotaciones anatómicas,fisiológicas, patológicas o terapéuticas para el paciente.Estos principios primarios se pondrán en práctica utilizando los siguientes principios secundarios:3. Al idear la DCI de la primera sustancia de un nuevo grupo farmacológico, deberá tenerse en cuenta la posibilidad depoder formar DCI convenientes para las sustancias emparentadas que se agreguen al nuevo grupo.4. Al idear DCI para ácidos, se preferirán las de una sola palabra; sus sales deberán denominarse sin modificar el nombredel ácido: p. ej. «oxacilina» y «oxacilina sódica», «ibufenaco» y «ibufenaco sódico».5. Las DCI para las sustancias que se usan en forma de sal deberán en general aplicarse a la base activa o al ácido activo.Las denominaciones para diferentes sales o esteres de la misma sustancia activa solamente deberán diferir en el nombredel ácido o de la base inactivos.En los compuestos de amonio cuaternario, el catión y el anión deberán denominarse adecuadamente por separado, comocomponentes independientes de una sustancia cuaternaria y no como sales de una amina.6. Deberá evitarse el empleo de letras o números aislados; también es indeseable el empleo de guiones.7. Para facilitar la traducción y la pronunciación, se emplearán de preferencia las letras «f» en lugar de «ph», «t» en lugarde «th», «e» en lugar de «ae» u «oe», e «i» en lugar de «y»; se deberá evitar el empleo de las letras «h» y «k».8. Siempre que las denominaciones propuestas estén de acuerdo con estos principios, recibirán una consideraciónpreferente las denominaciones propuestas por la persona que haya descubierto las sustancias, o que fabrique ycomercialice por primera vez una sustancia farmacéutica, así como las denominaciones ya adoptadas oficialmente encualquier país.9. El parentesco entre sustancias del mismo grupo se pondrá de manifiesto en las DCI (véase el Principio 2) utilizando unapartícula común. En la lista que figura a continuación se indican ejemplos de partículas para grupos de sustancias, enparticular para grupos nuevos. Existen muchas otras partículas que se usan habitualmente. 2 Cuando una partícula aparecesin guión alguno, puede utilizarse en cualquier lugar de la palabra.1En su 20º informe (OMS, Serie de Informes Técnicos, Nº 581, 1975), el Comité de Expertos de la OMS en Denominaciones Comunes para las SustanciasFarmacéuticas revisó los Principios generales para formar denominaciones comunes internacionales (DCI), y su procedimiento de selección, a la luz de lasnovedades registradas en los últimos años en materia de compuestos farmacéuticos. El cambio más importante había consistido en hacer extensivo a ladenominación de sustancias químicas sintéticas el método utilizado hasta entonces para las sustancias originadas en productos naturales o derivadas de éstos.Dicho método conlleva la utilización de una «partícula» característica que indica una propiedad común a los miembros de un grupo. En el citado informe seexaminan en detalle las razones y consecuencias de este cambio.Los Principios generales de orientación se actualizaron durante la 13ª consulta sobre denominaciones comunes para sustancias farmacéuticas (Ginebra, 27 a 29 deabril de 1983) (PHARM S/NOM 928, 13 de mayo de 1983, revisado el 18 de agosto de 1983).2En el documento de trabajo WHO/EMP/QSM/2009.3, que se actualiza periódicamente y puede solicitarse al Programa sobre Denominaciones ComunesInternacionales, OMS, Ginebra, figura una lista más amplia de partículas.217

Proposed INN: List 105 WHO Drug Information Vol. 25, No. 2, 2011LatinEspañol-acum -aco antiinflamatorios derivados del ibufenaco-adolum -adol ) analgésicos-adol- -adol- )-astum -ast antiasmáticos, sustancias antialérgicas cuya acción principal no es la antihistamínica-astinum -astina antihistamínicos-azepamum -azepam derivados del diazepambol bol esteroides anabolizantes-cain- -caína- antiarrítmicos de clase I, derivados de procainamida y lidocaína-cainum -caína- anestésicos localescef- cef- antibióticos, derivados del ácido cefalosporánico-cillinum - cilina antibióticos derivados del ácido 6-aminopenicilánico-conazolum -conazol antifúngicos sistémicos derivados del miconazolcort cort corticosteroides, excepto derivados de prednisolona-coxibum -coxib inhibidores selectivos de ciclooxigenasa-entanum -entán antagonistas del receptor de endotelinagab gab gabamiméticosgado- gado- agentes para diagnóstico derivados de gadolinio-gartranum -gatrán inhibidores de la trombina antitrombóticosgest gest esteroides progestágenosgli gli hipoglucemiantes, antihiperglucémicosio- io- medios de contraste iodados-metacinum -metacina antiinflamatorios derivados de indometacina-mycinum -micina antibióticos producidos por cepas de Streptomyces-nidazolum -nidazol antiprotozoarios derivados de metronidazol-ololum -olol antagonistas de receptores β-adrenérgicos-oxacinum -oxacino antibacterianos derivados del ácido nalidíxico-platinum -platino antineoplásicos derivados del platino-poetinum -poetina factores sanguíneos similares a la eritropoyetina-pril(at)um -pril(at) inhibidores de la enzima conversora de la angiotensina-profenum -profeno antiinflamatorios derivados del ibuprofenoprost prost prostaglandinas-relinum -relina péptidos estimulantes de la liberación de hormonas hipofisarias-sartanum -sartán antihipertensivos (no peptídicos) antagonistas del receptorde angiotensina II-vaptanum -vaptán antagonistas del receptor de vasopresinavin- vin- ) alcaloides de la vinca-vin- -vin- )218