BNF for Children 2011-2012

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