Generic Immunosuppressants in the Specialist Area of Transplantation Consensus on Implications and Practical Recommendations

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1 Dear Clleague Generic Immunsuppressants in the Specialist Area f Transplantatin Cnsensus n Implicatins and Practical Recmmendatins Executive Summary Slid-rgan transplants are the best pssible treatment fr mst peple with rgan failure, but the survival f the graft and frequently the patient depends n treatment with immunsuppressive medicatin t prevent rejectin f the transplanted rgan. Fllwing patent expiries, the last tw years has seen the intrductin f an unprecedented number f generic immunsuppressants ntably fr ciclsprin, tacrlimus and mycphenlate mfetil fr use in transplantatin. When used apprpriately in the specialist transplant setting, generic immunsuppressants culd help reduce NHS csts. Hwever, the prime cncern fr all stakehlders including transplant specialists, GPs, specialist hspital and cmmunity pharmacists, and cmmissiners must be t ensure patient safety by aviding inadvertent switching frm immunsuppressant frmulatins n which patients have been stabilised by their transplant unit. Such medicatin errrs nt nly risk ptentially serius cnsequences fr patients in terms f drug txicity r graft rejectin 1-3, but the financial cst f such cmplicatins culd als utweigh any ptential savings fr the NHS resulting frm the intrductin f generic immunsuppressants. The situatin is particularly cmplicated in paediatric patients, wh may be n varius capsule, liquid and granule frmulatins f their different immunsuppressants. The ptential fr medicatin errrs within such regimens is even mre acute. Despite previus warnings cncerning the ptential dangers fr transplant patients 4-7, inadvertent medicatin switches are still ccurring, especially in the cmmunity setting. Fr this reasn, we believe that it is essential t reinfrce current advice by issuing clear, succinct and practical recmmendatins that can be universally applied: 1

2 1. The nly practical way t ensure safety f transplant patients, bth adults and children, is fr any change in immunsuppressant treatment t be initiated in secndary care under specialist medical supervisin, with apprpriate mnitring. 2. All prescriptins, and related crrespndence, shuld specify the brand n which the patient is stabilised, the dse and the frequency be it the riginatr brand r a generic immunsuppressant. 3. Everyne in a psitin t influence safe prescribing f immunsuppressants, frm transplant cnsultants thrugh t the patients themselves, shuld be aware f these recmmendatins and seek t reinfrce their implementatin. Backgrund licensing f generics Generic prducts are nt licensed n the basis f clinical assessment in the relevant patient grup, but n simple biequivalence assessment, generally in a small number f healthy vlunteers. Thus licensed biequivalence des nt autmatically mean clinical equivalence in practice 8. There may be n implicatins fr patient safety when switching between branded and generic versins f many drugs in cmmn use. But there are special cnsideratins when using immunsuppressants in transplant patients. Nt nly is it critical t avid any risk t the patient and the graft that may result frm inadvertent medicatin switches, but it is als imprtant t avid ptential drug-drug interactins in patients stabilised n medicatins fr c-existing cnditins. Backgrund evidence in practice f risks t patient safety Marked differences have been reprted between different frmulatins in clinical practice, including: Need fr dsage changes fllwing a switch between frmulatins, t maintain apprpriate bld levels which necessitates additinal patient mnitring 1. Increase in bipsy-prven acute rejectins which will require active patient management 2 Reduced lng-term graft survival, which culd mean a return t dialysis, the need fr repeat transplantatin r death 3. Backgrund ciclsprin, tacrlimus and MMF/ECMPS Ciclsprin is a calcineurin inhibitr (CNI). It is well established that it is a preeminent example f a critical dse drug, and cnsequently shuld always be prescribed and dispensed by brand Tacrlimus is, like ciclsprin, a CNI and a critical dse drug. As well as recently intrduced immediate-release generic versins, the riginating cmpany has prduced different immediate-release and prlnged release frmulatins. It is a particular cause fr cncern that sme f these riginal and generic brand names sund very similar. Fr example, by the end f February 2010, the MHRA had 2

3 received 12 case reprts invlving prescribing/dispensing errrs in assciatin with the riginating manufacturer s frmulatins f ral tacrlimus. Sme f these had serius cnsequences such as acute rejectin 9. Mycphenlate mfetil (MMF) is frm a different class, that f the prliferatin inhibitrs. It is imprtant t nte that anther frm f mycphenlate is available as enteric-cated mycphenlate sdium (ECMPS). Since MMF is nt interchangeable with ECMPS, it is essential t differentiate between the tw drugs when prescribing and dispensing. (The patent n ECMPS has als nt expired, and hence n generic versins are available.) Backgrund csts f transplantatin in cntext Slid rgan transplantatin is highly cst-effective fr the NHS 10. Fr example, 3% f the NHS budget is currently spent n treatment fr kidney failure. The average cst f kidney dialysis is 30,800 per patient per year. This cmpares with the indicative ne-ff cst f 17,000 fr a kidney transplant, with csts fr immunsuppressin f 5000 per patient per year. As a result, ver 10 years (the median transplant survival time) kidney transplantatin saves the NHS 241,000 r 24,100 per year fr each year that the patient has a functining graft. Acute rejectin that may result frm inadvertent medicatin switches clearly negates these cst savings if it leads t a return t dialysis. But successful treatment f acute rejectin is als expensive, csting anything frm circa 8,000 t 20,000 t manage, depending n whether r nt a patient respnds t sterids r requires mre expensive antibdy therapy. Cnclusin Ptential cst savings derived frm substitutin f generic immunsuppressants in transplantatin must be weighed against risks t patient safety and the csts t the NHS arising frm inadvertent switching. Given past evidence f serius medicatin errrs, the nly practical way t ensure patient safety is fr these immunsuppressants, including new generic versins, t be initiated nly within the specialist hspital setting, with apprpriate mnitring, and fr all prescriptins and crrespndence relating t that treatment t specify the brand n which the patient is stabilised be it the riginatr brand r a generic. 3

4 References 1. Qazi YA et al. The clinical impact f 1:1 cnversin frm Neral t a generic cyclsprine (Gengraf) in renal transplant recipients with stable graft functin. Clin.Transplant 2006; 20(3): Taber DJ et al. Des Biequivalence Between Mdified Cyclsprine Frmulatins Translate int Equal Outcmes? Transplantatin 2005; 80(11): Stlyarevich ES et al. Pharmackinetic characteristics and clinical efficacy f generic cyclsprine frmulatins cmpared t Sandimmun Neral. Pster presented at the Wrld Transplant Cngress, Bstn, July 27 th 2006, Abstract N News dated 30 th Nvember Accessed June 28 th News dated 15 th December Accessed June 28 th Accessed June 28 th Guidelines 3.12 t Accessed June 28 th Jhnstn A et al. Ptential clinical implicatins f substitutin f generic cyclsprine frmulatins fr cyclsprine micremulsin (Neral) in transplant recipients. Eur. J. Clin. Pharmacl. 2004; 60: Accessed 28 th June UK Transplant Fact Sheet The cst-effectiveness f transplantatin. Accessed June 28 th

5 Appendix As at the date f this dcument (August 2011), the fllwing riginatr brands and generics f ciclsprin, tacrlimus and the mycphenlates were available. Active ingredient Original brand(s) Generics Ciclsprin Neral Capimune, Deximune Tacrlimus Mycphenlate mfetil (MMF) Enteric cated mycphenlate sdium (ECMPS) Prgraf (immediate release frmulatin, taken twice a day) Advagraf (sustained release, taken nce a day) Mdigraf (granules) Cellcept Myfrtic NB: all generics are immediate release Adprt, Vivadex, Tacni Arzip Unbranded MMF versins als frm: Mylan, Dr Reddy, Sandz, Teva N generic available 5