Letters to the Editor Benzbromarone withdrawn from Table I. A PubMed search (excluding Japanese papers) for fatal outcome using 4 treatment options: the European market: Another allopurinol, probenecid, benzbromarone, and sulfinpyrazone. case of "absence of evidence is No. of No. of Year of evidence of absence"? Fatal/death papers cases publication Allopurinola 14 14 1970-2001 Sirs, Probenecidb 1 1 1957 Gout, already described by Hippocrates, Benzbromaronec 2 3 1995-2000 has been one of the most curable disorders Sulfinpyrazoned 0 0 1976-2004 of modern rheumatology for years due to European registration status: aFully registered for gout. potent urate lowering therapeutic options. bRegistration previously held by MSD, withdrawn due to lack of profitability in the past, but often applicable on spe- While in only a minority of our rheumato- cial request. logically pre-selected patients xanthine oxi- cUp to 2003, registration in all of Europe, England excluded. From January 2004 registered only in Spain, and in The Netherlands for strict indications only, i.e. for allopurinol intolerant/allergic gouty patients. dRegistration held by dase inhibition by allopurinol lowered Novartis (Anturane®) only in England and Ireland, withdrawn from the market in Spain, not registered in other Euro- serum uric acid (SUA) levels sufficiently to pean countries and therefore generally not applicable. prevent gouty attacks, in non-preselected gouty patients 300 mg allopurinol normal- ized SUAin 85% of patients (1, 2). In most countries neither the uricosuric probenecid J.R.B.J. BROUWERS, Prof. Pharmacotherapy, cases gout is caused by inadequate, low uric nor sulfinpyrazone have been registered for PhD, Clinical pharmacologist acid excretion, explaining why uricosuric the treatment of gout. An alternative regi- 1Department of Rheumatology and Department agents have long been considered the first men was suggested despite the aforemen- of Clinical Pharmacy & Pharmacology, Medical choice treatment option by many but not all tioned reports in the literature (5): allopuri- Centre Leeuwarden, POB 888, 8901 BR nol, on strict indication combined with pro- Leeuwarden, The Netherlands. rheumatologists. Not only for reasons of E-mail: [email protected] pathophysiology in low excretor gout, but benecid. A peculiar advice since probenecid also due to potential hazards associated has not been registered at all in The Nether- References with the combination of azathioprine and lands for the treatment of gout. 1 DAY RO, MINERS JO, BIRKETT DJ et al .: Allop- allopurinol, which is clearly not the case In clinical practice general practitioners and urinol dosage selection: relationships between dose when azathioprine is combined with benz- rheumatologists were left stunned. A lobby and plasma oxypurinol and urate concentrations bromarone. by general practitioners and the Dutch and uinary urate excretion. Br J Clin Pharmacol Association of Rheumatology has therefore 1988; 26: 423-8. Exactly how low should SUA levels be- 2 FAM AG: Hyperuricemia and gout. In RAKEL RE come in order to deplete crystal stores and recently brought our MEB to request the (Ed.): Conn’s Current Therapy, 51st ed., Philadel- prevent attacks (3)? Li-Yu et al. have dem- pharmaceutical company to restart benzbro- phia, W.B. Saunders Co., 1999; 561-6. onstrated that aiming at SUA levels < 0.36 marone production for the Dutch market, 3 LI-YU J, CLAYBURNE G, SIECK M et al.: Treat- mM may be suboptimal (3), but it is often and their request remarkably was granted. ment of chronic gout. Can we determine when urate clinically quite adequate to aim for levels of From January 2004 Dutch gouty patients stores are depleted enough to prevent attacks of again have the opportunity to be treated gout? J Rheumatol 2001; 28: 577-80. < 0.30 mM (2). This is comprehensible 4 ALLEN DJ, MILOSOVICH G, MAT TACKS A M: when studying the chemico-physical data with the potent uricosuric benzbromarone. Inhibition of monosodium urate crystal growth. (4). Perez-Ruiz et al. demonstrated in a I n t e r e s t i n g l y, the registration of benzbro- Arthritis Rheum 1965; 8: 1123. head-to-head comparison that allopurinol is marone only has been granted for cases 5 PEREZ-RUIZ F, ALONSO-RUIZ, CALABOZO M et inferior to benzbromarone in reducing SUA with allopurinol intolerance. But generally al.: Efficacy of allopurinol and benzbromarone for (5). We found similar results in 85 gout pa- allopurinol is well tolerated; only in about the control of hyperuricemia. A p a t h o g e n i c 2% of cases, in particular elderly individu- approach to the treatment of primary chronic gout. tients: SUA levels < 0.30 mM are reached Ann Rheum Dis 1998; 57: 545-9. in 79% by benzbromarone monotherapy als with renal dysfunction, is a pruritic mac- 6 VAN DE KLAUW MM, HOUTMAN PM, STRICK- (100 mg daily), and in just 10% by allopuri- ulopapular eruption with or without fever ER BH et al.: Hepatic injury caused by benzbro- nol monotherapy (200 mg daily). This may and facial/tongue swelling encountered. marone. J Hepatol 1994; 20: 276-9. explain why in Europe we all were quite Only for this small group of gout patients 7 L O C U S O N C W, WAHLSTROM JL, ROCK D A e t will benzbromarone be an option once al.: A new class of CYP2C9 inhibitors: probing 2C9 happy with benzbromarone. specificity with high affinity benzbromarone deriv- Therefore, why was there a sudden with- again according to Sanofi and the Nether- atives. Drug Metab Dispos 2003; 31: 967-71. drawal of this compound from the Europe- lands MEB. an market in 2003? Did Sanofi-Synthelabo Why did our European MEBs agree so easi- fear a lawsuit? Or was it due to the lack of ly with the pharmaceutical company’s re- Polymyositis associated with commercial profitability? quest to stop a generally safe treatment op- HIV infection during immune tion? Medico-legal and commercial reasons A PubMed search for fatal outcomes with restoration induced by highly the main urate lowering treatment options must cross our minds. One could speculate provides us no significant clue (Table I). about a novel class of benzbromarone deri- active anti-retroviral therapy There are only sporadic reports of hepatic vatives on the horizon (7), as the commer- failure secondary to benzbromarone (6); the cial profitability of benzbromarone may be Sirs, incidence was about 2 cases per 400 million low. If the pharmaceutical company is dri- Polymyositis associated with human immu- Europeans, i.e. 1:100,000 benzbromarone ven to prevent potential claims in the future, nodeficiency virus (HIV) infection was first prescriptions. Was this the argument for then other companies might follow a simi- described in 1983, and many reports in the Sanofi-Synthelabo, which owns the patent lar procedure. This case could serve as a past several years have confirmed this path- and therefore has a monopolist position warning for our European MEBs not to ologic association (1, 2). It usually occurs with regard to benzbromarone, to stop its bury older drugs before breeding new baby early in the course of HIV disease, but may production? In April 2003 the Netherlands drugs. presents at all stages, has a relatively good Medicine Evaluation Board (MEB) agreed prognosis, responds well to immunosup- T.L . T H.A. JAN S E N , MD, PhD, Rheumatologist1 pressive therapy, and has little evidence of with the request by Sanofi to stop benzbro- M.K. REINDERS, Pharm. D, Hospital pharma marone production for the Dutch market, adverse outcome on the HIV infection (3, cist in training 4). However, it is often difficult to distin- which took place simultaneously in most E.N. VAN ROON, Pharm. D, Clinical pharma European countries. In most European cologist guish HIV-related polymyositis from myo-

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