Nimesulide: Patients Still Exposed to a Risk of Severe Hepatitis

Translated from Rev Prescrire January 2011; 31 (327): 22-23

Nimesulide: patients still exposed to a risk of severe hepatitis

Abstract imesulide, a nonsteroidal anti- Severe liver damage at standard N inflammatory drug (NSAID), has doses, especially in young women. In Nimesulide, a nonsteroidal anti- been on the French market since 2007, the Italian Medicines Agency inflammatory drug (NSAID) that has 1998 (1). It is neither more effective nor released Italian pharmacovigilance data been marketed in France since 1998, is better tolerated than many other showing that hepatic adverse effects rep- neither more effective nor better tol- NSAIDs, and has been shown to cause resented 13.8% of reports implicating erated than other NSAIDs. potentially life-threatening liver da- nimesulide, compared to only 1.4% for mage (1-5). ibuprofen and 2.8% for diclofenac (3). Many reports and reviews published What is known concerning the hepatic The CHMP report published in 2008 by drug regulatory agencies in Spain, adverse effects of nimesulide in early included similar findings. Among the Ireland and Italy have warned of the 2011? 574 reports implicating nimesulide record- hepatic adverse effects of nimesulide. ed in the European EudraVigilance phar- In early 2008, 17 cases of nimesulide- An increasing number of reports of macovigilance database, the proportion of induced liver damage requiring trans- liver damage. Soon after it was first mar- hepatic disorders (cholestasis, jaundice, plantation had been reported in Ire- keted, cases of hepatitis were attributed liver failure, and hepatitis) was higher land, Italy, Spain, Finland and France. to nimesulide, including a case of fulmi- than with cox-2 inhibitors. The report also nant hepatitis (6). The number of reports emphasised that deaths from liver dam- An Italian retrospective study con- increased in all countries where age were more frequent with nime- ducted between 1997 and 2001, includ- nimesulide was sold (1,3,4). sulide (7). The CHMP concluded that ing about 400 000 patients exposed to In 2010, at Prescrire’s request, the nimesulide had an unfavourable risk-ben- NSAIDs, showed that the risk of severe European Committee for Human Medic- efit balance. liver damage was twice as high with inal Products (CHMP) released a report 67% cases of liver damage occurred in nimesulide as with other NSAIDs. on the hepatic adverse effects of women and 39% in patients aged nimesulide (a)(7). between 12 and 55 years (7,13). In 78% The European pharmacovigilance Between 1985 and 29 February 2008, of cases, the daily dose taken was that database shows that nimesulide is 574 cases of hepatic disorders associat- recommended in the summary of product associated with more cases of severe ed with nimesulide were reported, includ- characteristics (SPC) (14). liver damage than other NSAIDs, as ing 17 cases necessitating liver trans- well as more cases of liver damage plantation (6 in Italy, 6 in Ireland, 2 in During the first 15 days of treatment than with cox-2 inhibitors. Finland, 2 in France and 1 in Spain) in one-third of cases. In these (b)(7-10). 574 reports implicating nimesulide, onset Young women are particularly at of adverse effects occurred within 15 days risk. In the vast majority of cases of Twice the risk of severe liver damage in 31% of cases, from 16 to 29 days in liver damage, the dose of nimesulide as with other NSAIDs. A retrospective 14% of cases, and after more than used was that recommended in the study of 397 537 Italians using NSAIDs 30 days in 37% of cases; time to onset summary of product characteristics between 1997 and 2001 showed that the was not known in 18% of cases (8). (SPC). Liver damage occurred within risk of severe liver damage was twice as As expected, even though the maxi- 15 days after taking the first dose of high in patients treated with nimesulide as mum duration of nimesulide prescription nimesulide in one-third of cases. in those using other NSAIDs: the esti- has been limited to 15 days since Sep- mated relative risk adjusted for age and tember 2007, cases of severe hepatitis It is unacceptable that nimesulide gender was 1.9 (95% confidence interval continue to occur (3,7,13). still remains on the market in France (CI) 1.1 to 3.8). The difference was sta- and other countries: reports of severe tistically significant (c)(11). Unknown mechanism. The precise liver damage continue to accumulate, A case-control study conducted mechanism underlying the hepato- and many other therapeutic options between 2001 and 2004, but not published are available. until 2010, showed a statistically significant Rev Prescrire 2011; 31 (327): 22-23. 2.5-fold higher risk of hospitalisation for a- Many sections of this document were blacked out, espe- acute liver damage with nimesulide than cially numerical data (ref 7). b- Nimesulide was withdrawn from the market in Fin- with other NSAIDs, with the exception of land and Spain in 2002, and is no longer available in celecoxib, rofecoxib, diclofenac and Argentina, Belgium, Ireland and Singapore (ref 19). ibuprofen (estimated adjusted relative risk c- Fourteen cases of severe liver damage were reported among patients treated with nimesulide, representing a rate 2.63, 95% CI 1.8 to 3.8) (12). of 29 cases per 100 000 patient-years, versus 15.6 cases per 100 000 with other NSAIDs (ref 11).

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toxicity of nimesulide is unclear (15). inary assessment report” 28 March 2008: 17 pages. Rev Prescrire 2006; 26 (273): 426. 14- 18- A hypersensitivity reaction has been ”Nimesulide containing products EMEA/H/107/ Prescrire Rédaction “Tolcapone remboursable à 871 Preliminary assessment report” 10 September 35 %, et toujours un risque hépatique” Rev Prescrire suggested (13). In addition, the presence 2007: 54 pages. 2006; 16 (275): 575-576. of a nitroaromatic nucleus means that 15- EMEA - CHMP “Assessment report for nime- 19- Prescrire Rédaction “Nimésulide hépatotoxique: nimesulide nitro- sulide containing medicinal products for systemic la Commission européenne recense les greffes pour is chemically similar to use” 18 October 2007: 24 pages. hépatite fulminante au lieu de le retirer du marché” furantoin and tolcapone, both of which are 16- Prescrire Rédaction “Hépatites fulminantes sous and “Point de vue de la Rédaction. Demi-mesures toxic to the liver (15-18). tolcapone” Rev Prescrire 1998; 18 (189): 767. mortelles” Rev Prescrire 2010; 30 (323): 660-661. 17- Prescrire Rédaction “Nitrofurantoïne: atteintes pulmonaires, hépatiques, cutanées, neurologiques” In practice: use another NSAID. It is unacceptable to allow nimesulide to remain on the market in 2011: reports of severe liver damage continue to accumulate and many other valid therapeutic options exist. If paracetamol is inade- Translated from Rev Prescrire December 2010; 30 (326): 910 quately ineffective, oral ibuprofen is the NSAID with the best risk-benefit balance Azathioprine and mercaptopurine: when used at standard doses. ©Review prepared and translated by the Prescrire Editorial Staff lymphoma (no conﬂicts of interest)

Prospective follow-up for a median thioprine or mercaptopurine at the time of Literature search of 35 months of a French cohort of lymphoma diagnosis, 2 patients had pre- 19 486 patients with inflammatory viously taken one of these drugs, and 6 Our literature search was based on contin- uous prospective follow-up at the Prescrire bowel disease showed a nearly 4-fold had never taken either drug. The inci- library, contents listings of the main interna- increase in the risk of lymphoma in dence was 0.9 per 1000 among patients tional journals, Current Contents-Clinical Med- azathioprine azathioprine mercaptopurine icine, member bulletins of the International patients exposed to or taking or Society of Drug Bulletins (ISDB), and sys- mercaptopurine (relative risk 3.75; 95% versus 0.26 per 1000 among patients tematic consultation of clinical pharmacology confidence interval 1.59 to 8.85). never exposed to these drugs. textbooks (Martindale The Complete Drug Ref- erence, Stockley’s Drug Interactions). We also The risk of developing lymphoma was accessed Medline (2007-August week 5, 2010), This risk should be taken into about 4 times higher in patients exposed Embase/Excerpta Medica Drugs and Phar- account when weighing the likely ben- to azathioprine or mercaptopurine than in macology (2007-2010 3rd quarter), Reactions (2007-September 2010) and The Cochrane efits of these drugs in treatment of those who had never taken either drug Library (Central, DARE, HTA, Nhseed; 2010 patients with severe chronic inflam- (relative risk 3.75; 95% confidence inter- issue 6; and CDSR, 2010 issue 3). matory bowel disease no longer val 1.59 to 8.85). After adjustment for 1- Prescrire Rédaction “Nimésulide et hépatites” Rev Prescrire 2002; 22 (228): 356. responding to first-line treatment. variables known to be associated with 2- “Nimesulide“. In: ”Martindale The Complete Rev Prescrire 2010; 30 (326): 910. an increased risk of lymphoma (old age, Drug Reference” The Pharmaceutical Press, Lon- male sex, longer duration of inflammato- don. www.medicinescomplete.com accessed zathioprine 4 November 2010: 6 pages. and its metabolite ry bowel disease), the risk of developing 3- Prescrire Editorial Staff “Nimesulide and hepati- A6-mercaptopurine are immunosup- lymphoma was increased by a factor of 17 tis” Prescrire Int 2008; (93): 12. pressant drugs used to maintain remis- about 5 in patients exposed to azathio- 4- Prescrire Rédaction “Nimésulide: un anti-inflam- matoire non stéroïdien à l’origine d’hépatites sion in patients with chronic inflammato- prine or mercaptopurine (relative risk 5.26; mortelles” Rev Prescrire 2009; 29 (313): 824. ry bowel disease (ulcerative colitis or 95% confidence interval 2.20 to 12.6). 5- Andrade RJ et al. “Fatal hepatitis associated with nimesulide” J Hepatol 2000; 32 (1): 174. Crohn’s disease) (1-3). 6- Prescrire Rédaction “Nimésulide. Un antalgique Immunosuppressants carry an In practice. Azathioprine and mer- AINS sans intérêt particulier” Rev Prescrire 1998; 18 increased risk of infection and cancer in captopurine, like other immunosuppres- (183): 243-245. 7- EMEA - CHMP “Co-rapporteur (Ireland) - Fol- transplant patients (especially lympho- sants, increase the risk of lymphoma. low-up assessment report - EMEA/H/107/871 - ma) (1). This risk should be taken into account Nimesulide-containing medicinal products for sys- Prospective follow-up of a French when weighing the harm-benefit balance temic use” 28 March 2008: 18 pages. 8- EMEA - CHMP “Co-rapporteur (Ireland) - Assess- cohort of 19 486 inflammatory bowel dis- of these drugs in patients with severe ment report - EMEA/H/107/871 – Nimesulide-con- ease patients for a median of 35 months forms of chronic inflammatory bowel dis- taining medicinal products for systemic use”. 9- EMEA - CHMP “Interim assessment report (fol- has provided informative data on the risk ease no longer responding to first-line lowing suspension in accordance with Article 107 of of lymphoma associated with azathio- treatment. Directive 2001/83/EC) - Nimesulide-containing medi- prine and mercaptopurine (4). ©Prescrire cinal products for systemic use” 16 May 2007: 12 pages. 10- Page M et al. “Hépatite fulminante liée à un Risk of lymphoma about 4 times Selected references from Prescrire’s literature traitement par nimésulide: encore un cas et revue higher. At enrolment in this study, de la littérature” Ann Fr Anesth Reanim 2008; 27: search. 742-746. 5867 patients were taking azathioprine or 1- Prescrire Rédaction “10-1. Patients greffés” Rev 11- Traversa G et al. “Cohort study of hepatotoxi- mercaptopurine, 2809 patients had pre- Prescrire 2010; 30 (326 suppl. interactions médica- city associated with nimesulide and other non- menteuses). steroidal anti-inflammatory drugs” BMJ 2003; 327: viously been exposed to these drugs, 2- Prescrire Editorial Staff “Infliximab. Ulcerative 18-22. and 10 810 patients had never taken colitis: caution is needed due to long-term risks” Pres- 16 12- Lee CH et al. “Increased risk of hospitalization either drug. crire Int 2007; (91): 194. for acute hepatitis in patients with previous expo- 3- Prescrire Rédaction “La maladie de Crohn en sure to NSAIDs” Pharmacoepidemiol Drug Saf 2010; During follow-up, 22 patients devel- bref” Rev Prescrire 2000; 20 (205): 250. 19: 708-714. oped non-Hodgkin’s lymphoma and 4- Beaugerie L et al. “Lymphoproliferative disorders 13- in patients receiving thiopurines for inflammatory Afssaps “Nimesulide containing products 1 patient developed Hodgkin’s disease. EMEA/H/107/871 Second list of questions. Prelim- bowel disease: a prospective observational cohort Fifteen of these patients were taking aza- study” Lancet 2009; 374: 1617-1625.

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