PRESCRIRE INTERNATIONAL MAY 2011/VOLUME 20 N 116 PAGE 125

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

Nimesulide: patients still exposed to a risk of severe hepatitis

Nimesulide, a nonsteroidal anti-inflammatory drug (NSAID) that hasbeen marketed in France since 1998, isneither more effective nor better tol-erated than other NSAIDs.

Many reports and reviews publishedby drug regulatory agencies in Spain,Ireland and Italy have warned of thehepatic adverse effects of nimesulide.In early 2008, 17 cases of nimesulide-induced liver damage requiring trans-plantation had been reported in Ire-land, Italy, Spain, Finland and France.

An Italian retrospective study con-ducted between 1997 and 2001, includ-ing about 400 000 patients exposed toNSAIDs, showed that the risk of severeliver damage was twice as high withnimesulide as with other NSAIDs.

The European pharmacovigilancedatabase shows that nimesulide isassociated with more cases of severeliver damage than other NSAIDs, aswell as more cases of liver damagethan with cox-2 inhibitors.

Young women are particularly atrisk. In the vast majority of cases ofliver damage, the dose of nimesulideused was that recommended in thesummary of product characteristics(SPC). Liver damage occurred within15 days after taking the first dose ofnimesulide in one-third of cases.

It is unacceptable that nimesulidestill remains on the market in Franceand other countries: reports of severeliver damage continue to accumulate,and many other therapeutic optionsare available.

Rev Prescrire 2011; 31 (327): 22-23.

N imesulide, a nonsteroidal anti-inflammatory drug (NSAID), hasbeen on the French market since1998 (1). It is neither more effective norbetter tolerated than many otherNSAIDs, and has been shown to causepotentially life-threatening liver da-mage (1-5).

What is known concerning the hepaticadverse effects of nimesulide in early2011?

An increasing number of reports ofliver damage. Soon after it was first mar-keted, cases of hepatitis were attributedto nimesulide, including a case of fulmi-nant hepatitis (6). The number of reportsincreased in all countries where nimesulide was sold (1,3,4).

In 2010, at Prescrires request, theEuropean Committee for Human Medic-inal Products (CHMP) released a reporton the hepatic adverse effects of nimesulide (a)(7).

Between 1985 and 29 February 2008,574 cases of hepatic disorders associat-ed with nimesulide were reported, includ-ing 17 cases necessitating liver trans-plantation (6 in Italy, 6 in Ireland, 2 inFinland, 2 in France and 1 in Spain)(b)(7-10).

Twice the risk of severe liver damageas with other NSAIDs. A retrospectivestudy of 397 537 Italians using NSAIDsbetween 1997 and 2001 showed that therisk of severe liver damage was twice ashigh in patients treated with nimesulide asin those using other NSAIDs: the esti-mated relative risk adjusted for age andgender was 1.9 (95% confidence interval(CI) 1.1 to 3.8). The difference was sta-tistically significant (c)(11).

A case-control study conductedbetween 2001 and 2004, but not publisheduntil 2010, showed a statistically significant2.5-fold higher risk of hospitalisation foracute liver damage with nimesulide thanwith other NSAIDs, with the exception ofcelecoxib, rofecoxib, diclofenac andibuprofen (estimated adjusted relative risk2.63, 95% CI 1.8 to 3.8) (12).

Severe liver damage at standarddoses, especially in young women. In2007, the Italian Medicines Agencyreleased Italian pharmacovigilance datashowing that hepatic adverse effects rep-resented 13.8% of reports implicatingnimesulide, compared to only 1.4% foribuprofen and 2.8% for diclofenac (3).

The CHMP report published in 2008included similar findings. Among the574 reports implicating nimesulide record-ed in the European EudraVigilance phar-macovigilance database, the proportion ofhepatic disorders (cholestasis, jaundice,liver failure, and hepatitis) was higherthan with cox-2 inhibitors. The report alsoemphasised that deaths from liver dam-age were more frequent with nime-sulide (7). The CHMP concluded thatnimesulide had an unfavourable risk-ben-efit balance.

67% cases of liver damage occurred inwomen and 39% in patients agedbetween 12 and 55 years (7,13). In 78%of cases, the daily dose taken was thatrecommended in the summary of productcharacteristics (SPC) (14).

During the first 15 days of treatmentin one-third of cases. In these574 reports implicating nimesulide, onsetof adverse effects occurred within 15 daysin 31% of cases, from 16 to 29 days in14% of cases, and after more than30 days in 37% of cases; time to onsetwas not known in 18% of cases (8).

As expected, even though the maxi-mum duration of nimesulide prescriptionhas been limited to 15 days since Sep-tember 2007, cases of severe hepatitiscontinue to occur (3,7,13).

Unknown mechanism. The precisemechanism underlying the hepato-

Abstract

a- Many sections of this document were blacked out, espe-cially numerical data (ref 7).b- Nimesulide was withdrawn from the market in Fin-land and Spain in 2002, and is no longer available inArgentina, Belgium, Ireland and Singapore (ref 19).c- Fourteen cases of severe liver damage were reportedamong patients treated with nimesulide, representing a rateof 29 cases per 100 000 patient-years, versus 15.6 cases per100 000 with other NSAIDs (ref 11).

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toxicity of nimesulide is unclear (15).A hypersensitivity reaction has been suggested (13). In addition, the presenceof a nitroaromatic nucleus means thatnimesulide is chemically similar to nitro-furantoin and tolcapone, both of which aretoxic to the liver (15-18).

In practice: use another NSAID. It isunacceptable to allow nimesulide toremain on the market in 2011: reports ofsevere liver damage continue to accu-mulate and many other valid therapeuticoptions exist. If paracetamol is inade-quately ineffective, oral ibuprofen is theNSAID with the best risk-benefit balancewhen used at standard doses.

Review prepared and translated by the Prescrire Editorial Staff

(no conicts of interest)

Our literature search was based on contin-uous prospective follow-up at the Prescrirelibrary, contents listings of the main interna-tional journals, Current Contents-Clinical Med-icine, member bulletins of the InternationalSociety of Drug Bulletins (ISDB), and sys-tematic consultation of clinical pharmacologytextbooks (Martindale The Complete Drug Ref-erence, Stockleys Drug Interactions). We alsoaccessed Medline (2007-August week 5, 2010),Embase/Excerpta Medica Drugs and Phar-macology (2007-2010 3rd quarter), Reactions(2007-September 2010) and The CochraneLibrary (Central, DARE, HTA, Nhseed; 2010issue 6; and CDSR, 2010 issue 3).1- Prescrire Rdaction Nimsulide et hpatites RevPrescrire 2002; 22 (228): 356.2- Nimesulide. In: Martindale The CompleteDrug Reference The Pharmaceutical Press, Lon-don. www.medicinescomplete.com accessed4 November 2010: 6 pages. 3- Prescrire Editorial Staff Nimesulide and hepati-tis Prescrire Int 2008; 17 (93): 12.4- Prescrire Rdaction Nimsulide: un anti-inflam-matoire non strodien lorigine dhpatitesmortelles Rev Prescrire 2009; 29 (313): 824.5- Andrade RJ et al. Fatal hepatitis associated withnimesulide J Hepatol 2000; 32 (1): 174.6- Prescrire Rdaction Nimsulide. Un antalgiqueAINS sans intrt particulier Rev Prescrire 1998; 18(183): 243-245.7- EMEA - CHMP Co-rapporteur (Ireland) - Fol-low-up assessment report - EMEA/H/107/871 -Nimesulide-containing medicinal products for sys-temic use 28 March 2008: 18 pages. 8- EMEA - CHMP Co-rapporteur (Ireland) - Assess-ment report - EMEA/H/107/871 Nimesulide-con-taining medicinal products for systemic use. 9- EMEA - CHMP Interim assessment report (fol-lowing suspension in accordance with Article 107 ofDirective 2001/83/EC) - Nimesulide-containing medi-cinal products for systemic use 16 May 2007:12 pages.10- Page M et al. Hpatite fulminante lie untraitement par nimsulide: encore un cas et revuede la littrature Ann Fr Anesth Reanim 2008; 27:742-746.11- Traversa G et al. Cohort study of hepatotoxi-city associated with nimesulide and other non-steroidal anti-inflammatory drugs BMJ 2003; 327:18-22.12- Lee CH et al. Increased risk of hospitalizationfor acute hepatitis in patients with previous expo-sure to NSAIDs Pharmacoepidemiol Drug Saf 2010;19: 708-714.13- Afssaps Nimesulide containing productsEMEA/H/107/871 Second list of questions. Prelim-

Literature search

PAGE 126 PRESCRIRE INTERNATIONAL MAY 2011/VOLUME 20 N 116

Adverse Effects

Translated from Rev Prescrire December 2010; 30 (326): 910

Azathioprine and mercaptopurine:lymphoma

Prospective follow-up for a medianof 35 months of a French cohort of19 486 patients with inflammatorybowel disease showed a nearly 4-foldincrease in the risk of lymphoma inpatients exposed to azathioprine ormercaptopurine (relative risk 3.75; 95%confidence interval 1.59 to 8.85).

This risk should be taken intoaccount when weighing the likely ben-efits of these drugs in treatment ofpatients with severe chronic inflam-matory bowel disease no longerresponding to first-line treatment.

Rev Prescrire 2010; 30 (326): 910.

Azathioprine and its metabolite 6-mercaptopurine are immunosup-pressant drugs used to maintain remis-sion in patients with chronic inflammato-ry bowel disease (ulcerative colitis orCrohns disease) (1-3).

Immunosuppressants carry anincreased risk of infection and cancer intransplant patients (especially lympho-ma) (1).

Prospective follow-up of a Frenchcohort of 19 486 inflammatory bowel dis-ease patients for a median of 35 monthshas provided informative data on the riskof lymphoma associated with azathio-prine and mercaptopurine (4).

Risk of lymphoma about 4 timeshigher. At enrolment in this study,5867 patients were taking azathioprine ormercaptopurine, 2809 patients had pre-viously been exposed to these drugs,and 10 810 patients had never takeneither drug.

During follow-up, 22 patients devel-oped non-Hodgkins lymphoma and1 patient developed Hodgkins disease.Fifteen of these patients were taking aza-

thioprine or mercaptopurine at the time oflymphoma diagnosis, 2 patients had pre-viously taken one of these drugs, and 6had never taken either drug. The inci-dence was 0.9 per 1000 among patientstaking azathioprine or mercaptopurineversus 0.26 per 1000 among patientsnever exposed to these drugs.

The risk of developing lymphoma wasabout 4 times higher in patients exposedto azathioprine or mercaptopurine than inthose who had never taken either drug(relative risk 3.75; 95% confidence inter-val 1.59 to 8.85). After adjustment forvariables known to be associated withan increased risk of lymphoma (old age,male sex, longer duration of inflammato-ry bowel disease), the risk of developinglymphoma was increased by a factor ofabout 5 in patients exposed to azathio-prine or mercaptopurine (relative risk 5.26;95% confidence interval 2.20 to 12.6).

In practice. Azathioprine and mer-captopurine, like other immunosuppres-sants, increase the risk of lymphoma.This risk should be taken into accountwhen weighing the harm-benefit balanceof these drugs in patients with severeforms of chronic inflammatory bowel dis-ease no longer responding to first-linetreatment.

Prescrire

Selected references from Prescrires literaturesearch.1- Prescrire Rdaction 10-1. Patients greffs RevPrescrire 2010; 30 (326 suppl. interactions mdica-menteuses). 2- Prescrire Editorial Staff Infliximab. Ulcerativecolitis: caution is needed due to long-term risks Pres-crire Int 2007; 16 (91): 194.3- Prescrire Rdaction La maladie de Crohn enbref Rev Prescrire 2000; 20 (205): 250.4- Beaugerie L et al. Lymphoproliferative disordersin patients receiving thiopurines for inflammatorybowel disease: a prospective observational cohortstudy Lancet 2009; 374: 1617-1625.

inary assessment report 28 March 2008: 17 pages.14- Nimesulide containing products EMEA/H/107/871 Preliminary assessment report 10 September2007: 54 pages.15- EMEA - CHMP Assessment report for nime-sulide containing medicinal products for systemicuse 18 October 2007: 24 pages.16- Prescrire Rdaction Hpatites fulminantes soustolcapone Rev Prescrire 1998; 18 (189): 767.17- Prescrire Rdaction Nitrofurantone: atteintespulmonaires, hpatiques, cutanes, neurologiques

Rev Prescrire 2006; 26 (273): 426.18- Prescrire Rdaction Tolcapone remboursable 35 %, et toujours un risque hpatique Rev Prescrire2006; 16 (275): 575-576.19- Prescrire Rdaction Nimsulide hpatotoxique:la Commission europenne recense les greffes pourhpatite fulminante au lieu de le retirer du marchand Point de vue de la Rdaction. Demi-mesuresmortelles Rev Prescrire 2010; 30 (323): 660-661.

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