Indian Journal of Pharmacology 2003; 35:

121-122

CORRESPONDENCE

NIMESULIDE: THE CURRENT CONTROVERSY

Nimesulide, a non-steroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic effects, was first launched in Italy in 1985. Since then it has been aggressively marketed in about 50 countries throughout the world and still commands a fair share of the NSAID market in the countries, where it continues to be sold. Though nimesulide is a preferential COX-2 inhibitor and therefore, assumed to be safer in clinical use, its gastrointestinal tolerance has not been proven to be superior to other NSAIDs because "various epidemiological studies give little weight to the hypothesis that selective inhibition of COX-2 may have a sparing effect on the GI Tract" 1. Some postmarketing surveillance studies confirmed the tolerability profile of nimesulide 2. Companies marketing this drug like M/s Wander Limited in its product literature even claimed that it was "devoid of common side effect of gastrointestinal ulceration encountered with the use of NSAIDs". The hype generated about efficacy and tolerability of nimesulide ensured that its sales picked up, leaving the other NSAIDs behind. Dr Reddy's Laboratories' brand became popular to take the leading position in OTC sales. Why the current controversy ? Nimesulide was aggressively promoted in India and attained the top position as anti-pyretic in private practice. But recently the status of nimesulide became questionable following reports of fatal adverse drug reactions (ADR). The National Pharmacovigilance Centre (CNF, Portugal) from 1993 to 99, received 17 ADR reports of nimesulide, which included skin (five), hepatic (four), peripheral edema (two), stomatitis (two), paraesthesia (one), thrombocytopenic purpura (one), irritability (one) and headache/reduced visual acuity in (one). The ADRs relating to skin were rash in three, urticaria/ angioedema in one and necrotising fasciitis in one, which evolved to septicemia and death. From the hepatic ADRs, two which occurred in children were compatible with Reyes syndrome and both resulted in fatality. Also seen was one case of cholestasis and

another of liver enzyme elevation and coagulopathy, the later being fatal3. Another report informed three cases of fixed drug eruptions with nimesulide4. Nimesulide induced liver injury gained investigative interest and was found to present with hepatocellular necrosis or cholestasis. Many cases of nimesulide induced hepatotoxicity have been reported5, some of which have been fatal6. Patients with liver toxicity had the hallmark of hypersensitivity with an increase in blood and tissue eosinophilia. From clinical and histological data, it appears that both immunological and metabolic idiosyncratic reactions can be involved as the pathogenetic mechanism of nimesulide induced liver disease. Even if the risk of hepatotoxicity is small and fatality rare, nimesulide use for fever particularly in children cannot be justified when a safer alternative like paracetamol is available. Neonatal renal failure following the use of nimesulide has been reported7. Not many of the doctors are aware of the fact that due to its toxicity, ADRs and suspected danger, nimesulide has never been licensed for use in developed economies like US, Canada, UK, Australia, New Zealand and Scandinavian countries. Small countries like Portugal, Israel and our neighbours SriLanka and Bangladesh have shown the guts and grit to withdraw the drug. Nimesulide was withdrawn in 2002 by the innovator, Boehringer from Spain and Finland. The European Union has recently issued a precautionary advice on the marketing of this drug following serious complications after its use. Medical activists highlighted the rampant misuse and overuse of nimesulide, and its ADRs leading to fatalities in children through various media, including cable TV. Letters appeared in press warning the nimesulide users of its toxicity8. It is a matter of great concern that while other countries banned the sale of this drug, the Drug Controller-General of India (DCGI) merely ordered a review of this drug. The DCGI has gone on record to admit that due to powerful commercial interests, it might be difficult to get objective answers even from doctors. True to the anticipated fears, Delhi Medical Association has declared nimesulide safe9! Criticising this act of DMA, leading paediatricians and neonatologists of India have questioned the validity of this survey from 50 doctors of Delhi who gave clean chit to nimesulide.

122

CORRESPONDENCE

Editor of Monthly Index of Medical Specialities (MIMS) has rightly pointed that ADR monitoring is not done by any professional body of doctors in the world 10 . Industrial interests surely prevail over professional ethics and obligations. Following the recent communication from the DCGI to various industry, consumer and professional bodies to be part of the review committee for nimesulide, it has been reported in the news that Dr. Reddys Laboratories whose branded nimesulide reportedly accounts for about 40-45 percent share of Rs 190 crore domestic market, is believed to have withdrawn its paediatric preparation of nimesulide from the market 11. If this is really true, we appreciate the concern of this company and hope others will follow suit. Most of the drug research is funded by the pharmaceutical industry. However let not the ADR monitoring be dictated by the manufacturers of drug, suspected to cause ADR. If this does not happen, the truthful reporting will never occur because of the vested interest of the powerful industry lobby. More disturbing is the influence, when organized gang of 50 private practitioners opines in favour of the dangerous drug and their opinion is considered to let the drug thrive in largest democracy, against the global rejection. While the leading countries of the world have not allowed / banned or withdrawn the drug, the opinion of a mere fifty private doctors has tilted the scale towards allowing the drug to continue to be marketed in India! It is also a matter of great sorrow that matters relating to serious and fatal ADRs of drugs are discussed in the media first and not in scientific bodies. Because we continue to miserably fail in taking a stand, the media continues to lead and beat us. No wonder that 50 organized private practitioners have succeeded in brain washing those who finally matter. At least they had the courage to say, even if wrong.

V. THAWANI, S. SONTAKKE, K. GHARPURE, S. PIMPALKHUTE Department of Pharmacology, Government Medical College, Nagpur-440 003. e-mail: thawani@nagpur.dot.net.in REFERENCES
1. Jouzeau JY, Terlain B, Abid A, Nedelec E, Netter P. Cyclooxygenase isoenzymes : how recent findings affect thinking about nonsteroidal antiinflammatory drugs. Drugs 1997;53: 563-82. Pochobradsky MG, Mele G, Beretta A. Postmarketing survey of nimesulide in the short term treatment of osteoarthritis. Drugs Exper Clin Res 1991;17:197-204. World Health Organisation. Nimesulide Adverse Reactions reported to the CNF. WHO ADR Newsletter 1999;2:6. Cordeiro MR, Goncalo M, Fernandes B. Nimesulide : Fixed drug eruption: 3 case reports. Contact Dermatitis 2000; 43:307. Dourakis SP, Sevastianos VA, Petraki K, Hadziyannis SJ. Nimesulide-induced acute icteric hepatitis. Society for Medical Studies 2001;79:3. Schattner A, Sokolovskaya N, Cohen J. Fatal hepatitis and renal failure during treatment with nimesulide. J Int Med 2000;247:153-5. Balasubramaniam J. Nimesulide and neonatal renal failure. Lancet 2000;355:575. Thawani V. Nimesulide, a dangerous drug. The Hitavada (Nagpur) 2002 Oct 15; p 8. Jain K. Controversial drug may get government consent. Times of India (Mumbai) 2002 Dec 17; p 7.

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10. Jain K. Doctors question IMA survey on nimesulide. Times of India (Mumbai) 2003 Jan 14; p 1. 11. Rajwadkar K. Paediatric nimesulide withdrawn from market. Nagpur: The Indian Express (Nagpur) 2003 Jan 2; p 13.

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