An analysis of serious hepatotoxic side effects registered with World Health Organization indicates that Nimesulide has the highest rate of side effects amongst non-steroidal anti-inflammatory drugs (NSAIDs).
This has been revealed by Swiss researchers who treated a 57-year-old woman patient with chronic lumbago who died of acute liver failure induced by Nimesulide.
Nimesulide has been a subject of controversy regarding its safety and side-effects for the last few years. The drug is used for long periods by patients of osteo-arthritis and rheumatoid arthritis. NSAIDs, as a class, is infamous for its hepatic side-effects.
The analysis was done on unsolicited reports reaching the World Health Organisation in relation to the total number of hepatic side-effects in relation to the total number of reported side-effects for any NSAID.
Nimesulide induces a high proportion of severe adverse hepatic reactions compared with other NSAIDs registered in Switzerland. Researchers of Zurich's University Hospital say that hepatotoxicity represents an important risk factor in nimesulide usage.
Similar to meloxicam, Nimesulide is classified as a preferential COX-2 inhibitor, but is not as a highly selective COX-2 inhibitor like rofecoxib. NSAIDs are established and important hepatotoxins.
According to the researchers, there have been 597 reported cases of nimesulide toxicity of which 42 (7 per cent) were hepatic. If one assumes that the total number of reports approximately reflects the relative prescription frequencies, the odds ratio for hepatotoxicity induced by nimesulide relative to ibuprofen is 6.4.
This means patients treated by nimesulide are 6.4 times more likely than those prescribed ibuprofen to experience drug-induced liver disease. The odds ratio for nimesulide is also statistically higher than for sulindac and diclofenac, two other NSAIDs associated with an increased probability of hepatotoxicity.
However, the Swiss researchers add a word of caution as these reports are unsolicited and may be influenced by factors such as reporting bias of medical professionals.
The mechanism of liver-induced disease is unknown, according to the Swiss researchers. Nimesulide is extensively metabolized in the liver. Nimesulide-induced hepatocellular damage usually presents with necrosis in the centrilobular region. Although at present speculative, a certain genetic predisposition could favour the production of abnormal metabolites which either exert a toxic effect directly or induce an immunological reaction.
Israeli researchers, who have also studied the drug, say drug-induced acute hepatitis is a well-recognised adverse effect of many drugs, including nimesulide. Identification of a drug as a cause for this life-threatening disease is important because the discontinuation of it may be life-saving.
A 54-year-old Arabic woman treated with nimesulide for chronic back pain was admitted to the hospital with acute hepatitis confirmed by biopsy. Her liver function test results returned to normal within one month after nimesulide discontinuation. An in-vitro lymphocyte toxicity assay confirmed that the liver injury was due to nimesulide exposure.
According to the researchers, although the occurrence of clinically significant liver damage due to NSAIDs is low, the increased consumption of these drugs can cause liver damage. Nimesulide can cause a wide range of liver injuries, from mild abnormal liver function to severe liver injuries. These effects are usually reversible on discontinuation of the drug, but occasionally.
The researchers say that clinicians must always keep in mind this drug as a cause when faced with a patient with unexplained liver injury, and perhaps, more importantly, monitor liver enzymes after initiating this drug.
The report which appeared in the September issue of "The Annals of Pharmacotherapy" confirms the occurrence of nimesulide-induced hepatitis. It also highlights the importance of monitoring liver function test results after initiating therapy with such a drug.
These researchers say that nimesulide, a relatively new NSAID, is widely prescribed in Europe, especially in Italy. It has a selective affinity to cyclooxgenase type 2 (COX-2), and a low gastrointestinal adverse effect profile.
Nimesulide has a therapeutic effect similar to that of celecoxib and rofecoxib, but is not yet available in the US. Nimesulide may cause asymptomatic liver enzyme abnormalities. Most serious toxicities in the form of acute hepatocellular necrosis or acute cholestatic hepatitis have been reported, they said.
As a sulphonanilide analogue, Helsinn says it is not related to conventional NSAIDs, which usually present a carboxyl or hydroxyl functional group. Helsinn claims nimesulide is proved safe and effective in the treatment of a wide range of inflammatory and painful conditions, including osteoarthritis, extra-articular disorders such as tendinitis and bursitis, post-operative pain, primary dysmenorrhoea.
The therapeutic effects of nimesulide are the result of its complete mode of action which targets a number of key mediators of the inflammatory process: COX-2 mediated prostaglandins, free radicals and proteolytic enzymes, histamine.
According to Helsinn, the Swiss pharmaceutical company which holds the worldwide rights for the commercialisation of Nimesulide, it is a non-steroidal anti-inflammatory analgesic and antipyretic drug with a specific mode of action.
Nimesulide, discovered by Riker 3M, is currently marketed in 44 countries under different brand names.
Nimesulide has annual sales of Rs 190 crore in India with as many as 84 brands. The turnover does not include 19 nimesulide combinations. The number of generic nimesulides available is not known, but could be even more, considering the ease with which it is prescribed.
According to an industry source, the nimesulide oral annual sales in India account for Rs 14.63 crore with an annual growth of 2.8 per cent while the liquid version has a higher sales at Rs 21.70 crore and a growth of 13.8 per cent. The liquid dosages are meant for children but side effects are unlikely as it is taken for a short period, an industry source said, adding that Portugal had banned the drug for use in children.
"The number of adverse reports associated with nimesulide usage are on the rise of late. The potential for hepatic adverse events following exposure to nimesulide is an ongoing concern. A report revealed that two hepatic failures proved to be fatal following nimesulide usage. In addition, nimesulide, when combined with amoxicillin and clavulanate, potentiates the hepatic dysfunction induced by any of these drugs," warned a December 1999 newsletter of the National Pharmacovigilance Centre at the Department of Pharmacology of the All India Institute of Medical Sciences which was published in the WHO ADR Newsletter.
According to an April 1999 report in the Scrip, Infarmed, the Portuguese Pharmacy and Medicines Institute, had suspended paediatric presentations of Nimesulide after that country's National Pharmacovigilance Centre (CNF) received serious ADR reports which also included hepatic reactions. There were three fatal cases in that country where four brands of the NSAID are available apart from Helsinn's own Aulin. Though it is difficult to establish a definite causal link with the administration of nimesulide, the possibility cannot be excluded, the report said. Italy is the only European country where the paediatric doses are sold.
Indian doctors who have seen the use of nimesulide differ on the effects. According to Delhi-based rheumatologist Dr Anand N Malaviya, most arthritis patients use nimesulide. And almost every one has a high liver enzyme. "It becames so bad that I could hardly start them on methotrexate right away. I had to keep on waiting before starting the drug. I have been telling my students and colleagues not to use it, especially if we plan to give methotrexate and/or leflunomide, used for rheumatoid arthritis. I have maintained this stand right from the beginning. I would much rather give a short course of steroids than NSAIDs, especially nimesulide, and then not being able to prescribe the life-saving drugs for rheumatoid, namely methotrexate and/or leflunomide."
But says Dr Arshad Ghulam Mohammed, a Mumbai-based surgeon, "I have not encountered any hepatic side effect during extensive, post-operative use of nimesulide.
According to a multinational company's medical director, Helsinn has been trying for US FDA and UK MCA approval. "The US FDA approval method is very clear-cut: If it is not the first in its class of drugs, then they have to show a meritocracy. That is whether it has efficacy superiority and minimal side-effects. If both are same, then they have to show whether it is pharmacoeconomical. In the case of nimesulide, Helsinn has been able to prove neither."
"Nimesulide has been a subject of sporadic hepato-toxicity reports for some time now. In between, we also read it was nephro-toxic though such reports did not recur. In any case, all NSAIDs are nephro-toxic," a medical advisor with an Indian pharma company told this correspondent.
A senior industry source who has been associated with the generic versions of the molecule for a long time here said that there is a veritable lack of published material in English on Nimesulide. "It is not a much referred chemical. Nimesulide does not have immediate side-effects as compared to diclofenac which leads to acidity, but nimesulide's hepatic effects start showing up later. Today, even combinations of nimesulide with paracetamol although not only irrational and also harmful, is widely available in this country. It is high time the Drug Controller General of India stopped the marketing of such products."
A senior rheumatologist recently said that combination therapy of an NSAID with leflunomide caused a side-effect. Leflunomide got the bad name whereas the side effect was entirely due to the NSAID, he said. It must be noted that nimesulide is widely used in arthritis.
In 1999, Helsinn's brands realised a cumulative turnover of $ 310 million corresponding to 48.2 million units sold throughout the world. The sales growth in respect to 1998 was of 7%. Approximately 40 million patients were treated with the compound in 1999.
Original Nimesulide brands sold by Helsinn in the world are: Aulin, Mesulid, Nimed, Nexen, Guaxan, Donulide, Nisulid, Ainex, Scaflam, Scaflan, Nimedex, Eskaflam, Antifloxil, Plaurium, Restasis and Edrygil.'