Nimesulide Stumbles on Safety Tests

Use Suspended in Spain, Finland, Turkey

Every drug must compulsorily pass two tests: safety and efficacy. In the past, drugs that have failed one or the other test were consigned to the dustbin, be it sleep-inducer thalidomide or anti-allergic agent terfenadine. If reports of serious side effects from countries that have an effective system of post-marketing surveillance are any indication, nimesulide is heading towards tough times.

Early this year, after the death of a patient due to liver failure and some others needing liver transplant there have been a total of 109 reports of other adverse drug reactions (66 of them pertaining to liver). The National Agency for Medicines of Finland ordered the suspension of the sale of nimesulide within 72 hours indicating the urgency and seriousness of the measure. Within two months, Spain followed suit and took even more drastic action: all stocks lying in the distribution channel were recalled and patients were instructed not to consume any nimesulide. Turkey has also prohibited its use. Though Ireland has ordered an observational study in 9,000 patients before taking legal steps, it has issued an official warning to all prescribers to be “aware of nimesulide’s potential for liver damage and adhere strictly to approved indications and dosage schedule.”

As per the usual procedure in European countries, the nimesulide issue has been referred to the European Council’s scientific advisory body, the Committee for Proprietary Medicinal Products (CPMP) for final adjudication. Once CPMP completes its review, the decision will be communicated to all member states for implementation.

The adverse effects of nimesulide on the liver have been known for some years though not adequately publicised. The main reason that the drug is not approved in most countries having large markets such as United States, Britain, Australia, New Zealand and Canada. Of the countries where nimesulide is marketed, very few have well-run post-marketing surveillance system for drugs. This has resulted in very few, if any, unbiased independent clinical trials. In fact most trials on nimesulide have been sponsored, financed or conducted by manufacturers and associated investigators. Therefore, they are unreliable if not biased.

In India’s immediate neighbourhood, the drug has failed to obtain approval in Bangladesh, Pakistan and Sri Lanka. Some would claim that simply because a drug is not marketed in the United States or Britain does not mean that it is not good. This is a simplistic argument designed to confuse and confound the issue. The discovery of a new molecule costs anywhere between 500 to 800 million US dollars (Rs. 2500 to 4000 crores). Once a new drug passes through mandatory trials, the first thing a sensible, commercial company will do is to recoup the expenditure incurred in the molecule's discovery. No one denies that the first place on earth to make money out of medicines is the United States of America followed closely by Britain where the government pays a multi-billion pounds bill to buy medicines. Why would a manufacturer go to countries like Yugoslavia and Luxembourg to sell its medicines unless it is apprehensive that its products will fail to procure permission in countries like the United States? In fact, it would be highly unwise on its part to apply for U. S. Federal Drug Administration (USFDA) approval if it is anticipated that the application is likely to be rejected. An American rejection will kill the product worldwide. Therefore, some molecules are too shy to face the tough assessors of the USFDA. An American manufacturer, named Lakeside Pharmaceuticals has obtained USFDA approval to manufacture the drug for export to Mexico but is not permitted to sell it within the United States! Is this not reason enough to doubt its safety profile?

Nimesulide obtained government approval in India in 1994 to be used for ‘painful inflammatory febrile disorders’. How an NSAID category drug primarily meant for musculo-skeletal disorders, became a first-line for fever - that too in children remains a mystery. It is true that all NSAIDs due to their inherent properties can be used to bring down fever. But this does not mean that an NSAID should be allowed to be a first-line fever therapy. Not only in India but elsewhere too doctors are under parental pressure to use drastic means to reduce fever in children. This must be avoided because the real cause of fever may be a life-threatening condition that would get masked. Therefore, rapid temperature-lowering agents, such as nimesulide, should have no place in paediatric practice. Not to mention the fact that two children taking nimesulide died of Reye’s syndrome in Portugal leading to ban on paediatric suspension in that country in 1999.

Irrespective of whether nimesulide does or does not cause Reye’s syndrome, why should one take risks unless there is some vested interest in this molecule? After all, nimesulide is not medicine for a serious life-threatening disease such as tuberculosis, cancer or AIDS. It is an NSAID with anti-pyretic effect with over two dozen alternatives that are known not to be linked to Reye’s syndrome. How does a prescriber decide whether to use or not use a drug with potential risks? Doctors whose passion for ethics is matched by their medical competence often say ‘I will not give a drug to my patients if I hesitate to give the same to my children, grand children, parents or grand parents.’ This advice is worth a ton of gold.