Nimesulide, a sulphonanilide derivative, is not considered a mainstream NSAID as it is not available in the top markets like USA, Japan, Germany, UK, Canada. Nimesulide is currently marketed in 50 countries worldwide under different brand names and through different licensing partners.Thanks to claver marketing, it was market leader in India, various European (Italy) and Latin American (Brazil) countries. The country of origin of the drug is Switzerland where Helsinn is based although the drug was licensed by Helsinn from 3M in the USA.

Nimesulide is approved in some European countries since 1995 for symptomatic treatment of oesteoarthritis, painful joint disorders such as tendinitis, post-operative dental pain and inflammation, and dysmenorrhoea.It is a selective cyclooxygenase - 2 (COX -2) enzyme inhibitor and is effective in the treatment of a wide range of inflammatory and painful conditions including osteoarthritis, extra-curricular disorders such as tendonitis and bursitis, post-operative pain and primary dysmenorrhoea. The efficacy and safety profile of the drug is similar to other NSAIDs. The incidence of GI side effects is around 5% of treated patients in clinical studies.

Companies marketing nimesulide are riding the COX 2 selectivity bandwagon and promoting it as a much safer on the GI tract then conventional NSAID and better efficacy or rapid onset of action. None of the European regulatory authorities like the Swiss Medic have accepted these arguments. Sir John Vane states that all NSAIDs show some COX 2 selectivity.

There is no convincing clinical evidence from well-controlled double blind comparative trials that nimesulide is better tolerated or more effective or has faster onset of action than diclofenac, naproxen, piroxicam or ibuprofen on the GI tract or more selective COX 2 inhibitor than other NSAID. Clinical trials showed an ulcer incidence of 3.4% as with other NSAID. Short-term studies in limited number of patients contribute very little to the safety or efficacy of the drug but become mainly a market promotional activity.In fact the COX 2 selectivity may increase the risk of cardiotoxicity and nephrotoxicity. It may even increase hypertension as observed with some newer COX 2 inhibitors. It is safe and effective like other NSAID for short-term use in adults. The maximum daily dose of nimesulide in Europe is limited to 200 mg i.e. 100 mg BID in adults. The maximum daily dose should be reduced for alcohol users, patients with hepatic abnormalities and underlying liver disease and those taking potentially liver-toxic medications in addition to nimesulide

Nimesulide is one of the most prescribed non-steroidal anti-inflammatory drugs worldwide. In 2001 Helsinn's brands realized a cumulative turnover of 330 Million USD, 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 nimesulide in 1999. The total analgesic and pain market was $11 Bn in the year 2002. Helsinn claims that more than 346 million treatment courses have been used during Nimesulide's 18 years of presence on the market (Italy was the first country to authorize the drug in 1985), in addition to more than 90,000 patients who have been treated in over 230 clinical studies. The drug approval in several European countries is on prescription only. The company has not generated safety data for its OTC use at lower doses.

Regulatory approvals in Europe

There were probably two phases prior to 1992 and post 1995.
In the early eighties, the regulatory outlook for newer NSAIDs was very tough and bleak. The withdrawal of Benoxaprofen in 1982 due to hepatotoxicity followed by few other withdrawal of NSAIDs from EU/US markets was followed by regulatory spotlight, hearings, expert meetings and labeling changes and new guidelines/requirements for approval of NSAIDs. This resulted in exit of big pharma from R&D of pain and new NSAID. Even Ciba Geigy decided to delay for several years, filing the NDA for Voltaren in the USA as it was considered in an internal review "not approvable in USA". Once NDA for Volatren was filed and approved, the drug became the best selling NSAID in the USA.

3M must have reached similar pessimistic conclusions about Nimesulide and looked for a development partner in Europe. It was probably not able to attract any top 50 pharma in Europe and it seems that only Helsinn was interested. But why select Helsinn, a small private unknown company based in Swiss Italian city of Lugano. We may never learn the real reason, 3M was probably looking for someone to get stealth development, low cost and quick approval with minimal data and away from the USA/UK/CPMP NSAID spotlight. The details of the first registration in Italy and initial phase are not known. Helsinn had the blessings of the Italian regulatory authorities to do a short development program and clinical trials to get approval. Helsinn did a very good job of registration and licensing out and now involving and winning the backing of top NSAIDs experts like Prof. Kim Rainsford.

The product somehow avoided the regulatory scrutiny accorded to a NCE. The second post 1995 wave of registrations as a patent expiry generic was probably based on good data, a lenient review of generics in general and long history of marketing in Italy. None of the Southern European Countries had a good Side Effect collection system in the past and only recently have put it into practice. This may partly explain the low incidence of ADRs from Italy. There is no common procedure for registration of generics in Europe at the EU level and each country has its own rules, regulations and standards.

The Italian approval of Nimesulide was probably sufficient to get approvals in Portugal, Brazil and South Korea. Helsinn was able to attracttop pharma such as Aventis, Boehringer, GSK, Novartis, Roche, Sanofi, Schering Plough, Pfizer, and Wyeth as licensing partners in selected countries. These licensing partners probably paid for generation of good quality data starting in early 90s and its registration post 1992 in several countries like France, Spain, Switzerland, Finland and Ireland. Nimesulide is a prescription drug only, and it is available as tablets, granules, suppositories and topical gel under different brand names.

There is considerable amount of clinical data for short-term use for less up to 4 weeks or so. Only two long term double blind randomized studies of 12 and 26 weeks duration had sufficient number of patients in each arm i.e. >95 each. Most of the other studies were short term or had low number of patients 20-30 to draw any conclusions about the safety or efficacy of the drug.

Additional data for its registration or long-term use in rheumatic conditions is required and its use should be limited to 1-3 months. All long-term patients on nimesulide should be monitored for GI, Liver, Heart and CNS abnormalities.Several clinical trials for its use in children aged 4-8 years are reported for up to 7 days with several doses. There is no data to justify its use in babies/neonates less than 4 years old and now EMEA has banned its use in children below 12 years.

For a USA NDA, whole toxicology, carcinogenicity and long term clinical studies requiring up to 1 year treatment in several thousands of patients will be required. It may take 5 years and cost over $100-150 millions. Helsinn probably had one or more marketing partners in the USA in the past.The development for USA was terminated in 1998 either because of costs, patent expiry as the company claims or lack of efficacy or unexpected toxicity in USA trials done by its partner company. Patients in USA tend to show higher incidence of ulcers/GI toxicity in NSAID trials due to their heavy use of aspirin as compared to European patients. As a result more NSAIDs are marketed in Europe than USA. Several NSAIDs were terminated in the USA due to higher incidence of ulcers in clinical studies.

Toxicity of NSAID

Nonsteroidal anti-inflammatory drugs, often referred to as NSAIDS, are assumed to be well tolerated and are widely used by millions for pain relief and as an initial therapy for common inflammation. They range from over the counter aspirin and ibuprofen to a whole host of prescription brands. These pharmaceutical agents constitute one of the most widely used class of drugs, with more than 70 million prescriptions and more than 30 billion over-the counter tablets sold annually in the United States alone.

It is generally stated that the side effects of NSAIDs are fairly mild causing a possible upset stomach and/or nausea and vomiting. It is often recommended that the stomach upset, nausea and vomiting can be avoided by taking the medication with a little food or milk.

A statement from a July 1998 issue of The American Journal of Medicine states the following:

"Conservative calculations estimate that approximately 107,000 patients are hospitalized annually for nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) complications and at least 16,500 NSAID-related deaths occur each year among arthritis patients alone. The figures of all NSAID users would be overwhelming, yet the scope of this problem is generally under-appreciated."

And again a year later (June 1999) in the prestigious New England Journal of Medicine there is a similar statement:

"It has been estimated conservatively that 16,500 NSAID-related deaths occur among patients with rheumatoid arthritis or osteoarthritis every year in the United States. This figure is similar to the number of deaths from the acquired immunodeficiency syndrome and considerably greater than the number of deaths from multiple myeloma, asthma, cervical cancer, or Hodgkin's disease. If deaths from gastrointestinal toxic effects from NSAIDs were tabulated separately in the National Vital Statistics reports, these effects would constitute the 15th most common cause of death in the United States.

Most patients have no warning signs that these drugs are causing them internal damage before they ended up in the hospital with a serious medical condition. And as we have seen from the statistics, approximately 10% of these hospitalizations end in death.

Since these medications are marketed and used worldwide one should expect there to be NSAID hospitalizations and deaths worldwide. Although the available information is limited, there is evidence of this occurring in Germany and Great Britain.

"We thus calculated the total number of NSAID-associated hospital admissions for gastrointestinal PUB [Perforations, Ulcers and Bleeding] in the GKV [German statutory health-insurance fund] to be 10,700 per year, necessitating 157,000 hospital days and total costs of DM 125 million. 1,100 to 2,200 fatal cases in the GKV annually were
thus expected. Multiplying these figures by a factor of 1.1 provides estimates for the entire German populations."

"... studies from Great Britain which show an estimated 12,000 NSAID-related hospital admissions and 4,000 NSAID-related deaths."

The FDA opted for a warning label on all NSAIDs.
"Gastrointestinal adverse reactions with long-term use of NSAIDs.

A general paragraph regarding the risk of gastrointestinal ulcers, bleeding, and perforation with long-term NSAID treatment is being developed for inclusion on the labels of all NSAIDs. By life table analysis of prospectively collected data from multiple NSAID submissions, the FDA estimates that these serious events occur in approximately 1-2% of patients using NSAIDs for 3 months, and in approximately 2-5% using them for 1 year. The cumulative risk appears to increase with the duration of therapy and to be greater in patients with previous peptic ulcer disease. Fatal outcomes are more likely in elderly or debilitated patients. Higher dosages of NSAID probably entail greater risk that lower dosages."

Hepatotoxicity of NSAID

The Food and Drug Agency Arthritis Advisory Committee estimated that 10% of patients on these drugs exhibit biochemical abnormalities that reflect mild hepatic injury. About 25% of these are serious and may require hospitalization, liver transplant or result in death. Some 100 million people a year take acetaminophen, and serious liver damage are rare, manufacturers insist. But more than 56,000 emergency room visits a year are due to acetaminophen overdoses, and about 100 people a year die after unintentionally taking too much according to the FDA data. If the same incidence was used for India and multiplied four times due to population difference, then we may have about 200,000 hospitalizations and over 400 deaths due to NSAID toxicity.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed medicines in the world, in addition to widespread over-the-counter use. NSAIDs are a well-known cause of liver dysfunction. Aspirin is intrinsically toxic to the liver, whereas most other NSAIDs induce injury to the liver by an idiosyncratic reaction. Many reports confirm that NSAIDs cause elevation of aminotransaminases with convincing episodes after rechallenge. A rise in transaminases above 1000 U/L (U/L) occurs rarely, in less than 10% of cases. Approximately 25% of patients with liver toxicity collected by the FDA had taken more than one acetaminophen-containing product. Acetaminophen hepatotoxicity results in over 26000 hospitalizations per year and results in 460 deaths in the USA.

The liver metabolizes virtually all analgesic drugs, therefore damage to this organ is associated with the majority of analgesics. NSAIDs actually carry a relatively low risk of liver toxicity. Serious toxicity is uncommon with proper therapeutic use. There have been isolated reports of chronic active hepatitis associated with use of salicylates. Reye's syndrome is a rare liver condition, which can be fatal. Salicylate has been linked with this condition and use of aspirin in the under-12s is not recommended as the condition resembles subacute salicylate toxicity in children.

Benoxaprofen: NSAID; was tested extensively before release in patients less than 60 yr of age, but was used after release mostly in osteoarthritis and mostly in elderly patients over 60 yr of age; caused approximately 12 deaths. Diclofenac:rarely causes severe liver injury but has caused moreinjury than any other approved drug; causes hepatocellular injury. Bromfenac "knockoff" of diclofenac and "was considered perfectly safe" if used up to 10 days, but people used it for >10 days; deaths occurred, and drug pulled from market. This drug was approved for pain in July 1997 and less than one yearlater, in June 1998, was banned because of liver toxicity. Bromfenac's liver toxicity was known before its approval and was the reason why it was approved only for short-term use to treat pain rather than to treat the symptoms of osteo- and rheumatoid arthritis. By the time this drug was banned it had been associated with at least four deaths and eight liver transplants.

In India, hepatitis B and C infections probably account for 70% of liver related hospital admissions and deaths. However low nutritional status, alcoholic drinks and drugs may contribute to the increased toxicity of hepatitis infections Acetaminophen is the poor men first choice as a drug because of low cost and easy availability in India. Due to overall low consumption of drugs, the incidence of drug induced serious hepatotoxicity in India may be lower as compared to the USA.

FDA new warning about NSAID in 2004 include:
The risk of liver damage increases if you have three or more alcoholic drinks while using acetaminophen.

It's rare for stomach bleeding to occur with NSAIDs using over-the-counter doses for short periods of time. Risk increases, however, for people who are over 60; take prescription blood thinners or steroids; have a history of stomach bleeding or other bleeding disorders; or have three or more alcoholic drinks a day.

NSAIDs can cause some reversible kidney problems; most at risk are people over 60, who have pre-existing kidney disease or who take blood pressure medicine known as diuretics.

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 reported, some of which have been fatal. The incidence of hepatic reactions is approximately 0,1 case out of 100'000 patients treated, thus comparable to the other NSAIDs.

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.

Until recently none of the European countries where Nimesulide is marketed had a strong PMS system of side effects monitoring. In fact, none of the advanced country has a good system of adverse event reporting system. The spontaneous reported ADRs represent only a small fraction 1% of real toxicity and point to a problem. Class litigation, in recent drug injury cases, in USA show that these figures get multiplied 100 times when a drug is withdrawn due to toxicity.

The Finnish National Agency for Medicines in March 2002 temporarily suspended the non-steroidal anti-inflammatory drug nimesulide from the market following reports of liver toxicity and one suspected fatality in patients taking the drug. There were109 reports of adverse events, 66 of which related to liver toxicity, had been reported since the drug received marketing authorization in August 1997. The death possibly linked to the drug was a result of liver necrosis. Aventis Pharma, which markets the drug under Nimed, said 43 of the 66 reports of liver toxicity were transient increases in liver enzyme values.

Helsinn states "Of 4.5 billion treatment days with nimesulide there have been only 195 liver adverse event reports," , adding that it is the most widely used prescription pain killer in Europe.

The Irish Medical Board IMB July 2002

Use of nimesulide is contraindicated in patients with hepatic impairment

The company was requested to perform post marketing authorization studies to address the safety issues. A pilot study in 500 Irish patients suggested that the safety profile of nimesulide was similar to that of other NSAIDs. An observational study in 9,000 Irish patients comparing the safety profile of nimesulide with diclofenac and ibuprofen is currently underway. Interim data provided by the company on 1, 212 patients indicate that at this stage, there is no apparent difference in the safety profiles of the three treatments. Recently, concerns with hepatotoxicity have also been discussed at European level, which have led to a re-assessment of the overall benefit/risk profile of nimesulide. Marketing of nimesulide has been suspended in a number of countries (Finland, Spain and Turkey), pending the outcome of the review.

In France, 30 cases of hepatotoxicity linked to nimesulide were reported since 1999, 8 of them severe resulting in 2 deaths and 1 required liver transplantation.

In Portugal, in 1999, following a risk-benefit assessment, a core SPC (Summary of Product Characteristics) was approved for nimesulide. Therapeutic indications were restricted to osteoarthritis, extra-articular rheumatic conditions, postoperative and/or post-traumatic pain and inflammation, oral/ dental inflammatory conditions and dysmenorrhoea.
The core SPC also stated that
q Nimesulide should not be used for periods longer than 7 days in the treatment of acute pain
q Use in patients with hepatic failure is contraindicated
q Liver function should be monitored in patients with previous history of hepatic injury
q Precaution is needed when nimesulide is used with other drugs that may cause hepatic injury

The Portuguese marketing authorizations for pediatric nimesulide formulations were suspended in March 1999.

The Spanish Health Authorities also decided the cautionary temporary suspension of nimesulide in this country. Independently, Turkey also decided for the cautionary temporary suspension of nimesulide.

The Finnish Health Authorities sent an alert to all EU member states and the EMEA decided to initiate the procedure to re-evaluate the risk/benefit ratio for this drug. The EMEA/CPMP has initiated a safety procedure on Nimesulide, following the alert sent to all European Member States by the Finnish Authorities on the basis of an unusually high frequency of hepatic adverse events occurred locally, whose causality relationship with Nimesulide is still to be proven.

The occurrence of hepatic reactions with nimesulide is similar to that of any other NSAIDs as confirmed by a cohort study in Italy by Traversa et al published in the British Medical Journal (BMJ 2003; 327: 18-22).

The European Agency for the Evaluation of Medicinal Products EMEA determined in 2003 that Nimesulide, a non-steroidal anti-inflammatory drug (NSAID) is safe and effective for use in patients suffering from a wide variety of inflammatory and painful conditions. The positive opinion was issued at the July meeting of the Committee for Proprietary Medicinal Products (CPMP) after a 16-months-long evaluation by the CPMP of the benefit/risk profile of the drug.

After a thorough analysis of the data on the safety and the efficacy for the use of Nimesulide, EMEA and Helsinn Healthcare SA, developer and licensor of the drug, have agreed on a new Summary of Product Characteristics (SPCs), which will harmonize the medical information on this product in the European Union countries where it is marketed for the symptomatic treatment and relief in acute stages and osteoarthritis.

Possible Actions in India

1. Remove higher dose, pediatric dosage forms and irrational nimesulide-containing combinations from the market

Combining with other NSAID or the higher 200 and 400 mg tablets in the absence of clinical data, scientific and medical rational and regulatory approval may multiply the risk of GI, Cardiovascular, renal, hepatic and CNS toxicity several fold and it is a criminal act.

It seems that in India a large percentage of nimesulide sales is in the form of combination products. Most of these combinations are irrational. Patients (and their parents) should be encouraged to use only the medication they need. The use of combination products with elaborate (often misleading) brand names discourages patients from learning the generic names of active ingredients, potentially leading to overdoses when taken with other nimesulide-containing drugs.

The Indian pharma companies seem to be promoting unapproved formulations/ combinations and higher doses, which increase the risks to patients and babies without providing any additional benefits. Drug Controller General of India DCGI can ensure a measure of objectivity and balance in scientific and educational programs concerning unapproved formulations and uses and has the primary responsibility in protecting the public from unsafe or ineffective drugs. If the DCGI relies on foreign data for drug approvals of copy products from Indian companies, similar action can be taken to remove products and combinations, which increase health risk. Regulatory action in India should be in line with EMEA/CPMP decision.

2.Reduce maximum daily doses

The maximum daily dose of nimesulide should be limited to 200 mg i.e. 100 mg BID in adults. The maximum daily dose should be reduced further for alcohol users, patients with hepatic abnormalities and underlying liver disease and those taking potentially liver-toxic medications in addition to nimesulide

3. Indian Council of Medical Research ICMR ADR Study

A survey of all hospital admissions in India over the last 2 years for all serious conditions and determination of links to any drugs the patients were on and how long will generate real data for appropriate action and decision making rather than relying on experts opinion. This data is already available in all Intensive Care Units ICUs in India and only needs to be collected, reviewed and analyzed.

An ADR survey nimesulide and other NSAID in India involving a few thousands patients in 6 metropolitan cities on five to ten leading NSAIDs or all drugs should be carried out for side effects over a 2-3 year period similar to the Irish ongoing study.

4. In India, there should be automatic approval for all new drugs, which are approved, in any two of the following USA/EMEA/Japan. For drugs approved in one of the above an expedited review should be carried out limited to 3-6 months after filing.

5. Public access to risk information

The nimesulide label must have a general warning about liver toxicity and GI toxicity, mention the early symptoms of liver/GI toxicity and instruct patients to discontinue the drug and seek medical attention should such symptoms appear. It should also warn against the simultaneous use of multiple nimesulide-containing products. A patient information leaflet in each package must be included and ban pharmacist/doctors cutting strips or selling odd number of tablets to patients.

6. India needs an Independent Watch Dog Consumer Health Group with no links to the Industry, Medical or Hospital Business, or to Government, with a mission to provide unbiased scientific and medical information to the public/patients, reviews medicines, devices and diagnostic tests, evaluate hospitals, laboratories, private hospitals and clinics and medical practices to expose corruption/fraud, inaction by officials, overcharging of patients and work with elected and government health authorities to take proper actions, change laws and take court action through PIL if needed. It will establish lists of safer medicines, cost effective hospitals and medical doctors in various specialties. The group should have its own health research group consisting of legal, scientific and medical expertise and will be an NGO.

-- The author is a pharma R&D specialist and based in Geneva, Switzerland