Several pharmaceutical companies in the country are phasing out the manufacture of pediatric dosage forms of nimesulide after recent reports of adverse drug reactions of the drug. Mumbai-based Blue Cross Laboratories has already withdrawn its pediatric suspensions from the market and many others including Dr Reddy's Labs, Cadila Pharma and Panacea are learnt to have decided to recall their pediatric dosages soon.

The decision of the companies to phase out their pediatric brands immediately from the market is due to strong views expressed by the Drugs and Clinical experts in India against the use of nimesulide for children. The clinical experts are in the view that although the occurrence of clinically significant liver damage due to nonsteroidal antiinflammatory drugs (NSAIDs) is low, the enormous consumption of these drugs has made them an important cause of liver damage. Nimesulide, a relatively new NSAID commonly used in Europe, with a relative selectivity to cyclooxygenase type 2, 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 can progress to fatal hepatic failure, they opined.

According to a senior clinical analyst in Mumbai, the drug-induced acute hepatitis is a well-recognized adverse effect of many drugs, including nimesuilde. Identification of a drug as a cause for this life-threatening disease is important because the discontinuation of it may be life saving. This article 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.

Nimesulide, which is currently on review at the DCGI committee, is reported to have very serious side effects on both adult and pediatric use. “However, it is better stop harming children immediately, after that we may wait for the regulatory decision to decide up on the adult dosages,” says N H Israni, chairman, Blue Cross Laboratory and also president, IDMA. “I hope that many more companies would follow this to keep the industry's social commitment,” Israni added.

According to a recent study on the effect of nimesulide on proliferation and apoptosis of human hepatoma SMMC-7721 Cells, the Gastroenterology department, at Renmin Hospital of Wuhan university, China, has suggested that when various concentrations of nimesulide (0, 200 micromol/L, 300 micromol/L, 400 micromol/L) were added and incubated, the cell proliferation was detected with MTT colorimetric assay, cell apoptosis by electron microscopy, flow cytometry and TUNEL.

The study result showed that nimesulide could significantly inhibit SMMC-7721 cells proliferation dose-dependent and in a dependent manner compared with that of the control group. The Chinese University study concluded that the selective COX-2 inhibitor, nimesulide can inhibit the proliferation of SMMC-7721 cells and increase apoptosis rate and apoptosis index of SMMC-7721 cells. The apoptosis rate and the apoptosis index are dose-dependent. Under electron microscope SMMC-7721 cells incubated with 300micromol and 400 micromol nimesulide show apoptotic characteristics. With the clarification of the mechanism of selective COX-2 inhibitors, These COX-2 selective inhibitors can become the choice of prevention and treatment of cancers.

A senior clinical expert and, currently, medical advisor with a leading pharmaceutical company in India, said that typically such findings are known only after the product is marketed because the number of patients in phase III trial are not likely to pick up such effects. “When side effects are as severe as hepatitis, and if safer drugs are available for managing same indications over a period of time people select to use safe drugs,” he said. He added that when nimesulide was launched, its hapatotoxic effects were not widely known and being the 1st gastro friendly analgesic everybody marketed it in India. “If you recall almost all drugs banned recently were banned after they were marketed for some time,” he said.

Another clinical study conducted at Department of Gastroenterology, Nahariya Hospital in Israel, on the nimesulide-induced acute hepatitis confirmed by biopsy and an in vitro lymphocyte toxicity assay, also confirmed that the patient's liver function test results returned to normal within one month after nimesulide discontinuation. An in vitro lymphocyte toxicity assay had confirmed that the liver injury was due to nimesulide exposure.

According to a recent study at the Medizinische Klinik B, Department of Internal Medicine, University Hospital, Zurich, Switzerland, also concluded that a fatal hepatoxicity is secondary to nimesulide use. This study suggested that nimesulide is a non-steroidal anti-inflammatory drug (NSAID), which preferentially inhibits cyclo-oxygenase 2 and has been associated with a total of 13 reported cases of severe liver injury including our case. On the basis of the literature reports, the following features of nimesulide-associated hepatotoxicity were identified: female sex (84% of cases), age (mean age 62 years), jaundice as a primary manifestation (90%) and the absence of peripheral blood eosinophilia. The average duration of therapy of the published cases was 62 days (range 7-180 days). Based on spontaneous reports to the World Health Organization, nimesulide induces a high proportion of severe adverse hepatic reactions compared with other NSAIDs registered in Switzerland. Hepatotoxicity thus represents an important risk factor of nimesulide usage.