Clinical Pharmacology

"Adverse Drug Event of the month"

Possible Nimesulide Induced GI bleed : - A preventable Adverse Event

Case report:
A three-month-old female infant weighing 4 kg was admitted in the pediatric ward of the hospital with a history of a single episode of blood-tinged vomiting. The mother was the informant and gave a history of fever in the child of a day duration, for which she gave syrup Nise 3ml (Nimesulide 50mg/5ml) to the infant on her own. The patient reportedly had an episode of hematemasis an hour after administration of Nimesulide.She was immediately rushed to the hospital. The child did not have any history suggestive of liver disease or bleeding diathesis. On admission the patient's vital parameters were stable and systemic examination did not reveal any abnormality. The results of investigations are depicted in the table.

On admission, the child received inta-venous fluids for a day (120ml/kg/d)and injection Ranitidine (1mg/kg/day). The child was then treated with syrup Gelusil (Magnesium trisilicate 625mg+dried aluminium hydroxide gel 312mg/5ml) 5ml three times a dayand injection vitamin K-3mg intramuscularly once daily for three days. There was no fresh episode of hematemesis in the ward. Patient was discharged on the third day post admission after an uneventful hospital stay.


Discussion
Nimesulide is a 4 - nitro-2 phenoxy phenyl, a sulphonanilide non-steroidal anti-inflammatory Drug (NSAID) .It is a preferential COX 2 inhibitor, which acts by inhibiting leukocyte function and blocking metalloproteinase activity of articular chondrocytes. It is currently approved for use in painful conditions like osteoarthritis, dysmenorrhoea, dental and postoperative pain. Nimesulide is rapidly and almost completely absorbed after oral administration. The drug is extensively bound to plasma proteins (> 95%) and its average elimination half-life is 3 hours .It is metabolized primarily to 4 - hydroxy derivative and excreted by the kidneys. (1).

3 M Ricker was the American company, which originally discovered the molecule, but for some undisclosed reasons the drug was never launched in the USA (2). After its first launch in Italy in 1985, it has been marketed in about 50 countries throughout the world including India (3). It was introduced in Indian market in 1990 as an analgesic and antipyretic agent, for painful musculoskeletal disorders and fever.

Side effects with nimesulide are observed in 5% to 10% of patients receiving nimesulide and most commonly involve the Gastrointestinal Tract, Skin and Nervous system. A study was conducted in Italy where data was obtained from spontaneous reporting system database of Veneto-Trentino, the principal contributor to the Italian spontaneous surveillance system. Results showed that incidence of gastrointestinal side effects with Nimesulide use (10.4%) was half that associated with other three NSAIDs (21.2% for diclofenac, 21.7% for ketoprofen, 18.6% for piroxicam) suggesting that its GI tolerence may be superior to other NSAIDs (4). However the pediatric and geriatric population is more vulnerable to these GI side effects due to poor gastric mucosal barrier.

The approval of Nimesulide worldwide was under debate following reports of fatal adverse events following Nimesulide administration especially in the pediatric population. Sarkar R et al reported a case of Nimesulide induced extensive fixed drug reaction with cross sensitivity to sulphonamoide in a 10-year-old child (5). Nimesulide induced liver injury has been another matter of concern since a report published in 1992 indicated that two children died of suspected Reye's syndrome in Portugal after using Nimesulide (2). The concern was heightened when deaths due to hepatic and renal failure after taking Nimesulide were reported in two elderly women in Israel and Chile. (6, 7)

With increasing reports of Adverse Drug Reactions, Nimesulide was banned in children in many countries around the world. After much debate, the Drugs Controller General Of India (DCGI) in a written communication to State licensing authorities in April 2003 asking them to take immediate steps to stop manufacturing and marketing of pediatric formulations of Nimesulide .In May 2003, Dr.Reddy's laboratory and Nicholas Primal voluntarily withdrew the drug from the market. (8) However Nimesulide suspension(50mg/5ml) and Nimesulide(100mg tablet) for adult use is still available in the market.

With nimesulide being available as an over the counter preparation for adults, children would continue to be exposed to the risk of Nimesulide administration. as happened in the case described above, and run the risk of adverse events like GI bleed which are highly preventable.Even if the risk of hepatotoxicity with nimesulide is rare ,the use of nimesulide for fever particularly in children cannot be justified when safer alternatives like paracetamol and ibuprofen are available.

References
1. Insel P A:Analgesic-Antipyretic and anti-inflammatory agents .In:Hadmen J,Limbird L E(Edi in chief), Alfred Goodman Gilman. Pharmacological basis Of Therapeutics.9th edition McGraw Hill Companies, USA 1996,Pp 644.

2. Available from http://www.indianpediatrics.net/feb2003/feb183-84

3. Thawani V, Sontakke K,Gharpe K, Pimpalkhute S.Correspondence.Ind Jr Pharmacol 2003;35:121-22

4. Conforti A, Leone R, Moretti U, Mozzo F, Velo G.Adverse Drug Reactions related to the use of NSAIDs with a focus on Nimesulide:results of spontaneous reporting from a Northen Italian area.Drug Saf. 2001; 24:1081-90

5. Sarkar R, Kaur C, and Kanwar AJ.Extensive fixed drug eruption to nimesulide with cross -sensitivity to sulfonamide in a child. Pediatr Dermatol.2002; 19:553-4

6. Schattnu A, Sokolovskya N,and Cohen J.Fatal hepatitis and renal failure during treatment with Nimesulide.J.Int Med 2000;247:153-55.

7. Tejos S, Torejon N, Reyes H, Mereses M.Bleeding gastric ulcers and acute hepatitis: two simultaneous adverse reations due to Numesulide.Rev Med Chil 2000; 128:1349-53.

8. Available from expresspharmapulse issue dated 22nd July 2004

Department of Clinical Pharmacology
Department of Pediatrics
Seth G S Medical College and KEM Hospital,
Mumbai.