APONIL Tablet Ref.[28116] Active ingredients: Nimesulide

Nimesulide is well absorbed after oral administration. After a single dose of 100 mg peak plasma levels of 3-4 mg/ml are reached within 2 to 3 hours. AUC = 20 to 35 mgxh/lt. No statistically significant difference has been found between these figures and those seen after 100 mg given twice daily for 7 days. Up to 97.5% binds to plasma proteins.

Nimesulide is extensively metabolized in the liver following multiple pathways, including cytochrome P450 (CYP) and 2C9 isoenzymes. Therefore a potential for a drug interaction in case of combined administration with drugs which are metabolised by CYP2C9 is envisaged (see section 4.5).

The main metabolite of nimesulide is the para-hydroxy derivative which is also pharmacologically active. The lag time before the appearance of this metabolite in the circulation is short (about 0,8 hours) but its constant formation is not high and is considerably lower than nimesulide absorption constant. Hydroxynimesulide is the only metabolite found in plasma and it is almost completely conjugated. Half-life is between 3.2 and 6 hours.

Nimesulide is excreted mainly in the urine (approximately 50% of the administered dose). Only 1 to 3% is excreted as the unmodified compound. Hydroxynimesulide, the main metabolite is found only as a glucuronate. Approximately 29% of the dose is excreted after metabolism in the faeces.

The pharmacokinetic profile of nimesulide remains unchanged in the elderly after single or repeated administration.

In a clinical trial conducted in patients with mild to moderate renal impairment (creatinine clearance 30 to 80 ml/min) versus healthy volunteers the administration of a single dose of nimesulide showed that peak plasma levels of nimesulide and its main metabolite were the same in both group of patients. AUC and t_½ beta were 50% higher in patients with renal failure, however always within the range of kinetic values observed with nimesulide for healthy volunteers. Repeated administration did not cause accumulation.

The administration of nimesulide is contra-indicated in patients with hepatic impairment (see section 4.3).

Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

Repeated dose toxicity studies showed that nimesulide shows gastrointestinal, renal and liver toxicity.

Embryotoxic and teratogenic effects (skeletal malformations, dilatation of cerebral ventricles) were observed in rabbits but not in rats at doses non-toxic for the mother.

Pup mortality was observed during early post-natal period in rats; adverse effects of nimesulide on the reproductive process were seen.