Contents : NIMUSLIDE-100 Packing : 10 Price : $ 0.50 per unit Quantity : 6090120150180

Description

NIMULID (Nimesulide) is described chemically as N-(4-Nitro-2-phenoxyphenyl) methanesulphonamide. It has the following structure:







Nimesulide is a yellowish crystalline powder. It is practically insoluble in water, freely soluble in acetone and slightly soluble in ethanol. The empirical formula for Nimesulide is C13 H12N2O5S, and the molecular weight is 308.311.

Each tablet of Nimulid for oral administration contains 100mg of Nimesulide BP and the following inactive ingredients: Lactose, Croscarmellose Sodium, Colloidal Silicon Dioxide, Maize Starch, Povidone, Polysorbate-80 and Magnesium Stearate.

Nimulid tablet is pale yellow, coloured, round, biconvex, uncoated tablet with imprints of "NIMULID" on one side and "picture of Logo" on the other.

CLINICAL Pharmacology

Mechanism of Action Nimesulide is a sulfonanilide non-steroidal anti-inflammatory drug whose anti-inflammatory analgesic and antipyretic activities have been demonstrated in several widely used animal experimental models2. At the recommended dose of 100 mg b.i.d., it is as effective an analgesic and anti-inflammatory agent as classical NSAIDs, and a well-tolerated drug with fewer side effects as evidenced by a number of controlled and non-controlled comparative trials3. Nimesulide is a unique NSAID, not only due to its chemical structure but also because of its specific affinity to inhibit Cyclooxygenase-2 thus exerting milder effects on the gastrointestinal mucosa.

Nimesulide appears to exert its therapeutics effects through a variety of mechanisms viz4:

Selective Cyclooxygenase-2 inhibitor
Reduced generation of superoxide anions by stimulated polymorphonuclear leucocytes
Inhibition of platelet aggregation factor synthesis by activated cells
Scavenger of inactivation of alpha1-protease inhibitor
Inhibition of histamine release
Inhibition of protein kinase C through inhibition of phosphodiesterase type IV
Reduced degradation of cartilage matrix through inhibition of metalloprotease synthesis
Potent inhibition of induced platelet aggregation
Prevention of bradykinin/cytokine induced hyperalgesia of nerves (inhibiting release of TNF- alpha)
Pharmacokinetics

Absorption Nimesulide is fairly rapidly absorbed from the gastrointestinal tract. After oral administration of a 100mg dose to healthy fasting volunteers, mean maximum plasma concentration (Cmax) values of 2.86 to 4.58 mg/L were achieved within 1.22 to 3.83 hours (Tmax). After oral administration of a 200mg dose in tablet form, urinary recovery was approximately 80% and faecal recovery about 20% over a 3-day period. Thus by mass balance, it can be deduced that at least 80% of the administered dose was absorbed by the gastrointestinal tract. Given that Nimesulide and/or its metabolites may also be excreted in the bile, the extent of Nimesulide absorption after oral administration is likely to be greater than 80%. After administration of Nimesulide 100mg to healthy fasting volunteers, the area under the plasma concentration-time curve (AUC) values ranged from 17.3 to 30.9mg/L.h. Appreciable Nimesulide concentrations of 0.12 to 1.03mg/L were still measurable 12 hours after administration, the time at which successive dose is given in the recommended dose regimen.

Nimesulide is absorbed at a similar rate and to the same extent whether administered in tablet, suspension or granular form5.

Food effects

Oral administration of Nimesulide 100mg tablets after a standard breakfast resulted in a Cmax value approximately 20% lower (3.02mg/L) than under fasting conditions. However, neither tmax (1.75h) nor AUC (15.9mg/L.h) values were significantly modified by food intake. In contrast, Ambrosioni (1986) reported that when the drug was administered in the presence of food, Nimesulide plasma concentrations were 2 to 4 fold higher than under fasting conditions, suggesting that the drug was better absorbed after meals.

Distribution

The volume of distribution in the post distribution phase for Nimesulide ranges from 0.19 to 0.39 L/kg, indicating that the drug is principally distributed in the extra cellular fluid compartment. Over a drug concentration range of 0.5 to 10 mg/L, the unbound fraction for Nimesulide varied from 0.007 to 0.04, which was indicative of its extensive plasma protein binding. Metabolism

Nimesulide is almost exclusively metabolized and cleared by the liver. Metabolic biotransformation of Nimesulide in the liver can occur at both the phenoxy ring moiety and the aromatic nitro group. The major oxidative metabolite found in the plasma is para-hydroxy nimesulide in both free and conjugated forms and this metabolite also appears to contribute to the anti-inflammatory activity of the compound6.

Elimination

After oral administration of Nimesulide 100 mg, the apparent mean elimination half-life (t½β) varied from 1.96 to 4.75 hours. Nimesulide is mainly eliminated by the renal route. Nimesulide total plasma clearance varied from 35.2 to 90.9 ml/h/kg and was almost exclusively attributed to metabolic clearance. Para hydroxy Nimesulide has an elimination half-life of 2.89 to 4.78 hours (t½β).

Special populations

Geriatric

The pharmacokinetic profile of Nimesulide and its para-hydroxy metabolite was similar in the elderly and young healthy volunteers and suggest that no Nimesulide dosage adjustment is necessary in patients less than 80 years of age7.

Gender

Gender does not appear to substantially affect the rate or the extent of Nimesulide absorption, distribution and elimination. It is noteworthy, however, that the mean peak plasma concentration, total plasma clearance and volume of distribution in the post-distributive phase were higher in females than in males.

Pediatric

Nimesulide seems to be rapidly and extensively absorbed in children. There was a 50% increase in Cmax and AUC values in children when compared with healthy adults, while the dose in children expressed on a bodyweight basis was only 20% greater (1.82 vs 1.54mg/kg). Furthermore, the terminal elimination half-life (t 1/β) of Nimesulide was shorter in children (2.36h) than in adults (3.02h) suggesting faster elimination in pediatric subjects.

Renal Insufficiency

The pharmacokinetic profile of Nimesulide in volunteers with moderate renal impairment was assessed in two non-blind studies. In the first study, a single dose of 100mg of Nimesulide was administered to 10 patients between 18 to 65 years of age. The apparent total clearance (Cltot) for Nimesulide was significantly lower (2.9 vs 4.8L/h) and the terminal elimination half-life for hydroxy nimesulide was significantly longer (6.05 vs 4.02h) in renally impaired patients.

The second investigation assessed the pharmacokinetic profile of repeat doses of Nimesulide in 10 patients between 49 to 69 years of age. Analysis of data showed that the AUC0-alpha for hydroxy nimesulide was slightly greater (19.7 vs15.4mg/L.h) following repeat dose administration. The urinary clearance for hydroxy nimesulide at steady state was higher than that after the first dose (1.02L/h).

Results of these studies suggested that the pharmacokinetic profiles of Nimesulide and its hydroxy metabolites are not altered significantly in patients with moderate renal failure.

Drug Interactions

Extensively plasma protein bound drugs Due to the extensive plasma protein-binding Nimesulide may be displaced from the binding site by concurrent administration of fenofibrate, salicylic acid, valproic acid and tolbutamide. Moreover, Nimesulide may displace salicylic acid, methotrexate and furosemide from binding sites8.

Furosemide Nimesulide reduced the diuretic effect for concomitantly administered furosemide.

Digoxin Concomitant administration of Nimesulide and Digoxin showed no effect on serum Digoxin concentrations at steady state.

Warfarin Nimesulide does not appear to interact with Warfarin, in clinical practice; although interaction with oral anticoagulants or other highly protein bound drugs cannot be ruled out.

Theophylline Nimesulide may cause enzymatic induction of Theophylline when administered concomitantly with