NMS-MD

Rx                NMS MD

COMPOSITION:

NMS MD 1 TAB

Each Mouth dissolving Tablet contains:

Nimesulide BP       100mg

DESCRIPTION:

NMS MD Nimesulide is described chemically as N-(4-Nitro-2-phenoxyphenyl) methanesulphonamide. NMS MD Nimesulide is a non-steroidal anti-inflammatory drug of the sulfonanilide class. The Anti-inflammatory, analgesic and antipyretic activities of Nimesulide have been demonstrated in a number of experimental models and in numerous clinical trials.The anti-inflammatory potency of nimesulide is similar or greater than that of Indomethacin, Diclofenac, Piroxicam and Ibuprofen.

Nimesulide has an analgesic potency similar to that of Ibuprofen and less than that of Indomethacin in an acetic acid writhing test in rats, and acetic acid and acetylcholine writhing tests in mice. The antipyretic potency of Nimesulide is superior to that of Indomethacin, Ibuprofen, Aspirin and Paracetamol in rats with yeast-induced fever.

 PHARMACODYNAMICS:

Nimesulide is a selective inhibitor of prostaglandin synthesis but appears to exert its therapeutic effect by a variety of other mechanisms like inhibition of platelet-activating factor (PAF), tumour necrosis factor-alpha (TNF alpha,) Proteinase & histamine etc. 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 trials. 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:

• 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 form

Food effects

Oral administration of Nimesulide 100mg tablets after a standard breakfast resulted in a C_max value approximately 20% lower (3.02mg/L) than under fasting conditions. However, neither t_max(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 compound.

Excretion:

After oral administration of Nimesulide 100 mg, the apparent mean elimination half-life (t_½β) 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 (t_½β).

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 age.

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 C_max 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 (Cl_tot) 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 AUC_0-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.

Indications:

Nimesulide is indicated in reducing pain, fever and inflammatory symptoms of:

• Chronic arthritis (Osteoarthritis)

• Respiratory tract infections

• Otorhinolaryngological diseases

• Soft tissues and oral cavity inflammation

• Dysmenorrhoea

• Phlebitis / thrombosis

• Urogenital disease

• Postoperative pain states

• Sports injuries.

CONTRAINDICATIONS:

·        History of allergy to NSAIDs

•         History of nasal polyps, angiodema and /or bronchospastic reactivity to any NSAID

•         Hypovolaemia/dehydration (>10% total body weight)

•         Peptic ulcer disease

•         Renal insufficiency

•         Hepatic insufficiency

•         Bleeding disorders

•         Concomitant administration of drugs known to interact with NSAIDs/Nimesulide such as anti-diabetics and anti-epileptics.

•         History of allergy to any of its components.

WARNING AND PRECAUTIONS:

Like other NSAIDs, nimesulide should be used with great caution in patients with compromised renal function, cirrhosis of liver, congestive heart failure, renovascular disease or those who are volume or salt depleted. It is important to monitor hepatic injury parameters when using NSAIDs. Therefore, it is recommended that the serum levels of liver function tests be assayed periodically when starting nimesulide for chronic use. Discontinue the drug immediately in cases with worsening liver tests.

Caution: Coadministration with other potentially hepatotoxic drugs should be avoided.

USE IN PREGNANCY AND LACTATION:

In late pregnancy Nimesulide should be avoided because it may cause neonatal as well as perinatal toxicity. Nimesulide use in pregnant women should only be done if the potential benefits overweigh the risks and under medical supervision.

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 sites.

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 it.

 Antidiabetic agents Nimesulide had no significant effect on fasting blood and glucose tolerance in patients treated with antidiabetic agents.

ADVERSE EFFECTS:

Epigastric discomfort, heartburn or abdominal cramps, nausea, vomiting and diarrhea;

Skin rash, pruritis, oedema, headache, dizziness, drowsiness;

Hypersensitivity reactions (e.g. bronchospasm, rhinitis, angioedema urticaria); GI haemorrhage/perforation;

Bullous/erosive stomatitis, purpura, thrombocytopenia, toxic epidermal necrolysis, haematuria, oliguria, and renal failure;

Increase in liver enzymes. Fatal hepatitis, Stevenms Johnson syndrome.

DOSAGE AND ADMINISTRATION:

The usual oral dosage of Nimesulide in adults is 100 to 200 mg twice daily.

OVERDOSAGE:

No data is available on overdosage toxicity. In the event of overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.

STORAGE:
Store in a cool and dry place

COMMERCIAL PACKAGING:

Ø  10 Blisters of 10 Tablets