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Drugs

, Volume 48, Issue 3, pp 431–454 | Cite as

Nimesulide

An Update of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy
  • Rick Davis
  • Rex N. Brogden
Drug Evaluation

Abstract

Synopsis

Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) administered orally or rectally twice daily for a variety of inflammatory and pain states. In mostly short term studies (up to 4 weeks), it was effective in reducing pain associated with osteoarthritis, cancer, thrombophlebitis, oral surgery and dysmenorrhea in adults, reducing pain associated with general surgery in adults and children, and pain, fever and inflammation accompanying respiratory tract infections, otorhinolaryngological diseases and traumatic injury in adults and children. Nimesulide appeared to be at least as effective as other NSAIDs in all of these indications.

Nimesulide has been well tolerated by adult, elderly and paediatric patients in clinical trials and large postmarketing surveillance studies. In general qualitative terms nimesulide exhibits the usual adverse events associated with NSAIDs (gastrointestinal, dermatological and neurological). However, it has a pharmacodynamic profile suggestive of a possibly reduced propensity to cause adverse gastrointestinal effects, although this has not been conclusively demonstrated in comparative clinical trials, many of which showed a similar incidence of such effects for nimesulide and the comparator agent. Additionally, nimesulide has been well tolerated by most aspirin (acetylsalicylic acid)- and/or NSAID-intolerant patients and in patients with asthma.

Thus, available evidence indicates that nimesulide is an effective and well tolerated alternative to other NSAIDs in the short term treatment of pain and inflammation of osteoarthritis and various other causes.

Pharmacodynamic Properties

The anti-inflammatory, analgesic and antipyretic activities of nimesulide, a non-steroidal anti-inflammatory drug (NSAID) of the sulfonanilide class, have been demonstrated in a number of experimental models and in numerous clinical trials. Nimesulide has exhibited potency similar to or greater than that of indomethacin, diclofenac, piroxicam and ibuprofen in standard animal models of inflammation such as carrageenin-induced rat paw oedema and inflammation, ultraviolet light-induced erythema in guinea-pigs and adjuvant arthritis in rats. The analgesic potency of nimesulide was 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. Nimesulide has shown superior antipyretic potency to indomethacin, ibuprofen, aspirin and paracetamol (acetaminophen) in rats with yeast-induced fever.

Nimesulide is a relatively weak inhibitor of prostaglandin synthesis in vitro and appears to exert its effects through a variety of mechanisms including free-radical scavenging, effects on histamine release, the neutrophil myeloperoxidase pathway, bradykinin activity, tumour necrosis factor-α release, cartilage degradation, metalloprotease synthesis, phosphodiesterase type IV inhibition, platelet aggregation and synthesis of platelet activating factor. Animal studies have suggested that nimesulide is less ulcerogenic than aspirin, indomethacin, naproxen, piroxicam and ibuprofen. Nimesulide appears to have little effect on renal prostaglandin synthesis in rats.

Pharmacokinetic Properties

After oral administration of nimesulide 50 to 200mg to healthy adult volunteers, peak serum concentrations of 1.98 to 9.85 mg/L are achieved within 1.22 to 3.17 hours. Compared with values obtained with oral drug administration, peak serum concentrations are slightly lower (2.14 to 2.32 mg/L) and are achieved more slowly (3 to 4.58h) after rectal administration of nimesulide 100 and 200mg. Oral drug absorption is nearly complete and concomitant administration of food may decrease the rate, but not the extent, of absorption of nimesulide. The drug is extensively bound (99%) to plasma proteins and has an estimated apparent volume of distribution of 0.19 to 0.35 L/kg following oral administration.

Nimesulide is extensively metabolised (1 to 3% of a dose is excreted unchanged in the urine) to several metabolites which are excreted mainly in the urine (≈70%) or the faeces (≈20%). The drug is almost completely biotransformed into 4-hydroxy-nimesulide in both free and conjugated forms and this metabolite appears to contribute to the anti-inflammatory activity of the compound. Peak concentrations of 4-hydroxy-nimesulide ranged from 0.84 to 3.03 mg/L and were attained within 2.61 to 5.33 hours after oral administration of nimesulide 50 to 200mg to healthy adult volunteers. The elimination half-life of 4-hydroxy-nimesulide ranges from 2.89 to 4.78 hours and is generally similar to or slightly higher than that of the parent compound (1.56 to 4.95h).

The pharmacokinetic profile of nimesulide is not significantly altered in children, elderly volunteers and patients with moderately impaired renal function [creatinine clearance 1.8 to 4.8 L/h (30 to 80 ml/min)]. Slight accumulation of 4-hydroxy-nimesulide was noted in patients with moderate renal impairment; however, the clinical significance of this finding is unknown.

Therapeutic Efficacy

Clinical studies have established the analgesic, anti-inflammatory and antipyretic effectiveness of orally (mostly 200 mg/day) or rectally (400 mg/day) administered nimesulide in the treatment of a variety of painful inflammatory conditions, including those associated with osteoarthritis, oncology, postoperative trauma, sports injuries, ear, nose and throat disorders, dental surgery, bursitis/tendinitis, thrombophlebitis, upper airways inflammation and gynaecological disorders. In these indications, nimesulide is more effective than placebo and is at least as effective as therapeutic dosages of other NSAIDs, including piroxicam, ketoprofen, naproxen, etodolac, mefenamic acid, diclofenac, niflumic acid, fentiazac, feprazone and flurbiprofen. Nimesulide therapy was characterised by a rapid onset of analgesia and symptomatic relief in studies where a significant difference in clinical efficacy between active treatments was observed. However, most of these studies evaluated small numbers of patients and were probably too small to identify any small differences in effectiveness.

In children, nimesulide suspension, granules and suppositories are more effective than placebo and are at least as effective as paracetamol, diclofenac, naproxen, lysine acetylsalicylate, mefenamic acid, ketoprofen and dipyrone in reducing the pain, inflammation and fever associated with respiratory tract infection, postoperative pain and musculoskeletal injury.

Tolerability

Nimesulide has been well tolerated by both young and elderly adults and children in 2 large postmarketing surveillance surveys. As with other NSAIDs, the most common adverse effects are gastrointestinal disturbances (epigastralgia, heartburn, nausea, diarrhoea and vomiting; 5.1 to 8.5% of patients), dermatological reactions (rash, pruritus; 0.2 to 0.6%) and central nervous system effects (dizziness, somnolence, headache; 0.3 to 0.4%). Withdrawal rates associated with short term (up to 30 days) nimesulide treatment range from 1.1 to 2.2% in adult, elderly and paediatric patients.

Available data indicate that the gastrointestinal tolerability of nimesulide in adults and children is similar to that of other NSAIDs. The rate of endoscopically verified gastroduodenal irritation with nimesulide appears to be similar to that with placebo and diclofenac, and less than that with indomethacin. The drug is well tolerated by most patients intolerant of aspirin and/or other NSAIDs and by patients with asthma.

Dosage and Administration

The usual oral and rectal dosages of nimesulide in adults are 100 and 200mg twice daily, respectively. In children, nimesulide dosage is commonly 5 mg/kg/day divided into 2 or 3 daily doses administered in the form of a suspension, granules or suppositories. The drug is contraindicated in patients with active peptic ulcer disease or moderate to severe hepatic impairment. Nimesulide is generally well tolerated in the elderly and patients with moderate renal insufficiency; however, caution should be used in this group of patients. Similarly, although nimesulide does not appear to interact with warfarin in patients and healthy volunteers, interactions with oral anticoagulants or other highly protein bound drugs cannot be ruled out in clinical practice.

Keywords

Adis International Limited Indomethacin Naproxen Piroxicam Ketoprofen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Rick Davis
    • 1
  • Rex N. Brogden
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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