Drugs

, Volume 45, Issue 1, pp 131–156 | Cite as

Nabumetone

A Reappraisal of its Pharmacology and Therapeutic Use in Rheumatic Diseases
  • Heather A. Friedel
  • Heather D. Langtry
  • Micaela M. Buckley
Drug Evaluation

Abstract

Synopsis

Nabumetone is a nonsteroidal anti-inflammatory drug (NSAID) used to treat rheumatic and inflammatory conditions. It is absorbed as a nonacidic prodrug and is rapidly converted in the liver to an active metabolite which is responsible for its anti-inflammatory and analgesic effects. Published data from earlier comparative studies indicate that nabumetone, administered in a single dose of 1 to 2g daily, is as effective as aspirin, diclofenac, ibuprofen, indomethacin, naproxen and sulindac for the symptomatic treatment of rheumatoid arthritis, osteoarthritis, various nonarticular rheumatic conditions and acute soft tissue injury. Adverse events with nabumetone occur less frequently than with aspirin, and the incidence of gastrointestinal adverse events with nabumetone compares favourably with that of other NSAIDs. Rates of gastrointestinal ulceration and bleeding with nabumetone are low, apparently less than 1% annually.

More recently, data from large-scale clinical trials and postmarketing surveillance studies have further confirmed the efficacy and tolerability of nabumetone. Thus, the drug should now be considered a well established member of this group of agents for the treatment of painful rheumatic and inflammatory conditions.

Pharmacodynamic Properties

Nabumetone possesses the typical pharmacodynamic properties of the nonsteroidal class of anti-inflammatory drugs. Its activity in animal tests of acute and chronic inflammation is similar to that of other NSAIDs, with intrinsic analgesic and antipyretic activity being demonstrated in animal studies and in humans. Nabumetone undergoes rapid metabolism in the liver to the principal active compound, 6-methoxy-2-naphthylacetic acid (6-MNA). The anti-inflammatory effects are thought to be related to the ability of the active metabolite to inhibit prostaglandin synthesis in synovial tissue and fluid and in other inflammatory exudates.

Absorbed as the nonacidic un-ionised prodrug, nabumetone does not appear to exert a significant direct toxic effect on the gastric mucosa during absorption. There also does not appear to be an indirect mucosal effect via biliary secretion of its active metabolite. In studies using endoscopic and radiolabelled erythrocyte evaluations, nabumetone produced a lower incidence of gastrointestinal erosions or microbleeding than aspirin, naproxen, piroxicam and ibuprofen.

Unlike most other NSAIDs, nabumetone is a weak inhibitor of platelet aggregation and has little or no effect on bleeding time or coagulation parameters. Nabumetone also only weakly inhibits vascular prostacyclin synthesis, a factor which is thought to be implicated in the hypertensive and nephrotoxic adverse effects of some NSAIDs.

Pharmacokinetic Properties

Nabumetone is absorbed primarily in the duodenum and undergoes extensive and rapid firstpass metabolism in the liver to the principal active compound, 6-MNA, and a range of inactive metabolites. The mean absolute bioavailability of 6-MNA is approximately 35%, the rate but not the extent of absorption being increased in the presence of milk or food. Plasma concentrations of 6-MNA are slightly less than linear over the range of nabumetone 500mg to 2g and steady-state is reached in about 3 to 6 days of once-daily administration.

6-MNA is extensively bound to plasma proteins (> 99%) and has a mean steady-state volume of distribution of 7.5L. Enterohepatic circulation does not occur to any significant extent. The metabolite diffuses readily into synovial tissue and fluid, fibrous capsule tissue and various inflammatory exudates at concentrations necessary to inhibit those prostaglandins which mediate inflammation. Final elimination of all metabolites in the urine accounts for approximately 80% of an administered dose of nabumetone. The terminal phase elimination half-life of 6-MNA is about 24 hours.

Steady-state plasma concentrations of 6-MNA are unaffected by renal dysfunction, and although volume of distribution increases and absorption and elimination rate constants decrease as renal function deteriorates, no dosage adjustment appears to be necessary. In elderly patients the elimination half-life appears to be longer than in young healthy volunteers (30 hours vs 23 hours). In addition, plasma concentrations attained in elderly patients are higher than those in young volunteers. However, drug accumulation does not occur with once daily administration.

Therapeutic Trials

Nabumetone has been studied in controlled clinical trials in patients with rheumatoid arthritis and osteoarthritis. The drug shows equivalent anti-inflammatory and analgesic efficacy to that of usual doses of other common NSAIDs such as aspirin, indomethacin, naproxen, sulindac, diclofenac and ibuprofen. Most recently, large-scale noncomparative clinical trials and postmarketing surveillance studies have confirmed the efficacy and tolerability of nabumetone in these indications. While the majority of patients respond to the 1g daily dosage, some patients will require an increase in dosage to 1.5 or 2g daily. The therapeutic efficacy of nabumetone in rheumatoid arthritis was maintained during long term treatment in trials of up to 5 years’ duration.

Nabumetone is also effective in the treatment of various acute and chronic nonarticular rheumatic syndromes. For soft tissue injuries nabumetone is superior in tolerability to soluble aspirin. Efficacy in relieving pain and limitation of movement appears to be equivalent to that of other NSAIDs such as ibuprofen and naproxen. While gastrointestinal tolerability is better with nabumetone than with aspirin, slow release diclofenac and possibly naproxen and indomethacin, the overall profile of gastrointestinal symptoms is qualitatively similar to that of other NSAIDs. Nabumetone may have some advantage in tolerability over indomethacin for the treatment of ankylosing spondylitis.

Tolerability

Nabumetone is generally well tolerated. While adverse events are common, these are predominantly mild to moderate in degree, and the number of patients withdrawn from treatment due to adverse events is relatively low. Large-scale drug monitoring studies have established that the range of adverse events occurring with nabumetone therapy is qualitatively similar to that with other NSAIDs. The most frequent events involve the gastrointestinal tract (e.g. abdominal pain, dyspepsia, diarrhoea, nausea, flatulence), followed by the central nervous system (e.g. headache, tinnitus, dizziness) and the skin (e.g. rash, pruritus).

The incidence of gastrointestinal adverse events associated with nabumetone is lower than that with aspirin or slow release diclofenac, and was lower than that of naproxen and indomethacin in some trials. Importantly, the annual incidence of endoscopically proven gastric or duodenal erosions associated with nabumetone therapy is in the order of 0.5%, lower than published values for other NSAIDs. In some retrospective studies, the incidence of gastrointestinal bleeding with nabumetone has appeared to be low in relation to reported values for other NSAIDs; however, the true relative potential for occurrence of this severe complication during nabumetone therapy remains to be confirmed.

Dosage and Administration

The usual initial dosage of nabumetone for patients with rheumatic diseases is 1g administered once daily. For severe or persistent symptoms or acute exacerbations an additional dose of 500mg to 1g daily may be administered. As with other agents of this therapeutic class, the lowest effective dose should be employed for maintenance treatment.

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Copyright information

© Adis International Limited 1993

Authors and Affiliations

  • Heather A. Friedel
    • 1
  • Heather D. Langtry
    • 1
  • Micaela M. Buckley
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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