CLINICAL PHARMACOLOGY
Studies in animals have shown tolmetin sodium to possess anti-inflammatory, analgesic, and antipyretic activity. In the rat, tolmetin sodium prevents the development of experimentally induced polyarthritis and also decreases established inflammation.
The mode of action of tolmetin sodium is not known. However, studies in laboratory animals and man have demonstrated that the anti-inflammatory action of tolmetin sodium is not due to pituitary-adrenal stimulation. Tolmetin sodium inhibits prostaglandin synthetase in vitro and lowers the plasma level of prostaglandin E in man. This reduction in prostaglandin synthesis may be responsible for the anti-inflammatory action. Tolmetin sodium does not appear to alter the course of the underlying disease in man.
In patients with rheumatoid arthritis and in normal volunteers, tolmetin sodium is rapidly and almost completely absorbed with peak plasma levels being reached within 30 to 60 minutes after an oral therapeutic dose. Tolmetin displays a biphasic elimination from the plasma consisting of a rapid phase with a half-life of 1 to 2 hours followed by a slower phase with a half-life of about 5 hours. Peak plasma levels of approximately 40 mcg/mL are obtained with a 400 mg oral dose. Essentially all of the administered dose is recovered in the urine in 24 hours either as an inactive oxidative metabolite or as conjugates of tolmetin. An 18 day multiple dose study demonstrated no accumulation of tolmetin when compared with a single dose.
In two fecal blood loss studies of 4 to 6 days duration involving 15 subjects each, tolmetin sodium did not induce an increase in blood loss over that observed during a 4 day drug-free control period. In the same studies, aspirin produced a greater blood loss than occurred during the drug-free control period, and a greater blood loss than occurred during the tolmetin sodium treatment period. In one of the two studies, indomethacin produced a greater fecal blood loss than occurred during the drug-free control period; in the second study, indomethacin did not induce a significant increase in blood loss.
Tolmetin sodium is effective in treating both the acute flares and in the long-term management of the symptoms of rheumatoid arthritis, osteoarthritis, and juvenile rheumatoid arthritis.
In patients with either rheumatoid arthritis or osteoarthritis, tolmetin sodium is as effective as aspirin and indomethacin in controlling disease activity, but the frequency of the milder gastrointestinal adverse effects and tinnitus was less than in aspirin-treated patients, and the incidence of central nervous system adverse effects was less than in indomethacin-treated patients.
In patients with juvenile rheumatoid arthritis, tolmetin sodium is as effective as aspirin in controlling disease activity, with a similar incidence of adverse reactions. Mean SGOT values, initially elevated in patients on previous aspirin therapy, remained elevated in the aspirin group and decreased in the tolmetin sodium group.
Tolmetin sodium has produced additional therapeutic benefit when added to a regimen of gold salts and, to a lesser extent, with corticosteroids. Tolmetin sodium should not be used in conjunction with salicylates since greater benefit from the combination is not likely, but the potential for adverse reactions is increased.
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