CLINICAL PHARMACOLOGY
Sulindac is a non-steroidal anti-inflammatory drug, also possessing analgesic and antipyretic activities. Its mode of action, like that of other non-steroidal anti-inflammatory agents, is not known; however, its therapeutic action is not due to pituitary-adrenal stimulation. Inhibition of prostaglandin synthesis by the sulfide metabolite may be involved in the anti-inflammatory action of sulindac.
Sulindac is approximately 90% absorbed in man after oral administration. The peak plasma concentrations of the biologically active sulfide metabolite are achieved in about two hours when sulindac is administered in the fasting state, and in about three to four hours when sulindac is administered with food. The mean half-life of sulindac is 7.8 hours while the mean half-life of the sulfide metabolite is 16.4 hours. Sustained plasma levels of the sulfide metabolite are consistent with a prolonged anti-inflammatory action which is the rationale for a twice per day dosage schedule.
Sulindac and its sulfone metabolite undergo extensive enterohepatic circulation relative to the sulfide metabolite in animals. Studies in man have also demonstrated that recirculation of the parent drug, sulindac, and its sulfone metabolite, is more extensive than that of the active sulfide metabolite. The active sulfide metabolite accounts for less than six percent of the total intestinal exposure to sulindac and its metabolites.
The primary route of excretion in man is via the urine as both sulindac and its sulfone metabolite (free and glucuronide conjugates). Approximately 50% of the administered dose is excreted in the urine, with the conjugated sulfone metabolite accounting for the major portion. Less than 1% of the administered dose of sulindac appears in the urine as the sulfide metabolite. Approximately 25% is found in the feces, primarily as the sulfone and sulfide metabolites.
The bioavailability of sulindac, as assessed by urinary excretion, was not changed by concomitant administration of an antacid containing magnesium hydroxide 200 mg and aluminum hydroxide 225 mg per 5 mL.
Because sulindac is excreted in the urine primarily as biologically inactive forms, it may possibly affect renal function to a lesser extent than other non-steroidal anti-inflammatory drugs, however, renal adverse experiences have been reported with sulindac (see ADVERSE REACTIONS). In a study of patients with chronic glomerular disease treated with therapeutic doses of sulindac, no effect was demonstrated on renal blood flow, glomerular filtration rate, or urinary excretion of prostaglandin E2 and the primary metabolite of prostacyclin, 6-keto-PGF1α. However, in other studies in healthy volunteers and patients with liver disease, sulindac was found to blunt the renal responses to intravenous furosemide, i.e., the diuresis, natriuresis, increments in plasma renin activity and urinary excretion of prostaglandins. These observations may represent a differentiation of the effects of sulindac on renal functions based on differences in pathogenesis of the renal prostaglandin dependence associated with differing dose-response relationships of different NSAIDs to the various renal functions influenced by prostaglandins. These observations need further clarification and in the interim, sulindac should be used with caution in patients whose renal function may be impaired (see WARNINGS).
In healthy men, the average fecal blood loss, measured over a two-week period during administration of 400 mg per day of sulindac, was similar to that for placebo, and was statistically significantly less than that resulting from 4800 mg per day of aspirin.
In controlled clinical studies sulindac was evaluated in the following five conditions:
- 1. Osteoarthritis
In patients with osteoarthritis of the hip and knee, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; improvement in ARA Functional Class; relief of night pain; improvement in overall evaluation of pain, including pain on weight bearing and pain on active and passive motion; improvement in joint mobility, range of motion, and functional activities; decreased swelling and tenderness; and decreased duration of stiffness following prolonged inactivity.
In clinical studies in which dosages were adjusted according to patient needs, sulindac 200 to 400 mg daily was shown to be comparable in effectiveness to aspirin 2400 to 4800 mg daily. Sulindac was generally well tolerated, and patients on it had a lower overall incidence of total adverse effects, of milder gastrointestinal reactions, and of tinnitus than did patients on aspirin. (See ADVERSE REACTIONS).
- 2. Rheumatoid arthritis
In patients with rheumatoid arthritis, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; reduction in overall joint pain; reduction in duration and severity of morning stiffness; reduction in day and night pain; decrease in time required to walk 50 feet; decrease in general pain as measured on a visual analog scale; improvement in the Ritchie articular index; decrease in proximal interphalangeal joint size; improvement in ARA Functional Class; increase in grip strength; reduction in painful joint count and score; reduction in swollen joint count and score; and increased flexion and extension of the wrist.
In clinical studies in which dosages were adjusted according to patient needs, sulindac 300 to 400 mg daily was shown to be comparable in effectiveness to aspirin 3600 to 4800 mg daily. Sulindac was generally well tolerated, and patients on it had a lower overall incidence of total adverse effects, of milder gastrointestinal reactions, and of tinnitus than did patients on aspirin. (See ADVERSE REACTIONS).
In patients with rheumatoid arthritis, sulindac may be used in combination with gold salts at usual dosage levels. In clinical studies, sulindac added to the regimen of gold salts usually resulted in additional symptomatic relief but did not alter the course of the underlying disease.
- 3. Ankylosing spondylitis
In patients with ankylosing spondylitis, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; decrease in disease activity as assessed by both patient and investigator; improvement in ARA Functional Class; improvement in patient and investigator evaluation of spinal pain, tenderness and/or spasm; reduction in the duration of morning stiffness; increase in the time to onset of fatigue; relief of night pain; increase in chest expansion; and increase in spinal mobility evaluated by fingers-to-floor distance, occiput to wall distance, the Schober Test, and the Wright Modification of the Schober Test. In a clinical study in which dosages were adjusted according to patient need, sulindac 200 to 400 mg daily was as effective as indomethacin 75 to 150 mg daily. In a second study, sulindac 300 to 400 mg daily was comparable in effectiveness to phenylbutazone 400 to 600 mg daily. Sulindac was better tolerated than phenylbutazone. (See ADVERSE REACTIONS.)
- 4. Acute painful shoulder (Acute subacromial bursitis/supraspinatus tendinitis)
In patients with acute painful shoulder (acute subacromial bursitis/supraspinatus tendinitis), the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both patient and investigator of overall response; relief of night pain, spontaneous pain, and pain on active motion; decrease in local tenderness; and improvement in range of motion measured by abduction, and internal and external rotation. In clinical studies in acute painful shoulder, sulindac 300 to 400 mg daily and oxyphenbutazone 400 to 600 mg daily were shown to be equally effective and well tolerated.
- 5. Acute gouty arthritis
In patients with acute gouty arthritis, the anti-inflammatory and analgesic activity of sulindac was demonstrated by clinical measurements that included: assessments by both the patient and investigator of overall response; relief of weight-bearing pain; relief of pain at rest and on active and passive motion; decrease in tenderness; reduction in warmth and swelling; increase in range of motion; and improvement in ability to function. In clinical studies, sulindac at 400 mg daily and phenylbuta zone at 600 mg daily were shown to be equally effective. In these short-term studies in which reduction of dosage was permitted according to response, both drugs were equally well tolerated.
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