Benzbromarone: A Review of its Pharmacological Properties and Therapeutic Use in Gout and Hyperuricaemia

Summary

Synopsis: Benzbromarone is a benzofuran derivative which lowers serum urate and increases urinary urate excretion in normal, hyperuricaemic and gouty subjects. In open short- and long-term studies benzbromarone reduced serum uric acid levels by one-third to one-half and maintained its effectiveness for periods of up to 8 years. Single-dose experimental studies have shown benzbromarone to have a urate-lowering effect similar to that of a therapeutic dose of probenecid or sulphinpyrazone, but unlike these drugs benzbromarone can be administered in a once daily regimen. In 2 short-term comparative therapeutic trials in a small number of patients with hyperuricaemia, 80mg of micronised benzbromarone daily was at least as effective as 1000mg of probenecid or 300mg of allopurinol daily in lowering serum uric acid levels. Side-effects during benzbromarone administration are usually mild and primarily gastrointestinal in nature.

Pharmacodynamic Studies: In studies in rats, benzbromarone decreased the reabsorption of uric acid injected into the proximal tubule but had no effect on excretion of distally-injected urate. In man, therapeutic doses of benzbromarone reduced serum uric acid levels in normal or hyperuricaemic individuals by one-third to one-half, with a concurrent rise in urinary uric acid excretion. In addition to uricosuric activity, an effect on enzymes involved in purine metabolism and an increase in faecal urate excretion have been proposed as the mechanisms of the lowering effect of benzbromarone on serum uric acid. Some urate-lowering effect has occurred in a small number of anephric patients, supporting the possible existence of an extrarenal mechanism of action. Further systematic studies are needed however, to confirm this. A dose of 80mg of micronised or 100mg of non-micronised benzbromarone has about the same effect on serum urate and urinary urate excretion as 1 to 1.5g of probenecid or 400 to 800mg of sulphinpyrazone. The duration of activity of a single dose is up to 48 hours and benzbromarone can thus be administered in a once daily dose, unlike other uricosuric drugs.

As with other uricosuric agents, concomitant administration of pyrazinamide or aspirin decreases the effectiveness of benzbromarone, but studies of the extent of this decrease in activity have produced variable results, depending on the dosages of the inhibiting drugs.

Pharmacokinetic Studies: Absorption of benzbromarone after oral dosing is affected by the particle size of the preparation administered; 100mg of a standard non-micronised dose showing the same bioavailability as about 80mg of micronised drug. About 50% of a single, non-micronised dose is absorbed and dehalogenated in the liver to form bromobenzarone and benzarone, which retain part of the activity of the parent compound. Excretion occurs primarily via the bile and faeces and to a lesser extent in the urine.

Therapeutic Trials: Although benzbromarone has undergone only limited direct comparative trials with other uricosuric agents, it is nevertheless an effective urate-lowering drug. In open studies, serum uric acid levels have been decreased by one-third to one-half in hyperuricaemic and gouty patients and maintained at the lower levels for periods of up to 8 years. Most tophaceous deposits either disappeared or were reduced in size after several months of therapy. In 2 short-term comparative studies, 80mg of micronised benzbromarone daily was at least as effective as 1000mg of probenecid or 300mg of allopurinol daily in lowering serum uric acid levels of a smaller number of patients with hyperuricaemia.

The effectiveness of benzbromarone is reduced in patients with impaired renal function and most authors consider the drug to be ineffective if the glomerular filtration rate is below 20ml per minute. Although a standard dose (100mg/day, non-micronised) has reduced serum urate to some extent in a few treated patients with severe renal dysfunction, increased doses, which may lead to troublesome side-effects, have usually been required to achieve adequate results.

Side-effects were usually mild, diarrhoea being reported in about 3 to 4% of patients. As with other uricosuric drugs, joint pains, acute attacks of gout and urinary urate precipitation can occur if colchicine cover, urinary pH adjustment and adequate fluid intake are not provided, particularly during initial treatment stages. A severe skin rash, in a patient with impaired renal function and a history of allergies, and allergic conjunctivitis have been reported in isolated instances.

Another benzofuran derivative, benziodarone, with a structure similar to benzbromarone, markedly enhances the effect of warfarin and some other oral coumarin and indanedione anticoagulants. Thus, although potentiation of oral anticoagulants did not occur in a few patients who have received concomitant therapy with benzbromarone, until further studies are available benzbromarone should be administered with caution to patients receiving anticoagulant therapy.

Dosage: Most gouty or hyperuricaemic patients with normal renal function have been optimally controlled on 40 to 80mg of micronised or 100 to 200mg of non-micronised benzbromarone administered once daily. As with other uricosuric agents, colchicine (0.5mg twice daily) should be administered concurrently for the first few months, until serum uric acid levels are reduced, to prevent joint pain or the precipitation of acute attacks of gout. Adequate fluid intake and maintenance of urinary pH at 6.3 to 6.7 will minimise the risk of urinary urate precipitation.