A Benefit-Risk Assessment of Benzbromarone in the Treatment of Gout: Was its Withdrawal from the Market in the Best Interest of Patients?

• Published in: Drug safety 2008-01, Vol.31 (8), p.643-665
• Main Authors: Lee, Ming-Han H., Graham, Garry G., Williams, Kenneth M., Day, Richard O.
• Format: Article
• Language: English
• Subjects: Animals; Benzbromarone - adverse effects; Benzbromarone - pharmacokinetics; Benzbromarone - therapeutic use; Biological and medical sciences; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Diseases of the osteoarticular system; Drug Approval; Drug Safety and Pharmacovigilance; Drug toxicity and drugs side effects treatment; Gout - drug therapy; Gout - epidemiology; Humans; Inflammatory joint diseases; Medical sciences; Medicine; Medicine & Public Health; Metabolic diseases; Miscellaneous. Osteoarticular involvement in other diseases; Other metabolic disorders; Pharmacology. Drug treatments; Pharmacology/Toxicology; Purines and pyrimidines (gout, hyperuricemia...); Review Article; Risk Factors; Toxicity: digestive system; Uricosuric Agents - adverse effects; Uricosuric Agents - pharmacokinetics; Uricosuric Agents - therapeutic use
• ISSN: 0114-5916; 1179-1942
• DOI: 10.2165/00002018-200831080-00002

Benzbromarone, a potent uricosuric drug, was introduced in the 1970s and was viewed as having few associated serious adverse reactions. It was registered in about 20 countries throughout Asia, South America and Europe. In 2003, the drug was withdrawn by Sanofi-Synthélabo, after reports of serious hepatotoxicity, although it is still marketed in several countries by other drug companies. The withdrawal has greatly limited its availability around the world, and increased difficulty in accessing it in other countries where it has never been available. The overall aim of this paper is to determine if the withdrawal of benzbromarone was in the best interests of gouty patients and to present a benefit-risk assessment of benzbromarone. To determine this, we examined (i) the clinical benefits associated with benzbromarone treatment and compared them with the success of alternative therapies such as allopurinol and probenecid, particularly in patients with renal impairment; (ii) the attribution of the reported cases of hepatotoxicity to treatment with benzbromarone; (iii) the incidence of hepatotoxicity possibly due to benzbromarone; (iv) adverse reactions to allopurinol and probenecid. From these analyses, we present recommendations on the use of benzbromarone. Large reductions in plasma urate concentrations in patients with hyperuricaemia are achieved with benzbromarone and most patients normalize their plasma urate. The half-life of benzbromarone is generally short (about 3 hours); however, a uricosuric metabolite, 6-hydroxybenzbromarone, has a much longer half-life (up to 30 hours) and is the major species responsible for the uricosuric activity of benzbromarone, although its metabolism by cytochrome P450 (CYP) 2C9 in the liver may vary between patients as a result of polymorphisms in this enzyme. It is effective in patients with moderate renal impairment. Standard dosages of benzbromarone (100 mg/day) tend to produce greater hypouricaemic effects than standard doses of allopourinol (300 mg/day) or probenecid (1000 mg/ day). Adverse effects associated with benzbromarone are relatively infrequent, but potentially severe. Four cases of benzbromarone-induced hepatotoxicity were identified from the literature. Eleven cases have been reported by Sanofi-Synthélabo, but details are not available in the public domain. Only one of the four published cases demonstrated a clear relationship between the drug and liver injury as demonstrated by rechallenge. The other three