HEPATIC-INJURY ASSOCIATED WITH KETOCONAZOLE THERAPY - ANALYSIS OF 33 CASES

Abstract

Of 54 reports of alleged ketoconazole[an antifungal agent]-induced liver injury submitted to the [USA] Food and Drug Administration from the time of initial marketing in 1980, 33 were considered likely instances of ketoconazole-induced hepatitis. The majority of these cases occurred in women more than 40 yr of age. Jaundice was recorded in 27 individuals after therapy of 11-168 days with an average daily dose of 200 mg. Anorexia, malaise, nausea and vomiting accompanied liver injury in 1/3 of cases. No instances of rash or eosinophilia were recorded. Serum transaminase and alkaline phosphatase values were consistent with acute hepatocellular injury in 18 patients, with primarily cholestatic injury in 5 patients, and with a mixed pattern in 9 individuals. Only 1 death seemed attributable to ketoconazole. In that patient, the drug was continued after the appearance of clinical and biochemical evidence of hepatic injury, and massive hepatocellular necrosis was present at autopsy. The incidence of symptomatic, potentially serious hepatic injury appears to be very low, perhaps 1 in 15,000 exposed individuals. The presumed mechanism of injury is metabolic idiosyncrasy, although hypersensitivity has not been completely dismissed in some cases. The incidence of mild, asymptomatic, reversible elevations in serum transaminases occurring in ketoconazole recipients is estimated to be 5-10%. Periodic biochemical testing and monitoring for symptoms of hepatitis during ketoconazole therapy is recommended to help prevent the developement of serious or fatal hepatic injury.