The azole antifungal agent ketoconazole has been available since 1981 for the treatment of fungal infections. In 2013, the American Food and Drug Administration and the European Medicines Agency issued warnings or prohibitions against the clinical use of oral ketoconazole due to the risk of liver injury which may lead to liver transplantation or death. From the available published evidence it is difficult to determine the actual incidence or prevalence of liver injury during clinical use of ketoconazole as an antifungal. Hepatic injury, when it occurs, is generally evident as asymptomatic and reversible abnormalities of liver function tests. However, serious liver injury has been reported. Alternatives to ketoconazole (such as itraconazole, fluconazole, voriconazole, and terbinafine) are available, but improved safety with respect to liver injury risk is not clearly established. We are not aware of published reports of significant ketoconazole-associated liver injury in volunteer study participants when ketoconazole has been used as a CYP3A inhibitor in the context of clinical research on drug metabolism. Possible alternatives to ketoconazole as prototype CYP3A inhibitors include ritonavir and potentially itraconazole, but not clarithromycin.
Keywords: azole antifungals; clarithromycin; fluconazole; hepatotoxicity; itraconazole; ketoconazole; liver injury; ritonavir; terbinafine; voriconazole.
© 2014, The American College of Clinical Pharmacology.