Liver injury associated with ketoconazole: review of the published evidence

J Clin Pharmacol. 2014 Dec;54(12):1321-9. doi: 10.1002/jcph.400. Epub 2014 Oct 1.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • Antifungal Agents / adverse effects*
  • Antifungal Agents / pharmacokinetics
  • Antifungal Agents / pharmacology
  • Antifungal Agents / therapeutic use
  • Chemical and Drug Induced Liver Injury / epidemiology
  • Chemical and Drug Induced Liver Injury / etiology*
  • Chemical and Drug Induced Liver Injury / metabolism
  • Cytochrome P-450 CYP3A Inhibitors / adverse effects*
  • Cytochrome P-450 CYP3A Inhibitors / pharmacokinetics
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology
  • Cytochrome P-450 CYP3A Inhibitors / therapeutic use
  • Drug Interactions
  • Humans
  • Ketoconazole / adverse effects*
  • Ketoconazole / pharmacokinetics
  • Ketoconazole / pharmacology
  • Ketoconazole / therapeutic use
  • Mycoses / drug therapy


  • Antifungal Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Ketoconazole