LAUSR

Five years have passed since the Food and Drug Administration (FDA) issued its directives restricting the use of ketoconazole as an antifungal agent in clinical practice, and discouraging the use of ketoconazole as an index inhibitor of cytochrome P450-3A (CYP3A) metabolic activity in drug-drug interaction studies involving healthy volunteers.1–3 The initial Drug Safety Communication dated July 25, 2013, stated that the FDA “conducted a comprehensive benefit-risk assessment of the safety and efficacy of Nizoral (ketoconazole) tablets in the context of the drug’s labeled indications for the treatment of superficial and systemic fungal infections . . . ” The communication goes on to state that data retrieved from the FDA Adverse Event Reporting System (AERS) were assessed independently by a hepatology expert in FDA. In a follow-up Drug Safety notice dated October 16 of the same year, the agency recommended that drug companies and researchers “avoid using oral ketoconazole in drug interaction studies.” Findings from the FDA’s analysis of ketoconazole liver injury have not been published in the biomedical literature, but are available in documents∗ relating to the Public Citizen Health Research Group’s petition to the FDA “ . . . to immediately require the removal from the market of the oral form of the antifungal agent ketoconazole,“ dated February 24, 2015. Appended to the petition was a document dated January 4, 2013, from the FDA’s Office of Surveillance and Epidemiology, titled “Benefit-Risk Assessment of Oral Ketoconazole Tablets.” On September 1, 2017, the FDA issued a response denying the petition. In this Commentary, we update the current state of scientific knowledge on the topic of liver injury associated with ketoconazole and other azole antifungal agents.