Drug safety assessment of oral formulations of ketoconazole

Abstract

Introduction: Ketoconazole was the first broad-spectrum oral antifungal approved by the FDA in 1981. Post-marketing reports of drug-related hepatotoxicity, endocrine dysregulation and drug interactions resulted in market withdrawal of the drug in some countries and strict product relabeling in others.

Areas covered: This drug safety review summarizes reports of oral ketoconazole-related adverse events retrieved from a search of the PubMed database using the search strategy ‘ketoconazole OR Nizoral AND hepat*’, references from relevant publications, and data from the FDA Adverse Event Reporting System.

Expert opinion: Although oral ketoconazole is effective in treating fungal infections, the potential for drug interactions, endocrine dysregulation, and hepatotoxicity may outweigh its benefits. Newer oral antifungals have similar or greater efficacy in treating dermatologic conditions and are associated with less risk. Likewise, newer agents with specific targets and fewer drug interactions have been developed to treat systemic fungal infections. Therefore, by the time ketoconazole prescribing guidelines were amended, its use had already largely been replaced with newer antifungals. Being that ketoconazole was the first broad-spectrum oral antifungal, experience with the drug made patient safety, and especially hepatic safety, an important consideration in future antifungal development.

Keywords:

• antifungal
• ergosterol synthesis inhibitor
• hepatic injury
• hepatotoxicity
• imidazole
• ketoconazole
• liver injury
• mycosis

Declaration of interest

D Daigle and KA Foley are employees of Mediprobe Research, Inc., which conducts clinical trials under the supervision of AK Gupta. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.