Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database

Abstract

Aim: To inform clinicians on the level of hepatotoxic risk among antimycotics in the post-marketing setting, following the marketing suspension of oral ketoconazole for drug-induced liver injury (DILI).

Methods: The publicly available international FAERS database (2004-2011) was used to extract DILI cases (including acute liver failure events), where antimycotics with systemic use or potential systemic absorption were reported as suspect or interacting agents. The reporting pattern was analyzed by calculating the reporting odds ratio and corresponding 95%CI, a measure of disproportionality, with time-trend analysis where appropriate.

Results: From 1687284 reports submitted over the 8-year period, 68115 regarded liver injury. Of these, 2.9% are related to antimycotics (1964 cases, of which 112 of acute liver failure). Eleven systemic antimycotics (including ketoconazole and the newer triazole derivatives voriconazole and posaconazole) and terbinafine (used systemically to treat onychomicosis) generated a significant disproportionality, indicating a post-marketing signal of risk.

Conclusion: Virtually all antimycotics with systemic action or absorption are commonly reported in clinically significant cases of DILI. Clinicians must be aware of this aspect and monitor patients in case switch is considered, especially in critical poly-treated patients under chronic treatment.

Keywords: Antimycotics; Drug safety; Drug-induced hepatotoxicity; Pharmacovigilance; Spontaneous reporting systems.

Figure 1

Flowchart describing data-mining approach to allocate cases of interest according to selection criteria and case definition.

Figure 2

Cumulative time trend analysis of disproportionality (i.e., lower limit of 95%CI) on overall liver injury for ketoconazole (recently restricted/suspended), voriconazole and posaconazole (the most recent antimycotics receiving marketing authorization in United States and Europe). Relevant regulatory milestones (i.e., marketing approvals) are indicated by arrows. The total number of cases is also indicated when disproportionality was calculated for the first time (the first point of the lower limit of the 95%CI is provided when at least 3 cases of interest were recorded); EU: Europe; US: United states.