Hepatic adverse events associated with ketamine and esketamine: A population-based disproportionality analysis

Background and objective: To determine whether there is disproportionate reporting of hepatobiliary disorders in the United States (US) FDA Adverse Event Reporting System (FAERS) for individuals prescribed ketamine or esketamine. Design: We identified Medical Dictionary for Regulatory Activities (MedDRA) terms in the FAERS related to hepatobiliary disorders. Main measures: Formulations of ketamine and esketamine were evaluated for the proportionality of reporting for each hepatobiliary disorder parameter using the reporting odds ratio (ROR). We also estimated the lower limits of 95 % confidence intervals of information components (IC025) to determine whether the association was significant. Acetaminophen was used as the positive reference agent and lithium as the neutral reference agent. Key results: We observed disproportionately lower reporting of hepatitis, liver disorder, liver injury, drug-induced liver injury, hepatic failure, and acute hepatic failure for ketamine compared to acetaminophen. Additionally, we observed disproportionately higher reporting of hepatic function abnormalities and hepatic cytolysis for ketamine compared to acetaminophen. For esketamine, we did not find disproportionate reporting of any hepatobiliary toxicity relative to acetaminophen. However, for ketamine, there was disproportionate lower reporting of hepatic function abnormalities, liver disorder and hepatic cirrhosis. In contrast, for esketamine, there was disproportionately higher reporting of hepatic failure. Conclusions: Although causality has not been established, the data support recommendations for periodic monitoring of liver function tests, as well as clinical surveillance for stigmata of hepatobiliary disease in individuals receiving chronic exposure to ketamine and esketamine.