Concomitant use of valproic acid was associated with greater likelihood of transaminase elevation. In patients taking both valproic acid and cannabidiol oral solution at the higher dose, 13% experienced transaminase elevations over five times the upper limit of normal.
However, many patients had mild transaminase elevations at baseline, and most cases of transaminase elevation did not require discontinuation of cannabidiol oral solution. Both the sponsor and the FDA agreed that no cases of severe liver injury meeting Hy’s law criteria were seen during the clinical trials; the two cases of “hepatic failure” reported were not associated with elevated bilirubin or international normalized ratio (INR) levels.
The FDA staff clinical reviewer who presented the agency’s overview of liver safety did note one still-unknown factor.
“There are not enough patients exposed to this drug to know whether some might have a smoldering inflammatory response that might potentially – and I can only say potentially – cause a problem down the line,” said Lara Dimick-Santos, MD, of the Division of Gastroenterology and Inborn Errors Products of the Office of Drug Evaluation III, Office of New Drugs.