Five years of post-marketing liver safety data from the tolvaptan Risk Evaluation and Mitigation Strategy.

Background: Approval of tolvaptan in the USA for the treatment of autosomal dominant polycystic kidney disease (ADPKD) was contingent on implementation of a Risk Evaluation and Mitigation Strategy (REMS) that includes monitoring for drug-induced liver injury (DILI). Liver safety data from the REMS were published previously for the period from program start (May 2018) to February 2021. To further characterize the post-marketing liver safety of tolvaptan, we provide a REMS update. Methods: We analyzed prospective pharmacovigilance data on ADPKD patients who initiated tolvaptan in the post-marketing setting. The data capture period was May 2018 to February 2023. Results: Among 10 879 tolvaptan-treated patients, exposure was >12 months for 45% and >18 months for 35%. Since the 3-year analysis, in which 60/6711 (0.9%) patients were reported with possible severe DILI, the frequency has remained consistent for 5 years [i.e. 82/10 879 (0.8%)]. Incidence of possible severe DILI in the REMS at 5 years was 0.52 events per 100 patient years. Confirmation of possible severe DILI events as serious and potentially fatal was made for 4/82 events, with no new cases confirmed since the 3-year reporting period. No fatalities or liver transplants attributable to tolvaptan-related DILI have been reported in the REMS. Conclusions: Five years of data support adherence to the per-label tolvaptan liver function monitoring schedule to promptly detect and manage liver toxicity. Conclusions are limited by data availability at the time of analysis cutoff, with the possibility that additional cases of possible severe DILI and/or serious and potentially fatal events may be identified.