Real-world safety profile of fezolinetant: a disproportionality analysis based on the FAERS database

Fezolinetant, the first approved non-hormonal neurokinin-3 receptor antagonist for moderate-to‑severe vasomotor symptoms of menopause, demonstrated acceptable safety in phase 3 trials. However, real-world postmarketing safety evidence remains limited, and rare but serious liver injury has emerged as a regulatory concern. This study aimed to systematically characterize adverse event (AE) signals associated with fezolinetant using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database and to assess their consistency with clinical trial data and regulatory warnings. Retrospective disproportionality analysis was performed using the FAERS database from the second quarter of 2023 to the first quarter of 2026. Only unique cases with fezolinetant designated as the primary suspect drug were included. Four algorithms, namely the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and Multi-item Gamma Poisson shrinker (MGPS), were applied to detect positive AE signals at the system organ class (SOC) and preferred term (PT) levels. Time-to-onset analysis, subgroup analyses stratified by age and reporting period, and sensitivity analysis restricted to physician-submitted reports were also conducted. A total of 1757 unique cases involving 3391 adverse events (AEs) were enrolled, with most cases involving female patients. At the PT level, 20 positive signals simultaneously satisfying all four algorithms were observed. Among these, liver-related laboratory abnormalities were prominent, including aspartate aminotransferase increased (ROR 41.72, 95%CI_(ROR): 34.97-49.76, PRR 38.57, 95%CI_(PRR): 32.77-45.39), alanine aminotransferase increased (ROR 48.31, 95%CI_(ROR): 41.34-56.46, PRR 43.49, 95% CI_(PRR): 37.80-50.04), gamma-glutamyltransferase increased (ROR 33.58, 95% CI_(ROR): 24.39-46.22, PRR 32.86, 95% CI_(PRR): 24.04-44.91), blood alkaline phosphatase increased (ROR 24.97, 95% CI_(ROR): 17.76-35.13, PRR 24.51, 95% CI_(PRR): 17.54-34.25), and blood bilirubin increased (ROR 14.81, 95%CI_(ROR): 9.97-22.01, PRR14.62, 95% CI_(PRR): 9.89-21.60). Compared with clinical trials focusing mainly on transaminase elevation, this real-world study further revealed disproportionate reporting of additional cholestatic liver-related laboratory abnormalities. The median onset time of AEs was 38 days, with most events occurring within the first 100 days of treatment, consistent with the onset latency of serious hepatotoxicity noted in FDA warnings. Nightmare (ROR 6.61, 95% CI_(ROR): 3.90-11.19, PRR 6.56, 95%CI_(PRR): 3.89-11.06) was detected as a potential novel safety signal not listed in the current prescribing information, though this signal was attenuated in physician-only sensitivity analysis. Age subgroup analysis suggested differences in the biochemical patterns of liver injury between patients aged ≤ 55 years and > 55 years. Compared with reports submitted before 2024, post-2024 reports showed a greater number and stronger liver-related signals, which may partly reflect stimulated reporting following FDA safety communications. Sensitivity analysis supported the robustness of core hepatic safety signals. This real-world pharmacovigilance analysis of fezolinetant revealed disproportionate reporting of hepatic adverse events suggestive of a broader biochemical phenotype than previously recognized in clinical trials. Nightmare may represent a potential AE requiring further evaluation. The early onset window (first 100 days) suggests that closer liver function monitoring may be considered during treatment initiation. These findings provide real-world evidence to complement clinical trial data and may inform clinical safety assessment and risk management.