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TOPLINE:

Fezolinetant is associated with a hepatic adverse event reporting signal characterized primarily by transaminase elevations rather than clinically overt liver injury, with marked disproportionality observed for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and liver function test increases. Median time to onset for hepatic events was 77 days, with an early failure pattern suggesting events tend to occur relatively early after treatment initiation.

METHODOLOGY:

• Researchers conducted a retrospective disproportionality analysis using the FDA Adverse Event Reporting System (FAERS) database from the second quarter of 2023 through the second quarter of 2025, covering the period after fezolinetant’s regulatory approval in the US.
• A total of 1282 individual case reports involving fezolinetant were identified, among which 381 cases were categorized as hepatic-related adverse events, extracted from 3,198,344 valid individual case reports in the database.
• Reporting odds ratios (RORs) and 95% CIs were calculated for adverse events with more than three reports, with a significant signal defined as a lower bound of the 95% CI ≥ 1.
• Subgroup analyses were performed by age, body weight, country of occurrence, and reporter type, and comparative hepatic adverse event assessments were conducted against reference hepatotoxic drugs (methotrexate, azathioprine, and tamoxifen) and hormone therapy agents (medroxyprogesterone acetate combined with estrogen and estradiol monotherapy).
• Time-to-onset analysis was conducted using the Weibull distribution to evaluate the temporal relationship between fezolinetant initiation and adverse event occurrence, with time to onset defined as the interval between treatment initiation and event onset.

TAKEAWAY:

• The most prominent hepatic signals were observed for ALT increase (ROR lower bound [ROR025], 35.72), AST increase (ROR025, 29.67), and liver function test increase (ROR025, 27.9), with ALT increases accounting for 23.0%, hepatic enzyme increases for 22.4%, and AST increases for 17.1% of all liver-related reports.
• Sensitivity analysis comparing reporting patterns before and after the FDA boxed warning (December 16, 2024) showed substantial increases in ROR025 for transaminase-related events, including ALT increase (from 17.82 to 65.18), AST increase (from 17.68 to 45.57), and hepatic enzyme increase (from 5.01 to 49.28) in the postwarning period.
• Subgroup analysis showed higher reporting signals in women (ROR025, 20.09) and individuals aged 18-64 years (ROR025, 15.02), with regional analysis showing higher ROR025 values in Europe (35.85) and Oceania (33.06).
• The Weibull shape parameter β was 0.44 (95% CI, 0.35-0.55), indicating an early failure pattern, with 28.33% of hepatic events occurring within 30 days, 15.0% within 31-60 days, 11.67% within 61-90 days, and 15.0% within 91-120 days.

IN PRACTICE:

“Data identify a signal of hepatic adverse event reporting for fezolinetant, primarily characterized by transaminase elevations rather than clinically overt liver injury. The early failure pattern suggests that hepatic events may tend to occur relatively early after treatment initiation, which highlights the importance of baseline assessment and early-phase monitoring, but continued clinical vigilance remains warranted,” wrote the authors of the study.

SOURCE:

The study was led by Nai Lee, MS, and Yun Kim, PharmD, PhD, College of Pharmacy and the Convergence Research Institute for Biomedical Sciences, Daegu Catholic University, Gyeongsan, Republic of Korea. It was published online in Obstetrics & Gynecology.

LIMITATIONS:

The findings should be interpreted in light of the limitations inherent to voluntary reporting systems. FAERS data are subject to underreporting, reporting bias, and potential surveillance bias related to increased clinical monitoring, which may influence the detection and reporting of hepatic events. The absence of denominator data limits interpretation to relative reporting measures, and incomplete clinical information may affect the assessment of individual cases. These factors underscore that the findings should be interpreted as signals rather than measures of clinical risk or causality. Additionally, temporal patterns of hepatic event reporting may be influenced by changes in monitoring intensity and regulatory context because lower Weibull shape parameter values were observed during periods of more intensive monitoring and regulatory oversight.

DISCLOSURES:

The study received support from a research grant provided by Daegu Catholic University in 2024 and the Regional Innovation System & Education (RISE) program through the Gyeongbuk RISE Center, which was funded by the Ministry of Education and Gyeongsangbuk-do, Republic of Korea (2025-RISE-15-107). The authors disclosed having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.