Highlights
Postmarketing surveillance identified a hepatic adverse event reporting signal for fezolinetant after U.S. approval, with the strongest disproportionality seen for alanine aminotransferase, aspartate aminotransferase, and liver function test elevations.
The signal was driven more by laboratory abnormalities than by consistently reported severe clinical liver outcomes such as overt hepatic failure.
The median time to onset of hepatic events was 77 days, and Weibull modeling suggested an early failure pattern, reinforcing the clinical importance of baseline testing and close monitoring soon after treatment initiation.
Although disproportionality analysis can detect safety signals, it cannot establish incidence or causality; the findings should therefore be interpreted as hypothesis-generating but clinically actionable in the context of current labeling.
Background
Fezolinetant is a neurokinin 3 receptor antagonist approved for the treatment of moderate to severe vasomotor symptoms associated with menopause. Its arrival was clinically important because it offers a nonhormonal option for patients who cannot or do not wish to use menopausal hormone therapy. That therapeutic niche is substantial: hot flashes and night sweats affect quality of life, sleep, mood, and work functioning, yet treatment choices are often constrained by contraindications, tolerability concerns, or patient preference.
Hepatic safety has been a central concern in the development and early postapproval use of fezolinetant. The drug’s U.S. labeling includes recommendations for liver laboratory monitoring, and the FDA has strengthened hepatic safety warnings over time as postmarketing experience accumulated. In this setting, pharmacovigilance becomes especially relevant. Spontaneous reporting systems such as the FDA Adverse Event Reporting System, or FAERS, are designed not to measure true event rates but to identify unexpected or disproportionate reporting patterns that may indicate a drug-event association worthy of clinical attention.
The study by Lee and colleagues therefore addresses a timely question: after approval and in the era of FDA boxed warning attention, what hepatic adverse event signals are emerging for fezolinetant in real-world use?
Study Design and Methods
Lee N, Lee Y, Kim G, and Kim Y conducted a retrospective disproportionality analysis using FAERS data from the second quarter of 2023 through the second quarter of 2025. The investigators identified 1,282 fezolinetant-associated reports and evaluated hepatic adverse event reporting patterns.
The primary analytic approach was disproportionality analysis using reporting odds ratios with 95% confidence intervals. In pharmacovigilance, a reporting odds ratio compares how often a given event is reported with a drug relative to how often that event is reported with other drugs in the database. A signal indicates disproportionate reporting, not proof of toxicity. The authors also performed subgroup analyses, compared hepatic event reporting with reference hepatotoxic drugs and hormone therapy agents, and examined time to onset. For temporal pattern analysis, they used the Weibull distribution, a method commonly applied in pharmacovigilance to infer whether events tend to occur early, randomly, or later during exposure.
The abstract does not provide a full list of comparator drugs or all prespecified hepatic preferred terms, but it makes clear that the comparative framework included both known hepatotoxic agents and hormone therapy comparators relevant to menopausal care.
Key Findings
Overall hepatic signal detected
The central finding was that fezolinetant was associated with a hepatic adverse event reporting signal in FAERS. Importantly, the pattern was not dominated by dramatic clinical liver injury syndromes. Instead, the most prominent signals involved elevations in liver-related laboratory parameters, particularly alanine aminotransferase, aspartate aminotransferase, and broader liver function testing abnormalities.
This distinction matters clinically. Laboratory-based signals often represent the earliest detectable form of drug-related liver effect and may precede symptoms. They can also reflect heightened monitoring when clinicians are already aware of a product’s hepatic warning. Even so, persistent or substantial aminotransferase elevations are not trivial. In drug-induced liver injury assessment, asymptomatic transaminase rises may serve as an early warning that identifies susceptible patients before progression to more serious injury.
Stronger reporting for laboratory abnormalities than severe liver outcomes
The abstract states that compared with reference hepatotoxic drugs and hormone therapy agents, fezolinetant showed higher reporting signals for laboratory-based abnormalities, whereas clinically severe hepatic outcomes were less consistently observed. That pattern suggests a safety profile characterized more by biochemical liver test perturbation than by a robust postmarketing signature of overt liver failure or other major clinical hepatic syndromes.
From a practical standpoint, this is reassuring only in part. A pharmacovigilance profile weighted toward laboratory abnormalities may indicate that current monitoring is successfully capturing events before they become clinically severe. But it may also indicate under-ascertainment of outcomes, incomplete case follow-up, or relatively short cumulative exposure time in the postapproval period. Therefore, clinicians should not interpret the lower consistency of severe event reporting as evidence that serious injury cannot occur.
Temporal pattern: early risk window
The median time to onset for hepatic events was 77 days, with an interquartile range of 30 to 149 days. The Weibull shape parameter was consistent with an early failure pattern. In pharmacovigilance terms, that generally means the hazard is higher early in therapy and tends to decline over time among continuing users.
This temporal signal aligns well with a monitoring strategy focused on the first months of treatment. It supports the logic of obtaining baseline liver tests and repeating them during early treatment intervals, particularly in the first three months, while maintaining vigilance thereafter. The relatively wide interquartile range also indicates that some events occur later, so clinicians should not rely solely on an early normal result to dismiss future hepatic risk.
How to interpret disproportionality
Disproportionality analyses are powerful for detecting emerging safety signals but have important interpretive constraints. A high reporting odds ratio does not mean the absolute risk is high. It can be influenced by stimulated reporting after regulatory warnings, channeling of susceptible patients, notoriety bias, duplicate reports, missing data, and the fact that FAERS lacks a true denominator of exposed patients. In the case of fezolinetant, reporting may have been amplified by heightened awareness surrounding liver monitoring requirements and label changes. That could accentuate laboratory event reporting more than symptomatic clinical injury reporting.
Clinical Interpretation
The study’s main translational message is straightforward: fezolinetant’s postmarketing hepatic safety signal appears real enough to justify careful liver monitoring, but the current signal profile is dominated by transaminase elevations rather than a clear excess of consistently reported severe clinical liver injury. For clinicians prescribing a nonhormonal treatment in menopausal care, this is a nuanced but manageable risk profile.
The findings reinforce several bedside principles. First, baseline hepatic assessment should not be treated as a formality. Second, patients should be educated to report symptoms that could indicate liver injury, including fatigue, anorexia, nausea, pruritus, dark urine, pale stools, right upper quadrant pain, or jaundice. Third, concomitant hepatotoxic exposures deserve attention, including alcohol misuse, preexisting liver disease, and interacting medications. Fourth, abnormal liver biochemistries should trigger prompt reassessment of the risk-benefit balance and adherence to product labeling regarding interruption or discontinuation.
For many women, fezolinetant remains an important alternative to estrogen-based therapy. That is particularly relevant for patients with contraindications to hormone therapy, such as certain histories of estrogen-sensitive cancer or thromboembolic disease. However, a nonhormonal mechanism does not mean a risk-free therapy. In practice, the decision is no longer simply hormone versus nonhormone; it is individualized symptom control weighed against distinct safety tradeoffs.
Mechanistic and Regulatory Context
Fezolinetant works centrally by antagonizing neurokinin 3 receptors involved in thermoregulatory dysfunction during menopause. Its therapeutic target is not the liver, so any hepatotoxicity is likely off-target or idiosyncratic rather than an extension of intended pharmacology. That pattern is common in drug-induced liver injury, where susceptibility may depend on host factors, metabolism, immune pathways, or exposure-related thresholds that are incompletely understood.
The postmarketing observations summarized by Lee and colleagues fit with the broader regulatory response to fezolinetant, in which liver safety monitoring has become more prominent. Real-world signal detection is especially valuable here because preapproval trials may not be powered to identify uncommon hepatic events or may underrepresent patients with comorbidity, polypharmacy, and heterogeneous baseline liver risk.
Limitations
Several limitations temper the interpretation of this study. FAERS is a spontaneous reporting system and therefore subject to underreporting, variable data quality, incomplete clinical details, and inability to validate diagnoses uniformly. Causality cannot be established, and incidence cannot be calculated because exposure denominators are unavailable.
Second, reports after FDA warnings are especially vulnerable to stimulated reporting. For fezolinetant, increased clinician attention to liver tests may have preferentially increased reports of laboratory abnormalities. Third, confounding by indication and patient selection may matter. Patients prescribed a new nonhormonal menopausal therapy may differ systematically from those receiving hormone therapy comparators. Fourth, the abstract does not provide detailed case-level severity metrics, dechallenge or rechallenge information, or Hy’s law analyses, all of which would help contextualize the clinical significance of transaminase elevations. Finally, the postmarketing window remains relatively early, and long-term hepatic safety characterization is still evolving.
Practice Implications
For clinicians, the key implication is not to abandon fezolinetant but to use it with disciplined monitoring and informed patient selection. Baseline liver chemistry testing should be performed before initiation, and follow-up testing should be emphasized during the first months of treatment, the period most consistent with the identified early failure pattern. Clinicians should also review hepatic history, alcohol intake, and concomitant drugs that may affect liver function.
When discussing treatment options with patients, it is reasonable to explain that postmarketing data show a signal mainly for liver enzyme elevations, not a uniformly strong pattern of severe liver injury, but that early laboratory surveillance remains essential because serious toxicity can emerge from initially asymptomatic abnormalities. Shared decision-making should frame this risk in comparison with the patient’s symptom burden, alternatives tried, and suitability for hormone therapy or other nonhormonal options.
Conclusion
This FAERS analysis adds important postmarketing evidence to the hepatic safety profile of fezolinetant. The drug shows a detectable hepatic adverse event reporting signal, driven predominantly by elevations in alanine aminotransferase, aspartate aminotransferase, and related liver function tests rather than by a consistent signal of overt clinical liver injury. The median onset of 77 days and the Weibull early failure pattern strengthen the rationale for baseline evaluation and close early-phase monitoring.
The findings should not be overread as a measure of absolute risk, nor as proof of causality. Even so, they support a pragmatic clinical message: fezolinetant remains a meaningful nonhormonal option for menopausal vasomotor symptoms, but liver safety surveillance is an integral part of prescribing it well. Future work should focus on validated case series, denominator-based pharmacoepidemiologic studies, and mechanistic research to clarify which patients are most vulnerable to clinically important hepatic injury.
Funding and Trial Registration
The abstract as provided does not report funding information or a ClinicalTrials.gov registration number. This is consistent with the study being a retrospective pharmacovigilance analysis of the FDA Adverse Event Reporting System rather than a prospective interventional trial.
References
Lee N, Lee Y, Kim G, Kim Y. Hepatic Adverse Event Signals of Fezolinetant in Real-World Use Based on Postmarketing Surveillance. Obstetrics and gynecology. 2026-05-28. PMID: 42210869. Available at: https://pubmed.ncbi.nlm.nih.gov/42210869/
U.S. Food and Drug Administration. VEOZAH (fezolinetant) prescribing information. FDA-approved labeling. Accessed for regulatory safety context.
National Institutes of Health. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases. Resource for interpretation of drug-induced liver injury patterns.
Faubion SS, Sood R, Kapoor E. Genitourinary syndrome of menopause and vasomotor symptoms management: contemporary menopause care reviews in major clinical literature. Used for clinical context regarding nonhormonal treatment needs in menopausal care.