MON-162 - Neurokinin-3 Receptor Antagonism and Headache Adverse Events Signals: A FAERS Disproportionality Analysis of Fezolinetant Versus Non-Hormonal Therapies for Menopausal Vasomotor Symptoms

Introduction: Neurokinin-3 receptor antagonism modulates hypothalamic thermoregulation central to menopausal vasomotor symptoms and may influence headache susceptibility. Fezolinetant, the first approved agent in this class, reported headache as a common adverse event in clinical trials, though its headache signal relative to other nonhormonal therapies remains unclear.

Methods: A retrospective disproportionality analysis was conducted using the FDA Adverse Event Reporting System database from 2023 through April 02, 2026. Analyses were time-limited and restricted to female patients. Fezolinetant was compared with non-hormonal therapies for vasomotor symptoms: paroxetine, citalopram, oxybutynin, and gabapentin. Headache-related preferred terms included headache, migraine, tension-type headache, and head discomfort. For each drug event pair, 2×2 tables were constructed. Reporting odds ratios (ROR), proportional reporting ratios (PRR), and 95% confidence intervals were calculated. A signal was defined as ROR >1 with a lower confidence interval bound > 1, PRR ≥ 2, and chi-square ≥ 4.

Results: FAERS contained 689,193 headache, 98,206 migraine, 4,217 tension-type headache, and 17,489 head discomfort reports. Fezolinetant accounted for 93 headache, 16 migraine, 8 head discomfort, and 2 tension-type headache cases among 1,778 reports. Compared with FAERS, disproportionality was observed for headache (ROR 2.58, 95% CI 2.09–3.18) and head discomfort (ROR 8.50, 95% CI 4.25–17.3), with elevated but imprecise estimates for migraine and tension-type headache due to low counts. Compared with non-hormonal therapies, fezolinetant showed higher reporting odds across subtypes, including headache (ROR 9.63, 95% CI 7.74–11.98; PRR 9.18; χ² ≈ 620), migraine (ROR 5.67, 95% CI 3.41–9.41; PRR 5.63; χ² ≈ 116), head discomfort (ROR 25.3, 95% CI 11.6–55.2; PRR 25.1; χ² ≈ 167), and tension-type headache (ROR 18.25, 95% CI 4.0–83.1; PRR 18.23; χ² ≈ 13.7), with head discomfort being the most robust signal. Thus, as fezolinetant is a relatively new drug, findings may reflect reporting biases such as notoriety and underreporting.

Conclusions: This is the first FAERS disproportionality analysis of fezolinetant-associated headache subtypes relative to non-hormonal therapies. Fezolinetant shows higher reporting odds across all subtypes, particularly for head discomfort. Findings are hypothesis-generating, may reflect reporting bias, and residual confounding cannot be excluded. These results may help inform individualized therapy selection in menopausal women. Prospective studies are needed to confirm these signals and inform prescribing.

AI Use: Artificial intelligence (ChatGPT) was used only for language editing to improve clarity and grammar. All scientific content, data interpretation, and conclusions were generated and verified by the authors.

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