Safety of Fezolinetant for Vasomotor Symptoms Associated With Menopause: A Randomized Controlled Trial.
Level 2 - randomized trial
Individual phase 3 randomized double-blind placebo-controlled trial
PubMed 36897180 · doi:10.1097/AOG.0000000000005114
What was done
A phase 3, randomized, double-blind, 52-week trial (SKYLIGHT 4) evaluated the safety, tolerability, and endometrial effects of once-daily oral fezolinetant (30 mg or 45 mg) versus placebo (1:1:1) in 1,830 postmenopausal women seeking treatment for vasomotor symptoms. Primary endpoints were treatment-emergent adverse events (TEAEs) and the percentage of participants with endometrial hyperplasia or malignancy (evaluated against FDA guidance criteria of <=1% point estimate and <=4% upper bound of one-sided 95% CI). Secondary endpoints included changes in bone mineral density (BMD) and trabecular bone score.
What was found
TEAEs occurred in 64.1% (391/610) on placebo, 67.9% (415/611) on fezolinetant 30 mg, and 63.9% (389/609) on fezolinetant 45 mg. TEAE-related discontinuations occurred in 4.3% (26/610), 5.6% (34/611), and 4.6% (28/609), respectively. Endometrial safety was evaluated in 599 participants: endometrial hyperplasia occurred in 1/203 (0.5%; upper limit of one-sided 95% CI 2.3%) in the 45-mg group and 0% in the placebo (0/186) and 30-mg (0/210) groups; endometrial malignancy occurred in 1/210 (0.5%; 95% CI 2.2%) in the 30-mg group and 0% in the other groups. Liver enzyme elevations >3 times the upper limit of normal occurred in 6/583 placebo, 8/590 fezolinetant 30 mg, and 12/589 fezolinetant 45 mg participants, with no Hy's law cases reported. Changes in BMD and trabecular bone score were similar across groups.
Why it matters
These findings establish the 1-year safety profile of fezolinetant, confirming endometrial and bone safety for this non-hormonal neurokinin-3 receptor antagonist in treating menopausal hot flashes.
Limits
Endometrial histological assessments were conducted in only a subgroup of 599 of the 1,830 enrolled participants. Safety data are limited to 52 weeks of exposure, leaving multi-year outcomes unexamined. Efficacy outcomes and specific demographic data were not reported in the abstract.
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