Safety of Fezolinetant for Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause: Pooled Analysis of Three Randomized Phase 3 Studies.
Level 1 - systematic review of randomized trials
Pooled analysis of three randomized controlled trials
PubMed 39739195 · doi:10.1007/s12325-024-03073-8
What was done
Authors pooled safety data from three 52-week, double-blind, placebo-controlled phase 3 trials (SKYLIGHT 1, SKYLIGHT 2, and SKYLIGHT 4) in women aged 40 to 65 years with moderate to severe vasomotor symptoms due to menopause. Participants were randomized to once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg (with placebo recipients in SKYLIGHT 1 and 2 re-randomized to fezolinetant after 12 weeks). Safety was assessed via treatment-emergent adverse events (TEAEs), hepatic transaminase elevations, and endometrial safety assessments.
What was found
A total of 3,155 women received at least one dose: 952 placebo, 1,103 fezolinetant 30 mg, and 1,100 fezolinetant 45 mg. TEAEs occurred in 55.3% of placebo, 65.4% of 30 mg, and 62.9% of 45 mg participants. The most frequent TEAEs with fezolinetant included upper respiratory tract infection (7.7–8.3%), headache (6.8–8.2%), COVID-19 (5.8–6.1%), back pain (3.1–3.7%), urinary tract infection (2.9–3.4%), arthralgia (2.9–3.2%), diarrhea (2.3–3.2%), and insomnia (2.0–3.0%). Hepatic transaminase elevations occurred in 1.5–2.3% of fezolinetant users, were mostly asymptomatic and transient, and showed no Hy's law severe liver injury. Drug-related serious TEAEs and treatment discontinuations were low, endometrial safety was within FDA criteria, and exposure-controlled neoplasm risk was not increased compared with placebo.
Why it matters
This pooled analysis establishes the 52-week safety profile of fezolinetant, providing large-sample confirmation of tolerability for a non-hormonal neurokinin-3 receptor antagonist in menopausal vasomotor symptoms.
Limits
Controlled exposure to placebo was limited to 12 weeks in two of the three trials before crossover to active treatment. Safety beyond 52 weeks was not evaluated. Exact numerical rates and confidence intervals for serious TEAEs, discontinuations, and specific endometrial outcomes were omitted from the abstract.
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