A new nonhormonal treatment, fezolinetant, for menopausal women with bothersome vasomotor symptoms (VMS) was approved by the FDA on May 12, 2023. It is the first neurokinin receptor antagonist to receive approval from the FDA to treat hot flashes due to menopause. Per the manufacturer, Astellas, it will be available shortly on the market.
What a breakthrough for women's health to provide women suffering from frequent (seven or more per day) moderate to severe hot flashes a nonhormone (non-estrogen) treatment that reduces their hot flashes and improves their quality of life!
Fezolinetant is a neurokinin receptor antagonist approved as a 45 mg daily oral therapy. The drug works by binding to and blocking the neurokinin 3 (NK3) receptor, which plays a role in regulating body temperature and leads to a reduction in hot flashes. The FDA approved it for treating VMS of menopause, i.e., hot flashes and night sweats, but it also appears to improve sleep disruption, mood, and quality of life.
In two phase 3 clinical trials, Skylight 1 and 2, fezolinetant 30mg and 45mg effectively reduced the frequency of VMS by about 65% compared to hormone therapy (HT) at 75% and, similar to HT, reduced the severity of VMS. Its onset of action was rapid, within a week. Reported adverse events occurred in 1–2% of healthy menopausal women participating in clinical trials, including headaches, abdominal pain, diarrhea, insomnia, back pain, hot flush, and reversible elevated hepatic transaminases. Serious treatment-emergent adverse events were infrequent.
Subgroup analysis of data presented at ACOG showed effectiveness compared to placebo for diverse populations, including those younger or older than age 55, different races, BMI of 30 kg/m2 or higher, smokers, former smokers, and never smokers, and those living in Europe or North America.
In a separate, 52-week placebo-controlled study, Skylight 4 confirmed sustained effect and long term safety. Adverse effects on the endometrium were not seen with this nonhormone, centrally acting medication. In the 52-week safety study, the incidence of endometrial hyperplasia and malignancy in fezolinetant treated participants was within the prespecified limit for endometrial safety. No significant differences were noted in change from baseline endometrial thickness on transvaginal ultrasound, and no loss of bone density was seen.
Prior trials of neurokinin receptor antagonists suggested the potential for hepatotoxicity. Increases in liver enzymes in the Skylight 1 trial were described as asymptomatic, isolated, intermittent, or transient and returned to baseline during treatment or after discontinuation. However, the FDA placed a warning about the potential for liver injury. Baseline liver tests are recommended before starting fezolinetant and then to be repeated at three, six, and nine months. In addition, the medication should not be used with moderate CYP1A2 inhibitors.
Until now, only one nonhormone therapy, 7.5 mg paroxetine salt, has been FDA-approved for VMS. However, neither this medication, nor off label use of other tested but not approved treatments, including SSRIs, SNRIs, gabapentinoids, oxybutynin, and clonidine, are as effective as hormone therapy in relieving moderate to severe VMS.
For those who can’t or choose not to take hormone therapy for bothersome menopausal hot flashes, such as those with estrogen-sensitive breast or uterine cancers, fezolinetant offers a much-needed effective, safe, nonhormone/nonestrogen option.
Dr. Pinkerton has no conflicts on interest to report.
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