By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved the first-in-class selective neurokinin 3 receptor antagonist to treat moderate-to-severe hot flashes caused by menopause.1 Scientists believe fezolinetant acts on the thermoregulatory center of the brain.2 The agency granted priority review to the solution, which will be distributed as Veozah.
INDICATIONS
Fezolinetant can be prescribed to treat moderate-to-severe vasomotor symptoms caused by menopause.2
DOSAGE
Administer 45 mg once daily, at about the same time each day, without regard to meals.2 Fezolinetant is available as 45-mg tablets.
POTENTIAL ADVANTAGES
Fezolinetant provides an alternative nonhormonal treatment option to manage vasomotor symptoms in patients for whom hormonal therapy is not preferable/appropriate or contraindicated.
POTENTIAL DISADVANTAGES
Fezolinetant does not treat other menopausal symptoms (e.g., vulvovaginal atrophy, loss of bone mineral density). Elevation of serum transaminases (alanine aminotransferase and/or aspartate aminotransferase) greater than three times the upper limit of normal occurred in 2.3% of patients exposed to fezolinetant vs. 0.9% in those exposed to placebo.2 Assess hepatic function before initiating therapy. Perform the assessment at three, six, and nine months after initiation and when symptoms, such as nausea or vomiting, occur that are suggestive of liver injury.2 Fezolinetant is contraindicated in patients with known cirrhosis, renal impairment, end-stage renal disease, or concomitant use with CYP1A2 inhibitors.2 The most common adverse reactions (range, 3% to 4.3%) are abdominal pain, diarrhea, insomnia, and back pain.2
COMMENTS
Vasomotor symptoms are caused by loss of thermoregulatory control, triggered by decline in estrogen levels at menopause and increasing blood flow to the skin.3 Fezolinetant, via neurokinin 3 receptor antagonism, may restore normal sensitivity of the temperature control center.3 Researchers evaluated the efficacy of fezolinetant in two double-blind, placebo-controlled, 12-week, Phase III trials with a 40-week active treatment extension.2,4,5 Subjects experienced a minimum average of seven moderate-to-severe vasomotor symptoms per day. They were randomized to 12 weeks of once-daily placebo, 30 mg of fezolinetant, and 45 mg of fezolinetant. Completers were re-randomized to fezolinetant 30 mg or 45 mg. The co-primary endpoints were mean changes in frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12.
Fezolinetant 45 mg (the FDA-approved dose; n = 174,167) significantly reduced the frequency and severity of moderate-to-severe vasomotor symptoms compared to placebo (n = 175,167). Frequency rates were lower at week 4 in the two trials by a mean of 5.4 and 6.3 from mean baselines of 10.4 and 11.8 compared to -3.3 and -3.7 (baselines, 10.5 and 11.6) for those randomized to placebo (mean differences of -2.1 and -2.6 over 24 hours). Mean differences at week 12 were -2.6 and -2.5. Approximately 60% of subjects achieved ≥ 50% (clinically meaningful) reduction in frequency at week 12 compared to about 36% for placebo. Mean severity scores were lower vs. placebo by -0.2 and -0.3 at week 4 and week 12 for each study, respectively, from a baseline of 2.4. Investigators observed improvements in frequency and severity as early as week 1. Those improvements continued through week 52.4,5 The 45-mg dose led to improvement in sleep disturbance in one of the studies.4,5 The authors identified one case of simple hyperplasia without atypia and one case of endometrial adenocarcinoma in 350 subjects treated with fezolinetant vs. 0% for 186 treated with placebo.2
CLINICAL IMPLICATIONS
Menopausal hormonal therapy is standard of care for menopausal symptoms, including hot flashes. It not only alleviates vasomotor symptoms but also genitourinary syndromes. Such therapy protects against bone loss and may reduce the risk of colon cancer.6,7 Current nonhormonal pharmacotherapies listed by the American College of Obstetricians and Gynecologists include antidepressants, selective estrogen modulators, gabapentin, and clonidine.6 Of these, only paroxetine is FDA-approved to treat moderate-to-severe vasomotor symptoms. There are no comparative studies with hormonal or other nonhormonal agents.
Fezolinetant offers another option for women in whom hormonal therapy is not a preference or not appropriate (e.g., breast cancer, risk of thromboembolism, coronary heart disease). Long-term safety remains to be established, particularly hepatic transaminase elevation.
The cost for fezolinetant is $550 for a 30-day supply ($6,700 per year). The Institute for Clinical and Economic Review (ICER) suggests this drug would achieve common threshold for cost-effectiveness if priced between $2,000 and $2,600 per year compared to no treatment.8 ICER stated there is insufficient evidence to provide a clear comparison of fezolinetant to hormonal therapy.
REFERENCES
1. U.S. Food & Drug Administration. FDA approves novel drug to treat moderate to severe hot flashes caused by menopause. May 12, 2023.
2. Astellas Pharma US, Inc. Veozah prescribing information. May 2023.
3. Depypere H, Lademacher C, Siddiqui E, Fraser GL. Fezolinetant in the treatment of vasomotor symptoms associated with menopause. Expert Opin Investig Drugs 2021;30:681-694.
4. Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of fezolinetant in moderate-to-severe vasomotor symptoms associated with menopause: A phase 3 RCT. J Clin Endocrinol Metab 2023; Feb 3:dgad058. doi: 10.1210/clinem/dgad058. [Online ahead of print].
5. Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): A phase 3 randomised controlled study. Lancet 2023;401:1091-1102.
6. American College of Obstetricians and Gynecologists. Hormonal therapy for menopause. Page last reviewed August 2022.
7. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause 2022;29:767-794.
8. Institute for Clinical and Economic Review. ICER publishes final evidence report on fezolinetant for vasomotor symptoms associated with menopause. Jan. 23, 2023.
Fezolinetant can be prescribed to treat moderate-to-severe vasomotor symptoms caused by menopause.
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