Do Not Use Fezolinetant (VEOZAH) for the Treatment of Hot Flashes (Vasomotor Symptoms)

Menopause is a normal stage in a woman’s life; in the United States, menopause starts around the age of 52 on average.[1] During menopause, the body’s production of the hormones estrogen and progesterone slows down and menstrual cycles permanently cease. Some women experience postmenopausal symptoms, such as hot flashes, mood swings and sleeping difficulty, as well as vaginal or vulvar atrophy.[2]

Hot flashes, or vasomotor symptoms, are a temporary sensation of heat, often with flushing and sweating, that can usually be managed with lifestyle-related strategies, such as keeping the core body temperature cool and exercising regularly. If medication is needed for severe hot flashes, Public Citizen’s Health Research Group recommends using menopausal hormone therapy[3] — mainly estrogen-only (such as conjugated estrogens [PREMARIN]) for a woman without a uterus and combined estrogen and progestin (a form of progesterone; such as conjugated estrogens and medroxyprogesterone [PREMPHASE, PREMPRO]) in women with an intact uterus.[4] Using estrogen alone can increase the risk of endometrial cancer (cancer in the lining of the uterus). This is why women with a uterus should take estrogen in combination with progestin, whereas women who have had a hysterectomy (no longer have a uterus) do not need to add progestin.[5]

Although these treatments are effective at preventing hot flashes and treating vaginal or vulvar atrophy, hormone therapy is associated with serious adverse effects, such as an increased risk of endometrial and breast cancer, blood clots and stroke, and is therefore no longer recommended for long-term use. Hormone therapy for menopause symptoms should be taken at the lowest dose and for the shortest duration that provides symptom relief.[6]

In May 2023, the Food and Drug Administration (FDA) approved fezolinetant (VEOZAH) for the treatment of moderate-to-severe vasomotor symptoms due to menopause. Fezolinetant is a neurokinin 3 receptor antagonist; it blocks a receptor in the brain that plays a role in how body temperature is regulated. However, the exact cause of hot flashes is unknown.[7],[8] Unlike hormone therapy, fezolinetant is approved only for the treatment of hot flashes, not any of the other symptoms of menopause.[9] It is taken orally as a 45-milligram (mg) tablet once a day.

The prescribing information for fezolinetant includes a general warning about elevated levels of a liver enzyme known as hepatic transaminase. Prior to starting the medication, and regularly during the first nine months of treatment, patients need to have blood tests to evaluate their liver function. If the hepatic transaminase level is too high, the drug should either not be started or should be stopped.[10]

Based on the limited benefits and the safety concerns associated with fezolinetant, Public Citizen’s Health Research Group has designated it as a Do Not Use drug.

Fezolinetant is the second nonhormonal drug that the FDA has approved for the treatment of hot flashes. Public Citizen’s Health Research Group has designated the first nonhormonal drug for hot flashes, paroxetine (BRISDELLE, approved in 1992) as a Do Not Use drug.[11],[12]

Limited short-term evidence of efficacy

Fezolinetant was approved based on efficacy data from two trials, both of which were funded by the maker of the drug. The trials followed the same design, randomizing a total of 1,022 subjects with an average age of 54 years to receive either a daily dose of placebo or 30 or 45 mg of fezolinetant for 12 weeks.[13] After 12 weeks, subjects could enter a 40-week extension period for a safety evaluation, in which subjects who were previously in the placebo group were randomized to receive either 30 or 45 mg of fezolinetant and those who had previously received the drug continued with their treatment. Because only the 45-mg dose was approved, only the results for this dose will be discussed.

At the beginning of both trials, subjects had an average of 10 to 12 hot flashes per day.[14],[15] It is important to note that 10 to 12 hot flashes per day is substantially more hot flashes than menopausal women experience overall. Typically, one in four menopausal women report having daily hot flashes; women experiencing hot flashes report an average of four to five per day.[16],[17]

In one trial, the frequency of daily hot flashes in subjects treated with fezolinetant was reduced by 6.3 hot flashes after four weeks and 7.5 hot flashes by week 12, compared with 3.7 and five hot flashes, respectively, in the placebo group. (To account for missing data, the researchers used a statistical technique known as least squares means.) Thus, the differences between the two groups in the frequency of daily hot-flashes was only 2.6 at four weeks and 2.5 at 12 weeks.[18] The difference in reduction of the severity of the hot flashes between groups was marginally significant at both four and 12 weeks.[19]

In the other trial, the difference in the daily reduction in hot-flash frequency between subjects in the fezolinetant and placebo groups was again only 2.1 and 2.6 hot flashes after four and 12 weeks, respectively, and the difference in reduction in hot-flash severity was marginally significant at weeks four and 12.[20]

Although the small reductions in hot-flash frequency and severity were statistically significant and were maintained until the end of both studies at 52 weeks, it is not clear whether these results are clinically meaningful for patients. Both trials demonstrated a strong placebo response that was the same or greater than the difference between the drug effects and placebo.

Limited evidence of safety

Fezolinetant’s safety was assessed in the two trials described above and their extensions, as well as a placebo-controlled, 52-week safety trial that randomized 1,830 subjects to receive either a daily dose of placebo or 30 or 45 mg fezolinetant.[21],[22] In the safety trial, serious adverse events were more common among those who had received the drug (3.8%) than among those who received placebo (2.3%). The most common adverse reactions included abdominal pain (4.3% in the fezolinetant groups vs. 2.1% in the placebo group), diarrhea (3.9% vs. 2.6%), insomnia (3.9% vs. 1.8%), back pain (3.0% vs. 2.1%), hot flush (2.5% vs. 1.6%) and elevated hepatic transaminase (2.3% vs. 0.8%). Importantly, because the drug is new, there are no data to establish its long-term safety. Because fezolinetant was only compared with placebo, it also is unclear how this drug’s safety and effectiveness compare to those of the standard treatment, hormone therapy.

What You Can Do

Public Citizen’s Health Research Group recommends that you do not take fezolinetant for hot flashes caused by menopause. If you experience hot flashes, first try lifestyle-related strategies, such as lowering room temperature, dressing in layers, drinking cold water and avoiding certain foods and drinks (such as coffee and alcoholic beverages), to address symptoms.

If nondrug approaches fail and your hot flashes are severe enough to prevent you from working or carrying out other important activities, discuss with your clinician whether hormone replacement therapy is an option for you. However, because hormone replacement therapy can have severe adverse events, it should be used at the lowest dose and for the shortest duration possible to relieve symptoms.
 

References

[1] Office on Women’s Health. Menopause basics. Updated January 6, 2023. https://www.womenshealth.gov/menopause/menopause-basics. Accessed March 5, 2024.

[2] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical review for fezolinetant (VEOZAH). NDA 216578. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000MedR.pdf. Accessed March 5, 2024.

[3] Postmenopausal women should not use the conjugated estrogens and bazedoxifene combination (DUAVEE). Worst Pills, Worst Pills News. January 2021. https://www.worstpills.org/newsletters/view/1374. Accessed March 13, 2024.

[4] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical review for fezolinetant (VEOZAH). NDA 216578. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000MedR.pdf. Accessed March 5, 2024.

[5] Cleveland Clinic. Hormone therapy for menopause symptoms. Last reviewed June 28, 2021. https://my.clevelandclinic.org/health/treatments/15245-hormone-therapy-for-menopause-symptoms. Accessed March 13, 2024.

[6] USPSTF reaffirms recommendations against using menopausal hormone therapy to prevent chronic conditions. Worst Pills, Worst Pills News. April 2023. https://www.worstpills.org/newsletters/view/1526. Accessed March 5, 2024.

[7] Food and Drug Administration. FDA approves novel drug to treat moderate to severe hot flashes caused by menopause. May 12, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-drug-treat-moderate-severe-hot-flashes-caused-menopause. Accessed March 5, 2024.

[8] Avis NE, Crawford SL, Green R. Vasomotor symptoms across the menopause transition: differences among women. Obstet Gynecol Clin North Am. 2018;45(4):629-640.

[9] Fugh-Berman A, Benicivenga P. Baltimore Sun. Heating up the hot flash market with unnecessary, and potentially harmful, drugs. May 17, 2023. https://www.baltimoresun.com/2023/05/17/heating-up-the-hot-flash-market-with-unnecessary-and-potentially-harmful-drugs-guest-commentary/. Accessed March 5, 2024.

[10] Astellas Pharma US. Label: fezolinetant (VEOZAH). May 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216578s000lbl.pdf. Accessed March 5, 2024.

[11] Do Not Use paroxetine (BRISDELLE) for treatment of hot flashes. Best Pills, Worst Pills News. March 2020. https://www.worstpills.org/newsletters/view/1321. Accessed March 5, 2024.

[12] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical review for fezolinetant (VEOZAH). NDA 216578. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000MedR.pdf. Accessed March 5, 2024.

[13] Ibid.

[14] 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;108(8):1981-1997.

[15] 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(10382):1091-1102.

[16] Avis NE, Crawford SL, Green R. Vasomotor symptoms across the menopause transition: differences among women. Obstet Gynecol Clin North Am. 2018;45(4):629-640.

[17] LaCroix A, Ensrud K. The flash dance of midlife: the Skylight 1 trial. Nat Med. 2023; 29(6):1324-1325.

[18] Astellas Pharma US. Label: fezolinetant (VEOZAH). May 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216578s000lbl.pdf. Accessed March 5, 2024.

[19] Food and Drug Administration. Center for Drug Evaluation and Research. Clinical review for fezolinetant (VEOZAH). NDA 216578. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216578Orig1s000MedR.pdf. Accessed March 5, 2024.

[20] 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(10382):1091-1102.

[21] Astellas Pharma US. Label: fezolinetant (VEOZAH). May 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216578s000lbl.pdf. Accessed March 5, 2024.

[22] Neal-Perry G, Cano A, Lederman S, et al. Safety of fezolinetant for vasomotor symptoms associated with menopause: a randomized controlled trial. Obstet Gynecol. 2023;141(4):737-747.