Nonhormonal Prescription Therapies for Moderate to Severe Menopause-Related Vasomotor Symptoms
Menopause is marked by the cessation of ovulation and is officially diagnosed after 12 consecutive months of amenorrhea.1 The median age at which menopause occurs is 51 years. However, premature menopause, which may be triggered by medical conditions such as chemotherapy or hysterectomy, can occur before age 40.2 Declining estrogen levels directly affect the hypothalamus, thereby altering the central thermal regulatory neutral zone and contributing to menopause-related vasomotor symptoms (VMS).3 VMS, including hot flashes, sleep disruption, and night sweats, are troublesome symptoms experienced by women during menopause. Other symptoms of menopause may include anxiety, depression, and fatigue, which can negatively affect work performance and quality of life.4 VMS reportedly can persist for up to 10 years and affect as many as 80% of women during the menopausal transition.5
Menopause-related VMS, especially when they reach moderate to severe status, have substantial negative impacts on physical and emotional well-being among women worldwide; these impacts are particularly concerning because the number of women reaching or at menopausal age is projected to increase as the global population grows.6 In the United States (US), people aged 65 years and older are expected to outnumber people aged 17 years and younger by 2034.7 Despite the negative impacts of moderate to severe VMS, many women do not seek treatment from health care professionals.5 Untreated VMS can increase health care costs (Figure 1) and negatively affect quality of life (Figure 2).8
According to the North American Menopause Society, hormone therapy remains the most effective treatment for menopause-related VMS.9 However, many women have refused hormone therapy, especially since the 2003 publication of the Women’s Health Initiative trial, which suggested an increased risk for breast cancer.10 Considering the significant negative impacts of menopause-related moderate to severe VMS, alternative nonhormonal treatment options are needed, particularly for women with contraindications to hormone therapy and women who refuse hormone therapy. This article focuses on nonhormonal US Food and Drug Administration (FDA)-approved therapies that alleviate VMS by targeting the underlying pathophysiological mechanisms.
Understanding the Pathophysiology of VMS
The suspected pathophysiology of VMS involves the neurokinin B (NKB) signaling pathway.11 Specifically, NKB is a neuropeptide that preferentially binds to the neurokinin 3 receptor (NK3R).12 The binding of the NKB neuropeptide to specialized kisspeptin, NKB, and dynorphin (KNDy) neurons is presumed to mediate the hypothalamic-pituitary-gonadal axis; these neurons are likely to act on thermoregulatory regions of the brain.11,13 Before menopause, NKB binding and activation of KNDy neurons is inhibited by estrogen. As estrogen levels decline during menopause, the inhibition of NKB binding to NK3R also declines, leading to altered activity within the brain’s thermoregulatory center. It has been suggested that the pathophysiology of VMS, particularly hot flashes, is triggered by decreasing estrogen levels and subsequent hypertrophy of KNDy neurons.13 Therefore, therapies that target NKB and KNDy neurons have emerged as the main nonhormonal treatments for VMS.
Treatment of VMS With Nonhormonal Therapies
In a cross-sectional survey of 3460 postmenopausal women with moderate to severe VMS conducted in the US, Europe, and Japan, 54% to 79% of women reported an aversion to hormone therapy; 8% to 12% of women had a contraindication to hormone therapy.5 Nonhormonal treatment is an option for these women. Currently, 2 nonhormonal therapies are FDA-approved: paroxetine and fezolinetant (Table 1).14,15
Paroxetine
Paroxetine is a selective serotonin reuptake inhibitor (SSRI), and the low-dose formulation (7.5 mg daily) is FDA-approved as a nonhormonal therapy for moderate to severe menopause-related VMS.14 Studies of patients with VMS showed that paroxetine treatment led to a 33% to 65% reduction in the frequency of hot flashes after 6 to 12 weeks of treatment, compared with 17% to 38% reduction among patients receiving placebo. After 4 weeks of paroxetine treatment, patients reported a significant decrease in VMS-related night-time awakening and a significant increase in sleep duration.3
Although clinical studies of paroxetine often used doses of 10 mg to 25 mg, VMS were significantly reduced with low-dose paroxetine (7.5 mg daily), which had a tolerable adverse effect profile and did not cause withdrawal symptoms when discontinued without tapering.3 The most common adverse effects reported in clinical trials of paroxetine were headache, fatigue, and nausea or vomiting. It should be noted that paroxetine carries a black box warning for suicidal ideation. Moreover, paroxetine is contraindicated in patients who are concurrently using thioridazine or pimozide, are concurrently using or have used monoamine oxidase inhibitors (MAOIs) within the past 14 days, are pregnant, or are hypersensitive to paroxetine or any other ingredient in its formulation. Paroxetine is also a strong CYP2D6 inhibitor and may alter the concentrations of other drugs metabolized by CYP2D6; this property should be considered before prescribing paroxetine to any patient.14
Fezolinetant
Fezolinetant was approved by the FDA in May 2023 as a 45-mg tablet taken once daily for the treatment of moderate to severe menopause-related VMS.15 Fezolinetant is a nonhormonal selective NK3R antagonist that blocks NKB binding on KNDy neurons; this effect restores normal sensitivity to the brain’s thermoregulatory center.13 The safety and efficacy of fezolinetant were investigated in the phase 3, randomized, placebo-controlled trials SKYLIGHT 1 (ClinicalTrials.gov identifier: NCT04003155) and SKYLIGHT 2 (ClinicalTrials.gov identifier: NCT04003142).
SKYLIGHT 1 and SKYLIGHT 2 included women aged 40 to 65 years with moderate to severe VMS who were randomly assigned to receive fezolinetant 30 mg once daily, fezolinetant 45 mg once daily, or placebo.In SKYLIGHT 1 and SKYLIGHT 2, both doses of fezolinetant produced statistically significant reductions from baseline in the frequency and severity of moderate to severe VMS per day at weeks 4 and 12, compared with placebo. Headache was the most common adverse event associated with fezolinetant use in both studies; treatment-emergent serious adverse events were rare (<2% of enrolled patients) in all study arms.13,16 However, it should be noted that fezolinetant is contraindicated in patients who have known cirrhosis, severe renal impairment, or end-stage renal disease, as well as patients who are concomitantly using CYP1A2 inhibitors. Furthermore, baseline bloodwork to evaluate hepatic function and identify any injury should be conducted before beginning fezolinetant treatment; follow-up bloodwork to evaluate hepatic function should be performed at 3, 6, and 9 months after initiation of fezolinetant and when symptoms of liver damage appear.15
References
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7. Older people projected to outnumber children for first time in U.S. history. News release. United States Census Bureau. October 8, 2019. Accessed May 28, 2023. https://www.census.gov/newsroom/press-releases/2018/cb18-41-population-projections.html
8. DePree B, Houghton K, Shiozawa A, et al. Treatment and resource utilization for menopausal symptoms in the United States: a retrospective review of real-world evidence from US electronic health records. Menopause. 2023;30(1):70-79. doi:10.1097/GME.0000000000002095
9. Faubion SS, Crandall CJ, Davis L, et al; The North American Menopause Society 2022 Hormone Therapy Position Statement Advisory Panel. The 2022 hormone therapy position statement of The North American Menopause Society. Menopause. 2022;29(7):767-794. doi:10.1097/GME.0000000000002028
10. Biglia N, Bounous VE, De Seta F, Lello S, Nappi RE, Paoletti AM. Non-hormonal strategies for managing menopausal symptoms in cancer survivors: an update. Ecancermedicalscience. 2019;13:909. doi:10.3332/ecancer.2019.909
11. Koysombat K, McGown P, Nyunt S, Abbara A, Dhillo WS. New advances in menopause symptom management. Best Pract Res Clin Endocrinol Metab. Published online April 11, 2023. doi:10.1016/j.beem.2023.101774
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13. 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. Published online February 3, 2023. doi:10.1210/clinem/dgad058
14. Brisdelle®. Prescribing information. Sebela Pharmaceuticals, Inc; 2017. Accessed June 7, 2023. http://www.accessdata.fda.gov/drugsatfda_docs/label/2017/204516s004lbl.pdf
15. VeozahTM. Prescribing information. Astellas Pharma US, Inc; 2023. Accessed June 7, 2023. http://www.astellas.com/us/system/files/veozah_uspi.pdf
16. 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. doi:10.1016/S0140-6736(23)00085-5
Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.
Reviewed June 2023
