By Alexandra Morell, MD
Clinical Instructor, Department of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY
SYNOPSIS: A meta-analysis of five randomized controlled studies showed that fezolinetant improved moderate-to-severe vasomotor symptoms with a pooled mean difference of 2.62 episodes per day (95% confidence interval [CI], 1.85-3.41) and had no significant adverse effects compared to placebo (odds ratio, 1.01; 95% CI, 0.84-1.22).
SOURCE: Bonga KN, Mishra A, Maiti AMR, et al. Efficacy and safety of fezolinetant for the treatment of menopause-associated vasomotor symptoms: A meta-analysis. Obstet Gynecol 2024;143:393-402.
Menopause is defined as the permanent cessation of menses for a minimum of 12 months.1 In the United States, menopause occurs at a median age of 51 years. Approximately 50% to 82% of women experience vasomotor symptoms (VMS) during the perimenopausal transition. It is unclear what pathophysiologic mechanism is responsible for VMS, but a narrowed thermoregulatory zone is thought to play a role.1,2
Systemic hormone therapy (HT), involving estrogen and progestin in patients with a uterus and estrogen alone in patients without a uterus, is the most effective treatment for VMS.1,2 However, systemic HT has several absolute and relative contraindications. Nonhormonal treatment agents can be considered for these patients or patients who want to avoid use of HT. Fezolinetant, a neurokinin-3 receptor antagonist, has emerged recently as a novel nonhormonal treatment for VMS.
This was a systematic review aimed at assessing the efficacy of fezolinetant for the treatment of menopause-associated VMS and the adverse effect profile of the medication. A systematic literature search was performed in the PubMed database to identify randomized controlled studies evaluating fezolinetant compared to placebo for VMS. Five randomized controlled studies with six published reports (one study had two published reports) ultimately were included, resulting in 2,080 participants (with an equal number of participants in the treatment and placebo groups). All participants were postmenopausal, between the ages of 40-65 years, and had moderate to severe VMS, defined as an average of 50-60 episodes per week or seven to eight episodes per day.
Exclusion criteria included participants receiving hormone therapy, hormonal contraception, cytochrome P450 1A2 inhibitors, and any other medications for the treatment of VMS. The treatment group was prescribed oral fezolinetant (three studies used 45 mg once daily, two used 60 mg once daily, and one used 90 mg twice daily) and the control group received a placebo.
The primary outcome of the study was moderate-to-severe VMS frequency. VMS frequency was defined as the number of VMS episodes experienced per day. Secondary outcomes pertaining to fezolinetant efficacy included Menopause-Specific Quality of Life (MENQOL) score changes, mean percentage change in moderate-to-severe VMS, 50% reduction in VMS frequency, 75% reduction in VMS frequency, and Patient Global Impression of Change in Sleep Disturbance (PGI-C SD) score. Change in VMS frequency was defined as change in symptoms experienced from baseline to 12 weeks of treatment. Secondary outcomes pertaining to fezolinetant safety included liver function test assessments (aspartate aminotransferase or alanine aminotransferase [ALT] greater than three times the upper limit of normal), Patient Global Impression of Severity in Sleep Disturbance (PGI-S SD) score, and incidence of adverse effects associated with treatment.
This meta-analysis was performed using the meta package in R studio. Meta-regression was used to assess the effect of treatment duration and fezolinetant drug dosage on VMS frequency. Heterogeneity assessments to evaluate for inconsistencies between studies were conducted using χ2 tests and I2 statistics.
For the primary outcome, fezolinetant was found to improve moderate-to-severe VMS frequency compared to placebo, with a mean pooled difference of 2.62 episodes per day among 860 participants from four studies (95% confidence interval [CI], 1.85-3.41). Fezolinetant demonstrated an improvement in MENQOL scores, with a pooled mean difference -0.60 in three studies (95% CI, -0.92 to 0.28). Fezolinetant demonstrated an improvement in percentage change of VMS frequency with a pooled mean difference from two studies of 22.51% (95% CI, 15.35% to 29.67%). No significant heterogeneity was identified between these studies (χ2 = 1.62; P = 0.20; I2 = 38%; n = 685).
The pooled odds ratio (OR) of three studies for 50% reduction in VMS was 2.78 for fezolinetant vs. placebo (95% CI, 1.81-4.27) and the pooled OR of three studies for 75% reduction in VMS was 3.07 (95% CI, 2.20-4.30). No significant heterogeneity between studies was identified (χ2 = 3.47; P = 0.18, I2 = 42%; n = 773 and χ2 = 1.48; P = 0.48, I2 = 0%; n = 773, respectively). Two studies reported PGI-C SD and PGI-S SD scores. Fezolinetant showed an improvement in PGI-C SD scores with a pooled OR of 2.39 (95% CI, 1.60- 3.58) and a decrease in PGI-S SD scores with a pooled OR of 0.28 (95% CI, 0.15-0.52).
Liver function was assessed in all five studies, and fezolinetant demonstrated an OR of 2.38 (95% CI, 1.4-5.41) compared to placebo of having an ALT greater than three times the upper limit of normal. Adverse effects also were assessed in all five studies, and there were no statistically significant adverse effects between fezolinetant and placebo (OR, 1.01; 95% CI, 0.84-1.22). Fezolinetant dose and frequency of administration were not found to significantly affect moderate-to-severe VMS frequency (QM [degrees of freedom (df) = 2] = 0.1556; P < 0.926), MENQOL score (QM [df = 2] = 0.1556; P < 0.926), or 50% reduction in VMS (QM [df = 1] = 1.8333; P < 0.176).
COMMENTARY
VMS affect approximately one-half to three-fourths of women during the menopausal transition and substantially affect quality of life.1 The North American Menopause Society posits that the benefits of HT for VMS outweigh the risks for women younger than 60 years of age who have undergone menopause within the last 10 years.2 Although HT is an effective treatment option, many patients have contraindications to receiving systemic hormone treatment or want to avoid hormonal treatments.
Absolute contraindications to HT include liver disease, history of breast cancer, history of stroke or myocardial infarction, known or suspected estrogen-dependent cancer, history of deep venous thrombosis or pulmonary embolism, or a thrombophilia such as antithrombin III deficiency.3 Relative contraindications where caution about prescribing should be considered include gallbladder disease, hypertriglyceridemia, diabetes, hypoparathyroidism, benign meningioma, high risk of breast cancer, high risk of heart disease, and migraine with aura.4 In addition, many patients want to avoid the use of HT because of associated risks identified in the Women’s Health Initiative.3
For estrogen treatment alone, this includes an increased risk of deep vein thrombosis and pulmonary embolism. For combination estrogen and progestin treatment, there is an increased risk of coronary artery disease, stroke, and breast cancer in addition to deep vein thrombosis and pulmonary embolism.
Nonhormonal classes of medication that have demonstrated effectiveness in reducing VMS include selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), and gabapentinoids. The first Food and Drug Administration (FDA)-approved nonhormonal treatment for VMS in the United States was paroxetine, an SSRI.1 Paroxetine has demonstrated a reduction in hot flashes and improvement in quality of life.5 One limitation to the use of paroxetine is that it is a CYP2D6 inhibitor and may lower the effectiveness of tamoxifen when the two medications are taken simultaneously.6 Tamoxifen is FDA-approved for the treatment of hormone-sensitive breast cancer, which also is a contraindication to HT. Alternative nonhormonal treatments have less risk in patients with a current or prior history of breast cancer and tamoxifen use.
Fezolinetant is the second nonhormonal medication for the treatment of VMS to receive FDA approval.2 It has a different mechanism of action compared to any other nonhormonal agents that have demonstrated effectiveness and is a neurokinin-3 receptor antagonist. It is thought that estrogen withdrawal accompanying the menopausal transition leads to hypertrophy of a subpopulation of neurons in the hypothalamus, including kisspeptin, neurokinin B, and dynorphin.7 This results in increased secretion of neurokinin B, which binds to the neurokinin-3 receptor, and functions via the hypothalamic median preoptic pathways to play a role in thermoregulation. As a result, antagonism of this pathway is suspected to target vasomotor changes associated with menopause.
The authors of this study performed a systematic review of fezolinetant, which demonstrated effectiveness in reducing moderate-to-severe VMS frequency. The side effect profile also is favorable. Furthermore, an additional benefit of fezolinetant is its effect on reducing sleep disturbances, given that the menopausal transition is associated with sleep disturbances related to sleep initiation, sleep maintenance, and early morning awakenings.8 The main limitation of use is avoidance in patients with baseline liver dysfunction. It is recommended to not start the medication if liver enzymes are greater than two times the upper limit of normal, and liver function tests should be checked every three months for the first nine months after starting the medication.9
Overall, this FDA-approved medication adds an another option for patients looking for a nonhormonal agent to help manage their symptoms, specifically patients who are unable to use HT or wish to avoid hormonal treatments.
REFERENCES
- ACOG Practice Bulletin No. 141: Management of menopausal symptoms. Obstet Gynecol 2014;123:202-216. Erratum in: Obstet Gynecol 2016;127:166. Erratum in: Obstet Gynecol 2018;131:604.
- The 2023 Nonhormone Therapy Position Statement of The North American Menopause Society Advisory Panel. The 2023 nonhormone therapy position statement of The North American Menopause Society. Menopause 2023;30:573-590.
- Crandall CJ, Mehta JM, Manson JE. Management of menopausal symptoms: A review. JAMA 2023;329:405-420.
- Santen RJ, Heitjan DF, Gompel A, et al. Approach to managing a postmenopausal patient. J Clin Endocrinol Metab 2020;105:dgaa623.
- Slaton RM, Champion MN, Palmore KB. A review of paroxetine for the treatment of vasomotor symptoms. J Pharm Pract 2015;28:266-274.
- Farrar MC, Jacobs TF. Tamoxifen. In: StatPearls [Internet]. StatPearls Publishing; 2024 Jan-. https://www.ncbi.nlm.nih.gov/books/NBK532905/
- Rance NE, Dacks PA, Mittelman-Smith MA, et al. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol 2013;34:211-227.
- Kravitz HM, Janssen I, Bromberger JT, et al. Sleep trajectories before and after the final menstrual period in The Study of Women’s Health Across the Nation (SWAN). Curr Sleep Med Rep 2017;3:235-250.
- Fezolinetant. Astellas Pharma US, Inc.; 2023. Prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216578s000lbl.pdf