Fezolinetant is a small molecule neurokinin 3 (NK3) receptor antagonist.1
Moderate to Severe Vasomotor Symptoms due to Menopause
Fezolinetant is used for the treatment of moderate to severe vasomotor symptoms (VMS) due to menopause.1
Efficacy and safety of fezolinetant are based principally on the results from two double-blind, randomized, placebo-controlled studies (SKYLIGHT 1 and 2).1,2,3,4 A total of 1,022 healthy postmenopausal women 40-65 years of age who were experiencing more than 7 daily episodes of moderate to severe VMS were randomized to receive fezolinetant (30 mg or 45 mg) or placebo once daily for 12 weeks.1,2,3,4 The mean age of patients was 54 years; 81% were Caucasian, 32% had prior hysterectomy, 21.6% had prior oophorectomy, and 19.9% had prior hormone therapy.1,3,4 Both trials demonstrated statistically significant reductions in the frequency and severity of VMS compared with placebo at weeks 4 and 12, with improvements seen as early as 1 week.1,3,4 The mean change from baseline to week 4 in frequency of VMS over 24 hours was a reduction of 5.4-6.3 with fezolinetant compared to a reduction of 3.3-3.7 with placebo.1,3,4 The mean change from baseline to week 12 in frequency of VMS over 24 hours was a reduction of 6.4-7.5 per day with fezolinetant compared with a reduction of 3.9-5 with placebo.1,3,4 The mean change from baseline to week 4 in severity of VMS over 24 hours was a reduction of 0.5-0.6 with fezolinetant compared with a reduction of 0.3 with placebo, and the mean change from baseline to week 12 in severity of VMS over 24 hours was a reduction of 0.6-0.8 with fezolinetant compared with a reduction of 0.4-0.5 with placebo.1,3,4 Efficacy persisted throughout the 40-week extension period.3,4 While both doses of fezolinetant demonstrated statistically significant reductions in frequency and severity of VMS compared with placebo, only the 45-mg dose met the clinical threshold of superiority, defined as a reduction by at least 2 episodes of VMS per day or 14 episodes per week.2 This greater efficacy, along with a similar safety profile to the 30-mg dose resulted in FDA approval of the 45-mg dose for this indication.2,5
A systematic review and network meta-analysis compared the efficacy of fezolinetant with hormone and nonhormonal therapies for treating moderate to severe VMS (mean frequency ≥7 per day or 50 per week) in postmenopausal women.6 The analysis, using Bayesian methods with 95% credible intervals, included data from two phase 3 fezolinetant trials and 23 trials of other therapies.6 Fezolinetant 45 mg significantly reduced VMS frequency compared to the nonhormonal therapies paroxetine, desvenlafaxine, and gabapentin as well as the hormone therapy tibolone (not available in the US), but showed no significant difference when compared to other hormone therapies.6 Fezolinetant significantly reduced VMS severity compared to low-dose (50 mg) desvenlafaxine and placebo, but did not differ significantly from higher doses of desvenlafaxine or gabapentin.6
The Institute for Clinical and Economic Review (ICER) conducted a systematic review and cost-effectiveness analysis comparing fezolinetant with other treatments such as menopausal hormone therapy, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and gabapentin in postmenopausal women with moderate to severe VMS.7 While fezolinetant reduced VMS frequency and severity in clinical trials (SKYLIGHT 1 and 2), the improvements did not consistently meet the minimum clinically important difference, defined as 3.57 hot flashes daily.7 Additionally, lack of long-term safety and cost-effectiveness were highlighted.7
The effect of fezolinetant on the endometrium is an important safety consideration in postmenopausal women; therefore, a comprehensive assessment of endometrial safety was performed as part of the pre-approval studies for the drug.1,2 The rates of endometrial hyperplasia and endometrial malignancy were ≤1%, which met the prespecified criteria; other assessments also did not identify any concerns related to endometrial safety.2
Vasomotor symptoms (VMS), including hot flashes and night sweats, affect up to 80% of menopausal women and can persist for an average of 7 to 9 years.8 Although hormone therapy remains the most effective treatment for VMS, its use has declined significantly after the Women's Health Initiative (WHI) publication, especially among younger women and those with more severe VMS.8 Hormone therapy may not be an option for some menopausal women because of personal preference or contraindications, such as a history of estrogen-sensitive cancer, heart disease, or thromboembolic disorders.8 For these women, nonhormonal treatments may offer an alternative.8 Nonhormone drugs that have been shown to reduce VMS include SSRIs, SNRIs, gabapentin, and oxybutynin; however, only paroxetine and fezolinetant are currently FDA-approved for this use.8
The North American Menopause Society (NAMS) 2023 position statement on nonhormonal management of menopause-associated VMS recommends fezolinetant as an effective nonhormonal option for treating moderate to severe VMS in women who cannot use hormone therapy.8 Other clinicians state that more long-term data are needed to support widespread use of fezolinetant since the median duration of moderate to severe VMS among women in the US is 9.4 years.7
Fezolinetant is administered orally with or without food.1 The tablets should be swallowed whole and should not be cut, crushed, or chewed.1
If a dose is missed, skip the dose if the next dose is scheduled within 12 hours.1
Store the tablets at 20-25°C; brief fluctuations between 15-30°C are acceptable.1
The recommended adult dosage of fezolinetant for the management of moderate to severe vasomotor symptoms due to menopause is 45 mg once daily.1
The manufacturer makes no specific dosage recommendations for patients with Child-Pugh class A or B hepatic impairment; use of fezolinetant has not been studied in patients with Child-Pugh class C hepatic impairment.1 Fezolinetant is contraindicated in patients with cirrhosis.1
No dosage adjustment is needed for women with mild (estimated glomerular filtration rate [eGFR] 60 to <90 mL/min/1.73 m2) or moderate (eGFR 30 to <60 mL/min/1.73 m2) renal impairment.1 Fezolinetant is contraindicated in patients with severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment or end-stage renal disease (eGFR <15 mL/min/1.73 m2)
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Hepatotoxicity has been reported in patients receiving fezolinetant in the postmarketing setting and a boxed warning has been included in the prescribing information for the drug regarding this risk.1 Cases of drug-induced liver injury with elevations of ALT, AST, alkaline phosphatase, and total bilirubin occurred within 40 days of starting fezolinetant.1 Patients reported a general sense of feeling unwell with symptoms of fatigue, nausea, pruritus, jaundice, pale feces, and dark urine; these abnormalities generally resolved after discontinuation of the drug.1 In premarketing clinical studies, elevations in serum transaminase levels (i.e., ALT, AST) to more than 3 times the upper limit of normal (ULN) were reported in 2.3% of patients receiving fezolinetant compared with 0.9% of patients receiving placebo in clinical trials.1 No elevations in serum total bilirubin (>2 times ULN) occurred.1 Patients who had elevated transaminase concentrations were generally asymptomatic, and transaminase levels returned to pretreatment levels with dose continuation, dose interruption, or discontinuation.1
Prior to initiating fezolinetant, perform baseline hepatic laboratory tests including serum ALT, AST, alkaline phosphatase, and serum bilirubin (total and direct).1 Do not initiate therapy if ALT or AST is ≥2 times the ULN or if total bilirubin is ≥2 times the ULN for the evaluating laboratory.1
After initiating of fezolinetant therapy, perform hepatic laboratory tests monthly for the first 3 months, then at 6 and 9 months.1
If signs or symptoms suggestive of liver injury occur (e.g., new-onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, abdominal pain), patients should discontinue fezolinetant immediately and seek medical attention including hepatic laboratory testing.1 Fezolinetant should be discontinued if transaminase elevations are >5 times the ULN or if transaminase elevations are >3 times the ULN and total bilirubin is >2 times the ULN.1 If transaminase elevations are >3 times the ULN, perform more frequent follow-up hepatic laboratory testing until resolution.1 Exclude alternative causes of hepatic laboratory test elevations.1
There are no data on fezolinetant use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1 In animal reproduction studies, embryolethality, but no teratogenicity, was observed at doses above the human therapeutic dose.1
There are no data on the presence of fezolinetant in human milk, the effects on the breastfed child, or the effects on milk production.1
There is no experience with fezolinetant in individuals younger than 18 years of age.1
There is not enough data to assess if women over 65 years of age respond differently to fezolinetant than younger women.1
Fezolinetant exposure increases in patients with Child-Pugh Class A or B hepatic impairment.1 Fezolinetant has not been studied in patients with Class C hepatic impairment.1 Use of fezolinetant is contraindicated in patients with cirrhosis.1
While fezolinetant exposure is not significantly impacted by severe renal impairment, the exposure of its metabolite (ES259564) increases substantially.1 Following administration of a single dose of fezolinetant, no effect on drug exposure was observed in patients with mild (eGFR 60 to <90 mL/min/1.73 m2) to severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment; however, exposure of ES259564 in patients with moderate (eGFR 30 to <60 mL/min/1.73 m2) or severe renal impairment increased by approximately 75 and 380%, respectively.1 Fezolinetant is contraindicated in patients with severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment or end-stage renal disease (eGFR <15 mL/min/1.73 m2).1
The most common adverse reactions with fezolinetant (reported in at least 2% of patients and more than placebo) are abdominal pain, diarrhea, insomnia, back pain, hot flush, and elevated hepatic transaminases.1
Fezolinetant is a substrate of cytochrome P-450 (CYP)1A2.1 Fezolinetant and its metabolite ES259564 do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and do not induce CYP1A2, CYP2B6, and CYP3A4.1
Fezolinetant is not a substrate or inhibitor of P-glycoprotein (P-gp).1 ES259564 is a substrate of P-gp, but not an inhibitor of P-gp.1 Fezolinetant and ES259564 are not substrates of breast cancer resistance protein (BCRP) and organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1, OATP1B3).1 ES259564 is not a substrate of organic anion transporters 1 and 3 (OAT1, OAT3), organic cation transporter 2 (OCT2), and multidrug and toxin extrusion proteins 1 and 2-K (MATE1, MATE2-K).1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Concomitant use of fezolinetant with drugs that are weak, moderate, or strong CYP1A2 inhibitors increases exposure of fezolinetant.1 Concomitant use of fezolinetant and CYP1A2 inhibitors is contraindicated.1
Concurrent use of fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant exposure by 840%.1 Concurrent use of mexiletine, a moderate CYP1A2 inhibitor, increased fezolinetant exposure by 360%.1 Concurrent use of cimetidine, a weak CYP1A2 inhibitor, increased fezolinetant exposure by 100%.1
No clinically significant differences in fezolinetant exposure were observed in smokers (moderate CYP1A2 inducer).1
Fezolinetant is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on kisspeptin/neurokinin B/dynorphin (KNDy) neurons.1 The thermoregulatory center in the hypothalamus is innervated by KNDy neurons; these neurons are stimulated by the neuropeptide NKB, acting at NK3 receptors, and inhibited by estrogen.2,3,8 During menopause, declining concentrations of estrogen alter the activation of KNDy neurons, resulting in hypertrophy of the neurons and dysregulation of the thermoregulatory center.2,3,8 By antagonizing NKB/NK3-mediated signaling, fezolinetant modulates KNDy neuronal activity in the thermoregulatory center.8 Fezolinetant exhibits over 450 times greater affinity for NK3 receptors than neurokinin 1 (NK1) or neurokinin 2 (NK2) receptors.1,1
In healthy women, fezolinetant plasma concentrations increase proportionally with daily doses of 20 to 60 mg, reaching steady-state after 2 doses with minimal accumulation.1 The median time to reach peak plasma concentrations is 1.5 hours.1 Food does not significantly affect fezolinetant pharmacokinetics.1 The plasma protein binding of fezolinetant is 51%.1 The effective half-life of fezolinetant is 9.6 hours.1 Fezolinetant is primarily metabolized by cytochrome P-450 (CYP)1A2, and to a lesser extent by CYP2C9 and CYP2C19.1 The major metabolite, ES259564, is 20 times less potent than fezolinetant.1 Most of the dose is excreted in the urine (76.9%), with a smaller amount in feces (14.7%).1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 45 mg | Veozah® | Astellas Pharma |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions February 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
1. Astellas Pharma US, Inc. VEOZAH®(fezolinetant) ORAL prescribing information. 2024 Dec.
2. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 216578Orig1s000: Summary review. From FDA website.
3. 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
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;108(8):1981-1997. doi:10.1210/clinem/dgad058
5. 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. doi:10.1097/AOG.0000000000005114
6. Morga A, Ajmera M, Gao E, et al. Systematic review and network meta-analysis comparing the efficacy of fezolinetant with hormone and nonhormone therapies for treatment of vasomotor symptoms due to menopause. Menopause. 2024;31(1):68-76. doi:10.1097/GME.0000000000002281
7. Wright AC, Beaudoin FL, McQueen RB, et al. The effectiveness and value of fezolinetant for moderate-to-severe vasomotor symptoms associated with menopause: A summary from the Institute for Clinical and Economic Review's Midwest Public Advisory Council. J Manag Care Spec Pharm. 2023;29(6):692-698. doi:10.18553/jmcp.2023.29.6.692
8. The 2023 Nonhormone Therapy Position Statement of The North American Menopause Society. Menopause. 2023;30(6):573-590. doi:10.1097/GME.0000000000002200
9. Food and Drug Administration. FDA drug safety communication. FDA adds warning about rare occurrence of serious liver injury with use of Veozah (fezolinetant) for hot flashes due to menopause. Sep 12, 2024. From FDA website. [Web]