Can fezolinetant be used in combination with estrogen?

Published

Prescribing Information including BOXED WARNING

According to Drugs^® and UpToDate^® Lexidrug™ drug interaction results, there is a risk of interaction between estrogen and fezolinetant, which is proposed to relate to weak CYP1A2 inhibition by estrogen. Fezolinetant is contraindicated in individuals using CYP1A2 inhibitors

Fezolinetant is primarily metabolized by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19.¹ Concomitant use of fezolinetant with drugs that are weak, moderate, or strong CYP1A2 inhibitors increases the maximum plasma concentration and area under the concentration-time curve of fezolinetant.

According to Drugs^® and UpToDate^® Lexidrug™ drug interaction results, there is a risk of interaction between fezolinetant and estrogens (estradiol [including estradiol valerate and estradiol acetate], conjugated equine estrogen, synthetic conjugated estrogens A, and ethinyl estradiol).^2,3
According to DynaMed^® there is no known risk of drug-drug interactions between fezolinetant and estrogens (estradiol [including estradiol valerate and estradiol acetate], conjugated equine estrogen, synthetic conjugated estrogens A, ethinyl estradiol and micronized estradiol).⁴
Physiologically-based pharmacokinetic modelling was conducted to analyze the potential interaction between fezolinetant and oral or low dose vaginal formulations of estradiol, a weak CYP1A2 inhibitor.⁵ The model predicted no clinically relevant effect between fezolinetant and chronic low dose vaginal estradiol treatment.
- Oral estradiol was predicted to increase fezolinetant area under the concentration-time curve to infinity (AUC_inf) by 57% and maximum plasma concentration (C_max) by 13%.⁵
- Low dose vaginal estradiol was predicted to increase fezolinetant AUC_inf by 22% and C_max by 5.9%.⁵
Hormone replacement therapies, hormonal contraceptives, and any treatment for vasomotor symptoms (VMS) were prohibited during the fezolinetant Phase 3 trials (SKYLIGHT 1, 2 and 4) in order to more accurately determine the efficacy of fezolinetant.^6–9
The Phase 4 OPTION-VMS real-world study (NCT06049797) is ongoing to assess the change from baseline in VMS bother in women initiating nonhormonal therapy, as decided by the treating healthcare professional, for the treatment of VMS. Vaginal/local estrogen preparations and levonorgestrel-releasing intrauterine systems are not prohibited in the study.^6,10,11

VEOZAH [Package Insert]. Northbrook, IL: Astellas Pharma US, Inc.
UpToDate® LexiDrug^TM. Interactions. Available at: https://online.lexi.com.
Drugs.com®. Interaction Checker. Available at: https://www.drugs.com.
DynaMed®. Drug Interactions. Available at: https://www.dynamed.com.
Choules M, Nielsen J, Chappa A, et al. Physiologically-based pharmacokinetic (PBPK) analysis of the potential interaction between fezolinetant and estradiol. [oral slide presentation]. Poster presented at Simcyp Consortium; September 24-26, 2024; London, UK. Poster #4;
Data on file.
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. Available at: https://doi.org/10.1210/clinem/dgad058.
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. Available at: https://doi.org/10.1016/s0140-6736(23)00085-5.
Neal-Perry G, Cano A, Lederman S, et al. Safety of Fezolinetant for Vasomotor Symptoms Associated With Menopause. Obstet. Gynecol. 2023;141(4):737-747. Available at: https://doi.org/10.1097/aog.0000000000005114.
Neal-Perry G, Lederman S, Mancuso S, et al. OPTION-VMS: Preliminary Analysis of a Phase IV Observational, Real-World Study of Non-hormonal Pharmacotherapies for Bothersome Menopause-Associated Vasomotor Symptoms [poster]. Orlando, FL, USA. The Menopause Society (TMS) 2025 Annual Meeting; 2025.
Maki PM, Mancuso S, Helbing M, et al. Preliminary Analysis of Work Productivity Outcomes in OPTION-VMS: A Phase IV Observational, Real-World Study of Non-hormonal Treatment for Bothersome Menopause-Associated Vasomotor Symptoms [poster]. Orlando, FL, USA. The Menopause Society (TMS) 2025 Annual Meeting; 2025.