Can fezolinetant be used with SERMs or aromatase inhibitors?

Published

Fezolinetant has no known risk of drug-drug interaction (DDI) with tamoxifen, toremifene, raloxifene, clomiphene, ospemifene, letrozole, or exemestane, according to Drugs interaction results, LexiDrug, and DynaMed. There is a risk of DDI between fezolinetant and anastrozole and fezolinetant and bazedoxifene according to Drugs interaction results, but not LexiDrug and DynaMed

  • In the Phase 3 trials, SKYLIGHT 1, 2 and 4, previous or current history of a malignant tumor, except basal cell carcinoma, was an exclusion criterion,1–3 and the Phase 3 DAYLIGHT trial excluded participants with a history of a malignant tumor within the last five years, except basal cell carcinoma.4 In participants with a medical history of cancer, no subgroup analyses of safety or efficacy were conducted.

  • Fezolinetant is primarily metabolised by CYP1A2, and to a lesser extent by CYP2C9 and CYP2C19.5 
  • An in vitro study demonstrated that anastrozole inhibits a number of CYP enzymes including CYP1A2 and CYP2C9, although concentrations required for in vitro inhibition are higher than required for therapeutic doses.6,7
  • According to Drugs drug interaction results, there is a risk of a major interaction between fezolinetant and bazedoxifene/conjugated estrogens.8 The proposed mechanism of this interaction with fezolinetant relates to CYP1A2 inhibition with conjugated estrogens. Bazedoxifene alone did not produce any results in Drugs.
  • A non-clinical study was conducted to investigate the effects of fezolinetant on the anticancer effect and hot flash-like symptoms induced by tamoxifen treatment in rats bearing MMRT-1 (mammary rat metastasis tumor-1) breast cancer cells.4 Fezolinetant was found to prevent tamoxifen-induced hot flash-like symptoms without affecting the anticancer effect of tamoxifen (tumor volume).
  • The ongoing HIGHLIGHT 1 Phase 3 clinical trial (NCT06440967) is investigating the safety and efficacy of fezolinetant 45 mg for the treatment of moderate to severe vasomotor symptoms (VMS) in women with Stage 0 to 3 HR+ (either HER-2+ or
    HER-2-) breast cancer who are receiving adjuvant endocrine therapy, including tamoxifen or daily aromatase inhibitors.4
  • The ongoing Phase 4 OPTION-VMS real-world study (NCT06049797) is assessing the change in VMS bother in women with a confirmed diagnosis of VMS who are initiating nonhormonal therapy, including fezolinetant. Participants with non-metastatic (Stage 0 to 3) breast cancer receiving a stable regimen of adjuvant endocrine therapy, including tamoxifen or aromatase inhibitors, for ≥ 3 months prior to screening can be included.4

  1. 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 Endocr Metab. 2023;108(8):1981-1997. Available at: https://doi.org/10.1210/clinem/dgad058.

  2. 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.

  3. 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. Available at: https://doi.org/10.1097/aog.0000000000005114.

  4. Data on file.

  5. Iwai M, Nielsen J, Miyagawa M, et al. In Vitro Evaluation of CYP-Mediated Metabolism of Fezolinetant and Pharmacokinetic Interaction Between Fezolinetant and Fluvoxamine in Healthy Postmenopausal Smokers and Nonsmokers. 2024; Available at: https://doi.org/10.1002/jcph.6157.

  6. Linardi A, Damiani D, Longui CA. The use of aromatase inhibitors in boys with short stature: what to know before prescribing? Arch. Endocrinol. Metab. 2017;61(4):391-397. Available at: https://doi.org/10.1590/2359-3997000000284.

  7. Grimm SW, Dyroff MC. Inhibition of human drug metabolizing cytochromes P450 by anastrozole, a potent and selective inhibitor of aromatase. Drug Metab. Dispos.: Biol. fate Chem. 1997;25(5):598-602.

  8. Electronic Citation. Drug Interactions Checker. Available at: https://www.drugs.com/. 

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