Fezolinetant Essentials for Healthcare Professionals

Fezolinetant Basics for Patients is available at this link: Fezolinetant Basics for Patients.

What is fezolinetant (Veozah^TM) and its mechanism of action?

Fezolinetant is a neurokinin-3 receptor antagonist.¹ The FDA approved it for treating menopausal vasomotor symptoms (aka hot flashes). The antagonism blocks neurokinin B from acting in the brain’s thermoregulatory center.¹ This decreases hot flash frequency and severity.¹

How is fezolinetant dosed and administered?

Prescribe fezolinetant as 45 mg orally once a day. Patients may take it with or without food.¹

Fezolinetant is contraindicated in patients with an eGFR < 30 mL/min/1.73m².¹

Use fezolinetant with caution in patients with Child-Pugh Class A or B hepatic impairment. Fezolinetant is contraindicated in patients with cirrhosis.¹

What trials led to fezolinetant’s approval and what were the trials’ results?

The FDA approved fezolinetant based on SKYLIGHT 1, 2, and 4 trials’ results.¹ SKYLIGHT 1 and 2 trials studied fezolinetant’s efficacy and safety.^2,3 SKYLIGHT 4 only studied safety.⁴

The SKYLIGHT-1 trial was a 12-week, double-blind, randomized, placebo-controlled, phase 3 trial.⁵ The trial had a 40-week extension.² The researchers randomized patients to either fezolinetant 30 mg, 45 mg, or placebo.⁵ The primary endpoints were hot flash frequency and severity at weeks 4 and 12.² The investigators found significant improvements in hot flash frequency and severity. The improvements occurred in the 30 mg and 45 mg groups at weeks 4 and 12. The results continued during the 40-week extension.^2,6

The SKYLIGHT-2 trial had the same study design, interventions, and primary endpoints as SKYLIGHT-1.³ The SKYLIGHT-2 results also showed significant improvements in hot flash frequency and severity. This occurred in both fezolinetant groups at weeks 4 and 12. This improvement continued through the 40-week trial extension.³

The SKYLIGHT-4 trial was a 52-week, double-blind, randomized, placebo-controlled, phase 3 safety trial. Researchers randomized patients to fezolinetant 30 mg, 45 mg, or placebo.⁴ The primary endpoints were treatment-emergent adverse events (TEAS) frequency and severity and percentage of participants with endometrial hyperplasia or malignancy.⁴

The study found similar TEAS rates in all three groups: 64.1% in the placebo, 67.9% in the 30 mg, and 63.9% in the 45 mg group.⁴ The trial found no instances of endometrial hyperplasia in the placebo and 30 mg groups. The 45 mg group had 0.5% of participants develop hyperplasia. No participants experienced endometrial malignancy in the placebo or 45 mg groups. The 30 mg group had 0.5% of participants develop endometrial malignancy.⁴

All trials discovered some participants with elevated liver enzymes.^2,3,4

Who should NOT receive fezolinetant?

Do not prescribe fezolinetant to patients with known cirrhosis, an eGFR < 30 mL/min/1.73m², or those receiving CYP1A2 inhibitors.¹

What are the possible side effects of fezolinetant?

The possible side effects include headache, abdominal pain, diarrhea, and insomnia.^1,4

A less common side effect is elevated liver enzymes. Most women did not experience symptoms in the clinical trials. Liver enzymes returned to normal levels after discontinuing fezolinetant.¹

How are patients monitored while receiving fezolinetant?

Check liver enzymes and serum bilirubin at baseline and at months 3, 6, and 9 after starting treatment.¹ After 9 months, patients do not need labs unless they experience symptoms of liver injury.¹

I heard that fezolinetant is not beneficial for patients of Asian descent. Is this true?

The MOONLIGHT 1 trial studied fezolinetant in Chinese, Korean, and Taiwanese women. The randomized, placebo-controlled trial studied fezolinetant’s efficacy and safety.⁷ MOONLIGHT 1 showed insignificant improvements in hot flashes.⁸ These results suggest a genetic role. Thus, fezolinetant may not benefit patients of Chinese, Korean, and Taiwanese descent.⁹

The Starlight-2 trial is recruiting Japanese women. The trial will determine fezolinetant’s efficacy in this population.¹⁰

Should patients receive fezolinetant or hormone replacement therapy (HRT) for hot flashes?

No trials exist comparing fezolinetant and HRT. Fezolinetant is an alternative for patients that cannot receive HRT.

References

1. Veozah. Prescribing Information. Astellas Pharma US Inc. Accessed April 2, 2024. https://www.astellas.com/us/system/files/veozah_uspi.pdf
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 trial. [ABSTRACT]. Lancet. 2023;401(10382): 1091-1102. doi: 10.1016/S0140-6736(23)00085-5. https://pubmed.ncbi.nlm.nih.gov/36924778/
3. 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.
4. 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. 
5. Welsh E. SKYLIGHT data: fezolinetant for vasomotor symptoms appears safe, well tolerated. Healio. March 24, 2023. Accessed December 1, 2023. https://www.healio.com/news/womens-health-ob-gyn/20230323/skylight-data-fezolinetant-for-vasomotor-symptoms-appears-safe-well-tolerated
6. Results from Astellas’ pivotal phase 3 SKYLIGHT 1^TM study of fezolinetant for vasomotor symptoms due to menopause published in The Lancet. News Release. PR Newswire; March 13, 2023.  https://www.prnewswire.com/news-releases/results-from-astellas-pivotal-phase-3-skylight-1-study-of-fezolinetant-for-vasomotor-symptoms-due-to-menopause-published-in-the-lancet-301770807.html
7. A study to find out if fezolinetant helps reduce moderate to severe hot flashes in women in Asia going through menopause (Moonlight 1). Clinicaltrials.gov identifier: NCT04234204. Updated September 25, 2023. Accessed December 1, 2023. https://clinicaltrials.gov/study/NCT04234204?cond=Vasomotor%20Symptoms%20Associated%20With%20Menopause&page=4&rank=36
8. Astellas announces topline 12-week results from phase 3 study of fezolinetant for the nonhormonal treatment of vasomotor symptoms in women in Asia. News Release. Astellas; March 15, 2022. https://www.astellas.com/en/news/25421
9. Gompel A, Stuenkel CA. Neurokinin 3 receptor antagonists for menopausal vasomotor symptoms, an appraisal. Cell Rep Med. June 20, 2023;4(6):101076. doi: 10.1016/j.xcrm.2023.101076. https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00195-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2666379123001957%3Fshowall%3Dtrue
10. A study to confirm if fezolinetant help reduce hot flashes in Japanese women going through menopause (Starlight 2). Clinicaltrials.gov identifier: NCT06206408. Updated April 9, 2024. Accessed April 10, 2024.