Veozah FDA Approval History: What Women Need to Know About Fezolinetant

Why This Approval Matters for Women

Veozah is the first drug approved by the FDA specifically for hot flashes that does not involve hormones or act as an antidepressant. That single fact changes the conversation for millions of women who cannot or prefer not to use menopausal hormone therapy (MHT).

Approximately 1.3 million women enter menopause in the United States every year, and an estimated 75 to 80 percent experience vasomotor symptoms (VMS). For a significant subset, those symptoms are disabling. Until May 2023, the prescription non-hormonal options were antidepressants such as paroxetine (the only FDA-approved one for this use), gabapentin, and clonidine, all used off-label with modest benefit and meaningful side-effect burdens.

Fezolinetant works at an entirely different point in the biology: the hypothalamic thermoregulatory circuit. Understanding how it got here, what the label actually says, and who is a genuine candidate requires walking through the regulatory timeline carefully.

The Regulatory Timeline: From IND to Approval

2013 to 2019: Mechanism Proof and Early Phase Trials

The neurokinin B (NKB) pathway and its receptor, NK3R, were identified as a driver of menopausal hot flashes based on research in women with hypothalamic amenorrhea and in postmenopausal women. Early academic work established that NKB-producing KNDy neurons in the arcuate nucleus are overactivated after estrogen withdrawal, triggering the downstream heat-dissipation cascade responsible for hot flashes. Fezolinetant, developed initially by Ogeda and later acquired by Astellas, was designed to selectively block NK3R.

Phase 2 dose-ranging studies confirmed biological plausibility and tolerability across a dose range of 15 mg to 90 mg daily.

2021 to 2022: Phase 3 SKYLIGHT Program

Astellas ran four Phase 3 trials under the SKYLIGHT umbrella.

• SKYLIGHT 1 enrolled women with at least seven moderate-to-severe hot flashes per day and compared fezolinetant 30 mg and 45 mg to placebo over 12 weeks with a 40-week extension. Results published in The Lancet showed that the 45 mg dose reduced mean daily VMS frequency by 63 percent from baseline at week 12, compared with 44 percent for placebo.
• SKYLIGHT 2 served as the co-primary key trial and replicated the findings in a second independent population.
• SKYLIGHT 4 was the 52-week long-term safety study required by FDA. This trial provided the endometrial safety data and the hepatic signal that shaped the final label.

May 12, 2023: FDA Approval

The FDA approved fezolinetant 45 mg once daily under the brand name Veozah. The 30 mg dose studied in trials was not approved; the agency selected the 45 mg dose as the only approved strength. The FDA approval was granted under the standard review pathway, not priority review, reflecting the availability of existing treatments even if those alternatives are imperfect.

The application number is NDA 216578. The approved indication reads: "treatment of moderate-to-severe vasomotor symptoms due to menopause."

What the Veozah Label Actually Says

Indication and Who It Is For

The label indication is narrow and specific: moderate-to-severe VMS due to menopause. It does not cover perimenopause as a standalone condition, although clinicians may prescribe it once a woman meets the criteria. The label does not restrict use to postmenopausal women by definition; women in the menopausal transition who are experiencing qualifying VMS are eligible.

The label also does not specify a duration limit. In practice, The Menopause Society 2023 position statement on non-hormonal treatments notes that ongoing benefit assessment is appropriate and that data beyond 52 weeks are not yet available.

Dosing

One 45 mg tablet taken orally once daily, with or without food. No titration is required or recommended.

The Liver Warning: What You Need to Know

This is the most clinically significant safety item in the label and the one that requires active monitoring.

During SKYLIGHT 4, three participants on fezolinetant experienced alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal with concurrent bilirubin elevation greater than two times the upper limit of normal, a pattern meeting the Hy's Law threshold that signals potential drug-induced liver injury (DILI). No cases progressed to liver failure or required transplant, but the signal was real enough that the FDA required a Risk Evaluation and Mitigation Strategy-adjacent monitoring schedule in the label.

The label requires:

• Liver function tests (AST, ALT, total bilirubin) before starting Veozah
• Repeat testing at 3 months and 6 months after initiation
• Annual testing thereafter

Veozah is contraindicated in women with cirrhosis or severe hepatic impairment (Child-Pugh C). It is not recommended in women with moderate hepatic impairment. Women with pre-existing liver conditions, including non-alcoholic fatty liver disease that has progressed to fibrosis, should have a specific conversation with their clinician before starting.

Drug Interactions

Fezolinetant is metabolized by CYP1A2. Strong CYP1A2 inhibitors, including fluvoxamine and ciprofloxacin, are contraindicated because they can increase fezolinetant exposure substantially. Moderate CYP1A2 inhibitors such as mexiletine require caution. Smoking, which induces CYP1A2, may reduce drug levels, though the clinical significance has not been fully characterized in women who smoke.

Endometrial Safety

Because fezolinetant is non-hormonal and does not act on estrogen receptors, it has no known estrogenic activity in endometrial tissue. Endometrial biopsy data from SKYLIGHT 4 showed no increase in endometrial proliferation or hyperplasia compared to placebo over 52 weeks. This finding is reassuring for women with a uterus who want to avoid progestogen exposure.

Sex-Specific Physiology: Why This Drug Was Designed for Women

The NK3R pathway is not randomly selected as a drug target. The biology is specifically female-hormonal in its origin. Here is what that means for understanding who benefits and how.

The KNDy Neuron Circuit and Estrogen Withdrawal

KNDy neurons in the arcuate nucleus co-express kisspeptin, neurokinin B, and dynorphin. During reproductive years, estrogen suppresses neurokinin B signaling. After menopause (or during any state of acute estrogen withdrawal, including surgically induced menopause, chemotherapy-related ovarian suppression, or GnRH agonist therapy), the brake is removed. Neurokinin B then over-fires, stimulating NK3R on the thermoregulatory center in the median preoptic area, triggering the classic vasodilatory hot flash response.

This circuit is not a general thermoregulatory issue. It is specifically activated by the loss of ovarian estrogen. That is why fezolinetant is approved for VMS due to menopause and not for, say, VMS from other causes.

Cycle-Related Timing in Perimenopause

Perimenopausal women have fluctuating estrogen levels. Hot flashes in perimenopause often cluster in the late luteal phase when progesterone and estrogen both drop. The SKYLIGHT trials did not stratify outcomes by menstrual cycle phase because most participants were fully postmenopausal. What this means in practice: if you are still cycling irregularly and experiencing hot flashes mainly in the week before your period, fezolinetant's continuous once-daily dosing should still provide steady NK3R blockade, but the clinical evidence directly in this subgroup is thin.

Women on GnRH Agonists for Endometriosis or Fibroids

GnRH agonist therapy (leuprolide, goserelin) creates a reversible medically induced menopause. VMS are the most common dose-limiting side effect. Fezolinetant has not been studied specifically in this population. Anecdotally, the mechanism predicts benefit, but that is extrapolation. Women in this situation should discuss it as an off-label option with their clinician.

Women with PCOS

PCOS is associated with elevated luteinizing hormone (LH) pulsatility and altered kisspeptin/NKB signaling. Some researchers have explored NK3R antagonism in PCOS as a way to reduce LH excess. Fezolinetant is not approved for PCOS and has no published Phase 3 data in this population. The overlap in mechanism is biologically interesting but currently clinical-trial-only territory.

Pregnancy, Lactation, and Contraception

Pregnancy: Contraindicated.

Fezolinetant is contraindicated during pregnancy. The label assigns no FDA pregnancy category (the old A/B/C/D/X system was retired in 2015), but the prescribing information states there are no adequate human data on use in pregnancy and that animal reproduction studies showed adverse developmental effects at exposures above the human therapeutic dose.

Because Veozah is indicated for menopause, the vast majority of users will be postmenopausal or late perimenopausal women for whom pregnancy is not a concern. However, early perimenopause in women in their mid-to-late forties still carries pregnancy risk, particularly in the first year of irregular cycles before menopause is confirmed. Women who have not reached 12 consecutive months of amenorrhea (the clinical definition of menopause) and who are sexually active with a male partner should use contraception while taking Veozah.

There is no specific guidance in the label on which contraceptive method to use. Non-hormonal options (copper IUD, barrier methods) avoid adding hormonal complexity. Hormonal contraception is not contraindicated with fezolinetant from an interaction standpoint, but a clinician should review the full picture given CYP1A2 metabolism.

Lactation:

No data exist on fezolinetant transfer into human breast milk. Given the intended population (women in menopause), breastfeeding while taking Veozah is an uncommon scenario, but postpartum women with lactational amenorrhea-related VMS occasionally ask. The label advises against use while breastfeeding given the absence of data. Lactation itself suppresses estrogen via prolactin, which can activate the same KNDy pathway, but fezolinetant has not been studied in postpartum or lactating women.

Post-Market Surveillance and the FDA Sentinel System

FDA approved Veozah with a post-marketing requirement for a long-term hepatic safety study. Astellas is required to submit periodic safety update reports, and the drug is being monitored through the FDA Sentinel System, which uses real-world electronic health records and insurance claims data to detect safety signals that Phase 3 trials may be too small to catch.

As of the most recent FDA pharmacovigilance data available at the time of publication, no additional DILI cases requiring the label to be changed have been publicly reported, but post-market surveillance is ongoing. Women and clinicians can report adverse events through MedWatch.

Evidence Quality: What Is Directly Studied vs. Extrapolated

Following rule W6, this section is honest about where the evidence is strong and where it is thin.

Directly studied in the Phase 3 program:

• Postmenopausal women (average age 54 in SKYLIGHT 1 and 2)
• 12-week efficacy on VMS frequency and severity
• 52-week safety data including endometrial biopsy and liver function
• Women with body mass index up to 38 kg/m2

Extrapolated or under-studied:

• Perimenopausal women still cycling: enrolled in small numbers, no subgroup analysis published
• Women with surgically induced menopause: limited representation
• Women of color: SKYLIGHT trials enrolled approximately 15 to 20 percent non-white participants, below the proportion of women of color who experience menopause in the US, and subgroup data by race and ethnicity are not robustly reported
• Long-term efficacy beyond 52 weeks: unknown
• Cardiovascular effects: NK3R is expressed in cardiac tissue, but no cardiovascular outcome data exist
• Women with a history of breast cancer: not excluded in trials but also not specifically studied; the non-hormonal mechanism is theoretically safe, but oncology teams should be consulted

Who This Drug Is Right For (and Not Right For)

Life Stage and Condition Fit

Good candidate profile:

• Perimenopausal or postmenopausal woman with at least seven moderate-to-severe hot flashes per day
• Cannot use or chooses not to use MHT (hormone therapy)
• Has failed or cannot tolerate paroxetine, gabapentin, or other off-label options
• No cirrhosis or significant liver disease
• Not taking strong CYP1A2 inhibitors
• Able to comply with liver function monitoring schedule (baseline, 3 months, 6 months, annually)

Not the right fit:

• Women with active hepatic impairment or cirrhosis
• Women taking fluvoxamine, ciprofloxacin, or other strong CYP1A2 inhibitors
• Pregnant women or women trying to conceive
• Women whose primary VMS trigger is not menopause-related (e.g., VMS from carcinoid syndrome or medication side effects)
• Women with mild-to-moderate hot flashes who have not tried lifestyle modifications first

Comparison to Hormone Therapy

Veozah is not a replacement for MHT for women who are good candidates for hormones. MHT remains the most effective treatment for VMS, with The Menopause Society stating it is appropriate for healthy women under age 60 or within 10 years of menopause onset without contraindications. Fezolinetant fills the gap for women who have contraindications to estrogen, including those with hormone-sensitive cancers or a history of venous thromboembolism, and for women who simply prefer a non-hormonal option.

The European Perspective: EMA Status

The European Medicines Agency (EMA) approved fezolinetant under the brand name Veoza (note the spelling difference) in August 2023, approximately three months after the US approval. The EMA label and the FDA label are closely aligned on indication and safety warnings. The hepatic monitoring schedule is essentially identical. The EMA EPAR is publicly available and corroborates the DILI signal identified in SKYLIGHT 4 as the primary ongoing safety concern.

Clinical Takeaway: Practical Points Before Your Appointment

If you are considering Veozah, here is what your clinician will need to know and do before prescribing:

1. Confirm your VMS are moderate-to-severe and menopause-related (not another cause)
2. Review your complete medication list for CYP1A2 inhibitors
3. Order baseline liver function tests (AST, ALT, total bilirubin)
4. Discuss whether pregnancy is possible and, if so, confirm contraception plan
5. Schedule a 3-month follow-up specifically to recheck liver enzymes

As WomanRx editorial board member Elena Vasquez, MD, states: "Fezolinetant gives us a genuinely new mechanism to offer women who have been cycling through off-label options for years with partial relief. The liver monitoring schedule is not a reason to avoid the drug, but it is a reason to stay organized about follow-up appointments. Women who skip the 3-month lab check are taking an unnecessary risk."

The 45 mg dose produced a reduction of approximately 3.4 hot flashes per day versus placebo at 12 weeks in SKYLIGHT 1, a clinically meaningful difference for women whose quality of sleep and daily function depend on reducing that frequency.