Fezolinetanto for hot flashes: liver and selection

A 53-year-old woman seeks primary care for intense hot flashes. She had hormone receptor positive breast cancer four years ago, underwent surgery, had radiotherapy and has been taking anastrozole since then. She reports about ten moderate or intense hot flashes per day, with night sweats that wake her three times a night. She has already tried behavioral measures, such as light clothing and a cool environment, without enough improvement. Her oncologist contraindicated hormone therapy. She does not drink alcohol, has no known liver disease and takes only anastrozole and a calcium supplement. Her last creatinine was normal. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. It covers fezolinetant, a neurokinin 3 receptor antagonist approved for moderate to intense vasomotor symptoms of menopause, without hormones. The text explains how hot flashes arise, what the studies showed, why the American label carries a boxed warning about the liver, what the contraindications are, where the woman with breast cancer stands and where elinzanetant comes in. It does not replace your institution's protocol or the local label. If you play the case of the day on NEXO, you will recognize the challenge: deciding with clues that arrive in sequence.

Key points

• Fezolinetant (brand name Veozah in the United States and Veoza in the European Union) blocks the neurokinin 3 receptor in the temperature control center.
• The dose is 45 mg orally once a day, with or without food.
• The American label carries a boxed warning about liver injury and requires tests before and during the first nine months.
• Cirrhosis, severe kidney disease and use of CYP1A2 inhibitors are contraindications.
• The main studies excluded women with prior cancer, so the evidence for the woman in the scene is indirect.
• The regulatory dates in this text were checked at the FDA and the EMA on October 24, 2026.

Why this is a reasoning scenario

Vasomotor symptoms are the most typical complaint of menopause. A review notes that up to 80 percent of perimenopausal women in the SWAN study reported hot flashes in the two weeks before the annual interview, and that many women spend up to 40 percent of their lives in postmenopause (DePree, 2023). A practical guide notes that menopausal hormone therapy can carry risks such as breast cancer with combined estrogen and progestogen, endometrial hyperplasia and cancer, venous thromboembolism and gallbladder disease (Khan et al., 2023). A review on hot flashes in people with cancer notes that hormone therapy is the reference treatment, but is usually contraindicated in hormone-sensitive cancers (Zhu et al., 2025).

The scenario is good for training because the most effective therapy is out of the question and each alternative has a pitfall. Paroxetine interferes with tamoxifen, gabapentin causes drowsiness, oxybutynin has anticholinergic effects and fezolinetant requires liver monitoring. The post on signs, symptoms and history helps measure the frequency and impact of hot flashes, and the post on clinical decision-making reminds you that every test ordered must change a decision.

What the scene teaches

The scene trains six habits. The first is to quantify hot flashes and their impact on sleep. The second is to confirm why hormone therapy is not an option. The third is to review all medications for interactions. The fourth is to order liver and kidney function tests before starting. The fifth is to set the testing schedule. The sixth is to talk with oncology about what the evidence shows and what it does not show.

What is not at stake

The text does not discuss breast cancer treatment, the choice of adjuvant endocrine therapy or genitourinary syndrome of menopause. It also does not compare prices or access. The post on diagnostic uncertainty helps explain to the patient what it means to use a drug in a population that was not included in the studies.

Hot flashes in the breast cancer survivor

A review on sleep recalls that the endocrine therapies most used in breast cancer reduce recurrence by lowering estrogen action, either by inhibiting its synthesis, as with aromatase inhibitors, or as receptor modulators, as with tamoxifen (Van Dyk and colleagues, 2021). The same review recalls that sleep disturbance can reach 60 percent of survivors on endocrine therapy, against 20 percent in the general population (Van Dyk and colleagues, 2021). The review on people with cancer recalls that cognitive behavioral therapy and clinical hypnosis have randomized studies with breast cancer survivors (Zhu and colleagues, 2025). A 2025 review on hot flashes in people with cancer says there is still no data on the effect and safety of fezolinetant in cancer survivors (Zhu and colleagues, 2025).

How hot flashes arise

The temperature center

A review on kisspeptin and neurokinin B explains that, in preclinical models, the KNDy neurons of the arcuate nucleus, which produce kisspeptin, neurokinin B and dynorphin, project to preoptic areas that control temperature (Koysombat and colleagues, 2025). One of these areas is the median preoptic nucleus, which integrates information from skin heat sensors and controls heat loss responses, such as cutaneous vasodilation (Koysombat and colleagues, 2025).

The role of estrogen

The EMA page summarizes that, before menopause, there is a balance between estrogen and neurokinin B, which regulates the temperature control center in the brain (EMA, Veoza page). With the drop in estrogen, this balance is lost and vasomotor symptoms may arise (EMA, Veoza page). The Lynkuet page adds that the same imbalance appears during endocrine therapy, which blocks the effect of estrogen (EMA, Lynkuet page). This is exactly the mechanism of the woman in the scene, who uses an aromatase inhibitor.

Measure before treating

The studies counted moderate to severe hot flashes per day in a diary (Johnson and colleagues, 2023). In practice, asking the patient to record over one or two weeks the number of hot flashes, their intensity and nighttime awakenings helps assess the response later. The post on differential diagnosis recalls that night sweats and heat can also come from thyroid, infection, medications or cancer recurrence, and that a new or atypical picture calls for investigation.

How fezolinetant works

The label describes fezolinetant as a neurokinin 3 receptor antagonist that blocks the binding of neurokinin B to the KNDy neuron and modulates neuronal activity in the temperature control center (US Veozah label, 12/2024). Its affinity for the neurokinin 3 receptor is more than 450 times higher than for neurokinin 1 or 2 receptors (US Veozah label, 12/2024). Treatment showed no clear trend in measured sex hormones (US Veozah label, 12/2024).

Difference from elinzanetant

Elinzanetant is an antagonist of neurokinin 1 and neurokinin 3 receptors (US Lynkuet label, 10/2025). The EMA summarizes that it prevents neurokinin B from binding to two of its targets in the brain (EMA, Lynkuet page). The US dose is 120 mg, two 60 mg capsules, once a day at bedtime (US Lynkuet label, 10/2025). The Lynkuet label carries a warning about central nervous system depressant effect, with somnolence, fatigue, vertigo and dizziness in 11.9 percent against 3.5 percent with placebo (US Lynkuet label, 10/2025). It contraindicates use during pregnancy and calls for adjustment with moderate CYP3A4 inhibitors and avoiding strong inhibitors (US Lynkuet label, 10/2025).

Interactions

Fezolinetant is a substrate of CYP1A2, and the label contraindicates use with weak, moderate or strong inhibitors of this enzyme (US Veozah label, 12/2024). Reviewing the medication list is therefore part of prescribing. For the woman in the scene, anastrozole is not on that list, but a future prescription of fluvoxamine or ciprofloxacin, for example, would change the approach. It is worth checking every new medication in the label or with the pharmacy.

Regulatory status: FDA and EMA

FDA

According to Drugs@FDA, Veozah, NDA 216578, was approved in the United States on May 12, 2023 as a new molecular entity, with priority review (Drugs@FDA, NDA 216578). Supplements 3, of August 31, 2024, and 4, of December 16, 2024, changed the labeling (Drugs@FDA, NDA 216578). The label consulted is the 12/2024 revision, which carries the boxed warning about the liver (US Veozah label, 12/2024).

Lynkuet, NDA 219469, was approved in the United States on October 24, 2025, also as a new molecular entity (Drugs@FDA, NDA 219469). The US indication is the treatment of moderate to severe vasomotor symptoms of menopause (US Lynkuet label, 10/2025).

EMA

In the European Union, Veoza received a positive opinion on October 12, 2023 and authorization on December 7, 2023 (EMA, Veoza page). The indication is the treatment of moderate to severe vasomotor symptoms of menopause, and the medicine is under additional monitoring (EMA, Veoza page). The page was updated on August 21, 2026 (EMA, Veoza page).

Lynkuet received a positive opinion on September 18, 2025 and authorization on November 17, 2025 (EMA, Lynkuet page). In the European Union, the EMA page describes use for vasomotor symptoms of menopause or caused by adjuvant endocrine therapy for breast cancer (EMA, Lynkuet page). The page was updated on September 11, 2026 (EMA, Lynkuet page). This difference between the agencies weighs on the conversation with the woman in the scene.

The table summarizes the dates.

Medication	Agency	Event	Date	Source
Veozah	FDA	Initial approval, NDA 216578	05/12/2023	(Drugs@FDA, NDA 216578)
Veozah	FDA	Last labeling change, supplement 4	12/16/2024	(Drugs@FDA, NDA 216578)
Veoza	EMA	Authorization in the European Union	12/07/2023	(EMA, Veoza page)
Lynkuet	FDA	Initial approval, NDA 219469	10/24/2025	(Drugs@FDA, NDA 219469)
Lynkuet	EMA	Authorization in the European Union	11/17/2025	(EMA, Lynkuet page)

What the studies showed

SKYLIGHT 1 and 2

Studies 1 and 2 in the label, SKYLIGHT 1 and SKYLIGHT 2, included 1022 women with at least seven moderate to severe hot flashes per day, with 12 weeks of comparison with placebo and then 40 weeks of extension (US Veozah label, 12/2024). Mean age was 54 years (US Veozah label, 12/2024). In study 1, daily frequency fell 6.4 with fezolinetant and 3.9 with placebo at week 12, a difference of 2.6 hot flashes per day (US Veozah label, 12/2024). In study 2, it fell 7.5 versus 5.0, a difference of 2.5 (US Veozah label, 12/2024). Baseline frequency was 10 to 12 hot flashes per day (US Veozah label, 12/2024).

The SKYLIGHT 2 criteria excluded current or prior history of malignant tumor, except basal cell carcinoma, and use of strong or moderate CYP1A2 inhibitors (Johnson et al., 2023). The woman in the scene, therefore, would not have entered this study.

SKYLIGHT 4

SKYLIGHT 4 was designed to provide 52 weeks of placebo-controlled safety data, with a focus on the endometrium (Neal-Perry et al., 2023). In the label, endometrial hyperplasia or carcinoma occurred in 2 of 350 women on fezolinetant, or 0.6 percent, and in none of 186 on placebo (US Veozah label, 12/2024). The most common effects were abdominal pain, diarrhea, insomnia, back pain, hot flash and increased transaminases (US Veozah label, 12/2024).

DAYLIGHT

The DAYLIGHT study included 452 women aged 40 to 65 considered unsuitable for hormone therapy, due to contraindication, caution, prior discontinuation or informed choice (Schaudig et al., 2024). Only 11.1 percent were in the contraindication group (Schaudig et al., 2024). At week 24, fezolinetant reduced the frequency of hot flashes by 1.93 per day more than placebo (Schaudig et al., 2024). The mean reduction was 8.15 hot flashes per day with fezolinetant and 6.09 with placebo (Schaudig et al., 2024).

Indirect comparisons and elinzanetant

A network meta-analysis concluded that the effect of fezolinetant on frequency did not differ from any hormone therapy regimen, and that it reduced frequency more than desvenlafaxine, paroxetine 7.5 mg and extended-release gabapentin (Morga et al., 2024). Indirect comparisons, however, do not replace direct studies (Morga et al., 2024). In OASIS 3, with 628 women and 52 weeks, elinzanetant reduced frequency by 5.4 hot flashes per day versus 3.5 with placebo at week 12 (Panay et al., 2025). The effects most often cited as related to treatment were drowsiness, fatigue and headache (Panay et al., 2025).

The table summarizes the main studies.

Study	Population	Participants	Main result	Source
SKYLIGHT 1, study 1	Menopause, no prior cancer	174 versus 175 in the analysis	Difference of 2.6 hot flashes per day at week 12	(US Veozah label, 12/2024)
SKYLIGHT 2, study 2	Menopause, no prior cancer	167 versus 167 in the analysis	Difference of 2.5 hot flashes per day at week 12	(US Veozah label, 12/2024) (Johnson et al., 2023)
SKYLIGHT 4, study 3	Safety over 52 weeks	609 versus 610 in the 45 mg arm	Endometrial hyperplasia or carcinoma in 0.6 percent	(Neal-Perry et al., 2023) (US Veozah label, 12/2024)
DAYLIGHT	Unsuitable for hormone therapy	226 versus 226	Difference of 1.93 hot flashes per day at week 24	(Schaudig et al., 2024)
OASIS 3, elinzanetant	Menopause, 52 weeks	313 versus 315	Drop of 5.4 versus 3.5 hot flashes per day at week 12	(Panay et al., 2025)

How to read these numbers

Placebo greatly reduces hot flashes, and the real difference is about two to three per day. The label considers a reduction of at least two hot flashes in 24 hours clinically significant (US Veozah label, 12/2024). For someone who has ten a day and wakes up three times a night, this can be worth a lot, but expectations need to be honest.

From selection to follow-up

Before starting

• Count hot flashes per day and night awakenings for one to two weeks.
• Confirm with oncology why hormone therapy is not an option.
• Order ALT, AST, alkaline phosphatase and total and direct bilirubin.
• Do not start if ALT or AST are at twice the upper limit of normal or more, or if total bilirubin is too.
• Confirm that there is no cirrhosis or severe kidney disease.
• Review all medicines for CYP1A2 inhibitors.

Dose

The dose is 45 mg orally once a day, with or without food, swallowing the tablet whole (US Veozah label, 12/2024). If a dose is missed, the patient should take it as soon as she remembers, unless less than 12 hours remain until the next one (US Veozah label, 12/2024).

The liver warning

The black box warning describes severe liver injury observed after marketing (US Veozah label, 12/2024). In these reports, the injury appeared within the first 40 days of use, with fatigue, nausea, itching, jaundice, pale stools and dark urine, and the tests improved gradually after discontinuation (US Veozah label, 12/2024). The label instructs repeating liver tests every month for the first three months and then at six and nine months (US Veozah label, 12/2024). It instructs stopping at once if symptoms such as new fatigue, loss of appetite, nausea, vomiting, itching, yellow skin or eyes, pale stools, dark urine or abdominal pain appear (US Veozah label, 12/2024). It also instructs stopping if transaminases exceed five times the upper limit of normal, or three times with bilirubin above twice (US Veozah label, 12/2024). Above three times, the tests should be repeated more often until resolution (US Veozah label, 12/2024).

In the studies, transaminases above three times the upper limit of normal occurred in 2.3 percent with fezolinetant and in 0.9 percent with placebo, without a rise in bilirubin above twice, generally without symptoms and with a return to baseline (US Veozah label, 12/2024). In practice, this means tests at the start and at months 1, 2, 3, 6 and 9 (US Veozah label, 12/2024).

Kidneys and liver

Fezolinetant is contraindicated in severe kidney disease, with glomerular filtration from 15 to less than 30, and in end-stage kidney disease (US Veozah label, 12/2024). No adjustment is needed in mild or moderate kidney disease (US Veozah label, 12/2024). Cirrhosis is also a contraindication, and Child-Pugh A or B hepatic impairment increases exposure (US Veozah label, 12/2024).

Options without hormones

A review on hot flashes in people with cancer notes that selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, gabapentin and fezolinetant are the preferred options of the North American menopause society, with level I evidence, and oxybutynin with level I to II (Zhu and colleagues, 2025). The same review recommends avoiding paroxetine in those taking tamoxifen (Zhu and colleagues, 2025). Another review explains that paroxetine inhibits CYP2D6, the enzyme that converts tamoxifen into endoxifen, its more active metabolite (Young Moss and colleagues, 2025). For the woman in the scene, who takes anastrozole, this interaction does not apply, but the choice still depends on sleep, mood, blood pressure and preferences.

Follow-up

Follow-up includes the liver test schedule, the hot flash diary after four to twelve weeks and a review of effects such as insomnia and diarrhea (US Veozah label, 12/2024). The post on diagnostic pause helps reassess before concluding that the drug failed. The post on interprofessional clinical reasoning shows how primary care, oncology, gynecology and pharmacy can share this plan.

Pregnancy

The label states that there are no data on use in pregnancy (US Veozah label, 12/2024). In perimenopause, pregnancy is still possible and must be kept in mind. The elinzanetant label is more restrictive and contraindicates use in pregnancy (US Lynkuet label, 10/2025).

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the ICD-10 code. Hot flashes after breast cancer are a good exercise because a liver test, a new drug or endocrine therapy change the approach. The post on case-based learning explains why this format fixes knowledge.

Three exercises with cases

Change the lab result. Say what to do if the month-two ALT came back at four times the upper limit of normal, without symptoms.

Change the medications. Say what changes if she needed ciprofloxacin for a urinary infection.

Change the endocrine therapy. Say what changes if she used tamoxifen instead of anastrozole.

The post about simulated consultations helps train the conversation about expectations, tests and warning signs.

The limits on using the game are described on the Economy page of NEXO. If you research the teaching of clinical reasoning, the page for Researcher explains how to get in touch. Professionals who write or review cases find information on Curator and on Creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Is fezolinetant a hormone?

No. It blocks the neurokinin 3 receptor and showed no clear trend in sex hormones (US prescribing information for Veozah, 12/2024).

What is the dose?

45 mg orally once a day (US prescribing information for Veozah, 12/2024).

Which tests should be ordered?

Liver tests before starting, every month for the first three months and at six and nine months (US prescribing information for Veozah, 12/2024).

Can it be used after breast cancer?

The US prescribing information does not address this group, and the main studies excluded prior cancer (Johnson et al., 2023). A 2025 review says there is still no data in this population (Zhu et al., 2025). The decision should be shared with oncology.

What about elinzanetant?

In the European Union, the EMA describes its use also for hot flashes from adjuvant endocrine therapy for breast cancer (EMA, Lynkuet page). In the United States, the indication is for menopausal hot flashes (US prescribing information for Lynkuet, 10/2025).

Final checklist

• I counted hot flashes and awakenings before treating.
• I confirmed the contraindication to hormone therapy.
• I ordered liver tests before starting.
• I ruled out cirrhosis and severe kidney disease.
• I reviewed CYP1A2 inhibitors.
• I scheduled tests at months 1, 2, 3, 6 and 9.
• I gave guidance on symptoms of liver injury.
• I discussed the limits of the evidence with oncology.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. Astellas Pharma US. VEOZAH® (fezolinetant) tablets, for oral use. Prescribing Information. Revised 12/2024. Accessed 10/24/2026. Official source.
2. Bayer HealthCare Pharmaceuticals. LYNKUET® (elinzanetant) capsules, for oral use. Prescribing Information. Revised 10/2025. Accessed 10/24/2026. Official source.
3. European Medicines Agency. Lynkuet | European Medicines Agency (EMA). Accessed 10/24/2026. Official source.
4. European Medicines Agency. Veoza | European Medicines Agency (EMA). Accessed 10/24/2026. Official source.
5. DePree B. Fezolinetant: A Potential Treatment for Moderate to Severe Vasomotor Symptoms of Menopause. touchREV Endocrinol. 2023. PMID 38187079.
6. 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. PMID 36734148.
7. Khan SJ, Kapoor E, Faubion SS, et al. Vasomotor Symptoms During Menopause: A Practical Guide on Current Treatments and Future Perspectives. Int J Womens Health. 2023. PMID 36820056.
8. Koysombat K, Tsoutsouki J, Patel AH, et al. Kisspeptin and neurokinin B: roles in reproductive health. Physiol Rev. 2025. PMID 39813600.
9. 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. PMID 38016166.
10. 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. PMID 36897180.
11. Panay N, Joffe H, Maki PM, et al. Elinzanetant for the Treatment of Vasomotor Symptoms Associated With Menopause: A Phase 3 Randomized Clinical Trial. JAMA Intern Med. 2025. PMID 40920404.
12. Schaudig K, Wang X, Bouchard C, et al. Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial. BMJ. 2024. PMID 39557487.
13. U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. NDA 216578, Veozah. Accessed 10/24/2026. Official source.
14. U.S. Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. NDA 219469, Lynkuet. Accessed 10/24/2026. Official source.
15. Van Dyk K, Joffe H, Carroll JE. Sleep and endocrine therapy in breast cancer. Curr Opin Endocr Metab Res. 2021. PMID 34095605.
16. Young Moss S, Lee A, Simon JA. Advances in Pharmacotherapy for Menopausal Vasomotor Symptoms. Drugs. 2025. PMID 41028653.
17. Zhu L, Hshieh TT, Iyer TK, et al. Management of vasomotor symptoms in cancer patients. Oncologist. 2025. PMID 40037618.