Fezolinetant: The Non-Hormone Drug for Hot Flashes

Table of Contents

1. Fezolinetant in Brief
2. KNDy Neurons and the Hot Flash
3. What a Neurokinin-3 Blocker Does
4. SKYLIGHT 1 and 2: The Efficacy Trials
5. SKYLIGHT 4: One Year of Safety Data
6. DAYLIGHT: Women Unsuited to Hormone Therapy
7. The 2023 Approval and the 2024 Boxed Warning
8. The Liver Blood-Test Schedule in the Label
9. Interactions and Who the Label Excludes
10. How It Compares With Elinzanetant and Other Options
11. What Is Not Known
12. Connections
13. Key Research Papers
14. Featured Videos

Fezolinetant in Brief

Fezolinetant is a daily pill for moderate to severe hot flashes and night sweats caused by menopause. Doctors call these two symptoms together "vasomotor symptoms". The drug is not a hormone. It works on a brain signal that helps set off a hot flash, and it does this without adding estrogen or any other sex hormone to the body.

The United States Food and Drug Administration (FDA) approved it in May 2023, the first medicine of its kind. In December 2024 the Food and Drug Administration added a boxed warning for liver injury to the label. A boxed warning is the most prominent warning a United States drug label carries.

The results in short form:

• In the two main trials, the 45 mg dose cut moderate to severe episodes by about 2.5 a day more than placebo at week 12.
• In a 24-week trial of women unsuited to or unwilling to use hormone therapy, the difference from placebo was 1.93 episodes a day.
• In an East Asian trial of the 30 mg dose, the drug did not separate from placebo.
• Serious liver injury appeared after the drug reached the market, not in the trials, and the label now lists a schedule of liver blood tests.

The Night Sweats page covers the many causes of night sweats and gives a short note on this drug. The Non-Hormonal Options page sets it beside the older non-hormone choices. This page goes through the trials, the label and the open questions for fezolinetant alone.

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KNDy Neurons and the Hot Flash

The brain keeps body temperature steady from a small area called the hypothalamus. Part of the story of a hot flash centers on a group of nerve cells there, named KNDy neurons after three messengers they make: kisspeptin, neurokinin B and dynorphin.

A 2013 review by Rance and colleagues set out the idea that these cells help cause hot flashes. Its reasoning came from several lines of evidence:

• The cells show marked changes in postmenopausal women.
• In rats, the same cells send fibers to the temperature-control area, which carries neurokinin-3 receptors, the main receptor for neurokinin B.
• In rats, destroying these cells reduced the widening of skin blood vessels and partly blocked the effects of estrogen on temperature control.

The review called this a hypothesis: the cells relay the estrogen signal to the areas that shed heat. A later trial paper describes the balance in simple terms. The temperature center is stimulated when the neurokinin-3 receptor is switched on and held back by estrogen, and menopause disturbs that balance.

A small human experiment added direct evidence in 2015. Ten healthy women received a 30-minute infusion of neurokinin B and, on another occasion, an inactive infusion, without knowing which was which. Eight of the ten had flushing during neurokinin B and none had it during the inactive infusion. Heart rate and skin temperature rose during the episodes in the pattern seen in menopausal flushing.

A 2017 crossover trial then tested the reverse. In 37 women, an experimental neurokinin-3 blocker coded MLE4901 cut weekly hot flashes by 45 percentage points compared with placebo. That molecule is not fezolinetant. Three women on it had a rise in a liver enzyme to 4.5 to 5.9 times the upper limit of normal 28 days after starting, which returned to normal within 90 days. The liver question therefore appeared early in this drug family.

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What a Neurokinin-3 Blocker Does

A receptor is a docking site on a cell, and a messenger molecule switches it on. A blocker, which pharmacologists call an antagonist, occupies the site so the messenger cannot act. The United States label states that fezolinetant blocks neurokinin B from binding on the KNDy neuron, which changes the activity of the nerve cells in the temperature-control center.

Facts from the label's pharmacology section, in plain terms:

• The drug binds the neurokinin-3 receptor more than 450 times more tightly than the neurokinin-1 or neurokinin-2 receptors.
• Measured sex hormones (follicle-stimulating hormone, testosterone, estrogen and dehydroepiandrosterone sulfate) showed no clear trend in menopausal women. Luteinizing hormone dipped briefly at peak drug levels.
• The effective half-life, the time for the blood level to fall by half, is 9.6 hours in women with hot flashes.
• The liver breaks it down mainly through an enzyme called cytochrome P450 1A2 (CYP1A2), and less through two related enzymes. This one fact drives the interaction rules further down this page.
• At 20 times the approved dose, it did not lengthen the QT interval on a heart tracing to any clinically relevant extent.

The label lists one strength, a 45 mg tablet taken once a day. Earlier trials explored other doses. A 12-week phase 2a trial in 87 women gave 90 mg twice a day and reported about five fewer moderate to severe episodes a day than placebo. A phase 2b trial in 352 treated women compared seven dosing plans, with differences from placebo of 1.8 to 2.6 episodes a day at week 12.

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SKYLIGHT 1 and 2: The Efficacy Trials

These two matching trials are the main evidence behind the approval. Women aged 40 to 65 with an average of at least seven moderate to severe hot flashes a day received placebo, 30 mg or 45 mg once a day for 12 weeks. After that, everyone received the drug for another 40 weeks, so the placebo comparison lasted only 12 weeks. SKYLIGHT 1 was funded by the drug's maker, and employees of the maker are among the authors of the trial reports.

SKYLIGHT 1

The trial assigned 527 women out of 2,205 recruited, at 97 sites in North America and Europe. Differences from placebo in daily episodes:

• Week 4: 1.87 fewer on 30 mg and 2.07 fewer on 45 mg.
• Week 12: 2.39 fewer on 30 mg and 2.55 fewer on 45 mg.
• Severity score at week 12: 0.24 lower on 30 mg and 0.20 lower on 45 mg.

Adverse events of any cause during the first 12 weeks were reported by 37% on 30 mg, 43% on 45 mg and 45% on placebo. Raised liver enzymes were reported in 2 women on 30 mg, none on 45 mg and 1 on placebo.

SKYLIGHT 2

The label counts 500 women in this trial. Differences from placebo in daily episodes:

• Week 4: 1.82 fewer on 30 mg and 2.55 fewer on 45 mg.
• Week 12: 1.86 fewer on 30 mg and 2.53 fewer on 45 mg.
• Severity score at week 12: 0.16 lower on 30 mg and 0.29 lower on 45 mg.

Serious adverse events were reported by 2% on 30 mg, 1% on 45 mg and 0% on placebo.

The placebo response was large

The differences above are easier to read next to the raw numbers in the label. Women in SKYLIGHT 1 began with about 10.4 episodes a day. By week 12 the count had fallen by 6.4 on 45 mg and by 3.9 on placebo. In SKYLIGHT 2 women began with about 11.8 a day, and the count fell by 7.5 on 45 mg and by 5.0 on placebo. Every severity score started near 2.4. The label treats a drop of at least 2 hot flashes in 24 hours as clinically meaningful.

Pooled results from the two trials

• Half or more of the episodes were gone at week 12 in 58.7% on 45 mg and 36.0% on placebo.
• The difference from placebo in daily episodes was 1.46 at week 1 and 2.51 at week 12, and the authors report improvement from the first day. The gains held through 52 weeks, including during the night, though without a placebo group after week 12.
• On a sleep-disturbance questionnaire at week 12, the score was 1.5 points better than placebo on 45 mg. The 30 mg result (0.6 points) was not clearly different from placebo, since its confidence interval crossed zero.
• Women who said their sleep disturbance was much or moderately better numbered 51.0% on 45 mg and 33.6% on placebo.
• On a menopause quality-of-life score, the 45 mg dose was 0.47 points better than placebo at week 12.
• The overall effect was 2.51 fewer episodes a day. In subgroups it was 3.67 in women who identified as Black, 3.48 in current smokers and 3.48 in current alcohol users.

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SKYLIGHT 4: One Year of Safety Data

SKYLIGHT 4 is the longest placebo-controlled trial in the label. It placed 1,830 women on placebo, 30 mg or 45 mg for 52 weeks, and it was designed to look for harm rather than benefit. It was funded by the drug's maker.

• Any adverse event, whatever the cause: 64.1% on placebo, 67.9% on 30 mg and 63.9% on 45 mg.
• Stopping because of an adverse event: 4.3% on placebo, 5.6% on 30 mg and 4.6% on 45 mg.
• Liver enzymes above three times the upper limit of normal: 6 of 583 on placebo, 8 of 590 on 30 mg and 12 of 589 on 45 mg. No case met Hy's law, the pattern of raised enzymes plus raised bilirubin that signals severe drug-induced liver injury.
• Womb lining: among 599 women assessed, 1 of 203 on 45 mg had endometrial hyperplasia (a thickening of the lining), and 1 of 210 on 30 mg had endometrial cancer. Neither occurred in the other groups. Both rates fell within the limits set by Food and Drug Administration guidance.
• Bone: changes in bone density and bone quality scores were similar across the groups.

From this 52-week trial, the label lists these reactions for the 45 mg dose against placebo:

• Abdominal pain: 4.3% and 2.1%.
• Diarrhea: 3.9% and 2.6%.
• Insomnia: 3.9% and 1.8%.
• Back pain: 3.0% and 2.1%.
• Hot flush: 2.5% and 1.6%.
• Raised liver enzymes: 2.3% and 0.8%.

A 2025 pooled analysis of all three trials covered 1,100 women on 45 mg, 1,103 on 30 mg and 952 on placebo. It reported raised liver enzymes in 1.5% to 2.3% of women on the drug, usually without symptoms and temporary, with no evidence of severe drug-induced liver injury. A trial of this size can miss a rare harm, and the serious cases described below surfaced only after approval.

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DAYLIGHT: Women Unsuited to Hormone Therapy

DAYLIGHT asked a narrower question. It enrolled 453 women aged 40 to 65 in 16 countries who were considered unsuitable for hormone therapy, and gave 45 mg or placebo for 24 weeks, twice the length of the SKYLIGHT placebo period.

The phrase "unsuitable" covered four groups, and a companion paper gives their sizes:

• Hormone therapy not allowed for medical reasons: 50 women (11%).
• Caution because of their medical history: 165 women (37%).
• Previously stopped hormone therapy: 69 women (15%).
• Made an informed choice not to use it: 168 women (37%).

Results at week 24, compared with placebo:

• Daily moderate to severe episodes: 1.93 fewer (95% confidence interval 1.22 to 2.64).
• Severity score: 0.39 lower.
• Sleep-disturbance score: 2.5 points better.
• Menopause quality-of-life score: 0.44 points better.

Adverse events of any cause were reported by 65.0% on the drug and 61.1% on placebo, and serious ones by 4.4% and 3.5%. The most common on the drug were covid-19 (13.3%), headache (8.8%) and fatigue (5.8%). In all, 81.7% of the women finished the trial. Most participants (96.7%) were white, which limits what the trial shows for other groups. Only about one woman in nine had a firm medical bar to hormones. The journal later published a correction to this paper.

A separate pooled analysis looked at the same kind of woman inside SKYLIGHT 1 and 2 and found 2.55 fewer daily episodes than placebo at week 12 on 45 mg.

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The 2023 Approval and the 2024 Boxed Warning

Fezolinetant received its first approval in the United States in May 2023 for moderate to severe vasomotor symptoms due to menopause. That remains the only use listed in the United States label on DailyMed (revised February 2026, the version read for this page). The European Medicines Agency approved it in the same year, and a 2025 drug bulletin reported liver warnings from both agencies.

The label's list of major changes dates the boxed warning for hepatotoxicity (liver toxicity) to December 2024. A 2025 chemistry paper dates an earlier Food and Drug Administration flag about liver injury to September 2024.

What the label reports

The boxed warning states that liver toxicity has occurred after the drug reached the market. The detail in the label:

• Timing: cases of serious drug-induced liver injury occurred within 40 days of starting.
• Peak blood values: liver enzymes up to 50 times the upper limit of normal, alkaline phosphatase up to 4 times and bilirubin up to 5 times.
• Symptoms in those patients: fatigue, nausea, itching, yellowing of the skin (jaundice), pale stools and dark urine.
• Outcome: the abnormal results gradually resolved after the drug was stopped.
• Frequency: unknown. These reports are voluntary and come from a population of uncertain size, so the label states it is not always possible to estimate how often this happens.

In the three clinical trials pooled by the label, liver enzymes above three times the upper limit of normal occurred in 2.3% of women on 45 mg and 0.9% on placebo, usually without symptoms and with no bilirubin rise above twice normal. The liver reference LiverTox, from the United States National Institutes of Health, describes a low rate of raised enzymes and rare instances of clinically apparent liver injury with jaundice.

What reporting databases show

Three recent analyses searched databases of spontaneous reports. They measure how often a side effect is reported for this drug compared with others. They do not measure how many users are harmed, and one author group states plainly that its findings "do not reflect absolute risk or incidence". Publicity can also raise reporting.

• Food and Drug Administration data through mid-2025 (1,282 reports): a liver signal, mainly raised enzymes rather than clinically obvious injury. Median time to a liver event was 77 days.
• The same database through early 2026 (1,757 cases): the signal also included other liver tests, such as gamma-glutamyltransferase and alkaline phosphatase. Median onset of all reported events was 38 days, most within the first 100 days. Nightmares appeared as a possible new signal, weaker when only physician reports were counted. Reports after 2024 were more numerous and stronger, which the authors say may partly reflect the safety announcements.
• World Health Organization VigiAccess data (1,091 reports): a cluster of liver test signals, along with insomnia, headache, dizziness and brain fog.

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The Liver Blood-Test Schedule in the Label

This section reports what the label states. The label is written for prescribers, and decisions about a medicine belong with a clinician.

Before the first dose

The label lists baseline blood tests for alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin (total and direct). It states the drug is not started if either aminotransferase, or the total bilirubin, is at least twice the upper limit of normal for the laboratory doing the test.

After starting

The label lists follow-up tests:

• Every month for the first 3 months.
• At 6 months.
• At 9 months.

With the baseline test, that makes six blood draws in the first nine months. The label names no scheduled test after month 9. Patient information from the same label adds a test whenever signs suggest liver problems.

Results that lead the label to direct stopping

• Liver enzymes above 5 times the upper limit of normal.
• Liver enzymes above 3 times the upper limit of normal together with total bilirubin above 2 times normal.

Enzymes above 3 times normal without those features lead the label to direct more frequent testing until they settle, and it also directs a search for other causes of the raised results.

Symptoms the label names

The label directs patients to stop the drug immediately and seek medical attention, including liver tests, if these signs of possible liver injury appear:

• New tiredness.
• Loss of appetite.
• Nausea or vomiting.
• Itching.
• Yellowing of the eyes or skin.
• Pale stools or dark urine.
• Pain in the abdomen.

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Interactions and Who the Label Excludes

Drugs that block cytochrome P450 1A2

The label contraindicates the drug with any cytochrome P450 1A2 inhibitor, weak, moderate or strong. A contraindication is a situation in which the label says a drug is not to be used. Blocking this enzyme slows the drug's breakdown, so it builds up. The label gives three measured examples:

• Fluvoxamine (strong blocker): peak level up 80%, total exposure up 840%.
• Mexiletine (moderate blocker): peak level up 40%, total exposure up 360%.
• Cimetidine (weak blocker): peak level up 30%, total exposure up 100%.

A published study in 18 healthy postmenopausal women, 9 of them smokers, gave single 30 mg doses with and without fluvoxamine. Peak level reached 182% and total exposure 939% of the level without fluvoxamine. The label does not give a complete list of blockers. Its counseling section asks that patients report all prescription and nonprescription medicines and dietary supplements.

Smoking

Smoking speeds up the same enzyme. In that same small study, total exposure in smokers was 48.3% of the level in nonsmokers. The label states there were no clinically significant differences in exposure in smokers. The pooled trial analysis above reported a larger effect in current smokers.

The drug's effect on other medicines

The label states that fezolinetant and its main breakdown product did not block a list of seven cytochrome P450 enzymes in testing, and did not speed up three of them. A 2026 review notes safety questions about using this drug family alongside one type of breast cancer drug, the cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, without giving figures in its abstract.

Liver and kidney conditions

• Cirrhosis: contraindicated. Single-dose total exposure rose 56% in mild cirrhosis and 96% in moderate cirrhosis, and severe cirrhosis has not been studied.
• Severe kidney disease or kidney failure: contraindicated. In a single-dose study, the label reports no effect on exposure to the drug itself, but exposure to its main breakdown product rose about 75% in moderate and 380% in severe kidney impairment. The label lists no dose change for mild or moderate impairment.

Other groups in the label

• Pregnancy: no human data. In rats and rabbits, high doses far above the human exposure caused loss of embryos.
• Breastfeeding: no human data. In rats, drug-derived material reached higher levels in milk than in the mother's blood.
• Over age 65: too few women were studied to tell whether they respond differently.
• Under age 18: safety and efficacy not established.

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How It Compares With Elinzanetant and Other Options

The search for this page found no trial that gave elinzanetant and fezolinetant to women side by side. Elinzanetant blocks the neurokinin-1 receptor as well as the neurokinin-3 receptor. All the comparisons below are indirect: they compare results from separate trials using statistics, and they are weaker than a direct trial.

• A 2026 matching-adjusted comparison reweighted patient data from SKYLIGHT 1 and 2 to resemble the elinzanetant trials. It reported comparable reductions in frequency and severity, more improvement in sleep disturbance with elinzanetant, and no significant difference in overall quality of life. Several of its authors work for the maker of fezolinetant.
• A 2025 meta-analysis of ten studies and 4,663 patients gave a mean difference in symptom frequency of 1.38 for fezolinetant and 2.04 for elinzanetant. It reported a greater effect and a better side-effect profile for elinzanetant. Its authors state that further research is needed to compare the two directly.
• A 2026 narrative review on breast cancer notes that elinzanetant has phase 3 data from women with breast cancer on hormone-blocking treatment, while the role of fezolinetant in that group remains under investigation.

The two analyses above do not agree on efficacy, and they used different methods and sources. A third paper, a 2025 meta-analysis in Obstetrics & Gynecology, later received an expression of concern from the journal, so its numbers are not used here.

Other treatments

A 2024 network meta-analysis, with authors from the maker of fezolinetant, compared the 45 mg dose through separate trials. Frequency did not differ significantly from any of the 27 hormone regimens studied. It fell more than with paroxetine 7.5 mg (a difference of 1.66 episodes a day), desvenlafaxine 50 to 200 mg (1.12 to 2.16) and extended-release gabapentin 1,800 mg (1.63). Tibolone did better on severity, and two hormone regimens did better on the share of women with a large drop in episodes. Its literature search ended in June 2021.

The risks of hormone therapy are covered on the hormone therapy risks page.

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What Is Not Known

Why some women are hurt in the liver

The label gives no mechanism and no way to predict who is at risk. A 2025 chemistry paper used computer modelling and proposed that the body may turn the drug into a reactive breakdown product. This is a calculation, not a finding in patients.

How often serious liver injury happens

The label states the frequency cannot be reliably estimated. Reporting databases cannot supply a rate, and the trials reported no case meeting Hy's law.

Whether the drug affects cancer risk

This question is disputed in the journals, and the figures are small.

• A 2023 letter in The Lancet raised a possible neoplasm (tumor) risk, and a 2024 reply from trial investigators argued the evidence refutes it.
• A pooled trial analysis controlling for exposure reported no increased risk compared with placebo.
• A 2026 paper in Drug Safety counted non-benign tumors at 0.2, 0.7 and 1.2 per 100 subject-years on placebo, 30 mg and 45 mg. The relative risk at 45 mg was 6.6, with a confidence interval from 0.9 to 51.3, so the imbalance was not statistically significant. Those authors state regulators treated it as chance and they ask for structured monitoring.
• A 2026 review states that meta-analysis and pooled data show a significant increase in non-benign tumors, which differs from the two papers above, and it proposes possible mechanisms involving kisspeptin. Those mechanisms remain theories.
• The label reports no drug-related cancers in a 2-year study in female rats or a 26-week study in mice bred for cancer testing.

Use beyond one year

The placebo-controlled data stop at 52 weeks. Hot flashes often last much longer than that, as the Night Sweats page reports. The label names no limit on treatment length, and the trials do not show what happens to bone, liver or heart beyond a year.

Whether the effect is the same in all populations

MOONLIGHT I, a phase 3 trial in 301 East Asian women, gave 30 mg against placebo for 12 weeks. The difference at week 12 was 0.55 episodes a day with a confidence interval from 1.35 fewer to 0.26 more, and the authors concluded the drug did not reduce frequency or severity versus placebo. This trial did not test 45 mg. A smaller phase 2 trial in 147 Japanese women did show benefit at 15 mg and 30 mg, using episodes of any severity at week 8 (2.50 and 1.76 fewer a day). The reason for the difference is not settled by these abstracts.

Other groups

The role of the drug in breast cancer survivors remains under investigation. A 2025 letter in the New England Journal of Medicine addresses neurokinin-3 blockade for hot flashes in men, and the label's approved use is limited to menopause.

Decisions about medicines for hot flashes belong with a clinician who knows the person's history and other medicines.

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Connections

• All Drugs
• Elinzanetant
• Night Sweats
• Menopause
• Menopause and Hormone Therapy
• Vasomotor Symptoms: Hot Flashes and Night Sweats
• Non-Hormonal Options
• Hormone Therapy Risks
• Menopause Hormones Animation

Key Research Papers

1. Lederman S, Ottery FD, Cano A, Santoro N, Shapiro M, Stute P, Thurston RC, English M, Franklin C, Lee M, Neal-Perry G. 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. PubMed PMID: 36924778
2. Johnson KA, Martin N, Nappi RE, Neal-Perry G, Shapiro M, Stute P, Thurston RC, Wolfman W, English M, Franklin C, Lee M, Santoro N. 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. PubMed PMID: 36734148
3. Neal-Perry G, Cano A, Lederman S, Nappi RE, Santoro N, Wolfman W, English M, Franklin C, Valluri U, Ottery FD. Safety of Fezolinetant for Vasomotor Symptoms Associated With Menopause: A Randomized Controlled Trial. Obstet Gynecol. 2023;141(4):737-747. PubMed PMID: 36897180
4. Schaudig K, Wang X, Bouchard C, Hirschberg AL, Cano A, Shapiro C M M, Stute P, Wu X, Miyazaki K, Scrine L, Nappi RE. 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;387:e079525. PubMed PMID: 39557487 Note: erratum in BMJ. 2024;387:q2623.
5. Shapiro C M M, Wu X, Wang X, Miyazaki K, Morga A, Nappi RE, Stute P, Martins K, Schaudig K. Effect of fezolinetant on patient-reported quality-of-life outcomes: Data from a phase 3b study (DAYLIGHT) of the treatment of moderate to severe vasomotor symptoms associated with menopause in women considered unsuitable for hormone therapy. Maturitas. 2025;193:108159. PubMed PMID: 39809112
6. Kagan R, Cano A, Nappi RE, English ML, Mancuso S, Wu X, Ottery FD. Safety of Fezolinetant for Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause: Pooled Analysis of Three Randomized Phase 3 Studies. Adv Ther. 2025;42(2):1147-1164. PubMed PMID: 39739195
7. Shapiro C M M, Neal-Perry G, Stute P, Thurston RC, Wolfman W, English M, Wu X, Ottery FD. Early onset, maintenance of effect, and day-/night-time findings following fezolinetant treatment for moderate to severe vasomotor symptoms associated with menopause: A pooled phase 3 analysis. Maturitas. 2025;203:108740. PubMed PMID: 41259888
8. Shapiro C M M, Cano A, Nappi RE, Santoro N, English ML, Mancuso S, Morga A, Siddiqui E, Valluri U, Ottery FD. Effect of fezolinetant on sleep disturbance and impairment during treatment of vasomotor symptoms due to menopause. Maturitas. 2024;186:107999. PubMed PMID: 38749864
9. Cano A, Nappi RE, Santoro N, Stute P, Blogg M, English ML, Morga A, Scrine L, Siddiqui E, Ottery FD. Fezolinetant impact on health-related quality of life for vasomotor symptoms due to the menopause: Pooled data from SKYLIGHT 1 and SKYLIGHT 2 randomised controlled trials. BJOG. 2024;131(9):1296-1305. PubMed PMID: 38320967
10. Santoro N, Nappi RE, Neal-Perry G, English M, King DD, Yamaguchi Y, Ottery FD. Fezolinetant treatment of moderate-to-severe vasomotor symptoms due to menopause: effect of intrinsic and extrinsic factors in two phase 3 studies (SKYLIGHT 1 and 2). Menopause. 2024;31(4):247-257. PubMed PMID: 38517210
11. Santoro N, Neal-Perry G, Stute P, Blogg M, Mancuso S, Morga A, Ottery FD, Siddiqui E. Fezolinetant effect on vasomotor symptoms due to menopause in women unsuitable for hormone therapy. Curr Med Res Opin. 2025;41(2):375-384. PubMed PMID: 40044127
12. Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol. 2013;34(3):211-227. PubMed PMID: 23872331
13. Jayasena CN, Comninos AN, Stefanopoulou E, Buckley A, Narayanaswamy S, Izzi-Engbeaya C, Abbara A, Ratnasabapathy R, Mogford J, Ng N, Sarang Z, Ghatei MA, Bloom SR, Hunter MS, Dhillo WS. Neurokinin B administration induces hot flushes in women. Sci Rep. 2015;5:8466. PubMed PMID: 25683060
14. Prague JK, Roberts RE, Comninos AN, Clarke S, Jayasena CN, Nash Z, Doyle C, Papadopoulou DA, Bloom SR, Mohideen P, Panay N, Hunter MS, Veldhuis JD, Webber LC, Huson L, Dhillo WS. Neurokinin 3 receptor antagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet. 2017;389(10081):1809-1820. PubMed PMID: 28385352
15. Depypere H, Timmerman D, Donders G, Sieprath P, Ramael S, Combalbert J, Hoveyda HR, Fraser GL. Treatment of Menopausal Vasomotor Symptoms With Fezolinetant, a Neurokinin 3 Receptor Antagonist: A Phase 2a Trial. J Clin Endocrinol Metab. 2019;104(12):5893-5905. PubMed PMID: 31415087
16. Fraser GL, Lederman S, Waldbaum A, Kroll R, Santoro N, Lee M, Skillern L, Ramael S. A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause. Menopause. 2020;27(4):382-392. PubMed PMID: 32102086
17. Lee A. Fezolinetant: First Approval. Drugs. 2023;83(12):1137-1141. PubMed PMID: 37462862
18. Fezolinetant. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases; 2024. PubMed PMID: 39441946
19. Safety update: EMA and FDA warn of liver problems with fezolinetant. Drug Ther Bull. 2025;63(3):36. PubMed PMID: 39797682 Note: no abstract; cited for its title only.
20. Lee N, Lee Y, Kim G, Kim Y. Hepatic Adverse Event Signals of Fezolinetant in Real-World Use Based on Postmarketing Surveillance. Obstet Gynecol. 2026;148(5):e329-e337. PubMed PMID: 42210869
21. Wei S, Song Q, Wang L. Real-world safety profile of fezolinetant: a disproportionality analysis based on the FAERS database. Naunyn Schmiedebergs Arch Pharmacol. 2026 Aug 4; online ahead of print. PubMed PMID: 42547587
22. Li Y, Zhai L, Wang L, Deng S, Zhao B, Niu H, Zhang L, Gao X. Real-world safety signals of fezolinetant in women with menopausal vasomotor symptoms: a pharmacovigilance analysis of the WHO VigiAccess database. Menopause. 2026 Aug 18; online ahead of print. PubMed PMID: 42610452
23. Nuthi A, Mishra G, Dixit VA. Carbene reactive metabolite explains the hepatotoxicity of the hot flashes drug fezolinetant: A DFT investigation. Bioorg Chem. 2025;157:108291. PubMed PMID: 40015112
24. Iwai M, Nielsen J, Miyagawa M, Patton M, Bonate PL, Wang X, Wojtkowski T, Sinn A, Huang J. In Vitro Evaluation of CYP-Mediated Metabolism of Fezolinetant and Pharmacokinetic Interaction Between Fezolinetant and Fluvoxamine in Healthy Postmenopausal Smokers and Nonsmokers. J Clin Pharmacol. 2025;65(4):508-519. PubMed PMID: 39558800
25. Stute P, Shapiro C M M, Morga A, Tai TA, Ajmera M, Muresan B, Martins K, Hua Y, Zhao A, Liu J, Nappi RE. Fezolinetant compared with elinzanetant for the treatment of vasomotor symptoms associated with menopause: A matching-adjusted indirect comparison. Maturitas. 2026;205:108782. PubMed PMID: 41418588
26. de Oliveira HM, Diaz CAV, Barbosa LM, Flávio-Reis VHP, Zamora FV, Gonçalves Barbosa Júnior O. Efficacy and safety of fezolinetant and elinzanetant for vasomotor symptoms in postmenopausal women: A systematic review and meta-analysis. Maturitas. 2025;195:108220. PubMed PMID: 39987726
27. Expression of Concern: Fezolinetant and Elinzanetant Therapy for Menopausal Women Experiencing Vasomotor Symptoms: A Systematic Review and Meta-Analysis. Obstet Gynecol. 2026;147(3):e42. PubMed PMID: 41538797 Note: cited for the notice itself; the paper it concerns is not used here.
28. Pogoda K, Arecco L, Lambertini M. Neurokinin pathway antagonists for vasomotor symptoms in women with breast cancer: focus on elinzanetant and fezolinetant. Breast. 2026;88:104812. PubMed PMID: 42160911
29. Morga A, Ajmera M, Gao E, Patterson-Lomba O, Zhao A, Mancuso S, Siddiqui E, Kagan R. 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;31(1):68-76. PubMed PMID: 38016166
30. Douxfils J, Beaudart C, Dogné JM. Risk of neoplasm with the neurokinin 3 receptor antagonist fezolinetant. Lancet. 2023;402(10413):1623-1625. PubMed PMID: 37865107 Note: letter with no abstract; cited for its title only.
31. Neal-Perry G, Santoro N, Cano A, Nappi RE, Shapiro M, Ottery FD. Totality of evidence refutes neoplasm risk with fezolinetant. Lancet. 2024;403(10440):1987-1988. PubMed PMID: 38762322 Note: letter with no abstract; cited for its title only.
32. Clack G, Renwick J. Reassessing the Neoplasm Signal with Fezolinetant: Regulatory Inference, Mechanistic Plausibility, and the Case for Proactive Pharmacovigilance. Drug Saf. 2026 Oct 14; online ahead of print. PubMed PMID: 42873405
33. Boretti E, Dogné JM, Douxfils J. Potential risk of neoplasms with fezolinetant: clinical evidence, mechanisms, and post-marketing implications. J Endocr Soc. 2026;10(6):bvag082. PubMed PMID: 42137787
34. Ruan X, Bai W, Ren M, Kim T, Lee JY, Chuang FC, Wang PH, He W, Ma X, Miyazaki K, Song N, Wang X, Yu Q. Efficacy and safety of fezolinetant for moderate to severe vasomotor symptoms associated with menopause among women in East Asia: a phase 3 randomized study (MOONLIGHT I). J Int Med Res. 2024;52(5):3000605241247684. PubMed PMID: 38818888
35. Takamatsu K, Miki T, Miyazaki K, Hashimoto A, He W, Wang X. Phase II study of fezolinetant for treatment of vasomotor symptoms associated with menopause in Japan. Climacteric. 2024;27(4):389-397. PubMed PMID: 38864290
36. Lin KL, Shekar S, Crumbaker M, Joshua AM. Neurokinin-3 Receptor Antagonism for Refractory Hot Flashes in Men. N Engl J Med. 2025;392(2):202-203. PubMed PMID: 39778176 Note: letter with no abstract; cited for its title only.

PubMed Topic Searches

1. Fezolinetant liver injury and hepatotoxicity. Search PubMed: fezolinetant liver injury
2. KNDy neurons and hot flashes. Search PubMed: KNDy neurons hot flushes
3. Neurokinin-3 receptor antagonists for vasomotor symptoms. Search PubMed: neurokinin 3 receptor antagonist vasomotor symptoms

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