Patient Education · Menopause & Midlife Health

Nonhormonal Treatment for Hot Flashes

For years the nonhormonal options were medicines borrowed from other conditions. Two purpose-built drugs have since been approved — and one of them carries an FDA Boxed Warning for rare but serious liver injury, with liver testing required before you start.

Written . Approval status checked against FDA records on . Recommendations are attributed to the sources listed; where a claim rests on trade or clinical press rather than a guideline or FDA labelling, that is stated. Editorial standards

Until recently the honest answer to “what can I take that is not a hormone?” was a short list of medicines borrowed from other conditions. That changed twice in three years.

What is actually approved

The North American Menopause Society’s position statement on nonhormone therapy recorded that, at the time it was published, only two medicines were FDA-approved for reducing vasomotor symptoms in menopause: paroxetine mesylate 7.5 mg daily, a selective serotonin reuptake inhibitor, and fezolinetant 45 mg daily, a neurokinin-3 receptor antagonist. Both carried level I recommendations, meaning good and consistent scientific evidence.

Since then a third has arrived. Elinzanetant, a dual neurokinin-1 and neurokinin-3 receptor antagonist, was approved by the FDA on , under the brand name Lynkuet, for the treatment of moderate to severe vasomotor symptoms due to menopause. It is taken as two capsules once daily at bedtime, and the approval rests on three placebo-controlled trials, OASIS 1, OASIS 2 and OASIS 3.

The neurokinin drugs, and why they are different

Fezolinetant was approved on , the first of its class. These medicines do not act on estrogen at all. They work in the brain’s thermoregulatory centre, on the neurons whose signalling is disturbed when estrogen falls — which is why they can help women for whom estrogen is not an option.

That distinction is not theoretical. Elinzanetant was studied in women with hormone receptor-positive breast cancer receiving endocrine therapy such as tamoxifen or an aromatase inhibitor — a group whose hot flashes are often treatment-induced, severe, and for whom hormone therapy is generally unavailable.

Fezolinetant and the liver: what the Boxed Warning says

This is the most important safety point on the page. On the FDA added a Boxed Warning — its most prominent warning class — to fezolinetant’s prescribing information, for rare but serious liver injury. It followed an earlier safety communication in September 2024 and the agency’s review of a post-marketing report.

What that case looked like matters, because these are the symptoms you would be watching for. Within about 40 days of starting the drug, a patient developed fatigue, nausea, itching, yellowing of the eyes and skin, light-coloured stools and dark urine, with elevated liver enzymes and bilirubin. The symptoms and blood tests gradually returned to normal after the medicine was stopped.

Three practical consequences follow:

  • Liver function is checked before you start, not only during treatment.
  • Testing follows a schedule: monthly for the first two months after starting, then at months 3, 6 and 9.
  • Stop the medicine and contact your prescriber immediately if signs or symptoms of liver injury appear — the FDA notes that stopping could prevent worsening injury and allow liver function to return to normal.

None of this means the drug should not be used. The FDA describes the injury as rare, and the manufacturer states the overall benefit–risk assessment has not changed. It means the monitoring is part of the treatment, and that the symptom list above is worth knowing before you start rather than after.

The older medicines, used off-label

Several medicines developed for other purposes reduce hot flashes and are used off-label with level I evidence behind them: SSRIs other than paroxetine, serotonin-norepinephrine reuptake inhibitors, gabapentin, and oxybutynin.

Off-label is not a warning label. It means the medicine was approved for something else and the evidence for this use accumulated afterwards. These remain reasonable choices, particularly where cost or availability makes a newer drug impractical, or where a second problem — low mood, disturbed sleep, an overactive bladder — might be helped by the same prescription.

The comparison you will not find

The position statement notes there is limited comparative data between nonhormone therapies. That is worth knowing before asking which one is best: for the most part, the trials compared each drug against placebo rather than against each other. Claims that one is clearly superior should be treated carefully, and a clinician choosing between them is weighing side-effect profile, monitoring burden, cost and your other conditions rather than following a settled ranking.

What to bring to the visit

  • How many hot flashes a day, how severe, and specifically what they stop you doing — severity in function, not just count
  • Whether night sweats are breaking your sleep, since sleep disruption drives much of the daytime effect
  • Whether estrogen is unavailable to you, and why — breast cancer, clot history, or preference
  • Your other medicines, particularly antidepressants, and any history of liver disease or abnormal liver blood tests
  • What you have already tried and for how long

Main takeaway

There are now genuine nonhormonal options rather than only borrowed ones: paroxetine mesylate at low dose, fezolinetant, and elinzanetant, alongside off-label SSRIs, SNRIs, gabapentin and oxybutynin with good evidence behind them. Fezolinetant carries an FDA Boxed Warning for rare but serious liver injury, with testing before starting and on a schedule afterwards. And because these drugs have rarely been compared head to head, the choice is individual rather than a ranking.

Sources

  • The North American Menopause Society — 2023 position statement on nonhormone therapy for vasomotor symptoms. Source for: that at publication only paroxetine mesylate 7.5 mg daily and fezolinetant 45 mg daily were FDA-approved for reducing vasomotor symptoms, both with level I recommendations (good and consistent scientific evidence); that off-label alternatives with level I recommendations include SSRIs other than paroxetine, SNRIs, gabapentin and oxybutynin; and that there is limited comparative data between nonhormone therapies. As summarised by the University of Illinois Chicago Drug Information Group.
  • FDA approval of fezolinetant (Veozah), , as the first neurokinin-3 receptor antagonist for moderate to severe vasomotor symptoms — published account. Source for the approval date, the mechanism of action on KNDy neurons in the hypothalamus, and that it was first in class.
  • Drug Trials Snapshots: LYNKUET. U.S. Food and Drug Administration — fda.gov. Source for the approval date of , the approved use in moderate to severe vasomotor symptoms due to menopause, the two-capsule bedtime regimen, and the three trials (OASIS 1, OASIS 2, OASIS 3) supporting it.
  • LYNKUET (elinzanetant) capsules, for oral use — prescribing information. U.S. Food and Drug Administration — approved label (PDF). The controlling document for the indication and the conditions of use. It was not opened for this page; the indication above is taken from the agency’s Drug Trials Snapshot.
  • Reporting of the OASIS trial programme, including efficacy in patients with hormone receptor-positive breast cancer receiving endocrine therapy, and of the FDA recommendation for frequent liver function testing with fezolinetant — clinical review, 2026.
  • U.S. Food and Drug Administration — FDA adds warning about rare occurrence of serious liver injury with use of Veozah (fezolinetant), Drug Safety Communication, September 2024, updated to add a Boxed Warning. Source for: the Boxed Warning and that it is the agency’s most prominent warning; the rare but serious liver injury; the post-marketing case and its symptoms; that hepatic function is evaluated before initiating; the testing schedule of monthly for two months then months 3, 6 and 9; and that stopping the medicine could prevent worsening injury and return liver function to normal.

Provenance

  • Basis: the approval status, level I recommendations, off-label list and the absence of comparative data are taken from the 2023 position statement as summarised in the source cited. Approval dates and mechanisms are from the sources listed.
  • Route of retrieval: obtained through search results rendering these pages rather than by direct retrieval of the position statement itself. The position statement was not read in full; a summary of it was.
  • Primary source for the safety claim: the hepatic Boxed Warning, the testing schedule and the stop instruction come from the FDA’s own Drug Safety Communication, cited above. Secondary sources: the OASIS trial findings, including the result in women with hormone receptor-positive breast cancer receiving endocrine therapy, come from clinical press rather than from the trial publications, and are identified as such. The elinzanetant approval date, approved use and bedtime regimen are from the FDA’s own Drug Trials Snapshot; the approved label itself was not opened.
  • Deliberately excluded: a published meta-analysis comparing fezolinetant and elinzanetant carries an Expression of Concern from the journal, so its comparative findings are not used here.
  • Not asserted here: dosing beyond the two doses the position statement names, side-effect frequencies, and any ranking of one nonhormonal option against another.

Medical information notice: general educational information, not a substitute for individualized medical advice, diagnosis, or treatment.

Written by Kanwar Partap Singh Gill, MD, family medicine physician in Fresno, California ·