Fezolinetant (Veozah)

Fezolinetant (brand name Veozah) is a neurokinin 3 (NK3) receptor antagonist FDA-approved in May 2023 for the treatment of moderate-to-severe vasomotor symptoms (hot flashes) due to menopause. It is the first non-hormonal medication developed specifically to target the neural mechanism that drives hot flashes.

This matters because prior non-hormonal options (SSRIs, gabapentin, clonidine) were all repurposed from other indications. Fezolinetant was designed from the ground up for this specific problem, targeting the KNDy (kisspeptin/neurokinin B/dynorphin) neurons in the hypothalamus that become hyperactive when estrogen declines.

Women with moderate-to-severe hot flashes who have contraindications to HRT (hormone-sensitive breast cancer, active VTE, other absolute contraindications). Women who choose not to take hormonal therapy. Women on HRT with persistent vasomotor symptoms who need additional relief. Women on tamoxifen (fezolinetant does not have the CYP2D6 interaction that makes paroxetine inappropriate with tamoxifen, though drug interaction data should be confirmed with a pharmacist).

During menopause, declining estrogen disinhibits KNDy neurons in the hypothalamus. These neurons, which use neurokinin B as a signaling molecule, become hyperactive and destabilize the thermoregulatory center, narrowing the thermoneutral zone. The body perceives normal core temperature fluctuations as overheating and triggers the sweating, flushing, and heat dissipation response - a hot flash.

Fezolinetant blocks the NK3 receptor, dampening this hyperactive signaling. It directly targets the mechanism rather than working through a secondary pathway (like SSRIs, which modestly affect thermoregulation through serotonin). This targeted mechanism explains its relatively clean side effect profile compared to repurposed medications.

In the BRIGHT clinical trial program (SKYLIGHT 1, 2, and 4), fezolinetant 45 mg daily reduced hot flash frequency by approximately 60% and hot flash severity by approximately 40% at 12 weeks compared to placebo. Improvements were apparent within the first week and continued through the 52-week study period.

For context: HRT reduces hot flash frequency by 75-95%. Fezolinetant at approximately 60% is less effective than HRT but more effective than most other non-hormonal options (SSRIs at 40-65%, gabapentin at 45-55%).

Generally well-tolerated. The most notable concern is hepatic effects - elevated liver enzymes (ALT/AST) were observed in a small percentage of trial participants. FDA labeling requires liver function testing (LFTs) at baseline, then monthly for the first 3 months. Fezolinetant is contraindicated in cirrhosis of any severity (including Child-Pugh A) and in patients with severe renal impairment (eGFR <30). Contraindicated with concomitant use of CYP1A2 inhibitors (fluvoxamine, ciprofloxacin).

The FDA label includes a boxed warning for hepatotoxicity. Cases of drug-induced liver injury, including some requiring liver transplantation, have been reported post-marketing. Liver function tests must be obtained before starting treatment, then monthly for the first 3 months. Fezolinetant must be discontinued immediately if liver injury is suspected.

Other reported side effects: abdominal pain (4.2%), diarrhea (3.6%), insomnia (3.1%), back pain (2.7%). Most are mild to moderate.

Taken once daily, with or without food. No titration period - start at the therapeutic dose (45 mg). Effect begins within the first week (faster onset than SSRIs for vasomotor symptoms). Does not affect bone density, vaginal tissue, or other estrogen-dependent systems - it only addresses the vasomotor mechanism. It is not a replacement for HRT’s broader benefits (bone protection, GSM treatment, cardiovascular effects) - it addresses hot flashes only.

Approximately $485 to 690 per month. Insurance coverage is variable and often requires prior authorization. Manufacturer savings programs may be available for commercially insured patients. The cost is significantly higher than generic SSRIs or gabapentin, which limits its accessibility. For women with contraindications to HRT who have failed SSRI/gabapentin therapy, the cost may be justified.

• Is fezolinetant appropriate given my specific contraindications to HRT?
• Would it be covered by my insurance, and is there a manufacturer savings program?
• What liver function monitoring is required, and is it included in my care plan?
• Could I try a less expensive non-hormonal option first (SSRI, gabapentin) before fezolinetant?
• Can fezolinetant be combined with HRT if my hot flashes are not fully controlled by hormones alone?