Fezolinetant for Treating Hot Flashes in Menopausal Women
Fezolinetant (VEOZAH) is a highly effective first-in-class non-hormonal treatment for moderate to severe hot flashes in menopausal women, offering significant reduction in both frequency and severity of vasomotor symptoms with a favorable safety profile. 1, 2
Mechanism of Action
- Fezolinetant is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B binding on kisspeptin/neurokinin B/dynorphin neurons, modulating neuronal activity in the thermoregulatory center 1
- Unlike hormone therapy, fezolinetant does not show clear trends in affecting sex hormone levels (FSH, testosterone, estrogen, DHEAS), making it a true non-hormonal option 1
- It has high selectivity for NK3 receptors (450-fold higher than for NK1 or NK2 receptors), allowing for targeted action on the pathways involved in hot flash generation 1
Clinical Efficacy
- FDA-approved clinical trials demonstrated statistically significant and clinically meaningful reductions in both frequency and severity of moderate to severe vasomotor symptoms at weeks 4 and 12 compared to placebo 1
- In clinical trials, fezolinetant 45 mg reduced hot flash frequency by 5.4-6.3 events per day at week 4 and 6.4-7.5 events per day at week 12 (compared to 3.3-3.7 and 3.9-5.0 events with placebo, respectively) 1
- A meta-analysis of randomized controlled trials showed consistent superiority of fezolinetant over placebo for reducing both frequency (MD -2.38) and severity (MD -0.40) of daily vasomotor symptoms 3
- Benefits extend beyond hot flash reduction to include improvements in menopause-specific quality of life, sleep disturbances, and daily functioning 3, 2
Dosing and Administration
- The FDA-approved dose is 45 mg taken once daily 1
- Steady-state plasma concentrations are reached after just two daily doses, with minimal accumulation 1
- Fezolinetant can be taken with or without food, as high-calorie, high-fat meals do not significantly affect its pharmacokinetics 1
Safety Profile
- Treatment-emergent adverse events with fezolinetant are comparable to placebo in clinical trials 3
- The effective half-life is 9.6 hours in women with vasomotor symptoms 1
- At doses 20 times the maximum approved dose, fezolinetant does not prolong QT interval to any clinically relevant extent 1
- Unlike some SSRI/SNRI medications used off-label for hot flashes, fezolinetant doesn't have the common side effects of headache, nausea, reduced appetite, gastrointestinal disturbance, dry mouth, anxiety/agitation, sleep disturbance and sexual dysfunction 4, 2
Contraindications and Special Populations
- Contraindicated in patients with severe renal impairment (eGFR 15 to <30 mL/min/1.73 m²), end-stage renal disease (eGFR <15 mL/min/1.73 m²), or cirrhosis 1
- No dose adjustment needed for mild to moderate renal impairment 1
- Use caution in patients with hepatic impairment as Child-Pugh Class A or B hepatic impairment increases fezolinetant exposure 1
Advantages Over Traditional Treatments
- Unlike hormone therapy, fezolinetant offers a non-hormonal option without the increased risks of hormone-dependent cancers, stroke, or venous thromboembolism 5
- Compared to SSRIs/SNRIs (often used off-label for hot flashes), fezolinetant:
- Has a more targeted mechanism of action specific to hot flash pathophysiology 1, 5
- Shows more consistent efficacy with less variability in response 3
- Avoids the 10-20% treatment withdrawal rate seen with SSRIs/SNRIs due to adverse events 4
- Doesn't require gradual discontinuation to prevent withdrawal symptoms 4
- Doesn't have potential drug interactions with tamoxifen through CYP2D6 inhibition 4