What is the role of Fezolinetant (a neurokinin 3 receptor antagonist) in treating hot flashes in menopausal women?

Fezolinetant for Treating Hot Flashes in Menopausal Women

Fezolinetant (Veozah) is a first-line non-hormonal treatment option for moderate to severe vasomotor symptoms in menopausal women, particularly beneficial for those with contraindications to hormone therapy or breast cancer survivors on tamoxifen. 1, 2

Mechanism of Action and Efficacy

• Fezolinetant is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B binding on the kisspeptin/neurokinin B/dynorphin neuron to modulate neuronal activity in the thermoregulatory center 2
• Clinical trials demonstrate significant reduction in both frequency and severity of vasomotor symptoms compared to placebo, with improvements observed as early as 1 week and maintained over 52 weeks 3
• Meta-analysis confirms superior efficacy over placebo for both frequency (MD -2.38) and severity (MD -0.40) of daily vasomotor symptoms 4

Advantages Over Traditional Treatments

• Avoids the 10-20% treatment withdrawal rate seen with SSRIs/SNRIs due to adverse events 1
• Does not require gradual discontinuation to prevent withdrawal symptoms, unlike SSRIs/SNRIs 1
• No potential drug interactions with tamoxifen through CYP2D6 inhibition, making it particularly suitable for breast cancer survivors on tamoxifen 1
• More targeted mechanism of action specific to hot flash pathophysiology compared to other treatments 1

Clinical Considerations and Patient Selection

• Particularly beneficial for women who experienced inadequate response or intolerable side effects with SSRIs/SNRIs 1
• Significant improvements typically seen by week 4 of treatment 1, 3
• Ideal for women with contraindications to hormone therapy 1
• Specifically indicated for moderate to severe vasomotor symptoms due to menopause 2

Dosing and Administration

• Administered orally once daily 2
• Steady-state plasma concentrations reached after two once-daily doses, with minimal accumulation 2
• No clinically significant differences in pharmacokinetics when taken with food 2

Safety Considerations

• Contraindicated in patients with severe renal impairment (eGFR 15 to <30 mL/min/1.73 m²), end-stage renal disease, or cirrhosis 2
• No dose adjustment needed for mild to moderate renal impairment 2
• Treatment-emergent adverse events occur at rates comparable to placebo (43% vs 45%) 3
• Liver enzyme elevations are rare, generally asymptomatic, transient, and resolve during treatment or after discontinuation 3
• No QT interval prolongation at doses up to 20 times the recommended dose 2

Treatment Algorithm for Vasomotor Symptoms in Menopause

1. First-line options:

   • Fezolinetant for women seeking non-hormonal therapy or with contraindications to hormone therapy 1, 2
   • Menopausal hormone therapy remains most effective for vasomotor symptoms but carries risks including increased stroke and breast cancer risk 5

2. Alternative options if fezolinetant is unavailable or contraindicated:

   • SNRIs/SSRIs (e.g., venlafaxine, paroxetine) - caution with tamoxifen due to CYP2D6 interactions 5
   • Gabapentin or pregabalin - particularly useful when given at bedtime for patients with sleep disturbances 5
   • Clonidine - effective but with side effects including sleep difficulties and dry mouth 5

3. Non-pharmacologic adjuncts:

   • Cognitive behavioral therapy - shown to reduce perceived burden of hot flashes 5
   • Weight loss if overweight - those who lost ≥10% of body weight more likely to eliminate hot flash symptoms 5
   • Smoking cessation - improves frequency and severity of hot flashes 5
   • Acupuncture - shown to be equivalent to or better than some drug treatments 5

Monitoring and Follow-up

• Assess improvement in frequency and severity of vasomotor symptoms after 4 weeks of treatment 3
• Monitor liver function in patients with pre-existing liver conditions 3
• No specific monitoring of hormone levels required as fezolinetant does not show clear trends in sex hormone changes 2