What is the recommended use of Fezolinetant (neurokinin 3 receptor antagonist) for menopausal women experiencing hot flashes?

Fezolinetant for Menopausal Hot Flashes

Fezolinetant (VEOZAH) is recommended as an effective non-hormonal treatment option for moderate to severe vasomotor symptoms (hot flashes) in menopausal women, particularly for those who cannot or do not want to take hormone therapy. 1

Mechanism and Efficacy

Fezolinetant is a neurokinin 3 (NK3) receptor antagonist that works by targeting the neurobiological mechanisms underlying hot flashes:

• It reduces the frequency of moderate to severe hot flashes by 6.4-7.5 events per day after 12 weeks of treatment 1
• It significantly reduces the severity of hot flashes compared to placebo 1
• Improvements begin as early as 1 week after starting treatment and are maintained over 52 weeks 2

Dosing and Administration

• The FDA-approved dose is 45 mg once daily 1
• No dose adjustment is needed for smokers 1

Clinical Evidence

Two Phase 3 clinical trials (SKYLIGHT 1 and 2) demonstrated:

• Statistically significant and clinically meaningful reduction in hot flash frequency (≥2 hot flashes over 24 hours) compared to placebo at weeks 4 and 12 1
• Significant reduction in hot flash severity compared to placebo 1
• In SKYLIGHT 1, fezolinetant 45 mg reduced hot flash frequency by 6.4 events at week 12 compared to 3.9 events with placebo 2
• Improvements in patient-reported outcomes including sleep disturbance and menopause-specific quality of life 3

Safety Profile

The 52-week SKYLIGHT 4 safety study showed:

• Treatment-emergent adverse events were similar between fezolinetant and placebo groups (63.9-67.9% vs 64.1%) 4
• Discontinuation rates due to adverse events were low (4.6-5.6%) 4
• No significant impact on bone mineral density or trabecular bone score 4
• Low incidence of liver enzyme elevations (1.4-2.0%) with no severe drug-induced liver injury 4
• No concerns regarding endometrial hyperplasia or malignancy 4

Place in Therapy

Fezolinetant offers an important alternative to existing treatments for menopausal hot flashes:

1. First-line for women who cannot or choose not to use hormone therapy:

   • Women with history of hormone-dependent cancers 5
   • Women with contraindications to hormone therapy (history of thromboembolic events, active liver disease) 5
   • Women concerned about potential risks of hormone therapy 6

2. Alternative to other non-hormonal options:

   • When SSRIs/SNRIs (venlafaxine, paroxetine) are ineffective or poorly tolerated 5
   • When gabapentin or clonidine are ineffective or poorly tolerated 5

Clinical Considerations and Caveats

• Drug interactions: Minimal drug interaction potential as fezolinetant is not an inhibitor of major CYP enzymes 1
• Advantage over SSRIs/SNRIs: No concerns about CYP2D6 inhibition that can occur with some SSRIs (particularly paroxetine) in women taking tamoxifen 5
• Monitoring: While liver enzyme elevations are rare, monitoring liver function may be prudent, especially in patients with pre-existing liver conditions 4
• Duration of therapy: Long-term safety data supports use for at least 52 weeks 4

Algorithm for Management of Menopausal Hot Flashes

1. For women with moderate-to-severe hot flashes affecting quality of life:

   • If no contraindications to hormone therapy and within 10 years of menopause or <60 years old:
     • Consider hormone therapy (estrogen ± progestin) as most effective option
   • If contraindicated for hormone therapy or patient preference for non-hormonal therapy:
     • Try fezolinetant 45 mg daily as first-line non-hormonal option

2. If fezolinetant is ineffective or not tolerated:

   • Try SNRIs (venlafaxine 75 mg) or SSRIs (except paroxetine in women on tamoxifen)
   • Alternative options: gabapentin, pregabalin, or clonidine

3. Adjunctive measures for all patients:

   • Environmental modifications (cool rooms, dressing in layers)
   • Lifestyle interventions (weight loss if overweight, smoking cessation)
   • Avoidance of triggers (spicy foods, caffeine, alcohol)

Fezolinetant represents an important advancement in the non-hormonal management of menopausal hot flashes, offering significant improvements in both frequency and severity of symptoms with a favorable safety profile.