What is the role of fezolinetant in treating hot flashes in menopausal women?

Role of Fezolinetant in Treating Hot Flashes in Menopausal Women

Fezolinetant is a first-in-class neurokinin 3 receptor (NK3R) antagonist that should be considered as a primary non-hormonal option for treating moderate-to-severe vasomotor symptoms in menopausal women, particularly those who cannot or choose not to use hormone therapy. 1

Mechanism and Efficacy

Fezolinetant works by targeting the neurokinin 3 receptor pathway, which plays a key role in modulating the thermoregulatory center that triggers hot flashes. Unlike traditional treatments that address symptoms, fezolinetant targets the underlying mechanism of vasomotor symptoms 2.

Clinical evidence demonstrates:

• Significant reduction in frequency of moderate-to-severe hot flashes compared to placebo at both 4 weeks (difference -2.07) and 12 weeks (difference -2.55) 1
• Significant reduction in severity of hot flashes at 4 weeks (difference -0.19) and 12 weeks (difference -0.20) 1
• Improvements begin within 1 week of treatment and are maintained over 52 weeks 1
• Meta-analysis confirms consistent efficacy with mean difference of -2.38 in daily hot flash frequency compared to placebo 3

Appropriate Patient Selection

Fezolinetant is particularly valuable for:

1. Women unsuitable for hormone therapy (HT) due to:

   • Medical contraindications
   • Safety concerns
   • Previous adverse effects from HT
   • Personal preference against hormonal treatments 4

2. Women with moderate-to-severe vasomotor symptoms (≥7 hot flashes per day) 1

Dosing and Administration

• Recommended dose: 45 mg once daily 5
• No dosage adjustments needed for smokers (moderate CYP1A2 inducers) 5
• Onset of action is rapid, with benefits observed within 1 week and maximum effectiveness by 4-6 weeks 1

Safety Profile

The 52-week safety data shows:

• Similar rates of treatment-emergent adverse events between fezolinetant and placebo (63.9-67.9% vs 64.1%) 6
• Low discontinuation rates due to adverse events (4.6-5.6% vs 4.3% for placebo) 6
• No significant impact on bone mineral density or trabecular bone score 6
• Low incidence of liver enzyme elevations (approximately 2% for fezolinetant 45 mg) 6
• No evidence of endometrial hyperplasia or malignancy concerns (0.5% incidence with upper limit of 95% CI below 4%) 6

Advantages Over Other Non-Hormonal Options

Traditional non-hormonal options for hot flashes include:

• SSRIs/SNRIs (paroxetine, venlafaxine) 7, 8
• Anticonvulsants (gabapentin, pregabalin) 7
• Alpha-agonists (clonidine) 7

Fezolinetant offers several advantages:

1. Targets the specific neurobiological mechanism of hot flashes 2
2. Does not have CYP2D6 inhibition concerns that exist with paroxetine (important for women on tamoxifen) 7, 5
3. Fewer side effects than traditional options like SSRIs (which can cause dry mouth, decreased appetite, fatigue, nausea) 7
4. No need for gradual tapering when discontinuing (unlike SNRIs/SSRIs) 7

Treatment Algorithm

1. Initial Assessment:

   • Confirm moderate-to-severe vasomotor symptoms (≥7 hot flashes/day)
   • Evaluate contraindications for hormone therapy
   • Review current medications for potential interactions

2. First-line Treatment:

   • For women unsuitable for hormone therapy: Fezolinetant 45 mg daily
   • For women without contraindications to hormone therapy: Discuss risks/benefits of both hormone therapy and fezolinetant

3. Monitoring:

   • Assess response after 4 weeks
   • Monitor for liver enzyme elevations, particularly in the first months
   • Continue treatment as long as symptoms persist and treatment is tolerated

4. Alternative Options (if fezolinetant is ineffective or not tolerated):

   • Venlafaxine 75 mg/day (if not on tamoxifen)
   • Paroxetine 7.5 mg daily (avoid in women on tamoxifen)
   • Gabapentin 300-900 mg/day (particularly useful for night sweats disrupting sleep)

Practical Considerations

• Inform patients that improvements typically begin within 1 week but may take 4-6 weeks for maximum effect
• Advise that complete elimination of symptoms may not be achievable, but a 50% reduction is considered clinically meaningful
• Combine pharmacological treatment with non-pharmacological approaches like dressing in layers, maintaining healthy weight, and avoiding triggers

Potential Pitfalls and Caveats

• Fezolinetant is a relatively new medication with limited long-term data beyond 52 weeks
• Monitor liver function, particularly in patients with pre-existing liver conditions
• While fezolinetant appears to have minimal drug interactions, comprehensive medication review is still recommended
• Cost and insurance coverage may be barriers for some patients compared to older generic alternatives