What new medication was recently approved for perimenopausal symptoms?

Fezolinetant (VEOZAH™) - Recently FDA-Approved for Perimenopausal Vasomotor Symptoms

Fezolinetant (VEOZAH™) is the new medication recently approved by the FDA in May 2023 for moderate to severe vasomotor symptoms (hot flashes) due to menopause, representing the first non-hormonal neurokinin-3 receptor antagonist available for this indication. 1, 2

Mechanism of Action

• Fezolinetant works as an oral neurokinin-3 receptor (NK3R) antagonist that blocks signaling in the central nervous system to modulate thermoregulatory neurons, thereby reducing hot flash frequency and severity through a non-hormonal mechanism 2, 3
• This represents a novel therapeutic class distinct from traditional hormone therapy and antidepressants 4

Dosing and Administration

• The FDA-approved dose is 45 mg once daily 1
• Efficacy is observed within 1 week of initiation, with sustained improvements maintained over 52 weeks 5

Efficacy Data

• In two pivotal phase 3 trials (SKYLIGHT 1 and 2), fezolinetant 45 mg demonstrated statistically significant reductions in moderate to severe vasomotor symptoms compared to placebo 1
• At Week 4: reduction of 2.1-2.6 hot flashes per day versus placebo 1
• At Week 12: reduction of 2.5-2.6 hot flashes per day versus placebo 1
• Severity of vasomotor symptoms was also significantly reduced at both timepoints 1, 5

Critical Safety Monitoring Requirements

Baseline hepatic function tests (ALT, AST, alkaline phosphatase, total and direct bilirubin) are mandatory before initiating fezolinetant 1

Monthly hepatic monitoring is required for the first 3 months, then at 6 and 9 months after initiation 1

Hepatotoxicity Warning

• Elevated transaminases (>3x ULN) occurred in 2.3% of women receiving fezolinetant versus 0.9% on placebo 1
• Postmarketing cases of serious drug-induced liver injury occurred within 40 days of starting therapy, with transaminases up to 50x ULN, alkaline phosphatase up to 4x ULN, and bilirubin up to 5x ULN 1
• Patients experienced fatigue, nausea, pruritus, jaundice, pale feces, and dark urine 1
• Discontinue immediately if ALT or AST >5x ULN, or if ALT or AST >3x ULN with total bilirubin >2x ULN 1

Contraindications

• Fezolinetant is absolutely contraindicated in patients taking any CYP1A2 inhibitors (weak, moderate, or strong), as these significantly increase fezolinetant exposure 1
• Do not initiate if baseline ALT or AST ≥2x ULN or total bilirubin ≥2x ULN 1
• Contraindicated in pregnancy 1

Common Adverse Effects

• Abdominal pain (4.3% vs 2.1% placebo) 1
• Diarrhea (3.9% vs 2.6% placebo) 1
• Insomnia (3.9% vs 1.8% placebo) 1
• Back pain (3.0% vs 2.1% placebo) 1

Clinical Context and Positioning

• Fezolinetant provides a non-hormonal alternative for women who cannot or choose not to use menopausal hormone therapy 3, 4
• This is particularly relevant for breast cancer survivors or women with contraindications to hormone therapy, though specific safety data in these populations is limited 3
• The Menopause Society has updated recommendations to include neurokinin B antagonists as a new therapeutic class for vasomotor symptoms 4

Common Pitfalls to Avoid

• Failing to obtain baseline liver function tests before initiation is a critical error that prevents appropriate safety monitoring 1
• Missing the monthly hepatic monitoring schedule in the first 3 months increases risk of undetected hepatotoxicity 1
• Prescribing fezolinetant to patients on CYP1A2 inhibitors (including fluvoxamine, ciprofloxacin, or even moderate inhibitors) can lead to dangerous drug accumulation 1
• Patients must be counseled to immediately report symptoms of liver injury (new fatigue, nausea, jaundice, dark urine, pale stools) 1