Introduction
Veozah (fezolinetant) is a novel, first-in-class neurokinin 3 (NK3) receptor antagonist approved by the FDA in May 2023 for the treatment of moderate to severe vasomotor symptoms (hot flashes) associated with menopause. It represents a significant advancement in menopausal therapy as the first non-hormonal treatment specifically targeting the neurobiological pathway responsible for vasomotor symptoms.
Mechanism of Action
Fezolinetant works by competitively antagonizing the binding of neurokinin B (NKB) to NK3 receptors in the hypothalamic thermoregulatory center (the KNDy neurons). During menopause, declining estrogen levels lead to increased NKB signaling, which disrupts the body's temperature regulation. By blocking NK3 receptors, fezolinetant reduces the hyperactivity of KNDy neurons, thereby decreasing the frequency and severity of vasomotor symptoms without affecting estrogen levels.
Indications
Veozah is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause. It is specifically approved for:
- Reduction in frequency of moderate to severe vasomotor symptoms
- Reduction in severity of moderate to severe vasomotor symptoms
Dosage and Administration
Standard dosing: 45 mg orally once daily Administration: Can be taken with or without food Missed dose: Take as soon as remembered unless it is almost time for the next dose Special populations:- Renal impairment: Not recommended in patients with eGFR <30 mL/min/1.73m² or end-stage renal disease
- Hepatic impairment: Contraindicated in patients with cirrhosis or severe hepatic impairment
- Geriatric patients: No dosage adjustment required
- Race: No dosage adjustments based on race
Pharmacokinetics
Absorption: Rapidly absorbed with median Tmax of 1.5-2 hours Distribution: Apparent volume of distribution ~98 L; protein binding ~77% Metabolism: Primarily metabolized by CYP1A2 (major) and CYP2C9, CYP2C19, CYP3A4 (minor) Elimination: Half-life ~11.5 hours; primarily excreted in feces (81%) and urine (9%) Steady-state: Achieved within 3 days of once-daily dosingContraindications
- Known cirrhosis or severe hepatic impairment (Child-Pugh Class B and C)
- History of hypersensitivity to fezolinetant or any component of the formulation
- Concomitant use with strong CYP1A2 inhibitors
Warnings and Precautions
Hepatotoxicity: Elevations in liver transaminases (ALT) have been observed. Obtain bloodwork to assess liver function before initiation, at 3 months, 6 months, and 9 months, and as clinically indicated. CYP1A2 inhibitors: Avoid concomitant use with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) Pregnancy: Not indicated for use during pregnancy; may cause fetal harm based on animal studies Lactation: No data on presence in human milk; advise patients not to breastfeed during treatmentDrug Interactions
Strong CYP1A2 inhibitors: Significantly increase fezolinetant exposure (contraindicated) Moderate CYP1A2 inhibitors: May increase fezolinetant exposure (use with caution) CYP1A2 inducers: May decrease fezolinetant exposure (monitor efficacy) Oral contraceptives: No clinically significant interactions expected CYP2C9, CYP2C19, CYP3A4 substrates: Unlikely to cause clinically relevant interactionsAdverse Effects
Most common adverse reactions (≥2%):- Abdominal pain (4%)
- Diarrhea (4%)
- Insomnia (4%)
- Back pain (3%)
- Hot flush (2%)
- Hepatic transaminase elevation (2%)
- Hepatotoxicity with transaminase elevations
- Severe abdominal pain
Monitoring Parameters
Baseline:- Liver function tests (ALT, AST, bilirubin)
- Renal function assessment
- Documentation of vasomotor symptom frequency and severity
- Liver function tests at 3, 6, and 9 months
- Monitor for signs/symptoms of hepatotoxicity (fatigue, nausea, jaundice)
- Assessment of vasomotor symptom improvement
- Blood pressure monitoring (minimal effects expected)
Patient Education
- Take once daily with or without food at approximately the same time each day
- Report any symptoms of liver injury (yellowing of skin/eyes, dark urine, severe nausea)
- Inform healthcare providers about all medications being taken
- Not for use during pregnancy; use effective contraception if of reproductive potential
- Do not breastfeed while taking Veozah
- May take several weeks to notice full effect on hot flash reduction
- Store at room temperature in original container
References
1. FDA Approval Letter: Veozah (fezolinetant). May 2023. 2. Johnson KA, Martin N, Nappi RE, et al. Efficacy and safety of fezolinetant in moderate to severe vasomotor symptoms associated with menopause: a phase 3 trial. Lancet. 2023;401(10380):1091-1102. 3. Veozah [package insert]. Astellas Pharma US, Inc.; 2023. 4. Depypere H, Timmerman D, Donders G, et al. Treatment of menopausal vasomotor symptoms with fezolinetant, a neurokinin 3 receptor antagonist: a phase 2a trial. J Clin Endocrinol Metab. 2019;104(12):5893-5905. 5. Neal-Perry G, Santoro N, Simon J, et al. Safety and efficacy of fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause: results of a randomized controlled trial. Menopause. 2023;30(5):489-497.