Fezolinetant

China [CN]

Basic Information

Item | Details

English Name | Fezolinetant; Veozah (Trade Name)

Chinese Name | Fezolinetant

CAS Number | 1229705-11-1

Chemical Name | (4-Fluorophenyl)[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]methanone

Molecular Formula | C₁₆H₁₅FN₆OS

Molecular Weight | 358.39

Developer | Astellas Pharma

Target | Neurokinin 3 (NK3) receptor (Ki=25 nM, IC₅₀=20 nM)

Approval Date | May 2023 (US FDA); December 2023 (EU EMA)

II. Mechanism of Action and Advantages

Core Mechanism: By blocking NK3 receptors on hypothalamic KNDy neurons (kisspeptin/neurokinin B/dynorphin), it inhibits neurokinin B (NKB)-mediated signaling, regulates neuronal activity in the thermoregulatory center, and reduces the frequency and severity of hot flashes/night sweats.

Key Advantages

Non-hormonal treatment: Avoids risks associated with hormone therapy, such as breast cancer and thrombosis, suitable for people with contraindications to hormone therapy.

Convenient oral administration: Once daily oral administration, no injection required, high compliance.

Rapid onset of action: Reduces the frequency of daily moderate to severe hot flashes by approximately 53% within 4 weeks and approximately 63% within 12 weeks.

Long-lasting and stable effect: Steady-state plasma concentration reaches its peak within 2 days, and the efficacy remains stable. III. Clinical Applications

Indications | Dosage and Administration | Contraindications and Precautions

Moderate to severe vasomotor symptoms of menopause | Oral administration, 45 mg/dose, once daily, can be taken on an empty stomach or with food, at a fixed time. | Contraindications: Hypersensitivity to fezolinetant, severe renal impairment (eGFR < 30 mL/min/1.73m²), Child-Pugh class C cirrhosis, and concomitant use of strong CYP1A2 inhibitors (e.g., fluvoxamine); Precautions: Liver function monitoring is required for patients with mild to moderate hepatic/renal impairment.

Dosage Form and Strength | Film-coated tablets: 45 mg/tablet (containing 45 mg of free base) | If a dose is missed, it can be taken within 12 hours. If more than 12 hours have passed, skip the missed dose and take the next dose as scheduled the following day.

IV. Pharmacokinetics

Parameter | Data

Time to peak concentration (Tmax) | 1.5 hours (45 mg oral dose)

Elimination half-life (t₁/₂) | Approximately 10-12 hours

Bioavailability | Approximately 30% (oral administration)

Plasma protein binding rate | 51% (primarily bound to albumin)

Metabolic pathway | Primarily metabolized by CYP1A2, with minor metabolism by CYP3A4 and UGT1A1

Excretion pathway | Feces (approximately 60%); urine (approximately 30%, mainly as metabolites)

Steady-state distribution volume | 189 L

V. Safety and Drug Interactions

Common Adverse Reactions

Mild to moderate: Diarrhea (12%), abdominal pain (10%), headache (9%), insomnia (8%), back pain (7%), mostly transient and do not require discontinuation of the drug.

Of concern: Elevated liver transaminases (ALT/AST > 3 × ULN, incidence 2.3%, 0.9% in the placebo group), the FDA has added a black box warning regarding the risk of rare but serious liver injury. Liver function should be monitored regularly before and during treatment. Drug Interactions

Strong CYP1A2 inhibitors (e.g., fluvoxamine, cimetidine): Significantly increase plasma drug concentrations; concomitant use with PMC is contraindicated.

Strong CYP1A2 inducers (e.g., rifampicin, tobacco smoke): Decrease plasma drug concentrations, leading to reduced efficacy; concomitant use is not recommended.

CYP1A2 substrates (e.g., theophylline, caffeine): Concomitant use may increase substrate concentrations; dose adjustment may be necessary.

OATP1B1 inhibitors (e.g., cyclosporine): Increase exposure; liver function monitoring is required.