AHFS Class:

• Central Nervous System Agents, Miscellaneous 28:92

Brands:

• Veozah^®

Generic Name(s):

• Fezolinetant

Fezolinetant is a small-molecule neurokinin 3 (NK3) receptor antagonist.1

Fezolinetant has the following uses:

Fezolinetant is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause.1

Administration

Fezolinetant is available in the following dosage form(s) and strength(s):

Tablets: 45 mg1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Perform baseline bloodwork to evaluate for hepatic function and injury before beginning fezolinetant.1 While using fezolinetant, perform follow-up bloodwork at 3 months, 6 months, and 9 months after initiation of therapy and when symptoms suggest liver injury.1

Take a single 45 mg tablet orally once daily with or without food.1 Swallow whole with liquids; do not cut, crush, or chew tablet.1

Contraindications

• Known cirrhosis.1
• Severe renal impairment or end-stage renal disease.1
• Concomitant use with CYP1A2 inhibitors.1

Warnings/Precautions

Hepatic Transaminase Elevation

Elevations in serum transaminase [alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)] levels greater than 3 times the upper limit of normal (ULN) occurred in 2.3% [exposure adjusted incidence rate (EAIR) of 2.7 per 100 person-years] of women receiving fezolinetant and 0.9% (EAIR of 1.5 per 100 person-years) of women receiving placebo in 3 clinical trials.1 No serum elevations in total bilirubin (greater than 2 times the ULN) occurred.1 Women with ALT or AST elevations were generally asymptomatic.1 Transaminase levels returned to pretreatment levels (or close to these) without sequelae with dose continuation, and upon dose interruption, or discontinuation.1 Women with cirrhosis were not studied.1

Perform baseline bloodwork to evaluate for hepatic function and injury [including serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and serum bilirubin (total and direct)] prior to fezolinetant initiation.1 Do not start the drug if ALT or AST concentration is equal to or exceeds 2 times the ULN or if the total bilirubin is elevated (for example, equal to or exceeds 2 times the ULN) for the evaluating laboratory.1 If baseline hepatic transaminase evaluation is less than 2 times the ULN and the total bilirubin is normal, fezolinetant can be started.1 Perform follow-up evaluations of hepatic transaminase concentration at 3 months, 6 months, and 9 months after initiation of therapy and when symptoms (such as nausea, vomiting, or yellowing of the skin or eyes) suggest liver injury.1

Specific Populations

Pregnancy

There are no data on fezolinetant use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.1

In embryo-fetal toxicity animal studies with fezolinetant, embryo-lethality occurred at high doses above the human therapeutic dose in rats and rabbits, but no teratogenicity was observed.1 In the pre- and post-natal development animal study, delayed parturition and embryo-lethality occurred at high doses above the human therapeutic dose in rats.1 Additionally, in the male offspring, delayed male reproductive maturation was observed, characterized by incomplete preputial separation, which affected male fertility at doses above the human therapeutic dose in rats.1

In the U.S. general population, the estimated background risk of major birth defects or miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.1

Lactation

There are no data on the presence of fezolinetant in human milk, the effects on the breastfed child, or the effects on milk production.1 It is not known if fezolinetant is present in human milk.1

Pediatric Use

The efficacy and safety of fezolinetant in individuals less than 18 years of age have not been established.1

Geriatric Use

There have not been sufficient numbers of geriatric women involved in clinical trials utilizing fezolinetant to determine whether those over 65 years of age differ from younger women in their response to the drug.1

Hepatic Impairment

Child-Pugh Class A or B hepatic impairment increased the exposure of fezolinetant.1 The drug has not been studied in individuals with Child-Pugh Class C hepatic impairment.1

Fezolinetant is contraindicated in individuals with cirrhosis.1

Renal Impairment

Fezolinetant is contraindicated in individuals with severe (eGFR 15 to less than 30 mL/min/1.73 m²) renal impairment or end-stage renal disease (eGFR less than 15 mL/min/1.73 m²).1 No dose adjustment of fezolinetant is recommended for individuals with mild (eGFR 60 to less than 90 mL/min/1.73 m²) or moderate (eGFR 30 to less than 60 mL/min/1.73 m²) renal impairment.1

Common Adverse Effects

The most common adverse reactions with fezolinetant [at least 2% in fezolinetant 45 mg and greater than placebo] are abdominal pain, diarrhea, insomnia, back pain, hot flush, and hepatic transaminase elevation.1

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

• Fezolinetant is a neurokinin 3 (NK3) receptor antagonist that blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron to modulate neuronal activity in the thermoregulatory center.1 Fezolinetant has high affinity for the NK3 receptor (Ki value of 19.9 to 22.1 nmol/L), which is more than 450-fold higher than binding affinity to NK1 or NK2 receptors.1

Advice to Patients

• Advise patients to read the FDA-approved patient labeling (Patient Information).1 Advise patients to read the FDA-approved patient labeling (Patient Information).1
• Inform patients that they will have to have a blood test to evaluate their liver before beginning fezolinetant and while using the drug at 3 months, 6 months, and 9 months of use, and when clinically indicated to evaluate symptoms of liver abnormalities such as nausea, vomiting, or yellowing of the skin or eyes.1
• Inform patients of possible serious adverse reactions of fezolinetant including hepatic transaminase elevation.1
• Inform patients of possible less serious, but common, adverse reactions of fezolinetant including abdominal pain, diarrhea, insomnia, back pain, and hot flush.1
• Advise patients to report their use of any other prescription or nonprescription medications or dietary supplements.1

Additional Information

AHFS first Release™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Astellas Pharma US, Inc. VEOZAH^® (fezolinetant) ORAL prescribing information. 2023 May. [Web]