Fezolinetant (Monograph)

Brand name: Veozah
Drug class: Central Nervous System Agents, Miscellaneous

Medically reviewed by Drugs.com on Feb 10, 2025. Written by ASHP.

Warning

Perform hepatic laboratory tests prior to initiation of treatment to evaluate for hepatic function and injury. Do not initiate fezolinetant if aminotransferase is ≥2 times the ULN or if total bilirubin is ≥2 times the ULN for the evaluating laboratory.
Perform follow-up hepatic laboratory testing monthly for the first 3 months, at 6 months, and 9 months of treatment.
Advise patients to discontinue fezolinetant immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury (new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, or abdominal pain).
Discontinue fezolinetant if transaminase elevations are >5 times the ULN, or if transaminase elevations are >3 times the ULN and total bilirubin is >2 times the ULN.
If transaminase elevations >3 times the ULN occur, perform more frequent follow-up hepatic laboratory tests until resolution.

Introduction

A small-molecule neurokinin 3 (NK3) receptor antagonist.

Uses for Fezolinetant

Moderate to Severe Vasomotor Symptoms due to Menopause

Treatment of moderate to severe vasomotor symptoms (VMS) due to menopause.

Reduces frequency and severity of VMS in postmenopausal women.

The North American Menopause Society (NAMS) 2023 guidelines recommend fezolinetant as an effective nonhormonal treatment for moderate to severe VMS in women unable to use hormone therapy. Other clinicians state that more long-term data are needed to support widespread use of fezolinetant.

Fezolinetant Dosage and Administration

General

Pretreatment Screening

Perform baseline hepatic function tests (i.e., ALT, AST, alkaline phosphatase, total/direct bilirubin) before starting therapy. Do not initiate fezolinetant if ALT or AST levels are ≥2 times the ULN or if total bilirubin is ≥2 times the ULN for the evaluating laboratory.

Patient Monitoring

Measure ALT, AST, alkaline phosphatase, and bilirubin monthly for the first 3 months, then at 6 and 9 months.
If transaminase levels ≥3 times the ULN occur, perform liver function tests more frequently.

Administration

Administer orally with or without food.

Swallow tablets whole and do not cut, crush, or chew.

If a dose is missed, skip the dose if the next dose is within 12 hours.

Dosage

Adults

Moderate to Severe Vasomotor Symptoms due to Menopause

Oral

45 mg once daily.

Special Populations

Hepatic Impairment

No specific dosage recommendations for patients with Child-Pugh class A or B hepatic impairment. Not studied in patients with Child-Pugh class C hepatic impairment; contraindicated in patients with cirrhosis.

Renal Impairment

No dosage adjustment needed for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²). Contraindicated in patients with severe (eGFR 15 to <30 mL/min/1.73 m²) renal impairment or end-stage renal disease (eGFR <15 mL/min/1.73 m²).

Geriatric Patients

No specific dosage recommendations.

Cautions for Fezolinetant

Contraindications

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

Warnings/Precautions

Hepatotoxicity

Hepatotoxicity reported in the postmarketing setting (see Boxed Warning). Cases of drug-induced liver injury with elevations of ALT, AST, alkaline phosphatase, and total bilirubin occurred within 40 days of initiating fezolinetant. Patients reported a general sense of feeling unwell with symptoms of fatigue, nausea, pruritus, jaundice, pale feces, and dark urine; these abnormalities generally resolved after discontinuation of the drug.

Elevations in serum transaminase (ALT and/or AST) concentrations reported in premarketing clinical studies; patients were generally asymptomatic.

Prior to initiating fezolinetant, perform baseline hepatic laboratory tests including serum ALT, AST, alkaline phosphatase, and bilirubin (total and direct). Do not initiate therapy if ALT or AST is ≥2 times the ULN or if total bilirubin is increased ≥2 times the ULN for the evaluating laboratory.

After initiating of therapy, perform hepatic laboratory tests monthly for the first 3 months, then at 6 and 9 months.

If signs or symptoms suggestive of liver injury occur (e.g., new-onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale feces, dark urine, abdominal pain), advise patient to discontinue fezolinetant immediately and seek medical attention including hepatic laboratory testing.

Discontinue fezolinetant if transaminase elevations >5 times the ULN or if transaminase elevations >3 times the ULN and total bilirubin >2 times the ULN. If transaminase elevations >3 times the ULN, perform more frequent follow-up hepatic laboratory testing until resolution.

Exclude alternative causes of hepatic laboratory test elevations.

Specific Populations

Pregnancy

No data available on use during pregnancy.

Lactation

No data on excretion in breast milk, effects on milk production, or impact on the breastfed infant.

Pediatric Use

Not studied in patients <18 years of age.

Geriatric Use

Insufficient data in women >65 years of age.

Hepatic Impairment

Fezolinetant exposure increases in Child-Pugh Class A or B hepatic impairment; not studied in Class C hepatic impairment. Contraindicated in patients with cirrhosis.

Renal Impairment

Exposure of fezolinetant metabolite increases in severe renal impairment. Contraindicated in patients with severe renal impairment or end-stage renal disease.

Common Adverse Effects

The most common adverse reactions (>2%): abdominal pain, diarrhea, insomnia, back pain, hot flush, elevated hepatic transaminases.

Drug Interactions

CYP1A2 substrate.

Fezolinetant and ES259564 metabolite do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and do not induce CYP1A2, CYP2B6, and CYP3A4.

Fezolinetant is not a substrate or inhibitor of P-glycoprotein (P-gp). ES259564 is a substrate of P-gp, but not an inhibitor of P-gp. Fezolinetant and ES259564 are not substrates of breast cancer resistance protein (BCRP), and organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1, OATP1B3). ES259564 is not a substrate of organic anion transporters 1 and 3 (OAT1, OAT3), organic cation transporter 2 (OCT2), and multidrug and toxin extrusion proteins 1 and 2-K (MATE1, MATE2-K).

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Concomitant use with weak, moderate, or strong CYP1A2 inhibitors increases exposure of fezolinetant. Concomitant use with CYP1A2 inhibitors is contraindicated.

Specific Drugs

Drug	Interaction	Comments
Cimetidine	Cimetidine, a weak CYP1A2 inhibitor, increased fezolinetant AUC by 100%	Avoid concomitant use
Fluvoxamine	Fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant AUC by 840%	Avoid concomitant use
Mexiletine	Mexiletine, a moderate CYP1A2 inhibitor, increased fezolinetant AUC by 360%	Avoid concomitant use

Fezolinetant Pharmacokinetics

Absorption

Plasma Concentration

Median time to peak plasma concentration: 1.5 hours.

Distribution

Plasma Protein Binding

51%.

Elimination

Elimination Route

Primarily metabolized by CYP1A2, and to a lesser extent CYP2C9 and CYP2C19.

Half-life

Effective half-life: 9.6 hours.

Stability

Storage

Oral

Tablets

Store at 20-25°C; brief fluctuations between 15-30°C acceptable.

Actions

NK3 receptor antagonist; blocks neurokinin B (NKB) binding on kisspeptin/neurokinin B/dynorphin (KNDy) neurons.
The thermoregulatory center in the hypothalamus is innervated by KNDy neurons; these neurons are stimulated by NKB, acting on NK3 receptors, and inhibited by estrogen. During menopause, declining concentrations of estrogen alter the activation of KNDy neurons, resulting in hypertrophy of the neurons and dysregulation of the thermoregulatory center.
By antagonizing NKB/NK3-mediated signaling, fezolinetant modulates KNDy neuronal activity in the thermoregulatory center.

Advice to Patients

Advise patients to read the FDA-approved patient labeling (Patient Information).
Advise patients to stop fezolinetant and seek medical attention if they experience signs of liver injury, such as new onset fatigue, decreased appetite, nausea, vomiting, itching, jaundice, pale stools, dark urine, or abdominal pain.
Inform patients that liver function tests are required before starting fezolinetant, then monthly for the first 3 months, and again at 6 and 9 months after starting therapy.
Inform patients of the potential serious adverse reactions including elevated hepatic transaminases and liver injury.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements as well as any concomitant illnesses.
Advise patients to inform their clinician if they are or plan to become pregnant or plan to breast-feed.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.