Belzutifan (Monograph)

Brand name: Welireg
Drug class: Antineoplastic Agents

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

Warning

May cause fetal harm.
Avoid pregnancy during therapy.
Verify pregnancy status prior to initiation of belzutifan therapy in females of reproductive potential.
Advise females of reproductive potential and males who are partners of such females to use effective nonhormonal contraceptive methods during belzutifan therapy and for 1 week after the last dose. Concomitant use with hormonal contraceptives may result in hormonal contraceptive failure.

Introduction

Antineoplastic agent; hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor.

Uses for Belzutifan

Von Hippel-Lindau Disease

Treatment of von Hippel-Lindau (VHL) disease in adults who require therapy for associated renal cell carcinoma (RCC), CNS hemangioblastomas, or pancreatic neuroendocrine tumors (pNET) not requiring immediate surgery.

Advanced Renal Cell Carcinoma

Treatment of adults with advanced RCC following treatment with a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI).

Belzutifan Dosage and Administration

General

Pretreatment Screening

Assess for anemia prior to initiation of therapy.
Measure oxygen saturation prior to initiation of therapy.
Verify pregnancy status in females of reproductive potential.

Patient Monitoring

Monitor for anemia periodically during therapy. Patients who are dual UGT2B17 and CYP2C19 poor metabolizers have an increased risk of anemia; closely monitor for anemia in such patients.
Measure oxygen saturation periodically during therapy.

Administration

Oral Administration

Administer once daily, at the same time each day, without regard to food. Swallow tablets whole; do not chew, crush or split.

If a dose is missed, take the prescribed dose as soon as possible on the same day and resume regular daily schedule the following day; do not administer an additional dose to replace the missed dose.

If vomiting occurs any time after a dose of belzutifan is taken, do not replace the vomited dose; take the next dose at the next scheduled time.

Dosage

Adults

VHL Disease

Oral

120 mg orally once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Advanced RCC

Oral

120 mg orally once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification

If adverse reactions occur during belzutifan therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary. If dosage reduction is required, reduce dosage as described in Table 1.

Table 1: Recommended Dosage Reduction for Belzutifan Toxicity1
Dose Reduction Level	Dosage Reduction after Recovery from Toxicity
	(Initial Dosage = 120 mg once daily)
First	Resume at 80 mg once daily
Second	Resume at 40 mg once daily
Third	Permanently discontinue drug

If an adverse reaction occurs, modify dosage accordingly (see Table 2).

Table 2. Dosage Modification for Belzutifan Toxicity1
Adverse Reaction and Severity	Modification
Anemia
Hemoglobin <8 g/dL or anemia requiring RBC transfusion	Withhold therapy until hemoglobin ≥8 g/dL, and then resume at the same or reduced dosage or discontinue drug depending on severity
Life-threatening severity or anemia requiring urgent intervention	Withhold therapy until hemoglobin ≥8 g/dL, and then resume at reduced dosage or permanently discontinue drug
Hypoxia
Decreased oxygen saturation with exercise (e.g., pulse oximeter <88%)	Consider withholding therapy until hypoxia resolves, and then resume at same or reduced dosage depending on severity
Decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO₂ ≤55 mm Hg) or hypoxia requiring urgent intervention indicated	Withhold therapy until hypoxia resolves, and then resume at reduced dosage or permanently discontinue drug depending on severity
Life-threatening or recurrent symptomatic hypoxia	Permanently discontinue drug
Other Toxicity
Grade 3	Withhold therapy until toxicity improves to grade 2 or less, and then consider resuming at reduced dosage
	If grade 3 toxicity recurs on a reduced dosage, permanently discontinue drug
Grade 4	Permanently discontinue drug

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but ≤1.5 times the ULN, with any AST concentration): No dosage modification is recommended.

Moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN with any AST concentration): Not studied.

Renal Impairment

Mild or moderate renal impairment (eGFR 30–89 mL/minute per 1.73 m²): No dosage modification is recommended.

Severe renal impairment (eGFR 15–29 mL/minute per 1.73 m²): Not studied.

Geriatric Patients

The manufacturer makes no specific dosage recommendations.

Cautions for Belzutifan

Contraindications

None.

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm if administered to pregnant women; embryotoxicity and malformations demonstrated in animals. (See Boxed Warning.)

Avoid pregnancy during belzutifan therapy. Verify pregnancy status prior to initiation of belzutifan therapy in females of reproductive potential. Advise females of reproductive potential and males who are partners of such females to use effective nonhormonal contraceptive methods during belzutifan therapy and for 1 week after the last dose. Patients should be apprised of the potential hazard to the fetus if belzutifan is used during pregnancy.

Other Warnings and Precautions

Anemia

Severe anemia, sometimes requiring blood transfusion, reported. Median time to onset of anemia is 31 days (range: 1 day to 8.4 months) in von Hippel-Lindau (VHL) disease and 29 days (range: 1 day to 16.6 months) in renal cell carcinoma(RCC).

Monitor for anemia prior to initiation of belzutifan and periodically during therapy. Incidence or severity of anemia may be increased in patients who are dual UGT2B17 and CYP2C19 poor metabolizers; closely monitor such patients for anemia during therapy with belzutifan. If anemia occurs, temporary interruption of belzutifan therapy, dosage reduction, or discontinuance of therapy may be necessary; transfuse patients as clinically indicated.

Safety of ESAs for the treatment of belzutifan-associated anemia in patients with VHL disease has not been established.

Hypoxia

Severe hypoxia, sometimes requiring discontinuance of therapy, supplemental oxygen, or hospitalization, can occur in patients receiving belzutifan.

Monitor oxygen saturation prior to initiation of belzutifan and periodically during therapy. If hypoxia occurs, temporary interruption of belzutifan therapy, dosage reduction, or discontinuance of therapy may be necessary.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether belzutifan or its metabolites are distributed into human milk or if the drug has any effect on milk production or the breast-fed infant. Do not breast-feed during treatment with belzutifan and for 1 week after the last dose.

Females and Males of Reproductive Potential

Verify pregnancy status in females of reproductive potential prior to initiation of belzutifan therapy. Advise females of reproductive potential and males who are partners of such females to use effective nonhormonal contraception during treatment with belzutifan and for 1 week after the last dose.

May impair male and female fertility; reversibility unknown.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In patients with VHL, insufficient data to determine whether patients ≥65 years of age respond differently from younger adults. In patients with advanced RCC, no overall difference in efficacy between patients ≥65 years of age and younger patients.

Hepatic Impairment

Mild hepatic impairment: No clinically important effect on pharmacokinetics of belzutifan; no dosage adjustment required.

Moderate or severe hepatic impairment: Not studied.

Renal Impairment

Mild or moderate renal impairment: No clinically important effect on pharmacokinetics of belzutifan; no dosage adjustment required.

Severe renal impairment: Not studied.

Pharmacogenomic Considerations

Dual UGT2B17 and CYP2C19 poor metabolizers: Increased incidence and severity of adverse reactions (e.g., anemia, hypoxia) due to increased systemic exposure to belzutifan. Closely monitor patients who are dual UGT2B17 and CYP2C19 poor metabolizers for anemia and hypoxia during therapy.

Common Adverse Effects

Most common (≥25%) adverse reactions in patients with VHL disease: decreased hemoglobin, fatigue, increased S_cr, headache, dizziness, increased glucose levels, nausea.

Most common (≥25%) adverse reactions in patients with advanced RCC: decreased hemoglobin, fatigue, musculoskeletal pain, increased S_cr, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, increased aspartate aminotransferase.

Drug Interactions

Metabolized primarily by UGT2B17 and CYP2C19, and to a lesser extent by CYP3A4.

In vitro, does not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4. In vitro, does not induce CYP1A2 or 2B6.

Substrate of P-gp, OATP1B1, and OATP1B3, but not a substrate of BCRP. Inhibits MATE2K, but does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 or MATE1.

Drugs Affecting or Affected by Hepatic Microsomal Enzymes

UGT2B17 or CYP2C19 Inhibitors: Possible increased belzutifan plasma concentrations and increased incidence and severity of adverse effects (e.g., anemia, hypoxia). If concomitant use of belzutifan and inhibitors of UGT2B17 or CYP2C19 is necessary, monitor for anemia and hypoxia; reduce dosage of belzutifan for adverse effects as clinically indicated.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 Substrates: Possible decreased concentrations of the substrate drug and reduced efficacy. Pharmacokinetic interaction may be more pronounced in patients who are dual UGT2B17 and CYP2C19 poor metabolizers. Avoid concomitant use with sensitive CYP3A4 substrates for which a minimal decrease in systemic exposure may lead to therapeutic failure. If concomitant use cannot be avoided with sensitive CYP3A4 substrates, increase dosage of substrate drug according to manufacturer's labeling for the substrate drug.

Specific Drugs

Drug

Interaction

Comments

Midazolam

Midazolam AUC and peak plasma concentration decreased by 40 or 34%, respectively

Midazolam AUC predicted to decrease by up to 70% in patients who are dual UGT2B17 and CYP2C19 poor metabolizers

Avoid concomitant use with the sensitive CYP3A4 substrate midazolam; if concomitant use cannot be avoided, increase dosage of midazolam according to manufacturer's labeling for the drug

Hormonal contraceptives, oral

Because oral hormonal contraceptives are CYP3A4 substrates, decreased concentrations of the hormonal contraceptive, contraceptive failure, and increased risk of breakthrough bleeding may occur

Use a nonhormonal contraceptive method during therapy

Belzutifan Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentration and systemic exposure to belzutifan proportional over oral dose range of 20–120 mg.

Steady state concentrations achieved in approximately 3 days.

Peak plasma concentrations reached in a median of 1–2 hours following oral administration.

Food

Administration with a high-fat, high-calorie meal delays time to peak plasma concentration by approximately 2 hours; no clinically significant effect on peak plasma concentration or AUC.

Special Populations

Mild hepatic impairment: No clinically important effect on pharmacokinetics of belzutifan.

Mild or moderate renal impairment: No clinically important effect on pharmacokinetics of belzutifan.

Age (range 19–84 years), sex, race, and body weight (range 42–166 kg) do not have clinically important effects on belzutifan exposure.

Pharmacogenomics

Dual UGT2B17 and CYP2C19 poor metabolizers: Increased systemic exposure to belzutifan.

Distribution

Extent

Not known whether belzutifan or its metabolites are distributed into human milk.

Plasma Protein Binding

45% plasma protein bound.

Elimination

Metabolism

Metabolized primarily by UGT2B17 and CYP2C19, and to a lesser extent by CYP3A4.

Half-life

14 hours.

Stability

Storage

Oral

Tablets

20–25ºC. Excursions permitted between 15–30ºC.

Actions

Hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor.
Binds to HIF-2α and, in conditions of hypoxia or impairment of VHL protein function, blocks formation of the HIF-2α-HIF-1β transcriptional complex.
Reduces transcription and expression of HIF-2α target genes.
In vitro, anti-tumor activity observed in mouse xenograft models of renal cell carcinoma.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling.
Instruct patients to take their dose of belzutifan at the same time each day (once daily). Advise patients that belzutifan can be taken with or without food. Each tablet should be swallowed whole.
Inform patients that belzutifan can cause severe anemia that may require blood transfusions and that red blood cell levels will be monitored routinely during treatment. Advise patients to contact their healthcare provider if the patient experiences any symptoms suggestive of anemia.
Inform patients that belzutifan can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization, and that oxygen levels will be monitored routinely during treatment. Advise patients to contact their healthcare provider if the patient experiences any symptoms suggestive of hypoxia.
Advise pregnant women and females of reproductive potential of the risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential and males with female partners of reproductive potential to use effective non-hormonal contraception during treatment with belzutifan and for 1 week after the last dose.
Advise females not to breast-feed during treatment with belzutifan and for 1 week after the last dose.
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.

Belzutifan can only be obtained through designated specialty pharmacies. Contact manufacturer for specific availability information.