Belzutifan

Belzutifan
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tejasvi Aryaputra

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Black Box Warning

TITLE See full prescribing information for complete Boxed Warning. Condition Name: (Content)

Overview

Belzutifan is a hypoxia-inducible factor inhibitor that is FDA approved for the treatment of von Hippel-Lindau disease under certain conditions. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, increased creatinine, nausea, anemia, decreased hemoglobin, dizziness, fatigue, and increased glucose.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• 120 mg is the recommended dosage of Belzutifan given to patients through oral administration once daily.
• Recommended dosage is given until disease progression or unacceptable toxicity.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Belzutifan in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Belzutifan in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Belzutifan FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Belzutifan in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Belzutifan in pediatric patients.

Contraindications

There are no contraindications associated with Belzutifan.

Warnings

TITLE See full prescribing information for complete Boxed Warning. Condition Name: (Content)

Anemia

• Severe anemia can occur when taking Belzutifan.
• In Study 004, 90% of patients had experienced anemia in which 7% of these patients were experiencing Grade 3 Anemia when taking Belzutifan.
• In Study 004, median time to onset of anemia was 31 days.
• In Study 001, 76% of patients with advanced solid tumors displayed anemia. Of those patients with anemia, 28% displayed symptoms of Grade 3 anemia.
• Advise patients to be on the alert for anemia when treated with Belzutifan.
• Advise patients that severity of anemia can increase in patients who are dual CYP2C19 and UGT2B17 poor metabolizers.
• Withhold Belzutifan treatment in patients with hemoglobin <9g/dL or are experiencing life threatening anemia.
• Advise patients who's hemoglobin ≥9g/dL to either reduce their dosage or permanently stop Belzutifan use.
• Advise patients treated with Belzutifan that erythropoiesis stimulating agents is not recommended for anemia treatment.
• Advise patients that data from clinical studies show that the risk of serious cardiovascular reactions and death are increased when taking erythropoiesis stimulating agents.
• Advise patients that data from clinical studies show that there is a decrease in progression-free survival and/or overall survival when taking erythropoiesis stimulating agents.

Hypoxia

• Hypoxia may be caused by patients treated with Belzutifan that may lead to discontinuation of treatment, supplemental oxygen, or hospitalization.
• Study 004 showed that 1.6% of patients in the study that were treated with Belzutifan reported hypoxia.
• In Study 001, 29% of patients with advanced solid tumors displayed hypoxia. Of those patients with hypoxia, 16% displayed symptoms of Grade 3 hypoxia.
• Advise patients before start of, and throughout the treatment with Belzutifan to monitor oxygen saturation.
• Withhold treatment of Belzutifan in patients with decreased oxygen saturation (pulse oximeter <88% or PaO2 ≤55 mm Hg) until issue is resolved.
• Advise patients to permanently stop Belzutifan treatment if experiencing recurrent symptomatic hypoxia or life-threatening hypoxia.

Embryo-Fetal Toxicity

• Animal studies have shown that there is risk associated with the fetus in pregnant women who are taking Belzutifan.
• Studies done on pregnant rats have shown that reduced fetal body weight, embryo-fetal lethality, and fetal skeletal malformations when given maternal exposures ≥0.2 times the human exposures of Belzutifan during the period of organogenesis.
• Advise female patients with reproductive potential and pregnant women the risks associated to the fetus when treated with Belzutifan.
• Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Belzutifan and for at least 1 week after the last dose.
• Advise males with female partners of reproductive potential to use effective contraception during treatment with Belzutifan and for at least 1 week after the last dose.

Adverse Reactions

Clinical Trials Experience

Clinical Trials Experience

• Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Study 004, an open-label clinical trial, looked into the safety of Belzutifan in 61 patients with VHL disease who had at least one measurable solid tumor localized to the kidney. These patients received the recommended dosage of 120 mg of Belzutifan once daily for a median duration of 68 weeks.

Study 004

• 15% of patients reported serious adverse reactions when treated with Belzutifan which included anaphylaxis reaction, central retinal vein occlusion, hypoxia, retinal detachment and anemia. Adverse reactions caused 3.3% of patients to permanently discontinue Belzutifan treatment. Of the 3.3% of patients who discontinued treatment, opioid overdose and dizziness were the most common adverse reactions that led to discontinuation. Adverse reactions caused 39% of taking Belzutifan to interrupt the dosage being taken. Headache, fatigue, influenza-like illness, decreased hemoglobin, nausea, anemia, and abdominal pain are some of the adverse reactions that caused dosage interruptions. Adverse reactions caused 13% of patients taking Belzutifan to reduce their dosage. Fatigue was the most common adverse reaction that caused a dosage reduction.
• Fatigue, increased glucose, decreased hemoglobin, headache, nausea, dizziness, and increased creatinine are the most reported adverse reactions when patients are treated with Belzutifan.

Table 2 summarizes the Adverse Reactions that occurred during Study 004 of Patients taking Belzutifan.

Insert Table 2

Table 3 summarizes the Laboratory abnormalities in Study 004 in Patients taking Belzutifan.

Insert Table 3

Other Clinical Trials Experience

• Study 001 is a clinical trial that contained 58 patients with advanced solid tumors. These patients had a median age of 62.5 years and a median number of prior therapies for cancer was 3. These patients received the recommended dosage of Belzutifan once daily. The most common adverse reactions reported in this clinical trial was cough, dehydration, vomiting, edema, diarrhea, and musculoskeletal pain.

Postmarketing Experience

There is limited information regarding Belzutifan Postmarketing Experience in the drug label.

Drug Interactions

Effects of Other Drugs on Belzutifan

UGT2B17 or CYP2C19 Inhibitors

• Plasma exposures of Belzutifan may increase with coadministration of UGT2B17 or CYP2C19 inhibitors and Belzutifan.
• Adverse reactions of Belzutifan may increase when the plasma exposures of Belzutifan are elevated.
• Reduce the dosage of Belzutifan if patients is experiencing hypoxia or anemia.

Effect of WELIREG on Other Drugs

Sensitive CYP3A4 Substrates

• CYP3A substrates concentrations decreased with coadministration of CYP3A substrates and Belzutifan.
• Patients with dual UGT2B17 and CYP2C19 poor metabolizers are more likely to experience a pronounced decrease in the *CYP3A substrates concentrations.
• Advise patients to avoid coadministration of sensitive CYP3A4 substrates and Belzutifan.
• Advise patients the dosage of sensitive CYP3A4 substrate should be increased if coadministration cannot be avoided.

Hormonal Contraceptives

• Increase in breakthrough bleeding or contraceptive failure may occur in patients with coadministration of hormonal contraceptives and Belzutifan.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Fetal harm may occur in pregnant women who are treated with Belzutifan based on data from animal studies. Pregnant rat studies have shown that there was evidence of reduced fetal body weight, embryo-fetal lethality, and fetal skeletal malformations during the period of organogenesis when given maternal exposures ≥0.2 times the human exposure. Embryo-fetal lethality was seen in pregnant rats that were given doses ≥60 mg/kg/day of Belzutifan during the period of organogenesis. Reduced skeletal ossification, reduced fetal body weights, and fetal rib malformations were seen in pregnant rats that were given doses of 6 and 60 mg/kg/day of Belzutifan. Advise pregnant women or females with reproductive potential about the harms associated with the fetus when treated with Belzutifan.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Belzutifan in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Belzutifan during labor and delivery.

Nursing Mothers

No data is present on the effects done on the breastfed child and the effects on milk production when treated with Belzutifan. Advise women who are nursing to not nurse during or 1 week after the last of dose of Belzutifan treatment due to the potential serious adverse reactions associated with Belzutifan.

Pediatric Use

There is no FDA guidance on the use of Belzutifan in pediatric settings.

Geriatic Use

There were not enough patients in clinical studies to look into the differences of Belzutifan in younger patients to patients who are 65 years of age or older.

Gender

There is no FDA guidance on the use of Belzutifan with respect to specific gender populations.

Race

There is no FDA guidance on the use of Belzutifan with respect to specific racial populations.

Renal Impairment

Patients with mild or moderate renal impairment required no dose modifications in Belzutifan treatment. The effects of Belzutifan treatment on patients with severe renal impairment have not been established.

Hepatic Impairment

Patients with mild hepatic impairment required no dose modifications in Belzutifan treatment. The effects of Belzutifan treatment on patients with severe hepatic impairment have not been established.

Females of Reproductive Potential and Males

Advise patients that fetal harm may occur in pregnant women treated with Belzutifan. Verify the pregnancy status of the female patient before starting Belzutifan treatment. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with Belzutifan and for at least 1 week after the last dose. Advise male patients with females of reproductive potential to use effective contraception during treatment with Belzutifan and for at least 1 week after the last dose. Fertility may be impaired in both male and female patients who are treated with Belzutifan.

Immunocompromised Patients

There is no FDA guidance one the use of Belzutifan in patients who are immunocompromised.

Dual UGT2B17 and CYP2C19 Poor Metabolizers

Higher Belzutifan exposures in patients with dual CYP2C19 and UGT2B17 poor metabolizers. Serious adverse reactions susceptibility may increase when exposures of Belzutifan are high. Monitor patients with dual CYP2C19 and UGT2B17 poor metabolizers that are treated with Belzutifan for adverse reactions.

Administration and Monitoring

Administration

• Advise patients to swallow tablets whole.
• Prior to swallowing, advise patients to not crush, spit, or chew Belzutifan.
• If a dosage of Belzutifan is missed, then it can be taken the same day as soon as possible.
• Advise patients who missed a dose to not take extra tablets to make up for that dose which was missed.

Monitoring

Dose Reductions

• 80 mg orally once daily of Belzutifan would be the first dose reduction.
• 40 mg orally once daily of Belzutifan would be the second dose reduction.
• Permanently discontinue Belzutifan if a third dose reduction is needed.

Table 1 summarizes Dosage Modifications in Patients experiencing Adverse Reactions.

Insert Table 1

IV Compatibility

There is limited information regarding the compatibility of Belzutifan and IV administrations.

Overdosage

• No specific treatment is specified if a Belzutifan overdose occurs.
• Advise patients to withhold institute supportive care and Belzutifan if a suspected overdose has occurred.
• 120 mg twice a day of Belzutifan has resulted in Grade 3 hypoxia.
• 240 mg once daily of Belzutifan has resulted in Grade 4 Thrombocytopenia.

Pharmacology

There is limited information regarding Belzutifan Pharmacology in the drug label.

Mechanism of Action

• Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha.
• Ubiquitin-proteasomal degradation by VHL protein targets HIF-2α when there are normal oxygen levels.
• Accumulation and stabilization of HIF-2α when there is a lack of VHL protein.
• A transcriptional complex is formed between HIF-2α and HIF-1β upon stabilization that induces expression of downstream genes associated with angiogenesis, cellular proliferation, and tumor growth.
• HIF-2α-HIF-1β interaction is blocked when a patient is treated with Belzutifan.

Structure

• Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha. It has an empirical formula of C17H12F3NO4S and a molecular weight of 383.34 Daltons.

Insert Structure Photo

Pharmacodynamics

There is limited information regarding Belzutifan Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Belzutifan Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Belzutifan Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Belzutifan Clinical Studies in the drug label.

How Supplied

There is limited information regarding Belzutifan How Supplied in the drug label.

Storage

There is limited information regarding Belzutifan Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Belzutifan Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Belzutifan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Belzutifan Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Belzutifan Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.