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Indications
WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC) following 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).

Indications for WELIREG® (belzutifan) 40 mg tablets

WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC) following 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).

WELIREG is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

WELIREG is indicated for the treatment of adult and pediatric patients 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL).

Selected Safety Information
WARNING: EMBRYO-FETAL TOXICITY
  • Exposure to WELIREG during pregnancy can cause embryo-fetal harm.
  • Verify pregnancy status prior to the initiation of WELIREG.
  • Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.

Selected Safety Information for WELIREG® (belzutifan) 40 mg tablets

WARNING: EMBRYO-FETAL TOXICITY
  • Exposure to WELIREG during pregnancy can cause embryo-fetal harm.
  • Verify pregnancy status prior to the initiation of WELIREG.
  • Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.
Anemia
  • WELIREG can cause severe anemia that can require blood transfusion.
  • Monitor for anemia before initiation of, and periodically throughout, treatment with WELIREG. Transfuse patients as clinically indicated. Withhold, reduce dose, or permanently discontinue WELIREG based on severity.
  • In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months).
  • The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established.
  • In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced ccRCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received erythropoiesis-stimulating agents (ESAs) only, and 12% received both transfusion and ESAs.
  • In LITESPARK-015 (n=72), anemia occurred in 96% of patients with PPGL and 22% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 22.1 months). Of the patients with anemia, 20% received transfusions only, 26% received erythropoiesis-stimulating agents (ESAs) only, and 6% received both transfusion and ESAs.
Hypoxia
  • WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization.
  • Monitor oxygen saturation before initiation of, and periodically throughout, treatment with WELIREG. For decreased oxygen saturation with exercise (eg, pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (eg, pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a health care provider.
  • In LITESPARK-004, hypoxia occurred in 1.6% of patients with VHL disease.
  • In LITESPARK-005, hypoxia occurred in 15% of patients with advanced ccRCC and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months).
  • In LITESPARK-015, hypoxia occurred in 13% of patients with PPGL and 10% had Grade 3 hypoxia. Median time to onset of hypoxia was 35 days (range: 6 days to 23.9 months). Of the patients with hypoxia, 67% were treated with oxygen therapy.
Embryo-Fetal Toxicity
  • Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman.
  • Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.
Adverse Reactions
    Adverse Reactions in LITESPARK-004 (VHL disease)
  • Serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).
  • WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each).
  • Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness.
  • Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%).
  • The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).
    • Adverse Reactions in LITESPARK-005 (Advanced ccRCC)
  • Serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions (≥2%) were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%).
  • WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%), anemia (0.5%), and hemorrhage (0.5%).
  • Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%).
  • Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1%) were hypoxia (5%) and anemia (3.2%).
  • The most common adverse reactions (≥25%), including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (34%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%).
    • Adverse Reactions in LITESPARK-015 (PPGL)
  • Serious adverse reactions occurred in 36% of patients. The most frequently reported serious adverse reactions (≥2%) were anemia and hypertension (4.2% each) and pyelonephritis, pneumonia, hypoxia, dyspnea, and hemorrhage (2.8% each).
  • WELIREG was permanently discontinued due to adverse reactions in 2 patients (2.8%). Adverse reactions which resulted in permanent discontinuation were increased alanine aminotransferase and paraparesis (1.4% each).
  • Dosage interruptions due to an adverse reaction occurred in 40% of patients. Of the patients who received WELIREG, 13% were ≥65 years old and 4.2% were ≥75 years. Adverse reactions which required dosage interruption in >3% of patients were hypoxia, nausea, and fatigue (4.2% each).
  • Dose reductions due to an adverse reaction occurred in 14% of patients. The most frequently reported adverse reaction which required dose reduction was hypoxia (4.2%).
  • The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients were anemia (96%), fatigue (56%), musculoskeletal pain (56%), decreased lymphocytes (54%), increased alanine aminotransferase (51%), increased aspartate aminotransferase (42%), increased calcium (34%), dyspnea (33%), increased potassium (31%), decreased leukocytes (30%), headache (29%), increased alkaline phosphatase (25%), dizziness (26%), and nausea (25%).
Drug Interactions
  • Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended.
  • Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.
Lactation
  • Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose.
Females and Males of Reproductive Potential
  • WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG.
  • Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.
  • Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown.
Pediatric Use
  • Use of WELIREG in pediatric patients aged 12 years and older for PPGL is supported by evidence from an adequate and well-controlled study of WELIREG in adults with additional pharmacokinetic data demonstrating that belzutifan exposure is predicted to be within range of that observed in adults, and that the course of locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients.
  • The safety and effectiveness of WELIREG have not been established in pediatric patients with VHL or ccRCC, or in pediatric patients younger than 12 years of age with PPGL.
Renal Impairment
  • For patients with severe renal impairment (eGFR 15-29 mL/min estimated by MDRD), monitor for increased adverse reactions and modify the dosage as recommended.
Hepatic Impairment
  • For patients with moderate and severe hepatic impairment, monitor for increased adverse reactions and modify the dosage as recommended.
Before prescribing WELIREG, please read the accompanying Prescribing Information, including the Boxed Warning about embryo-fetal toxicity. The Medication Guide also is available.

Dosing for WELIREG® (belzutifan) in Adults With Certain VHL Disease–Associated Tumors

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Dosing
Dose Modification
DOSING

Convenient, once-daily, oral dosing

The recommended dose of WELIREG is 120 mg (three 40-mg tablets) once daily until disease progression or unacceptable toxicity

WELIREG® (belzutifan) 40-mg Tablets
Not actual size.

WELIREG should be taken at the same time each day and may be taken with or without food

Advise patients to swallow tablets whole.

Do not chew, crush, or split WELIREG prior to swallowing.

If a dose of WELIREG is missed, it can be taken as soon as possible on the same day.

Resume the regular daily dose schedule for WELIREG the next day. Do not take extra tablets to make up for the missed dose.

If vomiting occurs any time after taking WELIREG, do not retake the dose.

Take the next dose on the next day.

View the WELIREG Prescribing Information for details about dosing in adult and pediatric patients 12 years or older with advanced pheochromocytoma or paraganglioma (PPGL)

See Prescribing Information
DOSE MODIFICATION

Manage adverse reactions with recommended dose modifications in certain adults with VHL disease–associated tumors

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Infographic on Managing Adverse Reactions in Patients Taking WELIREG® (belzutifan)

Dose modification (if appropriate)

Infographic on Dose Modifications When Managing Adverse Reactions in Patients Taking WELIREG® (belzutifan)Infographic on Dose Modifications When Managing Adverse Reactions in Patients Taking WELIREG® (belzutifan)
a
Graded per NCI CTCAE v4.0.
PaO2 = partial pressure of oxygen; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.

Learn more about WELIREG:

Mechanism of ActionEfficacyResources & Dispensing

Indications

WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma with a clear cell component (ccRCC) following 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).

WELIREG is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

WELIREG is indicated for the treatment of adult and pediatric patients 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL).

Selected Safety Information

WARNING: EMBRYO-FETAL TOXICITY
  • Exposure to WELIREG during pregnancy can cause embryo-fetal harm.
  • Verify pregnancy status prior to the initiation of WELIREG.
  • Advise patients of these risks and the need for effective non-hormonal contraception as WELIREG can render some hormonal contraceptives ineffective.
Anemia
  • WELIREG can cause severe anemia that can require blood transfusion.
  • Monitor for anemia before initiation of, and periodically throughout, treatment with WELIREG. Transfuse patients as clinically indicated. Withhold, reduce dose, or permanently discontinue WELIREG based on severity.
  • In LITESPARK-004 (N=61), decreased hemoglobin occurred in 93% of patients with VHL disease and 7% had Grade 3 events. Median time to onset of anemia was 31 days (range: 1 day to 8.4 months).
  • The safety of erythropoiesis-stimulating agents (ESAs) for treatment of anemia in patients with VHL disease treated with WELIREG has not been established.
  • In LITESPARK-005 (n=372), decreased hemoglobin occurred in 88% of patients with advanced ccRCC and 29% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 16.6 months). Of the patients with anemia, 22% received transfusions only, 20% received erythropoiesis-stimulating agents (ESAs) only, and 12% received both transfusion and ESAs.
  • In LITESPARK-015 (n=72), anemia occurred in 96% of patients with PPGL and 22% had Grade 3 events. Median time to onset of anemia was 29 days (range: 1 day to 22.1 months). Of the patients with anemia, 20% received transfusions only, 26% received erythropoiesis-stimulating agents (ESAs) only, and 6% received both transfusion and ESAs.
Hypoxia
  • WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization.
  • Monitor oxygen saturation before initiation of, and periodically throughout, treatment with WELIREG. For decreased oxygen saturation with exercise (eg, pulse oximeter <88% or PaO2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same or a reduced dose. For decreased oxygen saturation at rest (eg, pulse oximeter <88% or PaO2 ≤55 mm Hg) or when urgent intervention is indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening or recurrent symptomatic hypoxia, permanently discontinue WELIREG. Advise patients to report signs and symptoms of hypoxia immediately to a health care provider.
  • In LITESPARK-004, hypoxia occurred in 1.6% of patients with VHL disease.
  • In LITESPARK-005, hypoxia occurred in 15% of patients with advanced ccRCC and 10% had Grade 3 events. Of the patients with hypoxia, 69% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 months).
  • In LITESPARK-015, hypoxia occurred in 13% of patients with PPGL and 10% had Grade 3 hypoxia. Median time to onset of hypoxia was 35 days (range: 6 days to 23.9 months). Of the patients with hypoxia, 67% were treated with oxygen therapy.
Embryo-Fetal Toxicity
  • Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman.
  • Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. WELIREG can render some hormonal contraceptives ineffective. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.
Adverse Reactions
    Adverse Reactions in LITESPARK-004 (VHL disease)
  • Serious adverse reactions occurred in 15% of patients, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each).
  • WELIREG was permanently discontinued due to adverse reactions in 3.3% of patients for dizziness and opioid overdose (1.6% each).
  • Dosage interruptions due to an adverse reaction occurred in 39% of patients. Those which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness.
  • Dose reductions due to an adverse reaction occurred in 13% of patients. The most frequently reported adverse reaction which required dose reduction was fatigue (7%).
  • The most common adverse reactions (≥25%), including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin (93%), fatigue (64%), increased creatinine (64%), headache (39%), dizziness (38%), increased glucose (34%), and nausea (31%).
    • Adverse Reactions in LITESPARK-005 (Advanced ccRCC)
  • Serious adverse reactions occurred in 38% of patients. The most frequently reported serious adverse reactions (≥2%) were hypoxia (7%), anemia (5%), pneumonia (3.5%), hemorrhage (3%), and pleural effusion (2.2%). Fatal adverse reactions occurred in 3.2% of patients who received WELIREG, including sepsis (0.5%) and hemorrhage (0.5%).
  • WELIREG was permanently discontinued due to adverse reactions in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) were hypoxia (1.1%), anemia (0.5%), and hemorrhage (0.5%).
  • Dosage interruptions due to an adverse reaction occurred in 39% of patients. Of the patients who received WELIREG, 28% were 65 to 74 years, and 10% were 75 years and over. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Adverse reactions which required dosage interruption in ≥2% of patients were anemia (8%), hypoxia (5%), COVID-19 (4.3%), fatigue (3.2%), and hemorrhage (2.2%).
  • Dose reductions due to an adverse reaction occurred in 13% of patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. The most frequently reported adverse reactions which required dose reduction (≥1%) were hypoxia (5%) and anemia (3.2%).
  • The most common adverse reactions (≥25%), including laboratory abnormalities, were decreased hemoglobin (88%), fatigue (43%), musculoskeletal pain (34%), increased creatinine (34%), decreased lymphocytes (34%), increased alanine aminotransferase (32%), decreased sodium (31%), increased potassium (29%), and increased aspartate aminotransferase (27%).
    • Adverse Reactions in LITESPARK-015 (PPGL)
  • Serious adverse reactions occurred in 36% of patients. The most frequently reported serious adverse reactions (≥2%) were anemia and hypertension (4.2% each) and pyelonephritis, pneumonia, hypoxia, dyspnea, and hemorrhage (2.8% each).
  • WELIREG was permanently discontinued due to adverse reactions in 2 patients (2.8%). Adverse reactions which resulted in permanent discontinuation were increased alanine aminotransferase and paraparesis (1.4% each).
  • Dosage interruptions due to an adverse reaction occurred in 40% of patients. Of the patients who received WELIREG, 13% were ≥65 years old and 4.2% were ≥75 years. Adverse reactions which required dosage interruption in >3% of patients were hypoxia, nausea, and fatigue (4.2% each).
  • Dose reductions due to an adverse reaction occurred in 14% of patients. The most frequently reported adverse reaction which required dose reduction was hypoxia (4.2%).
  • The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients were anemia (96%), fatigue (56%), musculoskeletal pain (56%), decreased lymphocytes (54%), increased alanine aminotransferase (51%), increased aspartate aminotransferase (42%), increased calcium (34%), dyspnea (33%), increased potassium (31%), decreased leukocytes (30%), headache (29%), increased alkaline phosphatase (25%), dizziness (26%), and nausea (25%).
Drug Interactions
  • Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases plasma exposure of belzutifan, which may increase the incidence and severity of adverse reactions. Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended.
  • Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates or lead to therapeutic failures. Avoid coadministration with sensitive CYP3A4 substrates. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding.
Lactation
  • Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose.
Females and Males of Reproductive Potential
  • WELIREG can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG.
  • Use of WELIREG may reduce the efficacy of hormonal contraceptives. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with WELIREG and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose.
  • Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential and the reversibility of this effect is unknown.
Pediatric Use
  • Use of WELIREG in pediatric patients aged 12 years and older for PPGL is supported by evidence from an adequate and well-controlled study of WELIREG in adults with additional pharmacokinetic data demonstrating that belzutifan exposure is predicted to be within range of that observed in adults, and that the course of locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients.
  • The safety and effectiveness of WELIREG have not been established in pediatric patients with VHL or ccRCC, or in pediatric patients younger than 12 years of age with PPGL.
Renal Impairment
  • For patients with severe renal impairment (eGFR 15-29 mL/min estimated by MDRD), monitor for increased adverse reactions and modify the dosage as recommended.
Hepatic Impairment
  • For patients with moderate and severe hepatic impairment, monitor for increased adverse reactions and modify the dosage as recommended.
Before prescribing WELIREG, please read the accompanying Prescribing Information, including the Boxed Warning about embryo-fetal toxicity. The Medication Guide also is available.