Belzutifan

1 INDICATIONS AND USAGE WELIREG is a hypoxia-inducible factor inhibitor indicated: von Hippel-Lindau (VHL) disease for 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. ( 1.1 ) Renal Cell Carcinoma with a Clear Cell Component (ccRCC) in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, for the adjuvant treatment of adult patients with ccRCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. ( 1.2 ) as monotherapy, for treatment of adult patients with advanced 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). ( 1.2 ) Pheochromocytoma or Paraganglioma (PPGL) for treatment of adult and pediatric patients 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL). ( 1.3 ) 1.1 von Hippel-Lindau (VHL) disease WELIREG is indicated for 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. 1.2 Renal Cell Carcinoma with a Clear Cell Component (ccRCC) WELIREG, in combination with pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph, is indicated for the adjuvant treatment of adult patients with ccRCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. WELIREG is indicated for the treatment of adult patients with advanced 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). 1.3 Pheochromocytoma or Paraganglioma (PPGL) 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).

5 WARNINGS AND PRECAUTIONS Anemia : Monitor for anemia before initiation of and periodically throughout treatment with WELIREG. Withhold, reduce dose, or permanently discontinue WELIREG based on severity. ( 2.2 , 5.1 ) Hypoxia : Monitor oxygen saturation before initiation of, and periodically throughout, treatment with WELIREG. For hypoxia at rest, withhold until resolved, resume at reduced dose, or discontinue depending on severity. For life-threatening hypoxia, permanently discontinue WELIREG. ( 2.2 , 5.2 ) 5.1 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 [see Dosage and Administration (2.2) ] . von Hippel-Lindau (VHL) disease In LITESPARK-004, decreased hemoglobin occurred in 93% of patients and 7% had Grade 3 events [see Adverse Reactions (6.1) ] . 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. Randomized controlled trials in patients with cancer receiving myelosuppressive chemotherapy with ESAs have shown that ESAs increased the risks of death and serious cardiovascular reactions, and decreased progression-free survival and/or overall survival. See the prescribing information for ESAs for more information. Renal Cell Carcinoma with a Clear Cell Component (ccRCC) In LITESPARK-005, decreased hemoglobin occurred in 88% of patients and 29% had Grade 3 events [see Adverse Reactions (6.1) ] . 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% of patients received ESAs only and 12% received both transfusion and ESAs. In LITESPARK-022, decreased hemoglobin occurred in 95% of patients and 11% had Grade 3 or higher events [see Adverse Reactions (6.1) ]. Median time to onset of anemia was 42 days (range: 1 day to 11.1 months). Of the patients with anemia, 5% received transfusions only, 8% received ESAs only, and 1.3% received both transfusion and ESAs. Pheochromocytoma or Paraganglioma (PPGL) In LITESPARK-015, anemia occurred in 96% of patients and 22% had Grade 3 events [see Adverse Reactions (6.1) ] . 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 ESAs only, and 6% received both transfusion and ESAs. 5.2 Hypoxia WELIREG can cause severe hypoxia that may require discontinuation, supplemental oxygen, or hospitalization [see Dosage and Administration (2.2) ]. Monitor oxygen saturation before initiation of, and periodically throughout, treatment with WELIREG. For decreased oxygen saturation with exercise (e.g., pulse oximeter <88% or P a O 2 ≤55 mm Hg), consider withholding WELIREG until pulse oximetry with exercise is greater than 88%, then resume at the same dose or at a reduced dose. For decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO2 ≤55 mm Hg) or urgent intervention indicated, withhold WELIREG until resolved and resume at a reduced dose or discontinue. For life-threatening hypoxia or for recurrent symptomatic hypoxia, permanently discontinue WELIREG [see Dosage and Administration (2.2) ] . Advise patients to report signs and symptoms of hypoxia immediately to a healthcare provider. von Hippel-Lindau (VHL) disease In LITESPARK-004, hypoxia occurred in 1.6% of patients [see Adverse Reactions (6.1) ] . Renal Cell Carcinoma with a Clear Cell Component (ccRCC) In LITESPARK-005, hypoxia occurred in 15% of patients and 10% had Grade 3 events [see Adverse Reactions (6.1) ] . 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-022, hypoxia occurred in 7% of patients and 5% had Grade 3 or higher events [see Adverse Reactions (6.1) ] . Of the patients with hypoxia, 47% were treated with oxygen therapy. Median time to onset of hypoxia was 93 days (range: 9 days to 11.7 months). Pheochromocytoma or Paraganglioma (PPGL) In LITESPARK-015, hypoxia occurred in 13% of patients and 10% had Grade 3 hypoxia [see Adverse Reactions (6.1) ] . 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. 5.3 Embryo-Fetal Toxicity Based on findings in animals, WELIREG can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of belzutifan to pregnant rats during the period of organogenesis caused embryo-fetal lethality, reduced fetal body weight, and fetal skeletal malformations at maternal exposures ≥0.2 times the human exposures (AUC) at the recommended dose of 120 mg daily. 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, since WELIREG can render some hormonal contraceptives ineffective [see Drug Interactions (7.1) ]. 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 [see Use in Specific Populations (8.1 , 8.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Anemia [see Warnings and Precautions (5.1) ] Hypoxia [see Warnings and Precautions (5.2) ] VHL disease : Most common (≥25%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. ( 6.1 ) ccRCC : Most common (≥25%) adverse reactions for WELIREG, including laboratory abnormalities, in combination with pembrolizumab were decreased hemoglobin, increased alanine aminotransferase (ALT), fatigue, increased aspartate aminotransferase (AST), decreased lymphocytes, and increased alkaline phosphatase. ( 6.1 ) Most common (≥25%) adverse reactions for WELIREG as monotherapy, including laboratory abnormalities were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased ALT, decreased sodium, increased potassium, and increased AST. ( 6.1 ) PPGL : Most common (≥25%) adverse reactions, including laboratory abnormalities were anemia, fatigue, musculoskeletal pain, decreased lymphocytes, increased ALT, increased AST, increased calcium, dyspnea, increased potassium, decreased leukocytes, headache, increased alkaline phosphatase, dizziness, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, 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. von Hippel-Lindau (VHL) disease LITESPARK-004 The safety of WELIREG was evaluated in an open-label clinical trial (LITESPARK-004) in 61 patients with VHL disease who had at least one measurable solid tumor localized to the kidney [see Clinical Studies (14.1) ] . Patients received WELIREG 120 mg orally once daily until disease progression or unacceptable toxicity. The median duration of exposure to WELIREG was 68 weeks (range: 8.4 to 104.7 weeks). Serious adverse reactions occurred in 15% of patients who received WELIREG, including anemia, hypoxia, anaphylaxis reaction, retinal detachment, and central retinal vein occlusion (1 patient each). Permanent discontinuation of WELIREG due to adverse reactions occurred in 3.3% of patients. Adverse reactions which resulted in permanent discontinuation of WELIREG were dizziness and opioid overdose (1.6% each). Dosage interruptions of WELIREG due to an adverse reaction occurred in 39% of patients. Adverse reactions which required dosage interruption in >2% of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache, and influenza-like illness. Dose reductions of WELIREG 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 (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Table 3 summarizes the adverse reactions reported in patients treated with WELIREG in LITESPARK-004. Table 3: Adverse Reactions Occurring in ≥10% of Patients Who Received WELIREG in LITESPARK-004 Adverse Reaction WELIREG (n=61) All Grades Graded per NCI CTCAE v4.0 (%) Grade 3-4 (%) General Fatigue Includes other related terms 64 5 Nervous system Headache 39 0 Dizziness 38 0 Gastrointestinal Nausea 31 0 Constipation 13 0 Abdominal pain 13 0 Eye Disorders Visual impairment Includes visual impairment, vision blurred, central retinal vein occlusion and retinal detachment 21 3.3 Infections Upper respiratory tract infection 21 0 Respiratory, Thoracic and Mediastinal Dyspnea 20 1.6 Musculoskeletal and Connective Tissue Arthralgia 18 0 Myalgia 16 0 Vascular Hypertension 13 3.3 Metabolism and Nutrition Weight increased 12 1.6 Table 4 summarizes the laboratory abnormalities in LITESPARK-004. Table 4: Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received WELIREG in LITESPARK-004 Laboratory Abnormality The denominator used to calculate the rate is based on all patients in the safety analysis population. WELIREG (n=61) Grades 1-4 % Grades 3-4 % Hematology Decreased hemoglobin 93 7 Decreased leukocytes 11 0 Chemistry Increased creatinine 64 0 Increased glucose 34 4.9 Increased ALT 20 0 Increased AST 16 0 Decreased calcium (corrected) 10 0 Decreased phosphate 10 1.6 Renal Cell Carcinoma with a Clear Cell Component (ccRCC) LITESPARK-022 The safety of WELIREG in combination with intravenous pembrolizumab versus placebo in combination with intravenous pembrolizumab was investigated in LITESPARK-022, a randomized, double-blind trial in 1,828 patients who had undergone nephrectomy for ccRCC [see Clinical Studies (14.2) ] . Patients received either WELIREG 120 mg orally once daily in combination with pembrolizumab 400 mg intravenously every 6 weeks (n=915), or oral placebo in combination with pembrolizumab 400 mg intravenously every 6 weeks (n=913) for up to 9 cycles (54 weeks) until disease recurrence or unacceptable toxicity. The median duration of exposure to WELIREG was 12.4 months (range 1 day to 20.1 months). Serious adverse reactions occurred in 30% of patients who received WELIREG in combination with pembrolizumab. Serious adverse reactions in ≥1% of patients included pneumonia (2%), hypoxia (1.9%), pneumonitis (1.6%), arrhythmia (1.5%), diarrhea (1.1%), and acute kidney injury (1.1%). Fatal adverse reactions occurred in 1.1% of patients who received WELIREG in combination with pembrolizumab, including sepsis (0.1%). Permanent discontinuation of WELIREG due to adverse reactions occurred in 27% of patients. Adverse reactions which resulted in permanent discontinuation of WELIREG in ≥1% of patients included anemia (4%), fatigue (2.2%), rash (2%), increased ALT (1.7%), hypoxia (1.6%), diarrhea (1.4%), pneumonitis (1.3%), increased AST (1.1%), and hepatic function abnormal (1%). Dosage interruptions of WELIREG due to an adverse reaction occurred in 52% of patients. Adverse reactions which required dosage interruption of WELIREG in ≥2% of patients included anemia (25%), fatigue (3.7%), increased ALT (3.5%), diarrhea (3.4%), increased AST (3.4%), COVID-19 (2.6%), hypoxia (2.5%), pyrexia (2.5%), musculoskeletal pain (2.1%), and rash (2.1%). Dose reductions of WELIREG due to an adverse reaction occurred in 34% of patients. Adverse reactions which required dose reduction in ≥3% of patients included anemia (17%), hypoxia (3.5%), increased ALT (3.2%), and fatigue (3.1%). The most common (≥25%) adverse reactions, including laboratory abnormalities, in patients who received WELIREG in combination with pembrolizumab were decreased hemoglobin, increased ALT, fatigue, increased AST, decreased lymphocytes, and increased alkaline phosphatase. Tables 5 and 6 summarize the adverse reactions and laboratory abnormalities, respectively, in LITESPARK-022. Table 5: Adverse Reactions (≥10%) in Patients with ccRCC Who Received WELIREG in Combination with Pembrolizumab [at a Higher Incidence (Between Arm Difference of ≥4%) Compared to Control] in LITESPARK-022 Adverse Reaction WELIREG plus Pembrolizumab (n=915) Placebo plus Pembrolizumab (n=913) All Grades Graded per NCI CTCAE v5.0 (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) General Fatigue Includes other related terms 49 3.1 33 0.7 Gastrointestinal Diarrhea 23 3 18 2.4 Nausea 16 0.3 12 0.2 Nervous system Dizziness 23 0.4 10 0.1 Headache 17 0.7 11 0.1 Respiratory, thoracic, and mediastinal Dyspnea 12 0.9 6 0.1 Clinically relevant adverse reactions in 20%) That Worsened from Baseline In Patients with ccRCC Who Received WELIREG in Combination With Pembrolizumab [at a Higher Incidence (Between Arm Difference of >10%) Compared to Control] in LITESPARK-022 Laboratory Test Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available: WELIREG + pembrolizumab (range: 907 to 911 patients), and placebo + pembrolizumab (range: 905 to 912 patients). WELIREG plus Pembrolizumab Placebo plus Pembrolizumab All Grades Graded per NCI CTCAE v5.0 % Grades 3-4 % All Grades % Grades 3-4 % Hematology Decreased hemoglobin 95 11 26 0.7 Decreased lymphocytes 38 9 25 7 Chemistry Increased ALT 57 13 33 3.2 Increased AST 46 8 29 3.1 Increased alkaline phosphatase 29 2.3 18 0.4 LITESPARK-005 The safety of WELIREG was evaluated in a randomized, active-controlled study (LITESPARK- 005) in 732 patients with advanced ccRCC that has progressed after prior PD-1 or PD-L1 checkpoint inhibitor and VEGF receptor targeted therapies [see Clinical Studies (14.2) ] . Patients received 120 mg WELIREG (n=372) or 10 mg everolimus (n=360) orally once daily until disease progression or unacceptable toxicity. The median duration of exposure to WELIREG was 7.6 months (range 0.1 to 28.5 months). Serious adverse reactions occurred in 38% of patients who received WELIREG. Serious adverse reactions in ≥2% of patients treated with WELIREG 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%). Permanent discontinuation of WELIREG due to adverse reactions occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation (≥0.5%) of WELIREG were hypoxia (1.1%), anemia (0.5%), and hemorrhage (0.5%). Dosage interruptions of WELIREG due to an adverse reaction occurred in 39% of 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 of WELIREG due to an adverse reaction occurred in 13% of patients. Adverse reactions which required dose reduction in ≥1% of patients were hypoxia (5%) and anemia (3.2%). The most common (≥25%) adverse reactions, including laboratory abnormalities, that occurred in patients who received WELIREG were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, and increased aspartate aminotransferase. Table 7 summarizes the adverse reactions in LITESPARK-005. Table 7: Adverse Reactions (≥10%) in Patients with Advanced RCC Receiving WELIREG in LITESPARK-005 Adverse Reaction WELIREG (n=372) Everolimus (n=360) All Grades Graded per NCI CTCAE v5.0 (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) General Fatigue Includes other related terms 43 3.2 41 6 Edema 20 0.5 23 0.6 Musculoskeletal and Connective Tissue Musculoskeletal Pain 34 1.1 27 2.2 Gastrointestinal Nausea 17 0.5 11 0.3 Constipation 15 0 8 0 Vomiting 11 0.8 8 0.8 Diarrhea 11 1.3 19 1.4 Abdominal Pain 10 0.8 8 0.3 Respiratory, Thoracic, and Mediastinal Dyspnea 16 1.6 16 2.5 Hypoxia 15 10 1.4 1.4 Metabolism and Nutrition Decreased Appetite 13 1.1 16 0 Nervous Systems Headache 12 0.5 8 0.3 Dizziness 11 0 1.9 0 Clinically relevant adverse reactions in 3% of patients were hypoxia, nausea and fatigue (4.2% each). Dose reductions of WELIREG 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 who received WELIREG were anemia, fatigue, musculoskeletal pain, decreased lymphocytes, increased alanine aminotransferase, increased aspartate aminotransferase, increased calcium, dyspnea, increased potassium, decreased leukocytes, headache, increased alkaline phosphatase, dizziness, and nausea. Table 9 summarizes the adverse reactions reported in patients treated with WELIREG in LITESPARK-015. Table 9: Adverse Reactions Occurring in ≥10% of Patients with PPGL Who Received WELIREG in LITESPARK-015 Adverse Reaction WELIREG (n=72) All Grades Graded per NCI CTCAE v5.0 (%) Grade 3-4 (%) Blood and Lymphatic Anemia 96 22 General Fatigue Includes other related terms 56 10 Edema 24 0 Musculoskeletal and Connective Tissue Musculoskeletal pain 56 6 Muscle spasms 13 0 Muscle weakness 13 2.8 Respiratory, Thoracic, and Mediastinal Dyspnea 33 1.4 Cough 15 0 Hypoxia 13 10 Nasal congestion 10 0 Nervous System Headache 29 1.4 Dizziness 26 2.8 Peripheral neuropathy 13 0 Gastrointestinal Nausea 25 1.4 Constipation 24 1.4 Diarrhea 15 0 Abdominal Pain 13 1.4 Vomiting 10 1.4 Vascular Disorders Hypertension 21 13 Hypotension 10 2.8 Hemorrhage 10 2.8 Infections COVID-19 17 2.8 Metabolism and Nutrition Disorders Decreased appetite 14 2.8 Investigations Weight increased 13 7 Cardiac Disorders Arrhythmia 11 2.8 Palpitations 10 0 Table 10 summarizes the laboratory abnormalities in LITESPARK-015. Table 10: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with PPGL Who Received WELIREG in LITESPARK-015 Laboratory Abnormality WELIREG (n=72) All Grades % Grades 3 or 4 % Hematology Decreased hemoglobin 90 21 Decreased lymphocytes 54 14 Decreased leukocytes 30 0 Decreased neutrophils 24 1.4 Decreased platelets 21 1.4 Chemistry Increased ALT 51 4.2 Increased AST 42 4.2 Increased calcium 34 0 Increased potassium 31 2.8 Increased alkaline phosphatase 25 0 Increased creatinine 24 1.4 Decreased sodium 21 0

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) Infertility : May impair fertility in males and females. ( 8.3 ) 8.1 Pregnancy Risk Summary Based on findings in animal studies, WELIREG can cause fetal harm when administered to a pregnant woman. There are no available data on the use of WELIREG in pregnant women to inform the drug-associated risk. In an animal reproduction study, oral administration of belzutifan to pregnant rats during the period of organogenesis caused embryo-fetal lethality, reduced fetal body weight, and fetal skeletal malformations at maternal exposures ≥0.2 times the human exposure (AUC) at the recommended dose of 120 mg daily ( see Data ). Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data In a pilot embryo-fetal development study, pregnant rats received oral doses of 6, 60, or 200 mg/kg/day of belzutifan during the period of organogenesis. Belzutifan caused embryo-fetal lethality at doses ≥60 mg/kg/day (approximately 1 time the human exposure at the recommended dose based on AUC). Reduced fetal body weights, fetal rib malformations, and reduced skeletal ossification occurred at doses of 6 and 60 mg/kg/day (approximately ≥0.2 times the human exposure at the recommended dose based on AUC). 8.2 Lactation Risk Summary There are no data on the presence of belzutifan or its metabolites in human milk or their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with WELIREG and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential WELIREG can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with WELIREG. Contraception Females 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 [see Drug Interactions (7.2) ] . Males Advise males with female partners of reproductive potential to use effective contraception during treatment with WELIREG and for 1 week after the last dose. Infertility Based on findings in animals, WELIREG may impair fertility in males and females of reproductive potential [see Nonclinical Toxicology (13.1) ] . The reversibility of the effect on fertility is unknown. 8.4 Pediatric Use The safety and effectiveness of WELIREG have been established in pediatric patients aged 12 years and older for the treatment of locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma. Use of WELIREG in pediatric patients aged 12 years and older 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 [see Clinical Pharmacology (12.3) , and Clinical Studies (14.3) ] . 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. 8.5 Geriatric Use Of the 61 patients who received WELIREG for VHL in LITESPARK-004, 3.3% were ≥65 years old [see Clinical Studies (14.1) ] Clinical trials of WELIREG in patients with VHL did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Of the 915 patients who received WELIREG in combination with pembrolizumab for ccRCC in LITESPARK-022, 30% were ≥65 years old and 5% were ≥75 years old. No overall differences in efficacy or safety were reported between patients who were ≥65 years of age and younger patients. Dose interruptions of WELIREG occurred in 57% of patients ≥65 years of age and in 49% of younger patients. Dose reductions of WELIREG occurred in 39% of patients ≥65 years of age and in 32% of younger patients. Of the 372 patients who received WELIREG for advanced ccRCC in LITESPARK-005, 62% of patients were younger than 65 years, 28% of patients were 65 to 74 years, and 10% were 75 years and over. No overall difference in efficacy was reported between patients who were ≥65 years of age and younger patients. Dose interruptions occurred in 48% of patients ≥65 years of age and in 34% of younger patients. Dose reductions occurred in 18% of patients ≥65 years of age and in 10% of younger patients. Of the 72 patients who received WELIREG for PPGL in LITESPARK-015, 13% were ≥65 years old and 4.2% were ≥75 years old [see Clinical Studies (14.3) ]. Clinical trials of WELIREG in patients with PPGL did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 8.6 Renal Impairment No dosage modification of WELIREG is recommended in patients with renal impairment including end-stage renal disease. 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 [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ]. 8.7 Hepatic Impairment No dosage modification of WELIREG is recommended in patients with mild [total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin >1 to 1.5 x ULN and any AST] or moderate (total bilirubin within range of >1.5 x ULN and ≤ 3 x ULN and any AST or Child-Pugh B) hepatic impairment. WELIREG has not been studied in patients with severe hepatic impairment (total bilirubin >3 x ULN and any AST). For patients with moderate and severe hepatic impairment, monitor for increased adverse reactions and modify the dosage as recommended [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ] . 8.8 Dual UGT2B17 and CYP2C19 Poor Metabolizers Patients who are dual UGT2B17 and CYP2C19 poor metabolizers have higher belzutifan exposures, which may increase the risk of adverse reactions of WELIREG. Monitor for increased adverse reactions in patients who are dual UGT2B17 and CYP2C19 poor metabolizers [see Warnings and Precautions (5) , Adverse Reactions (6) , Clinical Pharmacology (12.5) ] .