WELIREG

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 ) Advanced Renal Cell Carcinoma (RCC) for treatment of adult patients with advanced renal cell carcinoma (RCC) with a clear cell component 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 Advanced Renal Cell Carcinoma (RCC) WELIREG is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) with a clear cell component 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).

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 ) Advanced RCC : Most common (≥25%) adverse reactions, including laboratory abnormalities were decreased hemoglobin, fatigue, musculoskeletal pain, increased creatinine, decreased lymphocytes, increased alanine aminotransferase, decreased sodium, increased potassium, and increased aspartate aminotransferase. ( 6.1 ) PPGL : Most common (≥25%) adverse reactions, including laboratory abnormalities 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. ( 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 2 summarizes the adverse reactions reported in patients treated with WELIREG in LITESPARK-004. Table 2: 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 3 summarizes the laboratory abnormalities in LITESPARK-004. Table 3: 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 Advanced Renal Cell Carcinoma (RCC) LITESPARK-005 The safety of WELIREG was evaluated in a randomized, active-controlled study (LITESPARK- 005) in 732 patients with advanced RCC with a clear cell component 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 4 summarizes the adverse reactions in LITESPARK-005. Table 4: 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 <10% of patients who received WELIREG in LITESPARK-005 included hemorrhage (9%) [including intracranial/cerebral hemorrhage (0.8%)], rash (8%), hypertension (6%), visual impairment [including vision blurred (4%), visual acuity decreased (1.1%), visual impairment (0.5%), and retinal detachment (0.3%)] (6%) and increased weight (5%). Table 5 summarizes the laboratory abnormalities in LITESPARK-005. Table 5: Select Laboratory Abnormalities (≥20%) That Worsened from Baseline In Patients with Advanced RCC who Received WELIREG in LITESPARK-005 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 (range: 359 to 366 patients), and everolimus (range: 351 to 356 patients). WELIREG Everolimus All Grades Graded per NCI CTCAE v5.0 % Grades 3-4 % All Grades % Grades 3-4 % Hematology Decreased hemoglobin 88 29 76 17 Decreased lymphocytes 34 8 53 20 Chemistry Increased creatinine 34 4.7 43 5.1 Increased alanine aminotransferase 32 2.2 40 1.1 Decreased sodium 31 1.6 36 0.8 Increased potassium 29 2.5 20 2.8 Increased aspartate aminotransferase 27 2.2 38 2 Decreased glucose 22 1.1 19 1.1 Decreased calcium 21 1.1 45 3.1 Pheochromocytoma or Paraganglioma LITESPARK-015 The safety of WELIREG was evaluated in an open-label clinical trial (LITESPARK-015) in 72 patients with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL) [see Clinical Studies (14.3) ] . Patients received WELIREG 120 mg orally once daily until disease progression or unacceptable toxicity. The median duration of exposure to WELIREG was 20 months (range: 0.3 to 32.5 months). Serious adverse reactions occurred in 36% of patients who received WELIREG. Serious adverse reactions occurring in ≥2% of patients treated with WELIREG were anemia and hypertension (4.2% each) and pyelonephritis, pneumonia, hypoxia, dyspnea and hemorrhage (2.8% each). Permanent discontinuation of WELIREG due to adverse reactions occurred in 2 patients (2.8%). Adverse reactions which resulted in permanent discontinuation of WELIREG were increased alanine aminotransferase and paraparesis (1.4% each). Dosage interruptions of WELIREG due to an adverse reaction occurred in 40% of patients. Adverse reactions which required dosage interruption 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 6 summarizes the adverse reactions reported in patients treated with WELIREG in LITESPARK-015. Table 6: 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 7 summarizes the laboratory abnormalities in LITESPARK-015. Table 7: 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