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).

2 DOSAGE AND ADMINISTRATION The recommended dosage of WELIREG in adult patients is 120 mg administered orally once daily with or without food. ( 2.1 ) The recommended dosage of WELIREG in pediatric patients 12 years and older is based on bodyweight: Patients weighing ≥ 40 kg: 120 mg orally once daily Patients weighing < 40 kg: 80 mg orally once daily 2.1 Recommended Dosage The recommended dosage of WELIREG in adult patients is 120 mg administered orally once daily. The recommended dosage of WELIREG in pediatric patients 12 years and older is based on bodyweight: Patients weighing ≥ 40 kg: 120 mg orally once daily Patients weighing < 40 kg: 80 mg orally once daily Continue WELIREG until disease progression or unacceptable toxicity. 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. 2.2 Dosage Modifications for Adverse Reactions Dosage modifications for WELIREG for adverse reactions are summarized in Table 1 . The recommended dose reductions are: First dose reduction: WELIREG 80 mg orally once daily Second dose reduction: WELIREG 40 mg orally once daily Third dose reduction: Permanently discontinue Table 1: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Anemia [see Warnings and Precautions (5.1) ] Hemoglobin <8 g/dL or transfusion indicated Withhold until hemoglobin ≥8g/dL. Resume at the same or reduced dose; or discontinue depending on the severity of anemia. Life-threatening or urgent intervention indicated Withhold until hemoglobin ≥8g/dL. Resume at a reduced dose or permanently discontinue. Hypoxia [see Warnings and Precautions (5.2) ] Decreased oxygen saturation with exercise (e.g., pulse oximeter <88%) Consider withholding until resolved. Resume at the same dose or at a reduced dose depending on the severity of hypoxia. Decreased oxygen saturation at rest (e.g., pulse oximeter <88% or PaO 2 ≤55 mm Hg) or urgent intervention indicated Withhold until resolved. Resume at reduced dose or discontinue depending on the severity of hypoxia. Life-threatening or recurrent symptomatic hypoxia Permanently discontinue. Other Adverse Reactions [see Adverse Reactions (6) ] Grade 3 Withhold dosing until resolved to ≤ Grade 2. Consider resuming at a reduced dose (reduce by 40 mg). Permanently discontinue upon recurrence of Grade 3. Grade 4 Permanently discontinue.

5 WARNINGS AND PRECAUTIONS Anemia : Monitor for anemia before initiation of and periodically throughout treatment with WELIREG. Withhold WELIREG until hemoglobin ≥8g/dL, then resume at the same or reduced dose or discontinue. For life threatening anemia, or for anemia requiring urgent intervention, withhold WELIREG until hemoglobin ≥8g/dL and resume at a reduced dose or permanently discontinue WELIREG. ( 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. For patients with hemoglobin <8g/dL, withhold WELIREG until ≥8g/dL, then resume at the same or reduced dose or permanently discontinue WELIREG, depending on the severity of anemia. For life threatening anemia or when urgent intervention is indicated, withhold WELIREG until hemoglobin ≥8g/dL, then resume at a reduced dose or permanently discontinue WELIREG [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. Advanced Renal Cell Carcinoma (RCC) 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. 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) ] . Advanced Renal Cell Carcinoma (RCC) 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% w…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS UGT2B17 or CYP2C19 Inhibitors: Monitor for signs and symptoms of anemia and hypoxia and reduce the dosage of WELIREG as recommended. ( 2.2 , 7.1 ) 7.1 Effects of Other Drugs on WELIREG UGT2B17 or CYP2C19 Inhibitors Monitor for anemia and hypoxia and reduce the dosage of WELIREG as recommended [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.2) , Adverse Reactions (6) ] . Coadministration of WELIREG with inhibitors of UGT2B17 or CYP2C19 increases belzutifan exposure [see Clinical Pharmacology (12.3 , 12.5) ] , which may increase the risk of adverse reactions of WELIREG. 7.2 Effect of WELIREG on Other Drugs CYP3A4 Substrates Avoid coadministration of WELIREG with sensitive CYP3A4 substrates, for which minimal decrease in concentration may lead to therapeutic failures of the substrate. If coadministration cannot be avoided, increase the sensitive CYP3A4 substrate dosage in accordance with its Prescribing Information. Coadministration of WELIREG with CYP3A4 substrates decreases concentrations of CYP3A substrates [see Clinical Pharmacology (12.3) ] , which may reduce the efficacy of these substrates. The magnitude of this decrease may be more pronounced in patients who are dual UGT2B17 and CYP2C19 poor metabolizers [see Clinical Pharmacology (12.3) ]. Hormonal Contraceptives Coadministration of WELIREG with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding [see Clinical Pharmacology (12.3) , Use in Specific Populations (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).

12.5 Pharmacogenomics Patients who are UGT2B17, CYP2C19, or dual UGT2B17 and CYP2C19 poor metabolizers are estimated to have 2.5-, 1.3-, or 3.2-fold higher belzutifan steady state AUC 0-24h , respectively compared to patients who are UGT2B17 normal (extensive) metabolizers and CYP2C19 non-poor (ultrarapid, rapid, normal, and intermediate) metabolizers [see Use in Specific Populations (8.8) ]. UGT2B17 poor metabolizers who are homozygous for the UGT2B17*2 allele have no UGT2B17 enzyme activity. CYP2C19 poor metabolizers (such as *2/*2, *3/*3, *2/*3) have significantly reduced or absent CYP2C19 enzyme activity. Approximately 15% of White, 6% of Black or African American, and up to 77% of certain Asian populations are UGT2B17 poor metabolizers. Approximately 2% of White, 5% of Black or African American, and up to 19% of certain Asian populations are CYP2C19 poor metabolizers. Approximately 0.4% of White, 0.3% of Black or African American, and up to 15% of certain Asian populations are dual UGT2B17 and CYP2C19 poor metabolizers.

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 Abnormali…