Side Effects Overview
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
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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% were treated with oxygen therapy. Median time to onset of hypoxia was 30.5 days (range: 1 day to 21.1 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) ] .
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12.3 Pharmacokinetics The C max and AUC of belzutifan increase proportionally over a dose range of 20 mg to 120 mg (0.17 to 1 times the approved recommended dose). The estimated geometric mean steady-state (CV%) C max is 1.5 μg/mL (45%) and AUC 0-24h is 20 μg•hr/mL (62%) . Steady state is reached after approximately 3 days. Absorption The median T max occurs at 1 to 2 hours after WELIREG administration. Effect of Food A high-fat, high-calorie meal (total calories approximately 1000 kcal, 56 g fat, 55 g carbohydrate, and 31 g protein) delayed T max by approximately 2 hours with no clinically significant effect on C max and AUC of belzutifan. Distribution The estimated mean (CV%) volume of distribution is 119 L (28%) Plasma protein binding of belzutifan is 45%. The blood-to-plasma concentration ratio of belzutifan is 0.88. Elimination The estimated mean (CV%) clearance is 6 L/hr (58%) and the mean elimination half-life is 14 hrs. Metabolism Belzutifan is primarily metabolized by UGT2B17 and CYP2C19 and to a lesser extent by CYP3A4 [see Clinical Pharmacology (12.5) ] . Excretion Following a single oral dose of radiolabeled belzutifan , approximately 49.6% of the dose was excreted in urine and 51.7% in feces (primarily as inactive metabolites). Specific Populations Patients who are poor metabolizers of UGT2B17 and CYP2C19 had higher belzutifan AUC [see Clinical Pharmacology (12.5) ] . No clinically significant differences in the pharmacokinetics of belzutifan were observed based on age (15 to 90 years), sex, ethnicity (non-Hispanic, Hispanic), race (White (76%), Black (5%), Asian (15%), Native American, Pacific Islander), or body weight (40 to 166 kg). Pediatric patients The exposure of belzutifan in pediatric patients 12 years and older is predicted to be within range of that observed in adults at the recommended dosage. Patients with Renal Impairment No clinically significant differences in the mean belzutifan exposure were observed between subjects with normal renal function and those with mild (eGFR 60-89 mL/min) or moderate renal impairment (GFR 30-59 mL/min) and those with end-stage renal disease (eGFR <15 mL/min) requiring dialysis. Patients with Hepatic Impairment No clinically significant differences in the mean belzutifan exposure were observed between subjects with normal liver function (total bilirubin and AST ≤ ULN), and those with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin >1 to 1.5 x ULN and any AST). Belzutifan exposure (AUC) increased by 1.5-fold in patients with moderate hepatic impairment (Child-Pugh B) compared to subjects with normal hepatic function. Patients with severe hepatic impairment have not been studied. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Effect of Belzutifan on CYP3A Substrates: Coadministration of WELIREG 120 mg once daily with midazolam (a sensitive CYP3A4 substrate) decreased the midazolam AUC by 40% and the C max by 34%. Midazolam AUC is predicted to decrease up to 70% in patients with higher belzutifan concentrations (e.g., dual poor metabolizers) [see Clinical Pharmacology (12.5) ] . In Vitro Studies Cytochrome P450 (CYP) Enzymes: Belzutifan does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Belzutifan does not induce CYP1A2 or CYP2B6. Transporter Systems: Belzutifan is a substrate of P-gp, OATP1B1, and OATP1B3, but is not a substrate of BCRP. Belzutifan inhibits MATE2K. Belzutifan does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or MATE1.