Sunitinib Malate

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. • Hepatotoxicity [see Warnings and Precautions (5.1) ] • Cardiovascular Events [see Warnings and Precautions (5.2) ] • QT Interval Prolongation and Torsade de Pointes [see Warnings and Precautions (5.3) ] • Hypertension [see Warnings and Precautions (5.4) ] • Hemorrhagic Events [see Warnings and Precautions (5.5) ] • Tumor Lysis Syndrome [see Warnings and Precautions (5.6) ] • Thrombotic Microangiopathy [see Warnings and Precautions (5.7) ] • Proteinuria [see Warnings and Precautions (5.8) ] • Dermatologic Toxicities [see Warnings and Precautions (5.9) ] • Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10) ] • Thyroid Dysfunction [see Warnings and Precautions (5.11) ] • Hypoglycemia [see Warnings and Precautions (5.12) ] • Osteonecrosis of the Jaw [see Warnings and Precautions (5.13) ] • Impaired Wound Healing [see Warnings and Precautions (5.14) ] • The most common adverse reactions (≥ 25%) are fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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. The pooled safety population described in the Warnings and Precautions reflect exposure to sunitinib malate in 7527 patients with GIST, RCC (advanced and adjuvant), or pNET . In this pooled safety population, the most common adverse reactions (≥ 25%) were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia. Gastrointestinal Stromal Tumor The safety of sunitinib malate capsules was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received sunitinib malate capsules 50 mg daily on Schedule 4/2 (n = 202) or placebo (n = 102). Median duration of blinded study treatment was 2 cycles for patients on sunitinib malate capsules (mean: 3.0; range: 1-9) and 1 cycle (mean; 1.8; range: 1-6) for patients on placebo at the time of the interim analysis. Permanent discontinuation due to an adverse reaction occurred in 7% of patients in the sunitinib malate capsules arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received sunitinib malate capsules. Table 3 summarizes the adverse reactions for Study 1. Table 3. Adverse Reactions Reported in ≥ 10% of GIST Patients Who Received Sunitinib Malate Capsules in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 1 Abbreviations: GIST = gastrointestinal stromal tumor; N = number of patients. Adverse Reaction GIST Sunitinib Malate Capsules (N = 202) Placebo (N = 102) All Grades % Grade 3-4% All Grades % Grade 3-4% Any Adverse Reaction 94 56 97 51 Gastrointestinal Diarrhea 40 4 27 0 Mucositis/stomatitis 29 1 18 2 Constipation 20 0 14 2 Metabolism/Nutrition Anorexia Includes decreased appetite. 33 1 29 5 Asthenia 22 5 11 3 Dermatology Skin discoloration 30 0 23 0 Rash 14 1 9 0 Hand-foot syndrome 14 4 10 3 Neurology Altered taste 21 0 12 0 Cardiac Hypertension 15 4 11 0 Musculoskeletal Myalgia/limb pain 14 1 9 1 Other clinically relevant adverse reactions included oral pain other than mucositis/stomatitis in 6%; hair color changes in 7%; alopecia in 5% of patients who received sunitinib malate capsules. Table 4 summarizes the laboratory abnormalities in Study 1. Table 4. Laboratory Abnormalities Reported in ≥ 10% of GIST Patients Who Received Sunitinib Malate Capsules or Placebo in the Double-Blind Treatment Phase Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 1 Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GIST = gastrointestinal stromal tumor; LVEF = left ventricular ejection fraction; N = number of patients. Laboratory Abnormality GIST Sunitinib Malate Capsules (N = 202) Placebo (N = 102) All Grades % Grade 3-4 , Grade 4 laboratory abnormalities in patients on sunitinib malate capsules included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%). % All Grades % Grade 3-4 , Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%). % Any Laboratory Abnormality 34 22 Hematology Neutrophils decreased 53 10 4 0 Lymphocytes decreased 38 0 16 0 Platelets decreased 38 5 4 0 Hemoglobin decreased 26 3 22 2 Gastrointestinal AST/ALT increased 39 2 23 1 Lipase increased 25 10 17 7 Alkaline phosphatase increased 24 4 21 4 Amylase increased 17 5 12 3 Total bilirubin increased 16 1 8 0 Indirect bilirubin increased 10 0 4 0 Renal/Metabolic Creatinine increased 12 1 7 0 Potassium decreased 12 1 4 0 Sodium increased 10 0 4 1 Cardiac Decreased LVEF 11 1 3 0 After an interim analysis , the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label sunitinib malate capsules [see Clinical Studies (14.1) ] . For 241 patients randomized to the sunitinib malate capsules arm, including 139 who received sunitinib malate capsules in both the double-blind and open-label phases, the median duration of sunitinib malate capsules treatment was 6 cycles (mean: 8.5; range: 1–44). For the 255 patients who ultimately received open-label sunitinib malate capsules treatment, median duration of treatment was 6 cycles (mean: 7.8; range: 1–37) from the time of the unblinding. Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received sunitinib malate capsules. Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received sunitinib malate capsules. The most common Grade 3 or 4 adverse reactions in patients who received sunitinib malate capsules in the open-label phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%). Advanced Renal Cell Carcinoma The safety of sunitinib malate capsules was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received sunitinib malate capsules 50 mg daily on Schedule 4/2 (n = 375) or interferon alfa 9 million International Units (MIU) (n = 360). The median duration of treatment was 11.1 months (range: 0.4 to 46.1) for sunitinib malate capsules treatment and 4.1 months (range: 0.1 to 45.6) for interferon alfa treatment. Permanent discontinuation due to an adverse reaction occurred in 20% of patients in the sunitinib malate capsules arm. Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received sunitinib malate capsules. Table 5 summarizes the adverse reactions for Study 3. Table 5. Adverse Reactions Reported in ≥ 10% of Patients With RCC Who Received Sunitinib Malate Capsules or Interferon Alfa Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 3 Abbreviations: ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma. Adverse Reaction Treatment-Naïve RCC Sunitinib Malate Capsules (N = 375) Interferon Alfa (N = 360) All Grades % Grade 3-4 Grade 4 ARs in patients on sunitinib malate capsules included back pain (1%), arthralgia (< 1%), dyspnea (< 1%), asthenia (< 1%), fatigue (< 1%), limb pain (< 1%), and rash (< 1%). % All Grades % Grade 3-4 Grade 4 ARs in patients on interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (< 1%), and depression (< 1%). % Any Adverse Reaction 99 77 99 55 Gastrointestinal Diarrhea 66 10 21 < 1 Nausea 58 6 41 2 Mucositis/stomatitis 47 3 5 < 1 Vomiting 39 5 17 1 Dyspepsia 34 2 4 0 Abdominal pain Includes flank pain. 30 5 12 1 Constipation 23 1 14 < 1 Dry mouth 13 0 7 < 1 Oral pain 14 < 1 1 0 Flatulence 14 0 2 0 GERD/reflux esophagitis 12 < 1 1 0 Glossodynia 11 0 1 0 Hemorrhoids 10 0 2 0 Constitutional Fatigue 62 15 56 15 Asthenia 26 11 22 6 Fever 22 1 37 < 1 Weight decreased 16 < 1 17 1 Chills 14 1 31 0 Chest Pain 13 2 7 1 Influenza like illness 5 0 15 < 1 Metabolism/Nutrition Anorexia Includes decreased appetite. 48 3 42 2 Neurology Altered taste Includes ageusia, hypogeusia, and dysgeusia. 47 < 1 15 0 Headache 23 1 19 0 Dizziness 11 < 1 14 1 Hemorrhage/Bleeding Bleeding, all sites 37 4 Includes 1 patient with Grade 5 gastric hemorrhage. 10 1 Cardiac Hypertension 34 13 4 < 1 Edema peripheral 24 2 5 1 Ejection fraction decreased 16 3 5 2 Dermatology Rash 29 2 11 < 1 Hand-foot syndrome 29 8 1 0 Skin discoloration/yellow skin 25 < 1 0 0 Dry skin 23 < 1 7 0 Hair color changes 20 0 < 1 0 Alopecia 14 0 9 0 Erythema 12 < 1 1 0 Pruritus 12 < 1 7 < 1 Musculoskeletal Pain in extremity/limb discomfort 40 5 30 2 Arthralgia 30 3 19 1 Back pain 28 5 14 2 Respiratory Cough 27 1 14 < 1 Dyspnea 26 6 20 4 Nasopharyngitis 14 0 2 0 Oropharyngeal pain 14 < 1 2 0 Upper respiratory tract infection 11 < 1 2 0 Endocrine Hypothyroidism 16 2 1 0 Psychiatric Insomnia 15 < 1 10 0 Depression Includes depressed mood. 11 0 14 1 Table 6 summarizes the laboratory abnormalities in Study 3. Table 6. Laboratory Abnormalities Reported in ≥ 10% of RCC Patients Who Received Sunitinib Malate Capsules or Interferon Alfa in Study 3 Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; RCC = renal cell carcinoma. Laboratory Abnormality Treatment-Naïve RCC Sunitinib Malate Capsules (N = 375) Interferon Alfa (N = 360) All Grades Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. % Grade 3/4 , Grade 4 laboratory abnormalities in patients on sunitinib malate capsules included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (< 1%), creatine kinase (< 1%), creatinine (< 1%), glucose increased (< 1%), calcium decreased (< 1%), phosphorous (< 1%), potassium increased (< 1%), and sodium decreased (< 1%). % All Grades % Grade 3/4 , Grade 4 laboratory abnormalities in patients on interferon alfa included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (< 1%), calcium increased (< 1%), glucose decreased (< 1%), potassium increased (< 1%), and hemoglobin (< 1%). % Hematology Hemoglobin decreased 79 8 69 5 Neutrophils decreased 77 17 49 9 Platelets decreased 68 9 24 1 Lymphocytes decreased 68 18 68 26 Renal/Metabolic Creatinine increased 70 < 1 51 < 1 Creatine kinase increased 49 2 11 1 Uric acid increased 46 14 33 8 Calcium decreased 42 1 40 1 Phosphorus decreased 31 6 24 6 Albumin decreased 28 1 20 0 Glucose increased 23 6 15 6 Sodium decreased 20 8 15 4 Glucose decreased 17 0 12 < 1 Potassium increased 16 3 17 4 Calcium increased 13 < 1 10 1 Potassium decreased 13 1 2 < 1 Sodium increased 13 0 10 0 Gastrointestinal AST increased 56 2 38 2 Lipase increased 56 18 46 8 ALT increased 51 3 40 2 Alkaline phosphatase increased 46 2 37 2 Amylase increased 35 6 32 3 Total bilirubin increased 20 1 2 0 Indirect bilirubin increased 13 1 1 0 Long-Term Safety in RCC The long-term safety of sunitinib malate capsules in patients with metastatic RCC was analyzed across 9 completed clinical studies conducted in the first-line, bevacizumab-refractory, and cytokine-refractory treatment settings. The analysis included 5739 patients, of whom 807 (14%) were treated for at least 2 years and 365 (6%) for at least 3 years. Prolonged treatment with sunitinib malate capsules did not appear to be associated with new types of adverse reactions. There appeared to be no increase in the yearly incidence of adverse reactions at later time points. Hypothyroidism increased during the second year of treatment with new cases reported up to year 4. Adjuvant Treatment of RCC The safety of sunitinib malate capsules was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who had undergone nephrectomy for RCC received sunitinib malate capsules 50 mg daily on Schedule 4/2 (n = 306) or placebo (n = 304). The median duration of treatment was 12.4 months (range: 0.13 to 14.9) for sunitinib malate capsules and 12.4 months (range: 0.03 to 13.7) for placebo. Permanent discontinuation due to an adverse reaction occurred in 28% of patients in the sunitinib malate capsules arm. Adverse reactions leading to permanent discontinuation in > 2% of patients include hand-foot syndrome and fatigue/asthenia. Dosing interruptions occurred in 54% and dose reductions occurred in 46% of patients who received sunitinib malate capsules. Table 7 summarizes the adverse reactions in S-TRAC. Table 7. Adverse Reactions Reported in ≥ 10% of Patients With RCC Who Received Sunitinib Malate Capsules and More Commonly Than in Patients Given Placebo Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in S-TRAC Abbreviations: ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma. Adverse Reaction Adjuvant Treatment of RCC Sunitinib Malate Capsules (N = 306) Placebo (N = 304) All Grades % Grade 3-4 % All Grades % Grade 3-4 % Any Adverse Reaction 99 60 88 15 Gastrointestinal Mucositis/Stomatitis Includes mucosal inflammation, stomatitis aphthous ulcer, mouth ulceration, tongue ulceration, oropharyngeal pain, and oral pain. 61 6 15 0 Diarrhea 57 4 22 < 1 Nausea 34 2 15 0 Dyspepsia 27 1 7 0 Abdominal pain Includes abdominal pain, abdominal pain lower, and abdominal pain upper. 25 2 9 < 1 Vomiting 19 2 7 0 Constipation 12 0 11 0 Constitutional Fatigue/Asthenia 57 8 34 2 Localized edema Includes edema localized, face edema, eyelid edema, periorbital edema, swelling face, and eye edema. 18 < 1 < 1 0 Pyrexia 12 < 1 6 0 Dermatology Hand-foot syndrome 50 16 10 < 1 Rash Includes dermatitis, dermatitis psoriasiform, exfoliative rash, genital rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic. 24 2 12 0 Hair color changes 22 0 2 0 Skin discoloration/ Yellow skin 18 0 1 0 Dry skin 14 0 6 0 Cardiac Hypertension Includes hypertension, blood pressure increased, blood pressure systolic increased, blood pressure diastolic increased, and hypertensive crisis. 39 8 14 1 Edema/Peripheral edema 10 < 1 7 0 Neurology Altered taste Includes ageusia, hypogeusia, and dysgeusia. 38 < 1 6 0 Headache 19 < 1 12 0 Endocrine Hypothyroidism/TSH increased 24 < 1 4 0 Hemorrhage/Bleeding Bleeding events, all sites Includes epistaxis, gingival bleeding, rectal hemorrhage, hemoptysis, anal hemorrhage, upper gastrointestinal hemorrhage, and hematuria. 24 < 1 5 < 1 Metabolism/Nutrition Anorexia/Decreased appetite 19 < 1 5 0 Musculoskeletal Pain in extremity 15 < 1 7 0 Arthralgia 11 < 1 10 0 Grade 4 adverse reactions in patients on sunitinib malate capsules included hand-foot syndrome (1%), fatigue (< 1%), abdominal pain (< 1%), stomatitis (< 1%), and pyrexia (< 1%). Grade 3-4 laboratory abnormalities that occurred in ≥ 2% of patients receiving sunitinib malate capsules include neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%). Advanced Pancreatic Neuroendocrine Tumors The safety of sunitinib malate capsules was evaluated in Study 6, a randomized, double-blind, placebo-controlled trial in which patients with progressive pNET received sunitinib malate capsules 37.5 mg once daily (n = 83) or placebo (n = 82). The median number of days on treatment was 139 days (range: 13-532 days) for patients on sunitinib malate capsules and 113 days (range: 1-614 days) for patients on placebo. Nineteen patients (23%) on sunitinib malate capsules and 4 patients (5%) on placebo were on study for > 1 year. Permanent discontinuation due to an adverse reaction occurred in 22% in the sunitinib malate capsules arm. Dose interruptions occurred in 30% and dose reductions occurred in 31% of patients who received sunitinib malate capsules. Table 8 summarizes the adverse reactions in Study 6. Table 8. Adverse Reactions Reported in ≥ 10% of Patients With pNET Who Received Sunitinib Malate Capsules and More Commonly Than in Patients Given Placebo Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 6 Abbreviations: N = number of patients; pNET = pancreatic neuroendocrine tumors. Adverse Reaction pNET Sunitinib Malate Capsules (N = 83) Placebo (N = 82) All Grades % Grade 3-4 Grade 4 adverse reactions in patients on sunitinib malate capsules included fatigue (1%). % All Grades % Grade 3-4 % Any Adverse Reaction 99 54 95 50 Gastrointestinal Diarrhea 59 5 39 2 Stomatitis/oral syndromes Includes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth. 48 6 18 0 Nausea 45 1 29 1 Abdominal pain Includes abdominal discomfort, abdominal pain, and abdominal pain upper. 39 5 34 10 Vomiting 34 0 31 2 Dyspepsia 15 0 6 0 Constitutional Asthenia 34 5 27 4 Fatigue 33 5 27 9 Weight decreased 16 1 11 0 Dermatology Hair color changes 29 1 1 0 Hand-foot syndrome 23 6 2 0 Rash 18 0 5 0 Dry skin 15 0 11 0 Cardiac Hypertension 27 10 5 1 Hemorrhage/Bleeding Bleeding events Includes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia. 22 0 10 4 Epistaxis 21 1 5 0 Neurology Dysgeusia 21 0 5 0 Headache 18 0 13 1 Psychiatric Insomnia 18 0 12 0 Musculoskeletal Arthralgia 15 0 6 0 Table 9 summarizes the laboratory abnormalities in Study 6. Table 9. Laboratory Abnormalities Reported in ≥ 10% of Patients With pNET Who Received Sunitinib Malate Capsules in Study 6 Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; pNET = pancreatic neuroendocrine tumors. Laboratory Abnormality pNET Sunitinib Malate Capsules Placebo All Grades The denominator used to calculate the rate varied from 52 to 82 for sunitinib malate capsules and 39 to 80 for Placebo based on the number of patients with a baseline value and at least one post-treatment value. Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. % Grade 3-4 , Grade 4 laboratory abnormalities in patients on sunitinib malate capsules included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%), and total bilirubin (1%). % All Grades % Grade 3-4 , Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%), and lipase (1%). % Gastrointestinal AST increased 72 5 70 3 Alkaline phosphatase increased 63 10 70 11 ALT increased 61 4 55 3 Total bilirubin increased 37 1 28 4 Amylase increased 20 4 10 1 Lipase increased 17 5 11 4 Hematology Neutrophils decreased 71 16 16 0 Hemoglobin decreased 65 0 55 1 Platelets decreased 60 5 15 0 Lymphocytes decreased 56 7 35 4 Renal/Metabolic Glucose increased 71 12 78 18 Albumin decreased 41 1 37 1 Phosphorus decreased 36 7 22 5 Calcium decreased 34 0 19 0 Sodium decreased 29 2 34 3 Creatinine increased 27 5 28 5 Glucose decreased 22 2 15 4 Potassium decreased 21 4 14 0 Magnesium decreased 19 0 10 0 Potassium increased 18 1 11 1 Venous Thromboembolic Events In pooled safety population, 3.5% of patients experienced a venous thromboembolic event, including Grade 3-4 in 2.2% of patients. Pancreatic Function Pancreatitis was observed in 1 patient (1%) in the pNET study, 5 patients (1%) in the treatment-naïve RCC study, and 1 patient (< 1%) in the adjuvant treatment for RCC study on sunitinib malate capsules. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sunitinib malate capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: hemorrhage associated with thrombocytopenia * . Gastrointestinal Disorders: esophagitis. Hepatobiliary Disorders: cholecystitis, particularly acalculous cholecystitis. Immune System Disorders: hypersensitivity reactions, including angioedema. Infections and Infestations: serious infection (with or without neutropenia) * . The infections most commonly observed with sunitinib malate capsules include respiratory, urinary tract, skin infections, and sepsis/septic shock. Musculoskeletal and Connective Tissue Disorders: fistula formation, sometimes associated with tumor necrosis and/or regression * ; myopathy and/or rhabdomyolysis with or without acute renal failure*. Renal and Urinary Disorders: renal impairment and/or failure * . Respiratory Disorders: pulmonary embolism * , pleural effusion * . Skin and Subcutaneous Tissue Disorders: pyoderma gangrenosum, including positive de-challenges. Vascular Disorders: arterial (including aortic) aneurysms, dissections*, and rupture*; arterial thromboembolic events * . The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral infarction. General Disorders and Administration Site Conditions: impaired wound healing. * including some fatalities

4 CONTRAINDICATIONS None. • None ( 4 )

11 DESCRIPTION Sunitinib is a kinase inhibitor present in sunitinib malate capsules as the malate salt. Sunitinib malate is described chemically as N -[2-(Diethylamino)ethyl]-5-[( Z )-(5-fluoro-2-oxo-1,2-dihydro-3 H -indol-3-ylidene)methyl]-2,4-dimethyl-1 H -pyrrole-3-carboxamide hydrogen (2 S )-2-hydroxybutanedioate. The molecular formula is C 22 H 27 FN 4 O 2 • C 4 H 6 O 5 and the molecular weight is 532.6. The chemical structure of sunitinib malate is: Sunitinib malate is a yellow to orange powder with a pKa of 8.95. The solubility of sunitinib malate in aqueous media over the range pH 1.2 to pH 6.8 is in excess of 25 mg/mL. The log of the distribution coefficient (octanol/water) at pH 7 is 5.2. Sunitinib malate capsules are supplied as printed hard-shell capsules containing 12.5 mg, 25 mg, 37.5 mg or 50 mg of sunitinib (equivalent to 16.7 mg, 33.4 mg, 50.1 mg, or 66.8 mg of sunitinib malate, respectively). The capsules contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, gelatin, magnesium stearate, mannitol, sodium lauryl sulfate and titanium dioxide. The 12.5 mg and 25 mg strengths also contain red iron oxide. The 25 mg, 37.5 mg and 50 mg strengths also contain yellow iron oxide. In addition, the black imprinting ink contains the following: ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze. Sunitinib Structural Formula

2 DOSAGE AND ADMINISTRATION GIST and Advanced RCC : • The recommended dosage is 50 mg orally once daily for the first 4 weeks of each 6-week cycle (Schedule 4/2). ( 2.1 ) Adjuvant Treatment of RCC : • The recommended dosage is 50 mg orally once daily for the first 4 weeks of a 6-week cycle (Schedule 4/2) for a maximum of 9 cycles. ( 2.2 ) pNET : • The recommended dosage is 37.5 mg orally once daily. ( 2.3 ) 2.1 Recommended Dosage for GIST and Advanced RCC The recommended dosage of sunitinib malate capsules for gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC) is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) until disease progression or unacceptable toxicity. Sunitinib malate capsules may be taken with or without food. 2.2 Recommended Dosage for Adjuvant Treatment of RCC The recommended dosage of sunitinib malate capsules for the adjuvant treatment of RCC is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2), for nine 6-week cycles. Sunitinib malate capsules may be taken with or without food. 2.3 Recommended Dosage for pNET The recommended dosage of sunitinib malate capsules for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily until disease progression or unacceptable toxicity. Sunitinib malate capsules may be taken with or without food. 2.4 Dosage Modifications for Adverse Reactions To manage adverse reactions, the recommended dosage modifications are provided in Table 1. Table 2 provides the recommended dosage reductions of sunitinib malate capsules for adverse reactions . Table 1. Recommended Dosage Reductions of Sunitinib Malate Capsules for Adverse Reactions Indications GIST RCC pNET Advanced RCC Adjuvant RCC First dose reduction 37.5 mg once daily 37.5 mg once daily 37.5 mg once daily 25 mg once daily Second dose reduction 25 mg once daily 25 mg once daily NA NA Table 2. Recommended Dosage Modifications for Sunitinib Malate Capsules for Adverse Reactions Adverse Reaction Severity Dosage Modifications for Sunitinib Malate Capsules Hepatotoxicity [see Warnings and Precautions (5.1) ] Grade 3 • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose. • For recurring Grade 3 permanently discontinue. Grade 4 • Permanently discontinue. Cardiovascular events [see Warnings and Precautions (5.2) ] Asymptomatic cardiomyopathy (left ventricular ejection fraction greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline was not obtained) • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at reduced dose. Clinically manifested congestive heart failure (CHF) • Permanently discontinue. Hypertension [see Warnings and Precautions (5.4) ] Grade 3 • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose. Grade 4 • Permanently discontinue. Hemorrhagic events [see Warnings and Precautions (5.5) ] Grade 3 or 4 • Withhold until resolution to Grade 0 to 1 or baseline. • Either resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction. Thrombotic microangiopathy [see Warnings and Precautions (5.7) ] Any Grade • Permanently discontinue. Proteinuria or Nephrotic syndrome [see Warnings and Precautions (5.8) ] 3 or more grams proteinuria in 24 hours in the absence of nephrotic syndrome • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose. Nephrotic syndrome or recurrent proteinuria of 3 or more grams per 24 hours despite dose reductions • Permanently discontinue. Dermatological toxicities Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Necrotizing fasciitis [see Warnings and Precautions (5.9) ] Any Grade • Permanently discontinue. Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10) ] Any Grade • Permanently discontinue. Osteonecrosis of the jaw [see Warnings and Precautions (5.13) ] Any Grade • The safety of resumption of sunitinib malate capsules after osteonecrosis has not been established. • Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction. Impaired wound healing [see Warnings and Precautions (5.14) ] Any Grade • The safety of resumption of sunitinib malate capsules after resolution of wound healing has not been established. • Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction. 2.5 Dosage Modification for Drug Interactions Strong CYP3A4 Inhibitors Select an alternate concomitant medication with no or minimal enzyme inhibition potential. If coadministration of sunitinib malate capsules with a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction for sunitinib malate capsules to a minimum dosage as follows [see Drug Interactions (7.1) ]: • GIST and RCC: 37.5 mg orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) • pNET: 25 mg orally once daily Strong CYP3A4 Inducers Select an alternate concomitant medication with no or minimal enzyme induction potential. If coadministration of sunitinib malate capsules with a strong CYP3A4 inducer cannot be avoided, consider a dose increase for sunitinib malate capsules to a maximum dosage as follows: • GIST and RCC: 87.5 mg orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) • pNET: 62.5 mg orally once daily If the dose of sunitinib malate capsules is increased, monitor patients carefully for adverse reactions [see Drug Interactions (7.1) ] . 2.6 Dosage Modification for End-Stage Renal Disease Patients on Hemodialysis No starting dose adjustment is required in patients with end-stage renal disease (ESRD) on hemodialysis. However, given the decreased exposure compared to patients with normal renal function, subsequent doses may be increased gradually up to 2-fold based on safety and tolerability [see Clinical Pharmacology (12.3) ].

1 INDICATIONS AND USAGE Sunitinib malate capsules are a kinase inhibitor indicated for: • treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. ( 1.1 ) • treatment of adult patients with advanced renal cell carcinoma (RCC). ( 1.2 ) • adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy. ( 1.3 ) • treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease. ( 1.4 ) 1.1 Gastrointestinal Stromal Tumor Sunitinib malate capsules are indicated for the treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. 1.2 Advanced Renal Cell Carcinoma Sunitinib malate capsules are indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC). 1.3 Adjuvant Treatment of Renal Cell Carcinoma Sunitinib malate capsules are indicated for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy. 1.4 Advanced Pancreatic Neuroendocrine Tumors Sunitinib malate capsules are indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease.

10 OVERDOSAGE Treatment of overdose with sunitinib malate capsules should consist of general supportive measures. There is no specific antidote for overdosage with sunitinib malate capsules. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of sunitinib malate capsules, or without adverse reactions. In nonclinical studies, mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m 2 ) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection, and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations.

7 DRUG INTERACTIONS • CYP3A4 Inhibitors : Consider dose reduction of sunitinib malate capsules when administered with strong CYP3A4 inhibitors. ( 7.1 ) • CYP3A4 Inducers : Consider dose increase of sunitinib malate capsules when administered with strong CYP3A4 inducers. ( 7.1 ) 7.1 Effect of Other Drugs on Sunitinib Malate Capsules Strong CYP3A4 Inhibitors Co-administration with strong CYP3A4 inhibitors may increase sunitinib plasma concentrations [see Clinical Pharmacology (12.3) ] . Select an alternate concomitant medication with no or minimal enzyme inhibition potential. Consider a dose reduction for sunitinib malate capsules when it is co-administered with strong CYP3A4 inhibitors [see Dosage and Administration (2.5) ] . Strong CYP3A4 Inducers Co-administration with strong CYP3A4 inducers may decrease sunitinib plasma concentrations [see Clinical Pharmacology (12.3) ]. Select an alternate concomitant medication with no or minimal enzyme induction potential. Consider a dose increase for sunitinib malate capsules when it must be co-administered with CYP3A4 inducers [see Dosage and Administration (2.5) ] . 7.2 Drugs that Prolong QT Interval Sunitinib malate capsules are associated with QTc interval prolongation [see Warnings and Precautions (5.3) , Clinical Pharmacology (12.2) ] . Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (> 80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo . 12.2 Pharmacodynamics Exposure-Response Relationship Based on population pharmacokinetic/pharmacodynamic analyses, there were relationships between changes in different pharmacodynamic endpoints (i.e., safety and efficacy endpoints) over time and sunitinib plasma exposures. Cardiac Electrophysiology Sunitinib malate capsules can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes [see Warnings and Precautions (5.3) ] . 12.3 Pharmacokinetics The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in healthy subjects and in patients with solid tumors. Sunitinib AUC and C max increase proportionately over a dose range of 25 mg to 100 mg (0.5 to 2 times the approved RDD of 50 mg). The pharmacokinetics were similar in healthy subjects and in patients with a solid tumor, including patients with GIST and RCC. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 63 to 101 ng/mL. Absorption Following oral administration of sunitinib, the time to maximum plasma concentration (T max ) ranged from 6 to 12 hours. Effect of Food The administration of a single dose of sunitinib malate capsules 50 mg with a high-fat, high-calorie meal (consisting of approximately 150 protein calories and 500 to 600 fat calories) in healthy subjects had no clinically significant effect on sunitinib or active metabolites exposure. Distribution The apparent volume of distribution (Vd/F) for sunitinib is 2230 L. Binding of sunitinib and its primary active metabolite to human plasma protein in vitro is 95% and 90%, respectively, with no concentration dependence in the range of 100 to 4000 ng/mL. Elimination Following administration of a single oral dose in healthy subjects, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. Sunitinib total oral clearance (CL/F) ranged from 34 to 62 L/h with an interpatient variability of 40%. Metabolism Sunitinib is metabolized primarily by CYP3A4 to its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23% to 37% of the total exposure. After a radiolabeled dose, sunitinib and its active metabolite were the major compounds identified in plasma, accounting for 92% of radioactivity. Excretion After a radiolabeled dose of sunitinib, approximately 61% of the dose was recovered in feces and 16% in urine. Sunitinib and its primary active metabolite were the major compounds identified in urine and feces, representing 86% and 74% of radioactivity, respectively. Specific Populations No clinically significant differences in the pharmacokinetics of sunitinib or the primary active metabolite were observed based on age (18 to 84 years), body weight (34 to 168 kg), race (White, Black, or Asian), sex, Eastern Cooperative Oncology Group (ECOG) score, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Patients with Renal Impairment No clinically significant differences in the pharmacokinetics of sunitinib or its active metabolite were predicted or observed in patients with mild (CLcr 50 to 80 mL/min), moderate (CLcr 30 to < 50 mL/min), or severe (CLcr < 30 mL/min) renal impairment who are not on dialysis, compared to patients with normal renal function (CLcr > 80 mL/min). Although sunitinib was not eliminated through hemodialysis, the sunitinib systemic exposure was 47% lower in patients with end stage renal disease (ESRD) on hemodialysis compared to patients with normal renal function. Drug Interaction Studies Clinical Studies Effect of Strong CYP3A4 Inhibitors on Sunitinib Co-administration of a single sunitinib malate capsule dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite C max and AUC 0-inf by 49% and 51%, respectively, in healthy subjects. Effect of Strong CYP3A4 Inducers on Sunitinib Co-administration of a single sunitinib malate capsule dose with rifampin (strong CYP3A4 inducer) reduced the combined sunitinib and its active metabolite C max and AUC 0-inf by 23% and 46%, respectively in healthy subjects. In Vitro Studies In vitro studies in human hepatocytes and microsomes indicated that sunitinib and the primary active metabolite do not induce CYP1A2, CYP2E1, and CYP3A4/5, or inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 at clinically relevant concentrations.

12.1 Mechanism of Action Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (> 80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo .

12.2 Pharmacodynamics Exposure-Response Relationship Based on population pharmacokinetic/pharmacodynamic analyses, there were relationships between changes in different pharmacodynamic endpoints (i.e., safety and efficacy endpoints) over time and sunitinib plasma exposures. Cardiac Electrophysiology Sunitinib malate capsules can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes [see Warnings and Precautions (5.3) ] .

12.3 Pharmacokinetics The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in healthy subjects and in patients with solid tumors. Sunitinib AUC and C max increase proportionately over a dose range of 25 mg to 100 mg (0.5 to 2 times the approved RDD of 50 mg). The pharmacokinetics were similar in healthy subjects and in patients with a solid tumor, including patients with GIST and RCC. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 63 to 101 ng/mL. Absorption Following oral administration of sunitinib, the time to maximum plasma concentration (T max ) ranged from 6 to 12 hours. Effect of Food The administration of a single dose of sunitinib malate capsules 50 mg with a high-fat, high-calorie meal (consisting of approximately 150 protein calories and 500 to 600 fat calories) in healthy subjects had no clinically significant effect on sunitinib or active metabolites exposure. Distribution The apparent volume of distribution (Vd/F) for sunitinib is 2230 L. Binding of sunitinib and its primary active metabolite to human plasma protein in vitro is 95% and 90%, respectively, with no concentration dependence in the range of 100 to 4000 ng/mL. Elimination Following administration of a single oral dose in healthy subjects, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. Sunitinib total oral clearance (CL/F) ranged from 34 to 62 L/h with an interpatient variability of 40%. Metabolism Sunitinib is metabolized primarily by CYP3A4 to its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23% to 37% of the total exposure. After a radiolabeled dose, sunitinib and its active metabolite were the major compounds identified in plasma, accounting for 92% of radioactivity. Excretion After a radiolabeled dose of sunitinib, approximately 61% of the dose was recovered in feces and 16% in urine. Sunitinib and its primary active metabolite were the major compounds identified in urine and feces, representing 86% and 74% of radioactivity, respectively. Specific Populations No clinically significant differences in the pharmacokinetics of sunitinib or the primary active metabolite were observed based on age (18 to 84 years), body weight (34 to 168 kg), race (White, Black, or Asian), sex, Eastern Cooperative Oncology Group (ECOG) score, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Patients with Renal Impairment No clinically significant differences in the pharmacokinetics of sunitinib or its active metabolite were predicted or observed in patients with mild (CLcr 50 to 80 mL/min), moderate (CLcr 30 to < 50 mL/min), or severe (CLcr < 30 mL/min) renal impairment who are not on dialysis, compared to patients with normal renal function (CLcr > 80 mL/min). Although sunitinib was not eliminated through hemodialysis, the sunitinib systemic exposure was 47% lower in patients with end stage renal disease (ESRD) on hemodialysis compared to patients with normal renal function. Drug Interaction Studies Clinical Studies Effect of Strong CYP3A4 Inhibitors on Sunitinib Co-administration of a single sunitinib malate capsule dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite C max and AUC 0-inf by 49% and 51%, respectively, in healthy subjects. Effect of Strong CYP3A4 Inducers on Sunitinib Co-administration of a single sunitinib malate capsule dose with rifampin (strong CYP3A4 inducer) reduced the combined sunitinib and its active metabolite C max and AUC 0-inf by 23% and 46%, respectively in healthy subjects. In Vitro Studies In vitro studies in human hepatocytes and microsomes indicated that sunitinib and the primary active metabolite do not induce CYP1A2, CYP2E1, and CYP3A4/5, or inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 at clinically relevant concentrations.

20220309

2

3 DOSAGE FORMS AND STRENGTHS Sunitinib Malate Capsules are available containing 12.5 mg, 25 mg, 37.5 mg or 50 mg of sunitinib equivalent to 16.7 mg, 33.4 mg, 50.1 mg or 66.8 mg of sunitinib malate, respectively. • The 12.5 mg capsules are hard-shell gelatin capsules with a pink-brown opaque cap and pink-brown opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 12.5 in black ink on cap and body. • The 25 mg capsules are hard-shell gelatin capsules with a yellow opaque cap and pink-brown opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 25 in black ink on cap and body. • The 37.5 mg capsules are hard-shell gelatin capsules with an ivory opaque cap and ivory opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 37.5 in black ink on cap and body. • The 50 mg capsules are hard-shell gelatin capsules with a yellow opaque cap and yellow opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 50 in black ink on cap and body. • Capsules: 12.5 mg, 25 mg, 37.5 mg, 50 mg sunitinib ( 3 )

Sunitinib Malate sunitinib malate SUNITINIB MALATE SUNITINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM GELATIN, UNSPECIFIED MAGNESIUM STEARATE MANNITOL SODIUM LAURYL SULFATE TITANIUM DIOXIDE FERRIC OXIDE RED AMMONIA FERROSOFERRIC OXIDE PROPYLENE GLYCOL SHELLAC pink-brown opaque MYLAN;SM;12;5 Sunitinib Malate sunitinib malate SUNITINIB MALATE SUNITINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM GELATIN, UNSPECIFIED MAGNESIUM STEARATE MANNITOL SODIUM LAURYL SULFATE TITANIUM DIOXIDE FERRIC OXIDE RED FERRIC OXIDE YELLOW AMMONIA FERROSOFERRIC OXIDE PROPYLENE GLYCOL SHELLAC yellow opaque pink-brown opaque MYLAN;SM;25 Sunitinib Malate sunitinib malate SUNITINIB MALATE SUNITINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM GELATIN, UNSPECIFIED MAGNESIUM STEARATE MANNITOL SODIUM LAURYL SULFATE TITANIUM DIOXIDE FERRIC OXIDE YELLOW AMMONIA FERROSOFERRIC OXIDE PROPYLENE GLYCOL SHELLAC ivory opaque MYLAN;SM;37;5 Sunitinib Malate sunitinib malate SUNITINIB MALATE SUNITINIB SILICON DIOXIDE CROSCARMELLOSE SODIUM GELATIN, UNSPECIFIED MAGNESIUM STEARATE MANNITOL SODIUM LAURYL SULFATE TITANIUM DIOXIDE FERRIC OXIDE YELLOW AMMONIA FERROSOFERRIC OXIDE PROPYLENE GLYCOL SHELLAC yellow opaque MYLAN;SM;50

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of sunitinib has been evaluated in 2 species: rasH2 transgenic mice and Sprague-Dawley rats. There were similar positive findings in both species. In rasH2 transgenic mice, gastroduodenal carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background hemangiosarcomas were observed at sunitinib daily doses of ≥ 25 mg/kg/day in studies of 1 or 6 months duration. No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Similarly, in a 2-year rat carcinogenicity study, administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in findings of duodenal carcinoma at doses as low as 1 mg/kg/day [approximately 0.9 times the combined AUC (combined systemic exposure of sunitinib plus its active metabolite) in patients administered the RDD of 50 mg]. At the high dose of 3 mg/kg/day (approximately 8 times the combined AUC in patients administered the RDD of 50 mg), the incidence of duodenal tumors was increased and was accompanied by findings of gastric mucous cell hyperplasia and by an increased incidence of pheochromocytoma and hyperplasia of the adrenal gland. Sunitinib did not cause genetic damage when tested in in vitro assays [bacterial mutation (Ames test), human lymphocyte chromosome aberration] and an in vivo rat bone marrow micronucleus test. In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5, 1.5, 5 mg/kg/day) for 21 days prior to mating and for 7 days after mating. Preimplantation loss was observed in females administered 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg). No adverse effects on fertility were observed at doses ≤ 1.5 mg/kg/day (approximately equal to the combined AUC in patients administered the RDD of 50 mg). In addition, effects on the female reproductive system were identified in a 3-month oral repeat-dose monkey study (2, 6, 12 mg/kg/day). Ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg), while uterine changes (endometrial atrophy) were noted at ≥ 2 mg/kg/day (approximately 0.4 times the combined AUC in patients administered the RDD of 50 mg). With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day (approximately 0.8 times the combined AUC in patients administered the RDD of 50 mg) in a 9-month monkey study (0.3, 1.5, and 6 mg/kg/day administered daily for 28 days followed by a 14-day respite). In a male fertility study, no reproductive effects were observed in male rats dosed with 1, 3, or 10 mg/kg/day oral sunitinib for 58 days prior to mating with untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration, and motility) were unaffected by sunitinib at doses ≤ 10 mg/kg/day (approximately ≥ 26 times the combined AUC in patients administered the RDD of 50 mg).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of sunitinib has been evaluated in 2 species: rasH2 transgenic mice and Sprague-Dawley rats. There were similar positive findings in both species. In rasH2 transgenic mice, gastroduodenal carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background hemangiosarcomas were observed at sunitinib daily doses of ≥ 25 mg/kg/day in studies of 1 or 6 months duration. No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Similarly, in a 2-year rat carcinogenicity study, administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in findings of duodenal carcinoma at doses as low as 1 mg/kg/day [approximately 0.9 times the combined AUC (combined systemic exposure of sunitinib plus its active metabolite) in patients administered the RDD of 50 mg]. At the high dose of 3 mg/kg/day (approximately 8 times the combined AUC in patients administered the RDD of 50 mg), the incidence of duodenal tumors was increased and was accompanied by findings of gastric mucous cell hyperplasia and by an increased incidence of pheochromocytoma and hyperplasia of the adrenal gland. Sunitinib did not cause genetic damage when tested in in vitro assays [bacterial mutation (Ames test), human lymphocyte chromosome aberration] and an in vivo rat bone marrow micronucleus test. In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5, 1.5, 5 mg/kg/day) for 21 days prior to mating and for 7 days after mating. Preimplantation loss was observed in females administered 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg). No adverse effects on fertility were observed at doses ≤ 1.5 mg/kg/day (approximately equal to the combined AUC in patients administered the RDD of 50 mg). In addition, effects on the female reproductive system were identified in a 3-month oral repeat-dose monkey study (2, 6, 12 mg/kg/day). Ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg), while uterine changes (endometrial atrophy) were noted at ≥ 2 mg/kg/day (approximately 0.4 times the combined AUC in patients administered the RDD of 50 mg). With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day (approximately 0.8 times the combined AUC in patients administered the RDD of 50 mg) in a 9-month monkey study (0.3, 1.5, and 6 mg/kg/day administered daily for 28 days followed by a 14-day respite). In a male fertility study, no reproductive effects were observed in male rats dosed with 1, 3, or 10 mg/kg/day oral sunitinib for 58 days prior to mating with untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration, and motility) were unaffected by sunitinib at doses ≤ 10 mg/kg/day (approximately ≥ 26 times the combined AUC in patients administered the RDD of 50 mg).

ANDA201275

Sunitinib Malate

sunitinib malate

0378-6679

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL – 12.5 mg NDC 0378-6678-28 Sunitinib Malate Capsules 12.5 mg* PHARMACIST: Dispense the accompanying Medication Guide to each patient. Rx only 28 Capsules * Each capsule contains 12.5 mg sunitinib equivalent to 16.7 mg sunitinib malate. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Keep container tightly closed. Keep this and all medication out of the reach of children. Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Usual Dosage: See accompanying prescribing information. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in Puerto Rico Mylan.com RM6678BD3 Sunitinib Malate Capsules 12.5 mg Bottle Label

Dosage and Administration, Dosage Modifications for Adverse Reactions ( 2.4 ) 8/2021 Dosage and Administration, Dosage Modification for Drug Interactions ( 2.5 ) 8/2021 Warnings and Precautions, Hepatotoxicity ( 5.1 ) 8/2021 Warnings and Precautions, Hypertension ( 5.4 ) 8/2021 Warnings and Precautions, Hemorrhagic Events and Viscous Perforation ( 5.5 ) 8/2021 Warnings and Precautions, Reversible Posterior Leukoencephalopathy Syndrome ( 5.10 ) 8/2021 Warnings and Precautions, Hypoglycemia ( 5.12 ) 8/2021 Warnings and Precautions, Osteonecrosis of the Jaw ( 5.13 ) 8/2021

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Hepatotoxicity: Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity [see Warnings and Precautions (5.1) ]. Cardiovascular Events: Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.2) ]. QT Prolongation and Torsade de Pointes: Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately in the event of syncope, pre-syncopal symptoms, and cardiac palpitations [see Warnings and Precautions (5.3) ]. Hypertension: Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension [see Warnings and Precautions (5.4) ]. Hemorrhagic Events: Advise patients that sunitinib malate capsules can cause severe bleeding. Advise patients to immediately contact their healthcare provider for bleeding or symptoms of bleeding [see Warnings and Precautions (5.5) ]. Gastrointestinal Disorders: Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during sunitinib malate capsules treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking sunitinib malate capsules [see Warnings and Precautions (5.5) , Adverse Reactions (6.1) ]. Dermatologic Effects and Toxicities: Advise patients that depigmentation of the hair or skin may occur during treatment with sunitinib malate capsules due to the drug color (yellow). Other possible dermatologic effects may include dryness, thickness or cracking of skin, blister or rash on the palms of the hands and soles of the feet. Severe dermatologic toxicities including Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, erythema multiforme, and necrotizing fasciitis have been reported. Advise patients to immediately inform their healthcare provider if severe dermatologic reactions occur [see Warnings and Precautions (5.9) , Adverse Reactions (6.1) ]. Reversible Posterior Leukoencephalopathy Syndrome: Inform patients of the signs and symptoms of reversible posterior leukoencephalopathy syndrome. Advise patients to contact their healthcare provider if they develop symptoms of reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10) ]. Thyroid Dysfunction: Advise patients that sunitinib malate capsules can cause thyroid dysfunction. Advise patient to contact their healthcare provider if symptoms of abnormal thyroid function occur [see Warnings and Precautions (5.11) ] . Hypoglycemia: Advise patients that sunitinib malate capsules can cause severe hypoglycemia and may be more severe in patients with diabetes taking antidiabetic medications. Inform patients of the signs, symptoms, and risks associated with hypoglycemia. Advise patients to immediately inform their healthcare provider if severe signs or symptoms of hypoglycemia occur [see Warnings and Precautions (5.12) ] . Osteonecrosis of the Jaw: Advise patients regarding good oral hygiene practices and to inform their healthcare provider of any planned dental procedures. Advise patients to immediately contact their healthcare provider for signs or symptoms associated with osteonecrosis of the jaw [see Warnings and Precautions (5.13) ] . Impaired Wound Healing: Advise patients that sunitinib malate capsules impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedures [see Warnings and Precautions (5.14) ] . Concomitant Medications: Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements [see Drug Interactions (7) ] . Embryo-Fetal Toxicity: Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.15) , Use in Specific Populations (8.1) ] . Advise females of reproductive potential to use effective contraception during treatment and for 4 weeks after receiving the last dose of sunitinib malate capsules [see Use in Specific Populations (8.3) ] . Advise males with female partners of reproductive potential to use effective contraception during treatment and for 7 weeks after receiving the last dose of sunitinib malate capsules [see Use in Specific Populations (8.3) ] . Lactation: Advise women not to breastfeed during treatment with sunitinib malate capsules and for at least 4 weeks after the last dose [see Use in Specific Populations (8.2) ]. Infertility: Advise patients that sunitinib malate capsules may impair male and female fertility [see Use in Specific Populations (8.3) , Nonclinical Toxicology (13.1) ] . Missed Dose: Advise patients that miss a dose of sunitinib malate capsules by less than 12 hours to take the missed dose right away. Advise patients that miss a dose of sunitinib malate capsules by more than 12 hours to take the next scheduled dose at its regular time.

Medication Guide Sunitinib Malate Capsules (soo ni′ ti nib mal eyt) What is the most important information I should know about sunitinib malate capsules? Sunitinib malate capsules can cause serious side effects including: • Severe liver problems, that can lead to death. Tell your healthcare provider right away if you develop any of the following signs and symptoms of liver problems during treatment with sunitinib malate capsules: o itching o yellow eyes or skin o dark urine o pain or discomfort in the right upper stomach area Your healthcare provider should do blood tests to check your liver function before you start taking and during treatment with sunitinib malate capsules. Your healthcare provider may temporarily stop, reduce your dose, or permanently stop treatment with sunitinib malate capsules if you develop liver problems. See “What are the possible side effects of sunitinib malate capsules?” for more information about side effects. What are sunitinib malate capsules? Sunitinib malate capsules are a prescription medicine used to treat: • a rare cancer of the stomach, bowel, or esophagus called gastrointestinal stromal tumor (GIST) and when: o you have taken the medicine imatinib mesylate and it did not stop the cancer from growing, or o you cannot take imatinib mesylate. • advanced kidney cancer (advanced renal cell carcinoma or RCC). • adults with kidney cancer that has not spread (localized), and who are at high risk of RCC coming back again after having kidney surgery. • a type of pancreatic cancer called pancreatic neuroendocrine tumors (pNET), that has progressed and cannot be treated with surgery. It is not known if sunitinib malate capsules are safe and effective in children. Before taking sunitinib malate capsules tell your healthcare provider about all of your medical conditions, including if you: • have any heart problems • have high blood pressure • have thyroid problems • have a history of low blood sugar or diabetes • have kidney function problems (other than cancer) • have liver problems • have any bleeding problem • plan to have surgery or have had a recent surgery. You should stop taking sunitinib malate capsules at least 3 weeks before planned surgery. See “What are the possible side effects of sunitinib malate capsules?” • have seizures • have or have had pain in the mouth, teeth or jaw, swelling or sores inside the mouth, numbness or a feeling of heaviness in the jaw, or loosening of a tooth • are pregnant or plan to become pregnant. Sunitinib malate can harm your unborn baby. Females who are able to become pregnant: o Your healthcare provider should do a pregnancy test before you start treatment with sunitinib malate capsules. o You should use effective birth control (contraception) during treatment and for at least 4 weeks after your last dose of sunitinib malate capsules. o Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with sunitinib malate capsules. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment and for 7 weeks after your last dose of sunitinib malate capsules. Sunitinib malate capsules may cause fertility problems in males and females. Tell your healthcare provider if this is a concern for you. • are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with sunitinib malate capsules and for at least 4 weeks (1 month) after the last dose. Tell all of your healthcare providers and dentists that you are taking sunitinib malate capsules. They should talk to the healthcare provider who prescribed sunitinib malate capsules for you, before you have any surgery, or medical or dental procedure. Tell your healthcare provider about all the medicines you take, including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements. Using sunitinib malate capsules with certain other medicines can cause serious side effects. You may have an increased risk of severe jawbone problems (osteonecrosis) if you take sunitinib malate capsules and a bisphosphonate medicine. Especially tell your healthcare provider if you are taking or have taken an osteoporosis medicine. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take sunitinib malate capsules? • Take sunitinib malate capsules exactly the way your healthcare provider tells you. • Take sunitinib malate capsules 1 time each day with or without food. • If you take sunitinib malate capsules for GIST or RCC, you will usually take your medicine for 4 weeks (28 days) and then stop for 2 weeks (14 days). This is 1 cycle of treatment. You will repeat this cycle for as long as your healthcare provider tells you to. • If you take sunitinib malate capsules for pNET, take it 1 time each day until your healthcare provider tells you to stop. • Do not drink grapefruit juice or eat grapefruit during your treatment with sunitinib malate capsules. They may cause you to have too much sunitinib malate in your body. • Your healthcare provider may do blood tests before each cycle of treatment to check you for side effects. • If you miss a dose of sunitinib malate capsules by less than 12 hours, take the missed dose right away. If you miss a dose of sunitinib malate capsules by more than 12 hours, just take your next dose at your regular time. Do not make up the missed dose. Tell your healthcare provider about any missed dose. • Call your healthcare provider right away, if you take too many sunitinib malate capsules. What are possible side effects of sunitinib malate capsules? Sunitinib malate capsules may cause serious side effects, including: • See “What is the most important information I should know about sunitinib malate capsules?” • Heart problems. Heart problems may include heart failure, heart attack and heart muscle problems (cardiomyopathy) that can lead to death. Tell your healthcare provider if you feel very tired, are short of breath, or have swollen feet and ankles. • Abnormal heart rhythm changes. Changes in the electrical activity of your heart called QT prolongation can cause irregular heart beats that can be life threatening. Your healthcare provider may do electrocardiograms and blood tests (electrolytes) to watch for these problems during your treatment with sunitinib malate capsules. Tell your healthcare provider right away if you feel dizzy, faint, or have abnormal heartbeats during your treatment with sunitinib malate capsules. o you feel faint or lightheaded, or you pass out o dizziness o feel your heart beat is irregular or fast • High blood pressure. High blood pressure is common with sunitinib malate capsules and may sometimes be severe. Follow your healthcare provider’s instructions about having your blood pressure checked regularly. Call your healthcare provider if your blood pressure is high or if you have any of the following signs or symptoms of high blood pressure: o severe headache o lightheadedness o dizziness o change in vision Your healthcare provider may prescribe medicine for you to treat high blood pressure, if needed. • Bleeding problems . Bleeding is common with sunitinib malate capsules, but sunitinib malate capsules can also cause severe bleeding problems that can lead to death. Your healthcare provider will monitor you for bleeding and may do blood tests if needed. Call your healthcare provider right away if you have any of these symptoms or a serious bleeding problem during treatment with sunitinib malate capsules, including: o painful, swollen stomach (abdomen) o vomiting blood o coughing up blood o black, sticky stools o bloody urine o headache o change in your mental status • Serious stomach and intestinal problems, that can sometimes lead to death. Some people have had tears in their stomach or intestine (perforation) or have developed an abnormal opening between the stomach and intestine (fistula). Get medical help right away if you get stomach-area (abdominal) pain that does not go away or is severe during treatment with sunitinib malate capsules. • Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells and may lead to death. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS. • Abnormal changes in the brain (Reversible Posterior Leukoencephalopathy Syndrome [RPLS]). RPLS can cause a collection of symptoms including headache, confusion, and vision loss. Some people who have taken sunitinib malate capsules have developed RPLS that can lead to death. • Thrombotic microangiopathy (TMA) including thrombotic thrombocytopenia purpura (TTP) and hemolytic uremic syndrome (HUS) . TMA is a condition that involves injury to the smallest blood vessels, and blood clots that can happen while taking sunitinib malate capsules. TMA is accompanied by a decrease in red cells and cells that are involved with clotting. TMA may harm your body’s organs such as the brain and kidneys and can sometimes lead to death. • Protein in your urine. Some people who have taken sunitinib malate capsules have developed protein in their urine, and in some cases, kidney problems that can lead to death. Your healthcare provider will check you for this problem. • Serious skin and mouth reactions. Treatment with sunitinib malate capsules has caused severe skin reactions that can lead to death, including: o severe rash with blisters or peeling of the skin. o painful sores or ulcers on the skin, lips or inside the mouth. o tissue damage (necrotizing fasciitis). If you have any signs or symptoms of severe skin reactions, stop taking sunitinib malate capsules and call your healthcare provider or get medical help right away. • Thyroid problems. Your healthcare provider may do tests to check your thyroid function during sunitinib malate capsules treatment. Tell your healthcare provider if you have any of the following signs and symptoms during your treatment with sunitinib malate capsules: o tiredness that gets worse and does not go away o loss of appetite o problems with heat o feeling nervous or agitated, tremors o sweating o nausea or vomiting o diarrhea o fast heart rate o weight gain or weight loss o feeling depressed o irregular menstrual periods or no menstrual periods o headache o hair loss • Low blood sugar (hypoglycemia). Low blood sugar can happen with sunitinib malate capsules, and may cause you to become unconscious, or you may need to be hospitalized. Low blood sugar with sunitinib malate capsules may be worse in people who have diabetes and take antidiabetic medicines. Your healthcare provider should check your blood sugar levels regularly during treatment with sunitinib malate capsules and may need to adjust the dose of your antidiabetic medicines. Call your healthcare provider right away if you have any of the following signs or symptoms of low blood sugar during your treatment with sunitinib malate capsules: o headache o drowsiness o weakness o dizziness o confusion o irritability o hunger o fast heart beat o sweating o feeling jittery • Jawbone problems (osteonecrosis). Severe jawbone problems have happened in some people who take sunitinib malate capsules. Certain risk factors such as taking a bisphosphonate medicine or having dental disease may increase your risk of getting osteonecrosis. Your healthcare provider may tell you to see your dentist before you start taking sunitinib malate capsules. Your healthcare provider may tell you to avoid dental procedures, if possible, during your treatment with sunitinib malate capsules, especially if you are receiving a bisphosphonate medicine into a vein (intravenous). Tell your healthcare provider if you plan to have any dental procedures before or during treatment with sunitinib malate capsules. o You should stop taking sunitinib malate capsules at least 3 weeks before planned dental procedures. o Your healthcare provider should tell you when you may start taking sunitinib malate capsules again after dental procedures. • Wound healing problems . Wound healing problems have happened in some people who take sunitinib malate capsules. Tell your healthcare provider if you plan to have any surgery before or during treatment with sunitinib malate capsules. o You should stop taking sunitinib malate capsules at least 3 weeks before planned surgery. o Your healthcare provider should tell you when you may start taking sunitinib malate capsules again after surgery. Your healthcare provider may temporarily stop, reduce your dose, or permanently stop treatment with sunitinib malate capsules if you develop serious side effects. Common side effects of sunitinib malate capsules include: • tiredness • weakness • diarrhea • pain, swelling or sores inside of your mouth • nausea • loss of appetite • indigestion • vomiting • stomach-area (abdominal) pain • blisters or rash on the palms of your hands and soles of your feet • high blood pressure • taste changes • low platelet counts The medicine in sunitinib malate capsules is yellow, and it may make your skin look yellow. Your skin and hair may get lighter in color. Sunitinib malate capsules may also cause other skin problems including: dryness, thickness or cracking of the skin. These are not all of the possible side effects of sunitinib malate capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How do I store sunitinib malate capsules? • Store sunitinib malate capsules at room temperature, between 20° to 25°C (68° to 77°F). Keep sunitinib malate capsules and all medicines out of the reach of children. General information about the safe and effective use of sunitinib malate capsules. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use sunitinib malate capsules for a condition for which they were not prescribed. Do not give sunitinib malate capsules to other people, even if they have the same symptoms that you have. They may harm them. You can ask your healthcare provider or pharmacist for information about sunitinib malate capsules that is written for health professionals. What are the ingredients in sunitinib malate capsules? Active ingredient: sunitinib malate Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, gelatin, magnesium stearate, mannitol, sodium lauryl sulfate and titanium dioxide. The 12.5 mg and 25 mg strengths also contain red iron oxide. The 25 mg, 37.5 mg and 50 mg strengths also contain yellow iron oxide. In addition, the black imprinting ink contains the following: ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Manufactured by: Auro PR Inc. RD 156 Caguas West Industrial Park, Lot 24 Caguas, PR 00725 U.S.A. Revised: 3/2022 SUNI:R7

Clinical Studies Effect of Strong CYP3A4 Inhibitors on Sunitinib Co-administration of a single sunitinib malate capsule dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite C max and AUC 0-inf by 49% and 51%, respectively, in healthy subjects. Effect of Strong CYP3A4 Inducers on Sunitinib Co-administration of a single sunitinib malate capsule dose with rifampin (strong CYP3A4 inducer) reduced the combined sunitinib and its active metabolite C max and AUC 0-inf by 23% and 46%, respectively in healthy subjects. In Vitro Studies In vitro studies in human hepatocytes and microsomes indicated that sunitinib and the primary active metabolite do not induce CYP1A2, CYP2E1, and CYP3A4/5, or inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 at clinically relevant concentrations.

8.5 Geriatric Use Of the 7527 patients with GIST, RCC (advanced and adjuvant), or pNET who received sunitinib malate capsules, 32% were 65 years and older, and 7% were 75 years and older. Patients aged 65 years of age and older had a higher incidence of Grade 3 or 4 adverse reactions (67%) than younger patients (60%). In the GIST study, 73 (30%) of the patients who received sunitinib malate capsules were 65 years and older. In the mRCC study, 152 (41%) of patients who received sunitinib malate capsules were 65 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. In the pNET study, 22 (27%) of the patients who received sunitinib malate capsules were 65 years and older. Clinical studies of sunitinib malate capsules did not include sufficient numbers of patients with pNET to determine if patients 65 years of age and older respond differently than younger patients.

8.4 Pediatric Use The safety and effectiveness of sunitinib malate capsules in pediatric patients have not been established. Safety and pharmacokinetics of sunitinib were assessed in an open-label study (NCT00387920) in pediatric patients 2 years to < 17 years of age (n = 29) with refractory solid tumors. In addition, efficacy, safety and pharmacokinetics of sunitinib was assessed in another open-label study (NCT01462695) in pediatric patients 2 years to < 17 years of age (n = 27) with high-grade glioma or ependymoma. The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults. Sunitinib was poorly tolerated in pediatric patients. The occurrence of dose-limiting cardiotoxicity prompted an amendment of the NCT00387920 study to exclude patients with previous exposure to anthracyclines or cardiac radiation. No responses were reported in patients in either of the trials. Apparent clearance and volume of distribution normalized for BSA for sunitinib and its active major metabolite were lower in pediatrics as compared to adults. The effect on open tibial growth plates in pediatric patients who received sunitinib malate capsules has not been adequately studied. See Juvenile Animal Toxicity Data below. Juvenile Animal Toxicity Data Physeal dysplasia was present in cynomolgus monkeys with open growth plates treated with sunitinib for ≥ 3 months (3 month dosing 2, 6, 12 mg/kg/day; 8 cycles of dosing 0.3, 1.5, 6.0 mg/kg/day) at doses that were > 0.4 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the RDD of 50 mg. The no-effect level (NOEL) was 1.5 mg/kg/day in monkeys treated intermittently for 8 cycles, but was not identified in monkeys treated continuously for 3 months. In developing rats treated continuously for 3 months (1.5, 5.0, and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day), bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses ≥ 5 mg/kg (approximately 10 times the combined AUC in patients administered the RDD of 50 mg). Additionally, tooth caries were present in rats at > 5 mg/kg. The incidence and severity of physeal dysplasia were dose related and reversible upon cessation of treatment; however, findings in the teeth were not. In rats, the NOEL in bones was ≤ 2 mg/kg/day.

8.1 Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action, sunitinib can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data in pregnant women to inform a drug-associated risk. In animal developmental and reproductive toxicology studies, oral administration of sunitinib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity (embryolethality, craniofacial and skeletal malformations) at 5.5 and 0.3 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the recommended daily doses (RDD) of 50 mg, respectively (see Data ) . Advise females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5, 1.5, 5 mg/kg/day) for 21 days prior to mating and for 7 days after mating. Embryolethality was observed at 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg). In embryo-fetal developmental toxicity studies, oral sunitinib was administered to pregnant rats (0.3, 1.5, 3, 5 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) during the period of organogenesis. In rats, embryolethality and skeletal malformations of the ribs and vertebrae were observed at the dose of 5 mg/kg/day (approximately 5.5 times the combined AUC in patients administered the RDD of 50 mg). No adverse fetal effects were observed in rats at doses ≤ 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg). In rabbits, embryolethality was observed at 5 mg/kg/day (approximately 3 times the combined AUC in patients administered the RDD of 50 mg), and craniofacial malformations (cleft lip and cleft palate) were observed at ≥ 1 mg/kg/day (approximately 0.3 times the combined AUC in patients administered the RDD of 50 mg). Sunitinib (0.3, 1, 3 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses ≥ 1 mg/kg/day (approximately 0.5 times the combined AUC in patients administered the RDD of 50 mg). At 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg), reduced neonate body weights were observed at birth and persisted in the offspring of both sexes during the preweaning period and in males during postweaning period. No adverse developmental effects were observed at doses ≤ 1 mg/kg/day.

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action, sunitinib can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data in pregnant women to inform a drug-associated risk. In animal developmental and reproductive toxicology studies, oral administration of sunitinib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity (embryolethality, craniofacial and skeletal malformations) at 5.5 and 0.3 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the recommended daily doses (RDD) of 50 mg, respectively (see Data ) . Advise females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5, 1.5, 5 mg/kg/day) for 21 days prior to mating and for 7 days after mating. Embryolethality was observed at 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg). In embryo-fetal developmental toxicity studies, oral sunitinib was administered to pregnant rats (0.3, 1.5, 3, 5 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) during the period of organogenesis. In rats, embryolethality and skeletal malformations of the ribs and vertebrae were observed at the dose of 5 mg/kg/day (approximately 5.5 times the combined AUC in patients administered the RDD of 50 mg). No adverse fetal effects were observed in rats at doses ≤ 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg). In rabbits, embryolethality was observed at 5 mg/kg/day (approximately 3 times the combined AUC in patients administered the RDD of 50 mg), and craniofacial malformations (cleft lip and cleft palate) were observed at ≥ 1 mg/kg/day (approximately 0.3 times the combined AUC in patients administered the RDD of 50 mg). Sunitinib (0.3, 1, 3 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses ≥ 1 mg/kg/day (approximately 0.5 times the combined AUC in patients administered the RDD of 50 mg). At 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg), reduced neonate body weights were observed at birth and persisted in the offspring of both sexes during the preweaning period and in males during postweaning period. No adverse developmental effects were observed at doses ≤ 1 mg/kg/day. 8.2 Lactation There is no information regarding the presence of sunitinib and its metabolites in human milk. Sunitinib and its metabolites were excreted in rat milk at concentrations up to 12-fold higher than in plasma (see Data ) . Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with sunitinib malate capsules and for at least 4 weeks after the last dose. Data Animal Data In lactating female rats administered 15 mg/kg, sunitinib and its metabolites were excreted in milk at concentrations up to 12-fold higher than in plasma. 8.3 Females and Males of Reproductive Potential Sunitinib can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating treatment with sunitinib malate capsules. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with sunitinib malate capsules and for at least 4 weeks after the last dose. Males Based on findings in animal reproduction studies, advise males with female partners of reproductive potential to use effective contraception during treatment with sunitinib malate capsules and for 7 weeks after the last dose. Infertility Based on findings in animals, sunitinib malate capsules may impair male and female fertility [see Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use The safety and effectiveness of sunitinib malate capsules in pediatric patients have not been established. Safety and pharmacokinetics of sunitinib were assessed in an open-label study (NCT00387920) in pediatric patients 2 years to < 17 years of age (n = 29) with refractory solid tumors. In addition, efficacy, safety and pharmacokinetics of sunitinib was assessed in another open-label study (NCT01462695) in pediatric patients 2 years to < 17 years of age (n = 27) with high-grade glioma or ependymoma. The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults. Sunitinib was poorly tolerated in pediatric patients. The occurrence of dose-limiting cardiotoxicity prompted an amendment of the NCT00387920 study to exclude patients with previous exposure to anthracyclines or cardiac radiation. No responses were reported in patients in either of the trials. Apparent clearance and volume of distribution normalized for BSA for sunitinib and its active major metabolite were lower in pediatrics as compared to adults. The effect on open tibial growth plates in pediatric patients who received sunitinib malate capsules has not been adequately studied. See Juvenile Animal Toxicity Data below. Juvenile Animal Toxicity Data Physeal dysplasia was present in cynomolgus monkeys with open growth plates treated with sunitinib for ≥ 3 months (3 month dosing 2, 6, 12 mg/kg/day; 8 cycles of dosing 0.3, 1.5, 6.0 mg/kg/day) at doses that were > 0.4 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the RDD of 50 mg. The no-effect level (NOEL) was 1.5 mg/kg/day in monkeys treated intermittently for 8 cycles, but was not identified in monkeys treated continuously for 3 months. In developing rats treated continuously for 3 months (1.5, 5.0, and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day), bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses ≥ 5 mg/kg (approximately 10 times the combined AUC in patients administered the RDD of 50 mg). Additionally, tooth caries were present in rats at > 5 mg/kg. The incidence and severity of physeal dysplasia were dose related and reversible upon cessation of treatment; however, findings in the teeth were not. In rats, the NOEL in bones was ≤ 2 mg/kg/day. 8.5 Geriatric Use Of the 7527 patients with GIST, RCC (advanced and adjuvant), or pNET who received sunitinib malate capsules, 32% were 65 years and older, and 7% were 75 years and older. Patients aged 65 years of age and older had a higher incidence of Grade 3 or 4 adverse reactions (67%) than younger patients (60%). In the GIST study, 73 (30%) of the patients who received sunitinib malate capsules were 65 years and older. In the mRCC study, 152 (41%) of patients who received sunitinib malate capsules were 65 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients. In the pNET study, 22 (27%) of the patients who received sunitinib malate capsules were 65 years and older. Clinical studies of sunitinib malate capsules did not include sufficient numbers of patients with pNET to determine if patients 65 years of age and older respond differently than younger patients. 8.6 Hepatic Impairment No dose adjustment is required in patients with mild or moderate (Child-Pugh Class A or B) hepatic impairment [see Clinical Pharmacology (12.3) ] . Sunitinib malate capsules were not studied in patients with severe (Child-Pugh Class C) hepatic impairment. 8.7 Renal Impairment No dose adjustment is recommended in patients with mild (CLcr 50 to 80 mL/min), moderate (CLcr 30 to < 50 mL/min), or severe (CLcr < 30 mL/min) renal impairment who are not on dialysis [see Clinical Pharmacology (12.3) ] . No dose adjustment is recommended for patients with end-stage renal disease (ESRD) on hemodialysis [see Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Sunitinib Malate Capsules are available containing 12.5 mg, 25 mg, 37.5 mg or 50 mg of sunitinib equivalent to 16.7 mg, 33.4 mg, 50.1 mg or 66.8 mg of sunitinib malate, respectively. The 12.5 mg capsules are hard-shell gelatin capsules with a pink-brown opaque cap and pink-brown opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 12.5 in black ink on cap and body. They are available as follows: NDC 0378-6678-28 bottles of 28 capsules The 25 mg capsules are hard-shell gelatin capsules with a yellow opaque cap and pink-brown opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 25 in black ink on cap and body. They are available as follows: NDC 0378-6679-28 bottles of 28 capsules The 37.5 mg capsules are hard-shell gelatin capsules with an ivory opaque cap and ivory opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 37.5 in black ink on cap and body. They are available as follows: NDC 0378-6681-28 bottles of 28 capsules The 50 mg capsules are hard-shell gelatin capsules with a yellow opaque cap and yellow opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 50 in black ink on cap and body. They are available as follows: NDC 0378-6680-28 bottles of 28 capsules Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription.

WARNING: HEPATOTOXICITY Hepatotoxicity may be severe, and in some cases, fatal. Monitor hepatic function and interrupt, dose reduce, or discontinue sunitinib malate capsules as recommended [see Warnings and Precautions (5.1) ]. WARNING: HEPATOTOXICITY See full prescribing information for complete boxed warning. Hepatotoxicity may be severe, and in some cases fatal. Monitor hepatic function and interrupt, dose reduce, or discontinue sunitinib malate capsules as recommended [see Warnings and Precautions (5.1) ].