Sunitinib Malate

1 INDICATIONS AND USAGE Sunitinib malate is 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.

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 )] .

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 Novugen Pharma (USA) LLC at 1-888-966-8843 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 7,527 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 was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received sunitinib malate 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 (mean: 3.0; range: 1 to 9) and 1 cycle (mean; 1.8; range: 1 to 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 arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received sunitinib malate. Table 3 summarizes the adverse reactions for Study 1. Table 3. Adverse Reactions Reported in ≥10% of GIST Patients Who Received Sunitinib Malate in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo* in Study 1 Adverse Reaction GIST Sunitinib Malate (N = 202) Placebo (N = 102) All Grades % Grade 3 to 4 % All Grades % Grade 3 to 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 a 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 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: GIST = gastrointestinal stromal tumor; N = number of patients. a Includes decreased appetite. 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. Table 4 summarizes the laboratory abnormalities in Study 1. Table 4. Laboratory Abnormalities Reported in ≥10% of GIST Patients Who Received Sunitinib Malate or Placebo in the Double-Blind Treatment Phase* in Study 1 Laboratory Abnormality GIST Sunitinib Malate (N = 202) Placebo (N = 102) All Grades* % Grade 3 to 4* ,a % All Grades* % Grade 3 to 4* ,b % 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 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GIST = gastrointestinal stromal tumor; LVEF = left ventricular ejection fraction; N = number of patients. a Grade 4 laboratory abnormalities in patients on sunitinib malate included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%). b Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%). After an interim analysis , the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label sunitinib malate [see Clinical Studies ( 14.1 )] . For 241 patients randomized to the sunitinib malate arm, including 139 who received sunitinib malate in both the double-blind and open-label phases, the median duration of sunitinib malate treatment was 6 cycles (mean: 8.5; range: 1 to 44). For the 255 patients who ultimately received open-label sunitinib malate treatment, median duration of treatment was 6 cycles (mean: 7.8; range: 1 to 37) from the time of the unblinding. Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received sunitinib malate. Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received sunitinib malate. The most common Grade 3 or 4 adverse reactions in patients who received sunitinib malate 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 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 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 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 arm. Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received sunitinib malate. Table 5 summarizes the adverse reactions for Study 3. Table 5. Adverse Reactions Reported in ≥10% of Patients with RCC Who Received Sunitinib Malate or Interferon Alfa* in Study 3 Adverse Reaction Treatment-Naïve RCC Sunitinib Malate (N = 375) Interferon Alfa (N = 360) All Grades % Grade 3 to 4 a % All Grades % Grade 3 to 4 b % 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 c 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 d 48 3 42 2 Neurology Altered taste e 47 <1 15 0 Headache 23 1 19 0 Dizziness 11 <1 14 1 Hemorrhage/Bleeding Bleeding, all sites 37 4 f 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 g 11 0 14 1 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma. a Grade 4 ARs in patients on sunitinib malate included back pain (1%), arthralgia (<1%), dyspnea (<1%), asthenia (<1%), fatigue (<1%), limb pain (<1%), and rash (<1%). b Grade 4 ARs in patients on interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (<1%), and depression (<1%). c Includes flank pain. d Includes decreased appetite. e Includes ageusia, hypogeusia, and dysgeusia. f Includes 1 patient with Grade 5 gastric hemorrhage. g Includes depressed mood. Table 6 summarizes the laboratory abnormalities in Study 3. Table 6. Laboratory Abnormalities Reported in ≥10% of RCC Patients Who Received Sunitinib Malate or Interferon Alfa in Study 3 Laboratory Abnormality Treatment-Naïve RCC Sunitinib Malate (N = 375) Interferon Alfa (N = 360) All Grades* % Grade 3 to 4* ,a % All Grades* % Grade 3 to 4* ,b % 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 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; RCC = renal cell carcinoma. a Grade 4 laboratory abnormalities in patients on sunitinib malate 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%). b 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%). Long-Term Safety in RCC The long-term safety of sunitinib malate 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 5,739 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 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 was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who had undergone nephrectomy for RCC received sunitinib malate 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 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 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. Table 7 summarizes the adverse reactions in S-TRAC. Table 7. Adverse Reactions Reported in ≥10% of Patients with RCC Who Received Sunitinib Malate and More Commonly Than in Patients Given Placebo* in S-TRAC Adverse Reaction Adjuvant Treatment of RCC Sunitinib Malate (N = 306) Placebo (N = 304) All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Any Adverse Reaction 99 60 88 15 Gastrointestinal Mucositis/Stomatitis a 61 6 15 0 Diarrhea 57 4 22 <1 Nausea 34 2 15 0 Dyspepsia 27 1 7 0 Abdominal pain b 25 2 9 <1 Vomiting 19 2 7 0 Constipation 12 0 11 0 Constitutional Fatigue/Asthenia 57 8 34 2 Localized edema c 18 <1 <1 0 Pyrexia 12 <1 6 0 Dermatology Hand-foot syndrome 50 16 10 <1 Rash d 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 e 39 8 14 1 Edema/Peripheral edema 10 <1 7 0 Neurology Altered taste f 38 <1 6 0 Headache 19 <1 12 0 Endocrine Hypothyroidism/TSH increased 24 <1 4 0 Hemorrhage/Bleeding Bleeding events, all sites g 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 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma. a Includes mucosal inflammation, stomatitis aphthous ulcer, mouth ulceration, tongue ulceration, oropharyngeal pain, and oral pain. b Includes abdominal pain, abdominal pain lower, and abdominal pain upper. c Includes edema localized, face edema, eyelid edema, periorbital edema, swelling face, and eye edema. d Includes dermatitis, dermatitis psoriasiform, exfoliative rash, genital rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic. e Includes hypertension, blood pressure increased, blood pressure systolic increased, blood pressure diastolic increased, and hypertensive crisis. f Includes ageusia, hypogeusia, and dysgeusia. g Includes epistaxis, gingival bleeding, rectal hemorrhage, hemoptysis, anal hemorrhage, upper gastrointestinal hemorrhage, and hematuria. Grade 4 adverse reactions in patients on sunitinib malate included hand-foot syndrome (1%), fatigue (<1%), abdominal pain (< 1%), stomatitis (<1%), and pyrexia (< 1%). Grade 3 to 4 laboratory abnormalities that occurred in ≥2% of patients receiving sunitinib malate 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 was evaluated in Study 6, a randomized, double-blind, placebo-controlled trial in which patients with progressive pNET received sunitinib malate 37.5 mg once daily (n = 83) or placebo (n = 82). The median number of days on treatment was 139 days (range: 13 days to 532 days) for patients on sunitinib malate and 113 days (range: 1 day to 614 days) for patients on placebo. Nineteen patients (23%) on sunitinib malate 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 arm. Dose interruptions occurred in 30% and dose reductions occurred in 31% of patients who received sunitinib malate. Table 8 summarizes the adverse reactions in Study 6. Table 8. Adverse Reactions Reported in ≥10% of Patients with pNET Who Received Sunitinib Malate and More Commonly Than in Patients Given Placebo* in Study 6 Adverse Reaction pNET Sunitinib Malate (N = 83) Placebo (N = 82) All Grades % Grade 3 to 4 a % All Grades % Grade 3 to 4 % Any Adverse Reaction 99 54 95 50 Gastrointestinal Diarrhea 59 5 39 2 Stomatitis/oral syndromes b 48 6 18 0 Nausea 45 1 29 1 Abdominal pain c 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 d 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 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: N = number of patients; pNET = pancreatic neuroendocrine tumors. a Grade 4 adverse reactions in patients on sunitinib malate included fatigue (1%). b Includes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth. c Includes abdominal discomfort, abdominal pain, and abdominal pain upper. d Includes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia. Table 9 summarizes the laboratory abnormalities in Study 6. Table 9. Laboratory Abnormalities Reported in ≥10% of Patients with pNET Who Received Sunitinib Malate in Study 6 Laboratory Abnormality pNET Sunitinib Malate Placebo All Grades* % Grade 3 to 4* ,a % All Grades* % Grade 3 to 4* ,b % 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 * The denominator used to calculate the rate varied from 52 to 82 for sunitinib malate 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. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; pNET = pancreatic neuroendocrine tumors. a Grade 4 laboratory abnormalities in patients on sunitinib malate 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%). b Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%), and lipase (1%). Venous Thromboembolic Events In pooled safety population, 3.5% of patients experienced a venous thromboembolic event, including Grade 3 to 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sunitinib malate. 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 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

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 times 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-fold to 4-fold while the primary metabolite accumulates 7-fold to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 days to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 63 ng/mL to 101 ng/mL. Absorption Following oral administration of sunitinib, the time to maximum plasma concentration (T max ) ranged from 6 hours to 12 hours. Effect of Food The administration of a single dose of sunitinib malate 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 malate or active metabolites exposure. Distribution The apparent volume of distribution (Vd/F) for sunitinib is 2,230 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 ng/mL to 4,000 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 hours to 60 hours and 80 hours to 110 hours, respectively. Sunitinib total oral clearance (CL/F) ranged from 34 L/h 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 radio-labeled dose, sunitinib and its active metabolite were the major compounds identified in plasma, accounting for 92% of radioactivity. Excretion After a radio-labeled 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 years to 84 years), body weight (34 kg 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 mL/min to 80 mL/min), moderate (CLcr 30 mL/min 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 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 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.