Sunitinib

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 .

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 o

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 =

7 DRUG INTERACTIONS CYP3A4 Inhibitors : Consider dose reduction of sunitinib malate when administered with strong CYP3A4 inhibitors. ( 7.1 ) CYP3A4 Inducers : Consider dose increase of sunitinib malate when administered with strong CYP3A4 inducers. ( 7.1 ) 7.1 Effect of Other Drugs on Sunitinib Malate 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 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 when it must be co‑administered with CYP3A4 inducers [see Dosage and Administration ( 2.5 )] . 7.2 Drugs that Prolong QT Interval Sunitinib malate is 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.