SUTENT

1 INDICATIONS AND USAGE SUTENT 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 SUTENT is 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 SUTENT is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC). 1.3 Adjuvant Treatment of Renal Cell Carcinoma SUTENT is indicated for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy. 1.4 Advanced Pancreatic Neuroendocrine Tumors SUTENT is 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 SUTENT 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. SUTENT may be taken with or without food. 2.2 Recommended Dosage for Adjuvant Treatment of RCC The recommended dosage of SUTENT 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. SUTENT may be taken with or without food. 2.3 Recommended Dosage for pNET The recommended dosage of SUTENT for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily until disease progression or unacceptable toxicity. SUTENT 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 SUTENT for adverse reactions. Table 1. Recommended Dosage Reductions of SUTENT 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 SUTENT for Adverse Reactions Adverse Reaction Severity Dosage Modifications for SUTENT 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 SUTENT after osteonecrosis has not been established. • Either resume at a reduced dose or d…

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity : Fatal liver failure has been observed. Monitor liver function tests at baseline, during each cycle, and as clinically indicated. Interrupt SUTENT for Grade 3 hepatotoxicity until resolution to Grade ≤1 or baseline and resume SUTENT at a reduced dose; discontinue if no resolution. Discontinue SUTENT in patients with Grade 4 hepatoxicity, in patients who have subsequent severe changes in liver function tests or other signs and symptoms of liver failure. ( 2.4 , 5.1 ) • Cardiovascular Events : Myocardial ischemia, myocardial infarction, heart failure, cardiomyopathy, and decreased left ventricular ejection fraction (LVEF) to below the lower limit of normal including death have occurred. Monitor for signs and symptoms of congestive heart failure and consider monitoring LVEF at baseline and periodically during treatment. Discontinue SUTENT for clinical manifestations of congestive heart failure. Interrupt and/or dose reduce for decreased LVEF. ( 5.2 ) • QT Interval Prolongation and Torsade de Pointes : Monitor patients at higher risk for developing QT interval prolongation. Consider monitoring of electrocardiograms and electrolytes. ( 5.3 ) • Hypertension : Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. Interrupt SUTENT for Grade 3 hypertension until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose. Discontinue SUTENT in patients who develop Grade 4 hypertension. ( 5.4 ) • Hemorrhagic Events : Tumor-related hemorrhage and viscus perforation (both with fatal events) have occurred. Perform serial complete blood counts and physical examinations. Interrupt SUTENT for Grade 3 or 4 hemorrhagic events until resolution to Grade ≤1 or baseline, then resume at a reduced dose; discontinue if no resolution. ( 5.5 ) • Tumor Lysis Syndrome (TLS) : TLS (some fatal) has been reported primarily in patients with RCC and GIST. Monitor these patients and treat as clinically indicated. ( 5.6 ) • Thrombotic microangiopathy (TMA) : TMA, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, has been reported. Discontinue SUTENT for TMA. ( 5.7 ) • Proteinuria : Renal failure or a fatal outcome has occurred. Monitor urine protein. Interrupt treatment for 24-hour urine protein of 3 or more grams. Discontinue for repeat episodes of 24-hour urine protein of 3 or more grams despite dose reductions or nephrotic syndrome. ( 5.8 ) • Dermatologic Toxicities : Necrotizing fasciitis, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (some fatal) have occurred. Discontinue SUTENT for these events. ( 5.9 ) • Reversible Posterior Leukoencephalopathy Syndrome (RPLS) : RPLS (some fatal) has been reported. Monitor for signs and symptoms of RPLS. Withhold SUTENT until resolution. ( 5.10 ) • Thyroid Dysfunction : Monitor thyroid function at baseline, periodically during treatment, and as clinically indicated. Initiate and/or adjust therapy for thyroid dysfunction as appropriate. ( 5.11 ) • Hypoglycemia : Check blood glucose levels regularly and assess if antidiabetic drug dose modifications are required. ( 5.12 ) • Osteonecrosis of the Jaw (ONJ) : Withhold SUTENT for at least 3 weeks prior to invasive dental procedure and for development of ONJ until complete resolution. ( 5.13 ) • Impaired Wound Healing : Withhold SUTENT for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of SUTENT after resolution of wound healing complications has not been established. ( 5.14 ) • Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.15 , 8.1 , 8.3 ) 5.1 Hepatotoxicity SUTENT can cause severe hepatotoxicity, resulting in liver failure…

4 CONTRAINDICATIONS None. None ( 4 )

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

8.1 Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action, SUTENT 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 are 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.

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 Pfizer Inc. at 1-800-438-1985 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 SUTENT 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 SUTENT was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received SUTENT 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 SUTENT (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 SUTENT arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received SUTENT. Table 3 summarizes the adverse reactions for Study 1. Table 3. Adverse Reactions Reported in ≥10% of GIST Patients Who Received SUTENT 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 Adverse Reaction GIST SUTENT (N=202) Placebo (N=102) All Grades % Grade 3–4 % All Grades % Grade 3–4 % Abbreviations: GIST=gastrointestinal stromal tumor; N=number of patients. 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 SUTENT. Table 4 summarizes the laboratory abnormalities in Study 1. Table 4. Laboratory Abnormalities Reported in ≥10% of …