Sunitinib Malate

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 S e verity 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)].

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 sunitinib malate for Grade 3 hepatotoxicity until resolution to Grade ≤1 or baseline and resume sunitinib malate at a reduced dose; discontinue if no resolution. Discontinue sunitinib malate 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 sunitinib malate 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 sunitinib malate for Grade 3 hypertension until resolution to Grade ≤1 or baseline, then resume sunitinib malate at a reduced dose. Discontinue sunitinib malate 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 sunitinib malate 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 sunitinib malate 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 sunitinib malate for these events. ( 5.9 ) Reversible Posterior Leukoencephalopathy Syndrome (RPLS) : RPLS (some fatal) has been reported. Monitor for signs and symptoms of RPLS. Withhold sunitinib malate 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 sunitinib malate for at least 3 weeks prior to invasive dental procedure and for development of ONJ until complete resolution. ( 5.13 ) Impaired Wound Healing : Withhold sunitinib malate 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 sunitinib malate 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 Sunitinib malate can cause severe hepatotoxicity, resulting in liver failure or death. In the pooled safety population, liver failure occurred in <1% of patients in clinical trials. Liver failure include jaundiced, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) at baseline, during each cycle, and as clinically indicated. Interrupt sunitinib malate for Grade 3 hepatotoxicity until resolution to Grade ≤1 or baseline, then resume sunitinib malate at a reduced dose. Discontinue sunitinib malate in patients with Grade 4 hepatotoxicity, in patients without resolution of Grade 3 hepatotoxicity, in patients who subsequently experience severe changes in liver function tests and in patients who have other signs and symptoms of liver failure. Safety in patients with ALT or AST >2.5 x upper limit of normal (ULN) or with >5 x ULN and liver metastases has not been established.

5.2 Cardiovascular Events Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been reported. In pooled safety population, 3% of patients experienced heart failure; 71% of the patients with heart failure were reported as recovered. Fatal cardiac failure was reported in <1% of patients. In the adjuvant treatment of RCC study, 11 patients experienced Grade 2 decreased ejection fraction (left ventricular ejection fraction [LVEF] 40% to 50% and a 10% to 19% decrease from baseline). In 3 of these 11 patients, the ejection fractions arm did not return to ≥50% or baseline by the time of last measurement. No patients who received sunitinib malate were diagnosed with CHF. Patients who presented with cardiac events within 12 months prior to sunitinib malate administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from sunitinib malate clinical studies. Patients with prior anthracycline use or cardiac radiation were also excluded from some studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing left ventricular dysfunction. Consider monitoring LVEF at baseline and periodically as clinically indicated. Carefully monitor patients for clinical signs and symptoms of congestive heart failure (CHF). Discontinue sunitinib malate in patients who experience clinical manifestations of CHF. Interrupt sunitinib malate and/or reduce the dose in patients without clinical evidence of CHF who have an ejection fraction of greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline ejection fraction was not obtained.

5.3 QT Interval Prolongation and Torsade de Pointes Sunitinib malate can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes.Torsade de Pointes was observed in <0.1% of patients. Monitor patients who are at higher risk of developing QT interval prolongation, including patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Consider periodic monitoring of electrocardiograms and electrolytes (i.e., magnesium, potassium) during treatment with sunitinib malate. Monitor QT interval more frequently when sunitinib malate is concomitantly administered with strong CYP3A4 inhibitors or drugs known to prolong QT interval. Consider dose reducing sunitinib malate [see Dosage and Administration (2.5) , Drug Interactions (7.2) ].

5.4 Hypertension In the pooled safety population, 29% of patients experienced hypertension. Grade 3 hypertension was reported in 7% of patients, and Grade 4 hypertension was reported in 0.2%. Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. In cases of Grade 3 hypertension, withhold sunitinib malate until resolution to Grade ≤1 or baseline, then resume sunitinib malate at a reduced dose. Discontinue sunitinib malate in patients with who develop Grade 4 hypertension.

5.5 Hemorrhagic Events and Viscus Perforation Hemorrhagic events, some of which were fatal, have involved the gastrointestinal tract, respiratory tract, tumor, urinary tract, and brain. In the pooled safety population, 30% of patients experienced hemorrhagic events, including Grade 3 or 4 in 4.2% of patients. Epistaxis was the most common hemorrhagic event and gastrointestinal hemorrhage was the most common Grade 3-5 event. Tumor-related hemorrhage was observed in patients treated with sunitinib malate. These events may occur suddenly, and in the case of pulmonary tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Pulmonary hemorrhage, some with a fatal outcome, was observed in patients treated with sunitinib malate for metastatic RCC, GIST, and metastatic lung cancer. Sunitinib malate is not approved for use in patients with lung cancer. Serious, sometimes fatal, gastrointestinal complications including gastrointestinal perforation, have been reported in patients with intra-abdominal malignancies treated with sunitinib malate. Include serial complete blood counts (CBCs) and physical examinations with the clinical assessment of hemorrhagic events. Interrupt sunitinib malate for Grade 3 or 4 hemorrhagic events until resolution to Grade ≤1 or baseline, then resume sunitinib malate at a reduced dose. Discontinue sunitinib malate in patients without resolution of Grade 3 or 4 hemorrhagic events.

5.6 Tumor Lysis Syndrome (TLS) Tumor Lysis Syndrome (TLS), some fatal, occurred in clinical trials and has been reported in postmarketing experience, primarily in patients with RCC or GIST. Patients generally at risk of TLS are those with high tumor burden prior to treatment. Monitor these patients for TLS and manage as appropriate.

5.7 Thrombotic Microangiopathy (TMA) Thrombotic Microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, occurred in clinical trials and in postmarketing experience of sunitinib malate as monotherapy and administered in combination with bevacizumab. Sunitinib malate is not approved for use in combination with bevacizumab. Discontinue sunitinib malate in patients developing TMA. Reversal of the effects of TMA has been observed after sunitinib malate was discontinued.

5.8 Proteinuria Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Monitor patients for the development or worsening of proteinuria. Perform baseline and periodic urinalyses during treatment, with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt sunitinib malate and dose reduce for 24-hour urine protein of 3 or more grams. Discontinue sunitinib malate for patients with nephrotic syndrome or repeat episodes of 24-hour urine protein of 3 or more grams despite dose reductions. The safety of continued sunitinib malate treatment in patients with moderate to severe proteinuria has not been evaluated.

5.9 Dermatologic Toxicities Severe cutaneous adverse reactions have been reported, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. Permanently discontinue sunitinib malate for these severe cutaneous adverse reactions. Necrotizing fasciitis, including fatal cases, has been reported in patients treated with sunitinib malate, including of the perineum and secondary to fistula formation. Discontinue sunitinib malate in patients who develop necrotizing fasciitis.

5.10 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in <1% of patients, some of which were fatal. Patients can present with hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness. Magnetic resonance imaging is necessary to confirm the diagnosis. Discontinue sunitinib malate in patients developing RPLS.

5.11 Thyroid Dysfunction Hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through postmarketing experience of sunitinib malate. Monitor thyroid function at baseline, periodically during treatment and as clinically indicated. Monitor patients closely for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, during treatment with sunitinib malate. Initiate and/or adjust therapies for thyroid dysfunction as appropriate.

5.12 Hypoglycemia Sunitinib malate can result in symptomatic hypoglycemia, which may lead to loss of consciousness, or require hospitalization. In the pooled safety population, hypoglycemia occurred in 2% of the patients treated with sunitinib malate. Hypoglycemia has occurred in clinical trials in 2% of the patients treated with sunitinib malate for advanced RCC (Study 3) and GIST (Study 1) (n=577) and in approximately 10% of the patients treated with sunitinib malate for pNET (Study 6) (n=83). For patients being treated with sunitinib malate for pNET, pre-existing abnormalities in glucose homeostasis were not present in all patients who experienced hypoglycemia. Reductions in blood glucose levels may be worse in patients with diabetes. Check blood glucose levels at baseline, regularly during treatment, as clinically indicated and after discontinuation of sunitinib malate. In patients with diabetes, assess if antidiabetic therapies need to be adjusted to minimize the risk of hypoglycemia.

5.13 Osteonecrosis of the Jaw (ONJ) Osteonecrosis of the Jaw (ONJ) occurred in patients treated with sunitinib malate. Concomitant exposure to other risk factors, such as bisphosphonates or dental disease/invasive dental procedures, may increase the risk of ONJ. Perform an oral examination prior to initiation of sunitinib malate and periodically during sunitinib malate therapy. Advise patients regarding good oral hygiene practices. Withhold sunitinib malate treatment for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold sunitinib malate for development of ONJ until complete resolution. The safety of resumption of sunitinib malate after resolution of osteonecrosis of the jaw has not been established.

5.14 Impaired Wound Healing Impaired wound healing has been reported in patients who received sunitinib malate [see Adverse Reactions (6.2) ]. Withhold sunitinib malate 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 sunitinib malate after resolution of wound healing complications has not been established.

5.15 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, sunitinib malate can cause fetal harm when administered to pregnant woman. Administration of sunitinib to pregnant rats and rabbits during the period of organogenesis resulted in teratogenicity at approximately 5.5 and 0.3 times the combined systemic exposure [combined area under the curve (AUC) of sunitinib plus its active metabolite] in patients administered the recommended daily dose (RDD) of 50 mg, respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with sunitinib malate and for 4 weeks following the final dose [see Use in Specific Populations (8.1 , 8.3 )].

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 Novadoz Pharmaceuticals LLC at 1-855-668-2369 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 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: 1-9) 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 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 3-4 % All Grades % Grade 3-4 % Any Adverse Reaction 94 56 97 51 Gastrointestinal Diarrhea Mucositis/stomatitis Constipation 40 29 20 4 1 0 27 18 14 0 2 2 Metabolism/Nutrition Anorexia a Asthenia 33 22 1 5 29 11 5 3 Dermatology Skin discoloration Rash Hand-foot syndrome 30 14 14 0 1 4 23 9 10 0 0 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 3-4* ,a % All Grades* % Grade 3-4* ,b % Any Laboratory Abnormality 34 22 Hematology Neutrophils decreased Lymphocytes decreased Platelets decreased Hemoglobin decreased 53 38 38 26 10 0 5 3 4 16 4 22 0 0 0 2 Gastrointestinal AST/ALT increased Lipase increased Alkaline phosphatase increased Amylase increased Total bilirubin increased Indirect bilirubin increased 39 25 24 17 16 10 2 10 4 5 1 0 23 17 21 12 8 4 1 7 4 3 0 0 Renal/Metabolic Creatinine increased Potassium decreased Sodium increased 12 12 10 1 1 0 7 4 4 0 0 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: 1–44). For the 255 patients who ultimately received open-label sunitinib malate treatment, median duration of treatment was 6 cycles (mean: 7.8; range: 1–37) 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 3-4 a % All Grades % Grade 3-4 b % Any Adverse Reaction 99 77 99 55 Gastrointestinal Diarrhea Nausea Mucositis/stomatitis Vomiting Dyspepsia Abdominal pain c Constipation Dry mouth Oral pain Flatulence GERD/reflux esophagitis Glossodynia Hemorrhoids 66 58 47 39 34 30 23 13 14 14 12 11 10 10 6 3 5 2 5 1 0 <1 0 <1 0 0 21 41 5 17 4 12 14 7 1 2 1 1 2 <1 2 <1 1 0 1 <1 <1 0 0 0 0 0 Constitutional Fatigue Asthenia Fever Weight decreased Chills Chest Pain Influenza like illness 62 26 22 16 14 13 5 15 11 1 <1 1 2 0 56 22 37 17 31 7 15 15 6 <1 1 0 1 <1 Metabolism/Nutrition Anorexia d 48 3 42 2 Neurology Altered taste e Headache Dizziness 47 23 11 <1 1 <1 15 19 14 0 0 1 Hemorrhage/Bleeding Bleeding, all sites 37 4 f 10 1 Cardiac Hypertension Edema peripheral Ejection fraction decreased 34 24 16 13 2 3 4 5 5 <1 1 2 Dermatology Rash Hand-foot syndrome Skin discoloration/yellow skin Dry skin Hair color changes Alopecia Erythema Pruritus 29 29 25 23 20 14 12 12 2 8 <1 <1 0 0 <1 <1 11 1 0 7 <1 9 1 7 <1 0 0 0 0 0 0 <1 Musculoskeletal Pain in extremity/limb discomfort Arthralgia Back pain 40 30 28 5 3 5 30 19 14 2 1 2 Respiratory Cough Dyspnea Nasopharyngitis Oropharyngeal pain Upper respiratory tract infection 27 26 14 14 11 1 6 0 <1 <1 14 20 2 2 2 <1 4 0 0 0 Endocrine Hypothyroidism 16 2 1 0 Psychiatric Insomnia Depression g 15 11 <1 0 10 14 0 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 3-4* ,a % All Grades* % Grade 3-4* ,b % Hematology Hemoglobin decreased Neutrophils decreased Platelets decreased Lymphocytes decreased 79 77 68 68 8 17 9 18 69 49 24 68 5 9 1 26 Renal/Metabolic Creatinine increased Creatine kinase increased Uric acid increased Calcium increased Phosphorus decreased Albumin decreased Glucose increased Sodium decreased Glucose decreased Potassium increased Calcium increased Potassium decreased Sodium increased 70 49 46 42 31 28 23 20 17 16 13 13 13 <1 2 14 1 6 1 6 8 0 3 <1 1 0 51 11 33 40 24 20 15 15 12 17 10 2 10 <1 1 8 1 6 0 6 4 <1 4 1 <1 0 Gastrointestinal AST increased Lipase increased ALT increased Alkaline phosphatase increased Amylase increased Total bilirubin increased Indirect bilirubin increased 56 56 51 46 35 20 13 2 18 3 2 6 1 1 38 46 40 37 32 2 1 2 8 2 2 3 0 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 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 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 3-4 % All Grades % Grade 3-4 % Any Adverse Reaction 99 60 88 15 Gastrointestinal Mucositis/Stomatitis a Diarrhea Nausea Dyspepsia Abdominal pain b Vomiting Constipation 61 57 34 27 25 19 12 6 4 2 1 2 2 0 15 22 15 7 9 7 11 0 <1 0 0 <1 0 0 Constitutional Fatigue/Asthenia Localized edema c Pyrexia 57 18 12 8 <1 <1 34 <1 6 2 0 0 Dermatology Hand-foot syndrome Rash d Hair color changes Skin discoloration/Yellow skin Dry skin 50 24 22 18 14 16 2 0 0 0 10 12 2 1 6 <1 0 0 0 0 Cardiac Hypertension e Edema/Peripheral edema 39 10 8 <1 14 7 1 0 Neurology Altered taste f Headache 38 19 <1 <1 6 12 0 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 Arthralgia 15 11 <1 <1 7 10 0 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, gingiva lbleeding, 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 3-4 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: 13-532 days) for patients on sunitinib malate and 113 days (range: 1-614 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 3-4 a % All Grades % Grade 3-4 % Any Adverse Reaction 99 54 95 50 Gastrointestinal Diarrhea Stomatitis/oral syndromes b Nausea Abdominal pain c Vomiting Dyspepsia 59 48 45 39 34 15 5 6 1 5 0 0 39 18 29 34 31 6 2 0 1 10 2 0 Constitutional Asthenia Fatigue Weight decreased 34 33 16 5 5 1 27 27 11 4 9 0 Dermatology Hair color changes Hand-foot syndrome Rash Dry skin 29 23 18 15 1 6 0 0 1 2 5 11 0 0 0 0 Cardiac Hypertension 27 10 5 1 Hemorrhage /Bleeding Bleeding events d Epistaxis 22 21 0 1 10 5 4 0 Neurology Dysgeusia Headache 21 18 0 0 5 13 0 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 3-4* ,a % All Grades* % Grade 3-4* ,b % Gastrointestinal AST increased Alkaline phosphatase increased ALT increased Total bilirubin increased Amylase increased Lipase increased 72 63 61 37 20 17 5 10 4 1 4 5 70 70 55 28 10 11 3 11 3 4 1 4 Hematology Neutrophils decreased Hemoglobin decreased Platelets decreased Lymphocytes decreased 71 65 60 56 16 0 5 7 16 55 15 35 0 1 0 4 Renal/Metabolic Glucose increased Albumin decreased Phosphorus decreased Calcium decreased Sodium decreased Creatinine increased Glucose decreased Potassium decreased Magnesium decreased Potassium increased 71 41 36 34 29 27 22 21 19 18 12 1 7 0 2 5 2 4 0 1 78 37 22 19 34 28 15 14 10 11 18 1 5 0 3 5 4 0 0 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 3-4 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

Lactation : Advise not to breastfeed. ( 8.2 )

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

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 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 malate 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. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with sunitinib malate 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 and for 7 weeks after the last dose. Infertility Based on findings in animals, sunitinib malate may impair male and female fertility [ see Nonclinical Toxicology (13.1) ].

8.4 Pediatric Use The safety and effectiveness of sunitinib malate 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 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 mg/kg/day) at doses that were >0.4 times the 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, and 15 mg/kg) or 5 cycles (0.3, 1.5, and 6 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, 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 were 65 years and older. In the mRCC study, 152 (41%) of patients who received sunitinib malate 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 were 65 years and older. Clinical studies of sunitinib malate 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 was 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) ].

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 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 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 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 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 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 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.

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 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 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 [ 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 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 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 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 impairs 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 [ 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 [ see Use in Specific Populations (8.3) ]. Lactation Advise women not to breastfeed during treatment with sunitinib malate and for at least 4 weeks after the last dose [ see Use in Specific Populations (8.2) ]. Infertility Advise patients that sunitinib malate 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 by less than 12 hours to take the missed dose right away. Advise patients that miss a dose of sunitinib malate by more than 12 hours to take the next scheduled dose at its regular time. This product’s labeling may have been updated. For the most recent prescribing information, please visit http://www.msnlabs.com. Manufactured by: MSN Laboratories Private Limited Telangana – 509 228, INDIA Distributed by: Novadoz Pharmaceuticals LLC Piscataway, NJ 08854 -3714 Issued on: February 2025