ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling.oHepatotoxicity [see Warnings and Precautions (5.1)]oCardiovascular Events [see Warnings and Precautions (5.2)]oQT Interval Prolongation and Torsade de Pointes [see Warnings and Precautions (5.3)]oHypertension [see Warnings and Precautions (5.4)]oHemorrhagic Events [see Warnings and Precautions (5.5)]oTumor Lysis Syndrome [see Warnings and Precautions (5.6)]oThrombotic Microangiopathy [see Warnings and Precautions (5.7)]oProteinuria [see Warnings and Precautions (5.8)]oDermatologic Toxicities [see Warnings and Precautions (5.9)]oReversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10)]oThyroid Dysfunction [see Warnings and Precautions (5.11)]oHypoglycemia [see Warnings and Precautions (5.12)]oOsteonecrosis of the Jaw [see Warnings and Precautions (5.13)]oImpaired Wound Healing [see Warnings and Precautions (5.14)]. oHepatotoxicity [see Warnings and Precautions (5.1)]. oCardiovascular Events [see Warnings and Precautions (5.2)]. oQT Interval Prolongation and Torsade de Pointes [see Warnings and Precautions (5.3)]. oHypertension [see Warnings and Precautions (5.4)]. oHemorrhagic Events [see Warnings and Precautions (5.5)]. oTumor Lysis Syndrome [see Warnings and Precautions (5.6)]. oThrombotic Microangiopathy [see Warnings and Precautions (5.7)]. oProteinuria [see Warnings and Precautions (5.8)]. oDermatologic Toxicities [see Warnings and Precautions (5.9)]. oReversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10)]. oThyroid Dysfunction [see Warnings and Precautions (5.11)]. oHypoglycemia [see Warnings and Precautions (5.12)]. oOsteonecrosis of the Jaw [see Warnings and Precautions (5.13)]. oImpaired Wound Healing [see Warnings and Precautions (5.14)]. oThe most common adverse reactions (>= 25%) are fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia. (6)To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oThe 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). 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The pooled safety population described in the Warnings and Precautions reflect exposure to sunitinib malate in 7527 patients with GIST, RCC (advanced and adjuvant), or pNET. In this pooled safety population, the most common adverse reactions (>= 25%) were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia.. Gastrointestinal Stromal Tumor. The safety of sunitinib malate capsules was evaluated in Study 1, randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received sunitinib malate capsules 50 mg daily on Schedule 4/2 (n 202) or placebo (n 102). Median duration of blinded study treatment was cycles for patients on sunitinib malate capsules (mean: 3.0; range: 1-9) and cycle (mean; 1.8; range: 1-6) for patients on placebo at the time of the interim analysis. Permanent discontinuation due to an adverse reaction occurred in 7% of patients in the sunitinib malate capsules arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received sunitinib malate capsules.Table summarizes the adverse reactions for Study 1.Table 3. Adverse Reactions Reported in >= 10% of GIST Patients Who Received Sunitinib Malate Capsules in the Double-Blind Treatment Phase and More Commonly Than in Patients Given PlaceboCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 1Abbreviations: GIST gastrointestinal stromal tumor; = number of patients.Adverse ReactionGISTSunitinib Malate Capsules(N 202)Placebo(N 102)All Grades %Grade 3-4%All Grades %Grade 3-4%Any Adverse Reaction94569751Gastrointestinal Diarrhea404270 Mucositis/stomatitis291182 Constipation200142Metabolism/Nutrition AnorexiaIncludes decreased appetite. 331295 Asthenia225113Dermatology Skin discoloration300230 Rash14190 Hand-foot syndrome144103Neurology Altered taste210120Cardiac Hypertension154110Musculoskeletal Myalgia/limb pain14191Other clinically relevant adverse reactions included oral pain other than mucositis/stomatitis in 6%; hair color changes in 7%; alopecia in 5% of patients who received sunitinib malate capsules.Table summarizes the laboratory abnormalities in Study 1. Table 4. Laboratory Abnormalities Reported in >= 10% of GIST Patients Who Received Sunitinib Malate Capsules or Placebo in the Double-Blind Treatment PhaseCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 1Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; GIST gastrointestinal stromal tumor; LVEF left ventricular ejection fraction; = number of patients.Laboratory AbnormalityGISTSunitinib Malate Capsules(N 202)Placebo(N 102)All Grades%Grade 3-4,Grade laboratory abnormalities in patients on sunitinib malate capsules included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%).%All Grades %Grade 3-4,Grade laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%).%Any Laboratory Abnormality3422Hematology Neutrophils decreased531040 Lymphocytes decreased380160 Platelets decreased38540 Hemoglobin decreased263222Gastrointestinal AST/ALT increased392231 Lipase increased2510177 Alkaline phosphatase increased244214 Amylase increased175123 Total bilirubin increased16180 Indirect bilirubin increased10040Renal/Metabolic Creatinine increased12170 Potassium decreased12140 Sodium increased10041Cardiac Decreased LVEF11130After an interim analysis, the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label sunitinib malate capsules [see Clinical Studies (14.1)]. For 241 patients randomized to the sunitinib malate capsules arm, including 139 who received sunitinib malate capsules in both the double-blind and open-label phases, the median duration of sunitinib malate capsules treatment was cycles (mean: 8.5; range: 1-44). For the 255 patients who ultimately received open-label sunitinib malate capsules treatment, median duration of treatment was cycles (mean: 7.8; range: 1-37) from the time of the unblinding. Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received sunitinib malate capsules. Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received sunitinib malate capsules.The most common Grade or adverse reactions in patients who received sunitinib malate capsules in the open-label phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%).. Advanced Renal Cell Carcinoma. The safety of sunitinib malate capsules was evaluated in Study 3, double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received sunitinib malate capsules 50 mg daily on Schedule 4/2 (n 375) or interferon alfa million International Units (MIU) (n 360). The median duration of treatment was 11.1 months (range: 0.4 to 46.1) for sunitinib malate capsules treatment and 4.1 months (range: 0.1 to 45.6) for interferon alfa treatment. Permanent discontinuation due to an adverse reaction occurred in 20% of patients in the sunitinib malate capsules arm. Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received sunitinib malate capsules. Table summarizes the adverse reactions for Study 3. Table 5. Adverse Reactions Reported in >= 10% of Patients With RCC Who Received Sunitinib Malate Capsules or Interferon AlfaCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 3Abbreviations: ARs adverse reactions; = number of patients; RCC renal cell carcinoma.Adverse ReactionTreatment-Naive RCCSunitinib Malate Capsules(N 375)Interferon Alfa(N 360)All Grades%Grade 3-4Grade ARs in patients on sunitinib malate capsules included back pain (1%), arthralgia (< 1%), dyspnea (< 1%), asthenia (< 1%), fatigue (< 1%), limb pain (< 1%), and rash (< 1%).%All Grades%Grade 3-4Grade ARs in patients on interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (< 1%), and depression (< 1%).%Any Adverse Reaction99779955Gastrointestinal Diarrhea661021< Nausea586412 Mucositis/stomatitis4735< Vomiting395171 Dyspepsia34240 Abdominal painIncludes flank pain. 305121 Constipation23114< Dry mouth1307< Oral pain14< 110 Flatulence14020 GERD/reflux esophagitis12< 110 Glossodynia11010 Hemorrhoids10020Constitutional Fatigue62155615 Asthenia2611226 Fever22137< Weight decreased16< 1171 Chills141310 Chest Pain13271 Influenza like illness5015< 1Metabolism/Nutrition AnorexiaIncludes decreased appetite. 483422Neurology Altered tasteIncludes ageusia, hypogeusia, and dysgeusia. 47< 1150 Headache231190 Dizziness11< 1141Hemorrhage/Bleeding Bleeding, all sites374Includes patient with Grade gastric hemorrhage. 101Cardiac Hypertension34134< Edema peripheral24251 Ejection fraction decreased16352Dermatology Rash29211< Hand-foot syndrome29810 Skin discoloration/yellow skin25< 100 Dry skin23< 170 Hair color changes200< 10 Alopecia14090 Erythema12< 110 Pruritus12< 17< 1Musculoskeletal Pain in extremity/limb discomfort405302 Arthralgia303191 Back pain285142Respiratory Cough27114< Dyspnea266204 Nasopharyngitis14020 Oropharyngeal pain14< 120 Upper respiratory tract infection11< 120Endocrine Hypothyroidism16210Psychiatric Insomnia15< 1100 DepressionIncludes depressed mood. 110141Table summarizes the laboratory abnormalities in Study 3.Table 6. Laboratory Abnormalities Reported in >= 10% of RCC Patients Who Received Sunitinib Malate Capsules or Interferon Alfa in Study Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; = number of patients; RCC renal cell carcinoma.Laboratory AbnormalityTreatment-Naive RCCSunitinib Malate Capsules(N 375)Interferon Alfa(N 360)All GradesCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. %Grade 3/4,Grade laboratory abnormalities in patients on sunitinib malate capsules included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (< 1%), creatine kinase (< 1%), creatinine (< 1%), glucose increased (< 1%), calcium decreased (< 1%), phosphorous (< 1%), potassium increased (< 1%), and sodium decreased (< 1%).%All Grades%Grade 3/4,Grade laboratory abnormalities in patients on interferon alfa included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (< 1%), calcium increased (< 1%), glucose decreased (< 1%), potassium increased (< 1%), and hemoglobin (< 1%).%Hematology Hemoglobin decreased798695 Neutrophils decreased7717499 Platelets decreased689241 Lymphocytes decreased68186826Renal/Metabolic Creatinine increased70< 151< Creatine kinase increased492111 Uric acid increased4614338 Calcium decreased421401 Phosphorus decreased316246 Albumin decreased281200 Glucose increased236156 Sodium decreased208154 Glucose decreased17012< Potassium increased163174 Calcium increased13< 1101 Potassium decreased1312< Sodium increased130100Gastrointestinal AST increased562382 Lipase increased5618468 ALT increased513402 Alkaline phosphatase increased462372 Amylase increased356323 Total bilirubin increased20120 Indirect bilirubin increased13110. Long-Term Safety in RCC. The long-term safety of sunitinib malate capsules in patients with metastatic RCC was analyzed across 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 years and 365 (6%) for at least years. Prolonged treatment with sunitinib malate capsules did not appear to be associated with new types of adverse reactions. There appeared to be no increase in the yearly incidence of adverse reactions at later time points. Hypothyroidism increased during the second year of treatment with new cases reported up to year 4.. Adjuvant Treatment of RCC. The safety of sunitinib malate capsules was evaluated in S-TRAC, randomized, double-blind, placebo-controlled trial in which patients who had undergone nephrectomy for RCC received sunitinib malate capsules 50 mg daily on Schedule 4/2 (n 306) or placebo (n 304). The median duration of treatment was 12.4 months (range: 0.13 to 14.9) for sunitinib malate capsules and 12.4 months (range: 0.03 to 13.7) for placebo. Permanent discontinuation due to an adverse reaction occurred in 28% of patients in the sunitinib malate capsules arm. Adverse reactions leading to permanent discontinuation in 2% of patients include hand-foot syndrome and fatigue/asthenia. Dosing interruptions occurred in 54% and dose reductions occurred in 46% of patients who received sunitinib malate capsules. Table summarizes the adverse reactions in S-TRAC.Table 7. Adverse Reactions Reported in >= 10% of Patients With RCC Who Received Sunitinib Malate Capsules and More Commonly Than in Patients Given PlaceboCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. in S-TRACAbbreviations: ARs adverse reactions; = number of patients; RCC renal cell carcinoma.Adverse ReactionAdjuvant Treatment of RCCSunitinib Malate Capsules(N 306)Placebo(N 304)All Grades%Grade 3-4%All Grades%Grade 3-4%Any Adverse Reaction99608815Gastrointestinal Mucositis/StomatitisIncludes mucosal inflammation, stomatitis aphthous ulcer, mouth ulceration, tongue ulceration, oropharyngeal pain, and oral pain. 616150 Diarrhea57422< Nausea342150 Dyspepsia27170 Abdominal painIncludes abdominal pain, abdominal pain lower, and abdominal pain upper. 2529< Vomiting19270 Constipation120110Constitutional Fatigue/Asthenia578342 Localized edemaIncludes edema localized, face edema, eyelid edema, periorbital edema, swelling face, and eye edema. 18< 1< 10 Pyrexia12< 160Dermatology Hand-foot syndrome501610< RashIncludes dermatitis, dermatitis psoriasiform, exfoliative rash, genital rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic. 242120 Hair color changes22020 Skin discoloration/ Yellow skin18010 Dry skin14060Cardiac HypertensionIncludes hypertension, blood pressure increased, blood pressure systolic increased, blood pressure diastolic increased, and hypertensive crisis. 398141 Edema/Peripheral edema10< 170Neurology Altered tasteIncludes ageusia, hypogeusia, and dysgeusia. 38< 160 Headache19< 1120Endocrine Hypothyroidism/TSH increased24< 140Hemorrhage/Bleeding Bleeding events, all sitesIncludes epistaxis, gingival bleeding, rectal hemorrhage, hemoptysis, anal hemorrhage, upper gastrointestinal hemorrhage, and hematuria. 24< 15< 1Metabolism/Nutrition Anorexia/Decreased appetite19< 150Musculoskeletal Pain in extremity15< 170 Arthralgia11< 1100Grade adverse reactions in patients on sunitinib malate capsules included hand-foot syndrome (1%), fatigue (< 1%), abdominal pain (< 1%), stomatitis (< 1%), and pyrexia (< 1%). Grade 3-4 laboratory abnormalities that occurred in >= 2% of patients receiving sunitinib malate capsules include neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%).. Advanced Pancreatic Neuroendocrine Tumors. The safety of sunitinib malate capsules was evaluated in Study 6, randomized, double-blind, placebo-controlled trial in which patients with progressive pNET received sunitinib malate capsules 37.5 mg once daily (n 83) or placebo (n 82). The median number of days on treatment was 139 days (range: 13-532 days) for patients on sunitinib malate capsules and 113 days (range: 1-614 days) for patients on placebo. Nineteen patients (23%) on sunitinib malate capsules and patients (5%) on placebo were on study for 1 year. Permanent discontinuation due to an adverse reaction occurred in 22% in the sunitinib malate capsules arm. Dose interruptions occurred in 30% and dose reductions occurred in 31% of patients who received sunitinib malate capsules.Table summarizes the adverse reactions in Study 6.Table 8. Adverse Reactions Reported in >= 10% of Patients With pNET Who Received Sunitinib Malate Capsules and More Commonly Than in Patients Given PlaceboCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 6Abbreviations: = number of patients; pNET pancreatic neuroendocrine tumors.Adverse ReactionpNETSunitinib Malate Capsules(N 83)Placebo(N 82)All Grades%Grade 3-4Grade adverse reactions in patients on sunitinib malate capsules included fatigue (1%).%All Grades%Grade 3-4%Any Adverse Reaction99549550Gastrointestinal Diarrhea595392 Stomatitis/oral syndromesIncludes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth. 486180 Nausea451291 Abdominal painIncludes abdominal discomfort, abdominal pain, and abdominal pain upper. 3953410 Vomiting340312 Dyspepsia15060Constitutional Asthenia345274 Fatigue335279 Weight decreased161110Dermatology Hair color changes29110 Hand-foot syndrome23620 Rash18050 Dry skin150110Cardiac Hypertension271051Hemorrhage/Bleeding Bleeding eventsIncludes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia. 220104 Epistaxis21150Neurology Dysgeusia21050 Headache180131Psychiatric Insomnia180120Musculoskeletal Arthralgia15060Table summarizes the laboratory abnormalities in Study 6.Table 9. Laboratory Abnormalities Reported in >= 10% of Patients With pNET Who Received Sunitinib Malate Capsules in Study 6Abbreviations: ALT alanine aminotransferase; AST aspartate aminotransferase; = number of patients; pNET pancreatic neuroendocrine tumors.Laboratory AbnormalitypNETSunitinib Malate CapsulesPlaceboAll GradesThe denominator used to calculate the rate varied from 52 to 82 for sunitinib malate capsules and 39 to 80 for Placebo based on the number of patients with baseline value and at least one post-treatment value. Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.%Grade 3-4,Grade laboratory abnormalities in patients on sunitinib malate capsules included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%), and total bilirubin (1%).%All Grades%Grade 3-4,Grade laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%), and lipase (1%).%Gastrointestinal AST increased725703 Alkaline phosphatase increased63107011 ALT increased614553 Total bilirubin increased371284 Amylase increased204101 Lipase increased175114Hematology Neutrophils decreased7116160 Hemoglobin decreased650551 Platelets decreased605150 Lymphocytes decreased567354Renal/Metabolic Glucose increased71127818 Albumin decreased411371 Phosphorus decreased367225 Calcium decreased340190 Sodium decreased292343 Creatinine increased275285 Glucose decreased222154 Potassium decreased214140 Magnesium decreased190100 Potassium increased181111. Venous Thromboembolic Events. In pooled safety population, 3.5% of patients experienced venous thromboembolic event, including Grade 3-4 in 2.2% of patients.. Pancreatic Function. Pancreatitis was observed in patient (1%) in the pNET study, patients (1%) in the treatment-naive RCC study, and patient (< 1%) in the adjuvant treatment for RCC study on sunitinib malate capsules.. 6.2Postmarketing Experience The following adverse reactions have been identified during postapproval use of sunitinib malate capsules. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and Lymphatic System Disorders: hemorrhage associated with thrombocytopenia. Gastrointestinal Disorders: esophagitis.Hepatobiliary Disorders: cholecystitis, particularly acalculous cholecystitis.Immune System Disorders: hypersensitivity reactions, including angioedema. Infections and Infestations: serious infection (with or without neutropenia). The infections most commonly observed with sunitinib malate capsules include respiratory, urinary tract, skin infections, and sepsis/septic shock. Musculoskeletal and Connective Tissue Disorders: fistula formation, sometimes associated with tumor necrosis and/or regression; myopathy and/or rhabdomyolysis with or without acute renal failure. Renal and Urinary Disorders: renal impairment and/or failure. Respiratory Disorders: pulmonary embolism, pleural effusion.Skin and Subcutaneous Tissue Disorders: pyoderma gangrenosum, including positive de-challenges.Vascular Disorders: arterial (including aortic) aneurysms, dissections, and rupture; arterial thromboembolic events. The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral infarction. General Disorders and Administration Site Conditions: impaired wound healing.including some fatalities.

BOXED WARNING SECTION.

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

GERIATRIC USE SECTION.

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

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sunitinib is 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 variety of kinases (> 80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFR and PDGFR), 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 (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 (PDGFR, 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 PDGFR- and VEGFR2-dependent tumor angiogenesis in vivo. 12.2 Pharmacodynamics. Exposure-Response Relationship. Based on population pharmacokinetic/pharmacodynamic analyses, there were relationships between changes in different pharmacodynamic endpoints (i.e., safety and efficacy endpoints) over time and sunitinib plasma exposures.. Cardiac Electrophysiology. Sunitinib malate capsules can cause QT interval prolongation in 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 Cmax increase proportionately over dose range of 25 mg to 100 mg (0.5 to times the approved RDD of 50 mg). The pharmacokinetics were similar in healthy subjects and in patients with 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 (Tmax) ranged from to 12 hours.. Effect of Food The administration of single dose of sunitinib malate capsules 50 mg with high-fat, high-calorie meal (consisting of approximately 150 protein calories and 500 to 600 fat calories) in healthy subjects had no clinically significant effect on sunitinib or active metabolites exposure.. Distribution. The apparent volume of distribution (Vd/F) for sunitinib is 2230 L. Binding of sunitinib and its primary active metabolite to human plasma protein in vitro is 95% and 90%, respectively, with no concentration dependence in the range of 100 to 4000 ng/mL.. Elimination. Following administration of 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 radiolabeled dose, sunitinib and its active metabolite were the major compounds identified in plasma, accounting for 92% of radioactivity.. Excretion After 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 single sunitinib malate capsule dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite Cmax and AUC0-inf by 49% and 51%, respectively, in healthy subjects.. Effect of Strong CYP3A4 Inducers on Sunitinib. Co-administration of single sunitinib malate capsule dose with rifampin (strong CYP3A4 inducer) reduced the combined sunitinib and its active metabolite Cmax and AUC0-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.

CLINICAL STUDIES SECTION.

Clinical Studies Effect of Strong CYP3A4 Inhibitors on Sunitinib. Co-administration of single sunitinib malate capsule dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite Cmax and AUC0-inf by 49% and 51%, respectively, in healthy subjects.. Effect of Strong CYP3A4 Inducers on Sunitinib. Co-administration of single sunitinib malate capsule dose with rifampin (strong CYP3A4 inducer) reduced the combined sunitinib and its active metabolite Cmax and AUC0-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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. oNone (4). oNone (4).

DESCRIPTION SECTION.

11 DESCRIPTION Sunitinib is kinase inhibitor present in sunitinib malate capsules as the malate salt. Sunitinib malate is described chemically as N-[2-(Diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide hydrogen (2S)-2-hydroxybutanedioate. The molecular formula is C22H27FN4O2 C4H6O5 and the molecular weight is 532.6. The chemical structure of sunitinib malate is: Sunitinib malate is yellow to orange powder with pKa of 8.95. The solubility of sunitinib malate in aqueous media over the range pH 1.2 to pH 6.8 is in excess of 25 mg/mL. The log of the distribution coefficient (octanol/water) at pH is 5.2. Sunitinib malate capsules are supplied as printed hard-shell capsules containing 12.5 mg, 25 mg, 37.5 mg or 50 mg of sunitinib (equivalent to 16.7 mg, 33.4 mg, 50.1 mg, or 66.8 mg of sunitinib malate, respectively). The capsules contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, gelatin, magnesium stearate, mannitol, sodium lauryl sulfate and titanium dioxide. The 12.5 mg and 25 mg strengths also contain red iron oxide. The 25 mg, 37.5 mg and 50 mg strengths also contain yellow iron oxide.In addition, the black imprinting ink contains the following: ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.. Sunitinib Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION GIST and Advanced RCC:oThe recommended dosage is 50 mg orally once daily for the first weeks of each 6-week cycle (Schedule 4/2). (2.1)Adjuvant Treatment of RCC:oThe recommended dosage is 50 mg orally once daily for the first weeks of 6-week cycle (Schedule 4/2) for maximum of cycles. (2.2)pNET:oThe recommended dosage is 37.5 mg orally once daily. (2.3). oThe recommended dosage is 50 mg orally once daily for the first weeks of each 6-week cycle (Schedule 4/2). (2.1). oThe recommended dosage is 50 mg orally once daily for the first weeks of 6-week cycle (Schedule 4/2) for maximum of cycles. (2.2). oThe recommended dosage is 37.5 mg orally once daily. (2.3). 2.1Recommended 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 schedule of weeks on treatment followed by weeks off (Schedule 4/2) until disease progression or unacceptable toxicity. Sunitinib malate capsules may be taken with or without food. 2.2Recommended 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 schedule of weeks on treatment followed by weeks off (Schedule 4/2), for nine 6-week cycles. Sunitinib malate capsules may be taken with or without food.. 2.3Recommended 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.. 2.4Dosage Modifications for Adverse Reactions To manage adverse reactions, the recommended dosage modifications are provided in Table 1. Table provides the recommended dosage reductions of sunitinib malate capsules for adverse reactions.Table 1. Recommended Dosage Reductions of Sunitinib Malate Capsules for Adverse ReactionsIndicationsGISTRCCpNETAdvanced RCCAdjuvant RCCFirst dose reduction 37.5 mg once daily37.5 mg once daily37.5 mg once daily25 mg once dailySecond dose reduction 25 mg oncedaily25 mg oncedailyNANA Table 2. Recommended Dosage Modifications for Sunitinib Malate Capsules for Adverse ReactionsAdverse Reaction SeverityDosage Modifications for Sunitinib Malate CapsulesHepatotoxicity [see Warnings and Precautions (5.1)] Grade oWithhold until resolution to Grade to or baseline.oResume at reduced dose.oFor recurring Grade permanently discontinue. Grade oPermanently 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)oWithhold until resolution to Grade to or baseline.oResume at reduced dose.Clinically manifested congestive heart failure (CHF)oPermanently discontinue.Hypertension [see Warnings and Precautions (5.4)] Grade 3oWithhold until resolution to Grade to or baseline. oResume at reduced dose.Grade 4oPermanently discontinue.Hemorrhagic events [see Warnings and Precautions (5.5)] Grade or 4oWithhold until resolution to Grade to or baseline. oEither resume at reduced dose or discontinue depending on the severity and persistence of adverse reaction.Thrombotic microangiopathy [see Warnings and Precautions (5.7)] Any Grade oPermanently discontinue. Proteinuria or Nephrotic syndrome [see Warnings and Precautions (5.8)] or more grams proteinuria in 24 hours in the absence of nephrotic syndromeoWithhold until resolution to Grade to or baseline.oResume at reduced dose.Nephrotic syndrome or recurrent proteinuria of or more grams per 24 hours despite dose reductions oPermanently discontinue. Dermatological toxicities Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Necrotizing fasciitis [see Warnings and Precautions (5.9)] Any Grade oPermanently discontinue. Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10)] Any Grade oPermanently discontinue. Osteonecrosis of the jaw [see Warnings and Precautions (5.13)] Any Grade oThe safety of resumption of sunitinib malate capsules after osteonecrosis has not been established.oEither resume at 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 oThe safety of resumption of sunitinib malate capsules after resolution of wound healing has not been established. oEither resume at reduced dose or discontinue depending on the severity and persistence of the adverse reaction. oWithhold until resolution to Grade to or baseline.. oResume at reduced dose.. oFor recurring Grade permanently discontinue. oPermanently discontinue. oWithhold until resolution to Grade to or baseline.. oResume at reduced dose.. oPermanently discontinue.. oWithhold until resolution to Grade to or baseline. oResume at reduced dose.. oPermanently discontinue.. oWithhold until resolution to Grade to or baseline. oEither resume at reduced dose or discontinue depending on the severity and persistence of adverse reaction.. oPermanently discontinue. oWithhold until resolution to Grade to or baseline.. oResume at reduced dose.. oPermanently discontinue. oPermanently discontinue. oPermanently discontinue. oThe safety of resumption of sunitinib malate capsules after osteonecrosis has not been established.. oEither resume at reduced dose or discontinue depending on the severity and persistence of the adverse reaction. oThe safety of resumption of sunitinib malate capsules after resolution of wound healing has not been established. oEither resume at reduced dose or discontinue depending on the severity and persistence of the adverse reaction. 2.5Dosage 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 strong CYP3A4 inhibitor cannot be avoided, consider dose reduction for sunitinib malate capsules to minimum dosage as follows [see Drug Interactions (7.1)]: oGIST and RCC: 37.5 mg orally once daily, on schedule of weeks on treatment followed by weeks off (Schedule 4/2)opNET: 25 mg orally once daily. oGIST and RCC: 37.5 mg orally once daily, on schedule of weeks on treatment followed by weeks off (Schedule 4/2). opNET: 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 strong CYP3A4 inducer cannot be avoided, consider dose increase for sunitinib malate capsules to maximum dosage as follows:oGIST and RCC: 87.5 mg orally once daily, on schedule of weeks on treatment followed by weeks off (Schedule 4/2)opNET: 62.5 mg orally once dailyIf the dose of sunitinib malate capsules is increased, monitor patients carefully for adverse reactions [see Drug Interactions (7.1)].. oGIST and RCC: 87.5 mg orally once daily, on schedule of weeks on treatment followed by weeks off (Schedule 4/2). opNET: 62.5 mg orally once daily. 2.6Dosage 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)].

DOSAGE FORMS & STRENGTHS SECTION.

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

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oCYP3A4 Inhibitors: Consider dose reduction of sunitinib malate capsules when administered with strong CYP3A4 inhibitors. (7.1)oCYP3A4 Inducers: Consider dose increase of sunitinib malate capsules when administered with strong CYP3A4 inducers. (7.1). oCYP3A4 Inhibitors: Consider dose reduction of sunitinib malate capsules when administered with strong CYP3A4 inhibitors. (7.1). oCYP3A4 Inducers: Consider dose increase of sunitinib malate capsules when administered with strong CYP3A4 inducers. (7.1). 7.1Effect of Other Drugs on Sunitinib Malate Capsules Strong CYP3A4 Inhibitors. Co-administration with strong CYP3A4 inhibitors may increase sunitinib plasma concentrations [see Clinical Pharmacology (12.3)]. Select an alternate concomitant medication with no or minimal enzyme inhibition potential. Consider dose reduction for sunitinib malate capsules when it is co-administered with strong CYP3A4 inhibitors [see Dosage and Administration (2.5)]. Strong CYP3A4 Inducers. Co-administration with strong CYP3A4 inducers may decrease sunitinib plasma concentrations [see Clinical Pharmacology (12.3)]. Select an alternate concomitant medication with no or minimal enzyme induction potential. Consider dose increase for sunitinib malate capsules when it must be co-administered with CYP3A4 inducers [see Dosage and Administration (2.5)]. 7.2Drugs that Prolong QT Interval Sunitinib malate capsules are associated with QTc interval prolongation [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)]. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential Sunitinib can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].. Pregnancy Testing. Verify pregnancy status of females of reproductive potential prior to initiating treatment with sunitinib malate capsules.. Contraception. Females Advise females of reproductive potential to use effective contraception during treatment with sunitinib malate capsules and for at least weeks after the last dose.. Males Based on findings in animal reproduction studies, advise males with female partners of reproductive potential to use effective contraception during treatment with sunitinib malate capsules and for weeks after the last dose.. Infertility. Based on findings in animals, sunitinib malate capsules may impair male and female fertility [see Nonclinical Toxicology (13.1)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oHepatotoxicity: Fatal liver failure has been observed. Monitor liver function tests at baseline, during each cycle, and as clinically indicated. Interrupt sunitinib malate capsules for Grade hepatotoxicity until resolution to Grade <= or baseline and resume sunitinib malate capsules at reduced dose; discontinue if no resolution. Discontinue sunitinib malate capsules in patients with Grade hepatotoxicity, in patients who have subsequent severe changes in liver function tests or other signs and symptoms of liver failure. (2.4, 5.1)oCardiovascular 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 capsules for clinical manifestations of congestive heart failure. Interrupt and/or dose reduce for decreased LVEF. (5.2)oQT Interval Prolongation and Torsade de Pointes: Monitor patients at higher risk for developing QT interval prolongation. Consider monitoring of electrocardiograms and electrolytes. (5.3)oHypertension: Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. Interrupt sunitinib malate capsules for Grade hypertension until resolution to Grade <= or baseline, then resume sunitinib malate capsules at reduced dose. Discontinue sunitinib malate capsules in patients who develop Grade hypertension. (5.4)oHemorrhagic Events: Tumor-related hemorrhage and viscus perforation (both with fatal events) have occurred. Perform serial complete blood counts and physical examinations. Interrupt sunitinib malate capsules for Grade or hemorrhagic events until resolution to Grade <= or baseline, then resume at reduced dose; discontinue if no resolution. (5.5)oTumor 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)oThrombotic Microangiopathy (TMA): TMA, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or fatal outcome, has been reported. Discontinue sunitinib malate capsules for TMA. (5.7)oProteinuria: Renal failure or fatal outcome has occurred. Monitor urine protein. Interrupt treatment for 24-hour urine protein of or more grams. Discontinue for repeat episodes of 24-hour urine protein of or more grams despite dose reductions or nephrotic syndrome. (5.8)oDermatologic Toxicities: Necrotizing fasciitis, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (some fatal) have occurred. Discontinue sunitinib malate capsules for these events. (5.9)oReversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (some fatal) has been reported. Monitor for signs and symptoms of RPLS. Withhold sunitinib malate capsules until resolution. (5.10)oThyroid 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)oHypoglycemia: Check blood glucose levels regularly and assess if antidiabetic drug dose modifications are required. (5.12)oOsteonecrosis of the Jaw (ONJ): Withhold sunitinib malate capsules for at least weeks prior to invasive dental procedure and for development of ONJ until complete resolution. (5.13)oImpaired Wound Healing: Withhold sunitinib malate capsules for at least weeks prior to elective surgery. Do not administer for at least weeks following major surgery and until adequate wound healing. The safety of resumption of sunitinib malate capsules after resolution of wound healing complications has not been established. (5.14)oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to fetus and to use effective contraception. (5.15, 8.1, 8.3). oHepatotoxicity: Fatal liver failure has been observed. Monitor liver function tests at baseline, during each cycle, and as clinically indicated. Interrupt sunitinib malate capsules for Grade hepatotoxicity until resolution to Grade <= or baseline and resume sunitinib malate capsules at reduced dose; discontinue if no resolution. Discontinue sunitinib malate capsules in patients with Grade hepatotoxicity, in patients who have subsequent severe changes in liver function tests or other signs and symptoms of liver failure. (2.4, 5.1). oCardiovascular 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 capsules for clinical manifestations of congestive heart failure. Interrupt and/or dose reduce for decreased LVEF. (5.2). oQT Interval Prolongation and Torsade de Pointes: Monitor patients at higher risk for developing QT interval prolongation. Consider monitoring of electrocardiograms and electrolytes. (5.3). oHypertension: Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. Interrupt sunitinib malate capsules for Grade hypertension until resolution to Grade <= or baseline, then resume sunitinib malate capsules at reduced dose. Discontinue sunitinib malate capsules in patients who develop Grade hypertension. (5.4). oHemorrhagic Events: Tumor-related hemorrhage and viscus perforation (both with fatal events) have occurred. Perform serial complete blood counts and physical examinations. Interrupt sunitinib malate capsules for Grade or hemorrhagic events until resolution to Grade <= or baseline, then resume at reduced dose; discontinue if no resolution. (5.5). oTumor 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). oThrombotic Microangiopathy (TMA): TMA, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or fatal outcome, has been reported. Discontinue sunitinib malate capsules for TMA. (5.7). oProteinuria: Renal failure or fatal outcome has occurred. Monitor urine protein. Interrupt treatment for 24-hour urine protein of or more grams. Discontinue for repeat episodes of 24-hour urine protein of or more grams despite dose reductions or nephrotic syndrome. (5.8). oDermatologic Toxicities: Necrotizing fasciitis, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (some fatal) have occurred. Discontinue sunitinib malate capsules for these events. (5.9). oReversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (some fatal) has been reported. Monitor for signs and symptoms of RPLS. Withhold sunitinib malate capsules until resolution. (5.10). oThyroid 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). oHypoglycemia: Check blood glucose levels regularly and assess if antidiabetic drug dose modifications are required. (5.12). oOsteonecrosis of the Jaw (ONJ): Withhold sunitinib malate capsules for at least weeks prior to invasive dental procedure and for development of ONJ until complete resolution. (5.13). oImpaired Wound Healing: Withhold sunitinib malate capsules for at least weeks prior to elective surgery. Do not administer for at least weeks following major surgery and until adequate wound healing. The safety of resumption of sunitinib malate capsules after resolution of wound healing complications has not been established. (5.14). oEmbryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to fetus and to use effective contraception. (5.15, 8.1, 8.3). 5.1Hepatotoxicity Sunitinib malate capsules 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 capsules for Grade hepatotoxicity until resolution to Grade <= or baseline, then resume sunitinib malate capsules at reduced dose. Discontinue sunitinib malate capsules in patients with Grade hepatotoxicity, in patients without resolution of Grade 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 upper limit of normal (ULN) or with 5 ULN and liver metastases has not been established.. 5.2Cardiovascular 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 decreased ejection fraction (left ventricular ejection fraction [LVEF] 40% to 50% and 10% to 19% decrease from baseline). In 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 capsules were diagnosed with CHF.Patients who presented with cardiac events within 12 months prior to sunitinib malate capsules 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 capsules 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 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 capsules in patients who experience clinical manifestations of CHF. Interrupt sunitinib malate capsules 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.. 5.3QT Interval Prolongation and Torsade de Pointes Sunitinib malate capsules can cause QT interval prolongation in 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 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 capsules. Monitor QT interval more frequently when sunitinib malate capsules are concomitantly administered with strong CYP3A4 inhibitors or drugs known to prolong QT interval. Consider dose reducing sunitinib malate capsules [see Dosage and Administration (2.5), Drug Interactions (7.2)]. 5.4Hypertension In the pooled safety population, 29% of patients experienced hypertension. Grade hypertension was reported in 7% of patients, and Grade 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 hypertension, withhold sunitinib malate capsules until resolution to Grade <= or baseline, then resume sunitinib malate capsules at reduced dose. Discontinue sunitinib malate capsules in patients who develop Grade hypertension.. 5.5Hemorrhagic 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 or 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 capsules. 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 fatal outcome, was observed in patients treated with sunitinib malate capsules for metastatic RCC, GIST, and metastatic lung cancer. Sunitinib malate capsules are 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 capsules. Include serial complete blood counts (CBCs) and physical examinations with the clinical assessment of hemorrhagic events. Interrupt sunitinib malate capsules for Grade or hemorrhagic events until resolution to Grade <= or baseline, then resume sunitinib malate capsules at reduced dose.Discontinue sunitinib malate capsules in patients without resolution of Grade or hemorrhagic events.. 5.6Tumor Lysis Syndrome 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 Thrombotic Microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or fatal outcome, occurred in clinical trials and in postmarketing experience of sunitinib malate capsules as monotherapy and administered in combination with bevacizumab. Sunitinib malate capsules are not approved for use in combination with bevacizumab.Discontinue sunitinib malate capsules in patients developing TMA. Reversal of the effects of TMA has been observed after sunitinib malate capsules were discontinued.. 5.8Proteinuria 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 capsules and dose reduce for 24-hour urine protein of or more grams. Discontinue sunitinib malate capsules for patients with nephrotic syndrome or repeat episodes of 24-hour urine protein of or more grams despite dose reductions. The safety of continued sunitinib malate capsules treatment in patients with moderate to severe proteinuria has not been evaluated.. 5.9Dermatologic 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 capsules for these severe cutaneous adverse reactions. Necrotizing fasciitis, including fatal cases, has been reported in patients treated with sunitinib malate capsules, including of the perineum and secondary to fistula formation. Discontinue sunitinib malate capsules in patients who develop necrotizing fasciitis.. 5.10Reversible Posterior Leukoencephalopathy Syndrome 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 capsules in patients developing RPLS.. 5.11Thyroid Dysfunction Hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through postmarketing experience of sunitinib malate capsules.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 capsules. Initiate and/or adjust therapies for thyroid dysfunction as appropriate. 5.12Hypoglycemia Sunitinib malate capsules 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 capsules. Hypoglycemia has occurred in clinical trials in 2% of the patients treated with sunitinib malate capsules for advanced RCC (Study 3) and GIST (Study 1) (n 577) and in approximately 10% of the patients treated with sunitinib malate capsules for pNET (Study 6) (n 83). For patients being treated with sunitinib malate capsules 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 capsules. In patients with diabetes, assess if antidiabetic therapies need to be adjusted to minimize the risk of hypoglycemia.. 5.13Osteonecrosis of the Jaw Osteonecrosis of the Jaw (ONJ) occurred in patients treated with sunitinib malate capsules. 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 capsules and periodically during sunitinib malate capsules therapy. Advise patients regarding good oral hygiene practices. Withhold sunitinib malate capsules treatment for at least weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold sunitinib malate capsules for development of ONJ until complete resolution. The safety of resumption of sunitinib malate capsules after resolution of osteonecrosis of the jaw has not been established.. 5.14Impaired Wound Healing Impaired wound healing has been reported in patients who received sunitinib malate capsules [see Adverse Reactions (6.2)].Withhold sunitinib malate capsules for at least weeks prior to elective surgery. Do not administer for at least weeks following major surgery and until adequate wound healing. The safety of resumption of sunitinib malate capsules after resolution of wound healing complications has not been established.. 5.15Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, sunitinib malate capsules 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 fetus. Advise females of reproductive potential to use effective contraception during treatment with sunitinib malate capsules and for weeks following the final dose [see Use in Specific Populations (8.1, 8.3)].

HOW SUPPLIED SECTION.

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

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

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

LACTATION SECTION.

8.2 Lactation There is no information regarding the presence of sunitinib and its metabolites in human milk. Sunitinib and its metabolites were excreted in rat milk at concentrations up to 12-fold higher than in plasma (see Data). Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with sunitinib malate capsules and for at least 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.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Sunitinib is 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 variety of kinases (> 80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFR and PDGFR), 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 (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 (PDGFR, 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 PDGFR- and VEGFR2-dependent tumor angiogenesis in vivo.

NONCLINICAL TOXICOLOGY SECTION.

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

OVERDOSAGE SECTION.

10 OVERDOSAGE Treatment of overdose with sunitinib malate capsules should consist of general supportive measures. There is no specific antidote for overdosage with sunitinib malate capsules. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of sunitinib malate capsules, or without adverse reactions. In nonclinical studies, mortality was observed following as few as daily doses of 500 mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection, and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 12.5 mg NDC 0378-6678-28SunitinibMalateCapsules12.5 mgPHARMACIST: Dispense the accompanyingMedication Guide to each patient.Rx only 28 Capsules Each capsule contains 12.5 mgsunitinib equivalent to 16.7 mgsunitinib malate.Dispense in original container.Keep container tightly closed.Keep this and all medicationout of the reach of children.Store at 20 to 25C (68 to 77F).[See USP Controlled RoomTemperature.]Usual Dosage: See accompanyingprescribing information.Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Mylan.comRM6678BD2. Sunitinib Malate Capsules 12.5 mg Bottle Label.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

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 Cmax increase proportionately over dose range of 25 mg to 100 mg (0.5 to times the approved RDD of 50 mg). The pharmacokinetics were similar in healthy subjects and in patients with 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 (Tmax) ranged from to 12 hours.. Effect of Food The administration of single dose of sunitinib malate capsules 50 mg with high-fat, high-calorie meal (consisting of approximately 150 protein calories and 500 to 600 fat calories) in healthy subjects had no clinically significant effect on sunitinib or active metabolites exposure.. Distribution. The apparent volume of distribution (Vd/F) for sunitinib is 2230 L. Binding of sunitinib and its primary active metabolite to human plasma protein in vitro is 95% and 90%, respectively, with no concentration dependence in the range of 100 to 4000 ng/mL.. Elimination. Following administration of 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 radiolabeled dose, sunitinib and its active metabolite were the major compounds identified in plasma, accounting for 92% of radioactivity.. Excretion After 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 single sunitinib malate capsule dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite Cmax and AUC0-inf by 49% and 51%, respectively, in healthy subjects.. Effect of Strong CYP3A4 Inducers on Sunitinib. Co-administration of single sunitinib malate capsule dose with rifampin (strong CYP3A4 inducer) reduced the combined sunitinib and its active metabolite Cmax and AUC0-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.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary. Based on animal reproduction studies and its mechanism of action, sunitinib can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform 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 fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively. Data. Animal Data In female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5, 1.5, mg/kg/day) for 21 days prior to mating and for days after mating. Embryolethality was observed at mg/kg/day (approximately 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, 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 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 <= mg/kg/day (approximately times the combined AUC in patients administered the RDD of 50 mg). In rabbits, embryolethality was observed at mg/kg/day (approximately times the combined AUC in patients administered the RDD of 50 mg), and craniofacial malformations (cleft lip and cleft palate) were observed at >= mg/kg/day (approximately 0.3 times the combined AUC in patients administered the RDD of 50 mg).Sunitinib (0.3, 1, mg/kg/day) was evaluated in pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses >= mg/kg/day (approximately 0.5 times the combined AUC in patients administered the RDD of 50 mg). At mg/kg/day (approximately 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 <= mg/kg/day.

RECENT MAJOR CHANGES SECTION.

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

RISKS.

Risk Summary. Based on animal reproduction studies and its mechanism of action, sunitinib can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data in pregnant women to inform 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 fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.

SPL MEDGUIDE SECTION.

Medication Guide Sunitinib Malate Capsules(soo ni ti nib mal eyt)What is the most important information should know about sunitinib malate capsulesSunitinib malate capsules can cause serious side effects including:oSevere liver problems, that can lead to death. Tell your healthcare provider right away if you develop any of the following signs and symptoms of liver problems during treatment with sunitinib malate capsules:oitchingoyellow eyes or skinodark urineopain or discomfort in the right upper stomach areaYour healthcare provider should do blood tests to check your liver function before you start taking and during treatment with sunitinib malate capsules. Your healthcare provider may temporarily stop, reduce your dose, or permanently stop treatment with sunitinib malate capsules if you develop liver problems. See What are the possible side effects of sunitinib malate capsules for more information about side effects.What are sunitinib malate capsulesSunitinib malate capsules are prescription medicine used to treat:oa rare cancer of the stomach, bowel, or esophagus called gastrointestinal stromal tumor (GIST) and when:oyou have taken the medicine imatinib mesylate and it did not stop the cancer from growing, oroyou cannot take imatinib mesylate.oadvanced kidney cancer (advanced renal cell carcinoma or RCC).oadults with kidney cancer that has not spread (localized), and who are at high risk of RCC coming back again after having kidney surgery.oa type of pancreatic cancer called pancreatic neuroendocrine tumors (pNET), that has progressed and cannot be treated with surgery.It is not known if sunitinib malate capsules are safe and effective in children.Before taking sunitinib malate capsules tell your healthcare provider about all of your medical conditions, including if you:ohave any heart problemsohave high blood pressureohave thyroid problemsohave history of low blood sugar or diabetesohave kidney function problems (other than cancer)ohave liver problemsohave any bleeding problemoplan to have surgery or have had recent surgery. You should stop taking sunitinib malate capsules at least weeks before planned surgery. See What are the possible side effects of sunitinib malate capsulesohave seizuresohave or have had pain in the mouth, teeth or jaw, swelling or sores inside the mouth, numbness or feeling of heaviness in the jaw, or loosening of toothoare pregnant or plan to become pregnant. Sunitinib malate can harm your unborn baby.Females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start treatment with sunitinib malate capsules.oYou should use effective birth control (contraception) during treatment and for at least weeks after your last dose of sunitinib malate capsules.oTell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with sunitinib malate capsules. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment and for weeks after your last dose of sunitinib malate capsules.Sunitinib malate capsules may cause fertility problems in males and females. Tell your healthcare provider if this is concern for you.oare breastfeeding or plan to breastfeed. Do not breastfeed during treatment with sunitinib malate capsules and for at least weeks (1 month) after the last dose.Tell all of your healthcare providers and dentists that you are taking sunitinib malate capsules. They should talk to the healthcare provider who prescribed sunitinib malate capsules for you, before you have any surgery, or medical or dental procedure. Tell your healthcare provider about all the medicines you take, including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements. Using sunitinib malate capsules with certain other medicines can cause serious side effects. You may have an increased risk of severe jawbone problems (osteonecrosis) if you take sunitinib malate capsules and bisphosphonate medicine. Especially tell your healthcare provider if you are taking or have taken an osteoporosis medicine. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take sunitinib malate capsulesoTake sunitinib malate capsules exactly the way your healthcare provider tells you.oTake sunitinib malate capsules time each day with or without food.oIf you take sunitinib malate capsules for GIST or RCC, you will usually take your medicine for weeks (28 days) and then stop for weeks (14 days). This is cycle of treatment. You will repeat this cycle for as long as your healthcare provider tells you to.oIf you take sunitinib malate capsules for pNET, take it time each day until your healthcare provider tells you to stop.oDo not drink grapefruit juice or eat grapefruit during your treatment with sunitinib malate capsules. They may cause you to have too much sunitinib malate in your body.oYour healthcare provider may do blood tests before each cycle of treatment to check you for side effects.oIf you miss dose of sunitinib malate capsules by less than 12 hours, take the missed dose right away. If you miss dose of sunitinib malate capsules by more than 12 hours, just take your next dose at your regular time. Do not make up the missed dose. Tell your healthcare provider about any missed dose.oCall your healthcare provider right away, if you take too many sunitinib malate capsules.What are possible side effects of sunitinib malate capsulesSunitinib malate capsules may cause serious side effects, including:oSee What is the most important information should know about sunitinib malate capsulesoHeart problems. Heart problems may include heart failure, heart attack and heart muscle problems (cardiomyopathy) that can lead to death. Tell your healthcare provider if you feel very tired, are short of breath, or have swollen feet and ankles.oAbnormal heart rhythm changes. Changes in the electrical activity of your heart called QT prolongation can cause irregular heart beats that can be life threatening. Your healthcare provider may do electrocardiograms and blood tests (electrolytes) to watch for these problems during your treatment with sunitinib malate capsules. Tell your healthcare provider right away if you feel dizzy, faint, or have abnormal heartbeats during your treatment with sunitinib malate capsules.oyou feel faint or lightheaded, or you pass outodizzinessofeel your heart beat is irregular or fastoHigh blood pressure. High blood pressure is common with sunitinib malate capsules and may sometimes be severe. Follow your healthcare providers instructions about having your blood pressure checked regularly. Call your healthcare provider if your blood pressure is high or if you have any of the following signs or symptoms of high blood pressure:osevere headacheolightheadednessodizzinessochange in vision Your healthcare provider may prescribe medicine for you to treat high blood pressure, if needed.oBleeding problems. Bleeding is common with sunitinib malate capsules, but sunitinib malate capsules can also cause severe bleeding problems that can lead to death. Your healthcare provider will monitor you for bleeding and may do blood tests if needed. Call your healthcare provider right away if you have any of these symptoms or serious bleeding problem during treatment with sunitinib malate capsules, including:opainful, swollen stomach (abdomen)ovomiting bloodocoughing up bloodoblack, sticky stoolsobloody urineoheadacheochange in your mental status oSerious stomach and intestinal problems, that can sometimes lead to death. Some people have had tears in their stomach or intestine (perforation) or have developed an abnormal opening between the stomach and intestine (fistula). Get medical help right away if you get stomach-area (abdominal) pain that does not go away or is severe during treatment with sunitinib malate capsules.oTumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells and may lead to death. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.oAbnormal changes in the brain (Reversible Posterior Leukoencephalopathy Syndrome [RPLS]). RPLS can cause collection of symptoms including headache, confusion, and vision loss. Some people who have taken sunitinib malate capsules have developed RPLS that can lead to death.oThrombotic microangiopathy (TMA) including thrombotic thrombocytopenia purpura (TTP) and hemolytic uremic syndrome (HUS). TMA is condition that involves injury to the smallest blood vessels, and blood clots that can happen while taking sunitinib malate capsules. TMA is accompanied by decrease in red cells and cells that are involved with clotting. TMA may harm your bodys organs such as the brain and kidneys and can sometimes lead to death.oProtein in your urine. Some people who have taken sunitinib malate capsules have developed protein in their urine, and in some cases, kidney problems that can lead to death. Your healthcare provider will check you for this problem.oSerious skin and mouth reactions. Treatment with sunitinib malate capsules has caused severe skin reactions that can lead to death, including:osevere rash with blisters or peeling of the skin.opainful sores or ulcers on the skin, lips or inside the mouth.otissue damage (necrotizing fasciitis). If you have any signs or symptoms of severe skin reactions, stop taking sunitinib malate capsules and call your healthcare provider or get medical help right away.oThyroid problems. Your healthcare provider may do tests to check your thyroid function during sunitinib malate capsules treatment. Tell your healthcare provider if you have any of the following signs and symptoms during your treatment with sunitinib malate capsules:otiredness that gets worse and does not go awayoloss of appetiteoproblems with heatofeeling nervous or agitated, tremorsosweatingonausea or vomitingodiarrheaofast heart rateoweight gain or weight lossofeeling depressedoirregular menstrual periods or no menstrual periodsoheadacheohair lossoLow blood sugar (hypoglycemia). Low blood sugar can happen with sunitinib malate capsules, and may cause you to become unconscious, or you may need to be hospitalized. Low blood sugar with sunitinib malate capsules may be worse in people who have diabetes and take antidiabetic medicines. Your healthcare provider should check your blood sugar levels regularly during treatment with sunitinib malate capsules and may need to adjust the dose of your antidiabetic medicines. Call your healthcare provider right away if you have any of the following signs or symptoms of low blood sugar during your treatment with sunitinib malate capsules:oheadacheodrowsinessoweaknessodizzinessoconfusionoirritabilityohungerofast heart beatosweatingofeeling jitteryoJawbone problems (osteonecrosis). Severe jawbone problems have happened in some people who take sunitinib malate capsules. Certain risk factors such as taking bisphosphonate medicine or having dental disease may increase your risk of getting osteonecrosis. Your healthcare provider may tell you to see your dentist before you start taking sunitinib malate capsules. Your healthcare provider may tell you to avoid dental procedures, if possible, during your treatment with sunitinib malate capsules, especially if you are receiving bisphosphonate medicine into vein (intravenous). Tell your healthcare provider if you plan to have any dental procedures before or during treatment with sunitinib malate capsules.oYou should stop taking sunitinib malate capsules at least weeks before planned dental procedures.oYour healthcare provider should tell you when you may start taking sunitinib malate capsules again after dental procedures.oWound healing problems. Wound healing problems have happened in some people who take sunitinib malate capsules. Tell your healthcare provider if you plan to have any surgery before or during treatment with sunitinib malate capsules. oYou should stop taking sunitinib malate capsules at least weeks before planned surgery.oYour healthcare provider should tell you when you may start taking sunitinib malate capsules again after surgery.Your healthcare provider may temporarily stop, reduce your dose, or permanently stop treatment with sunitinib malate capsules if you develop serious side effects. Common side effects of sunitinib malate capsules include:otirednessoweaknessodiarrheaopain, swelling or sores inside of your mouthonauseaoloss of appetiteoindigestionovomitingostomach-area (abdominal) painoblisters or rash on the palms of your hands and soles of your feetohigh blood pressureotaste changesolow platelet countsThe medicine in sunitinib malate capsules is yellow, and it may make your skin look yellow. Your skin and hair may get lighter in color. Sunitinib malate capsules may also cause other skin problems including: dryness, thickness or cracking of the skin. These are not all of the possible side effects of sunitinib malate capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How do store sunitinib malate capsulesoStore sunitinib malate capsules at room temperature, between 20 to 25C (68 to 77F).Keep sunitinib malate capsules and all medicines out of the reach of children.General information about the safe and effective use of sunitinib malate capsules.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use sunitinib malate capsules for condition for which they were not prescribed. Do not give sunitinib malate capsules to other people, even if they have the same symptoms that you have. They may harm them. You can ask your healthcare provider or pharmacist for information about sunitinib malate capsules that is written for health professionals.What are the ingredients in sunitinib malate capsulesActive ingredient: sunitinib malateInactive ingredients: colloidal silicon dioxide, croscarmellose sodium, gelatin, magnesium stearate, mannitol, sodium lauryl sulfate and titanium dioxide. The 12.5 mg and 25 mg strengths also contain red iron oxide. The 25 mg, 37.5 mg and 50 mg strengths also contain yellow iron oxide. In addition, the black imprinting ink contains the following: ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze. Manufactured for: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX). This Medication Guide has been approved by the U.S. Food and Drug Administration.Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Revised: 9/2021SUNI:R6. oSevere liver problems, that can lead to death. Tell your healthcare provider right away if you develop any of the following signs and symptoms of liver problems during treatment with sunitinib malate capsules:oitchingoyellow eyes or skinodark urineopain or discomfort in the right upper stomach area. oitching. oyellow eyes or skin. odark urine. opain or discomfort in the right upper stomach area. oa rare cancer of the stomach, bowel, or esophagus called gastrointestinal stromal tumor (GIST) and when:oyou have taken the medicine imatinib mesylate and it did not stop the cancer from growing, oroyou cannot take imatinib mesylate.. oyou have taken the medicine imatinib mesylate and it did not stop the cancer from growing, or. oyou cannot take imatinib mesylate.. oadvanced kidney cancer (advanced renal cell carcinoma or RCC).. oadults with kidney cancer that has not spread (localized), and who are at high risk of RCC coming back again after having kidney surgery.. oa type of pancreatic cancer called pancreatic neuroendocrine tumors (pNET), that has progressed and cannot be treated with surgery.. ohave any heart problems. ohave high blood pressure. ohave thyroid problems. ohave history of low blood sugar or diabetes. ohave kidney function problems (other than cancer). ohave liver problems. ohave any bleeding problem. oplan to have surgery or have had recent surgery. You should stop taking sunitinib malate capsules at least weeks before planned surgery. See What are the possible side effects of sunitinib malate capsules. ohave seizures. ohave or have had pain in the mouth, teeth or jaw, swelling or sores inside the mouth, numbness or feeling of heaviness in the jaw, or loosening of tooth. oare pregnant or plan to become pregnant. Sunitinib malate can harm your unborn baby.Females who are able to become pregnant:oYour healthcare provider should do pregnancy test before you start treatment with sunitinib malate capsules.oYou should use effective birth control (contraception) during treatment and for at least weeks after your last dose of sunitinib malate capsules.oTell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with sunitinib malate capsules. oYour healthcare provider should do pregnancy test before you start treatment with sunitinib malate capsules.. oYou should use effective birth control (contraception) during treatment and for at least weeks after your last dose of sunitinib malate capsules.. oTell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with sunitinib malate capsules.. Males with female partners who are able to become pregnant should use effective birth control (contraception) during treatment and for weeks after your last dose of sunitinib malate capsules.Sunitinib malate capsules may cause fertility problems in males and females. Tell your healthcare provider if this is concern for you.. oare breastfeeding or plan to breastfeed. Do not breastfeed during treatment with sunitinib malate capsules and for at least weeks (1 month) after the last dose.. oTake sunitinib malate capsules exactly the way your healthcare provider tells you.. oTake sunitinib malate capsules time each day with or without food.. oIf you take sunitinib malate capsules for GIST or RCC, you will usually take your medicine for weeks (28 days) and then stop for weeks (14 days). This is cycle of treatment. You will repeat this cycle for as long as your healthcare provider tells you to.. oIf you take sunitinib malate capsules for pNET, take it time each day until your healthcare provider tells you to stop.. oDo not drink grapefruit juice or eat grapefruit during your treatment with sunitinib malate capsules. They may cause you to have too much sunitinib malate in your body.. oYour healthcare provider may do blood tests before each cycle of treatment to check you for side effects.. oIf you miss dose of sunitinib malate capsules by less than 12 hours, take the missed dose right away. If you miss dose of sunitinib malate capsules by more than 12 hours, just take your next dose at your regular time. Do not make up the missed dose. Tell your healthcare provider about any missed dose.. oCall your healthcare provider right away, if you take too many sunitinib malate capsules.. oSee What is the most important information should know about sunitinib malate capsules. oHeart problems. Heart problems may include heart failure, heart attack and heart muscle problems (cardiomyopathy) that can lead to death. Tell your healthcare provider if you feel very tired, are short of breath, or have swollen feet and ankles.. oAbnormal heart rhythm changes. Changes in the electrical activity of your heart called QT prolongation can cause irregular heart beats that can be life threatening. Your healthcare provider may do electrocardiograms and blood tests (electrolytes) to watch for these problems during your treatment with sunitinib malate capsules. Tell your healthcare provider right away if you feel dizzy, faint, or have abnormal heartbeats during your treatment with sunitinib malate capsules.. oyou feel faint or lightheaded, or you pass out. odizziness. ofeel your heart beat is irregular or fast. oHigh blood pressure. High blood pressure is common with sunitinib malate capsules and may sometimes be severe. Follow your healthcare providers instructions about having your blood pressure checked regularly. Call your healthcare provider if your blood pressure is high or if you have any of the following signs or symptoms of high blood pressure:. osevere headache. olightheadedness. odizziness. ochange in vision. Your healthcare provider may prescribe medicine for you to treat high blood pressure, if needed.. oBleeding problems. Bleeding is common with sunitinib malate capsules, but sunitinib malate capsules can also cause severe bleeding problems that can lead to death. Your healthcare provider will monitor you for bleeding and may do blood tests if needed. Call your healthcare provider right away if you have any of these symptoms or serious bleeding problem during treatment with sunitinib malate capsules, including:. opainful, swollen stomach (abdomen). ovomiting blood. ocoughing up blood. oblack, sticky stools. obloody urine. oheadache. ochange in your mental status. oSerious stomach and intestinal problems, that can sometimes lead to death. Some people have had tears in their stomach or intestine (perforation) or have developed an abnormal opening between the stomach and intestine (fistula). Get medical help right away if you get stomach-area (abdominal) pain that does not go away or is severe during treatment with sunitinib malate capsules.. oTumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells and may lead to death. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.. oAbnormal changes in the brain (Reversible Posterior Leukoencephalopathy Syndrome [RPLS]). RPLS can cause collection of symptoms including headache, confusion, and vision loss. Some people who have taken sunitinib malate capsules have developed RPLS that can lead to death.. oThrombotic microangiopathy (TMA) including thrombotic thrombocytopenia purpura (TTP) and hemolytic uremic syndrome (HUS). TMA is condition that involves injury to the smallest blood vessels, and blood clots that can happen while taking sunitinib malate capsules. TMA is accompanied by decrease in red cells and cells that are involved with clotting. TMA may harm your bodys organs such as the brain and kidneys and can sometimes lead to death.. oProtein in your urine. Some people who have taken sunitinib malate capsules have developed protein in their urine, and in some cases, kidney problems that can lead to death. Your healthcare provider will check you for this problem.. oSerious skin and mouth reactions. Treatment with sunitinib malate capsules has caused severe skin reactions that can lead to death, including:osevere rash with blisters or peeling of the skin.opainful sores or ulcers on the skin, lips or inside the mouth.otissue damage (necrotizing fasciitis).. osevere rash with blisters or peeling of the skin.. opainful sores or ulcers on the skin, lips or inside the mouth.. otissue damage (necrotizing fasciitis).. If you have any signs or symptoms of severe skin reactions, stop taking sunitinib malate capsules and call your healthcare provider or get medical help right away.. oThyroid problems. Your healthcare provider may do tests to check your thyroid function during sunitinib malate capsules treatment. Tell your healthcare provider if you have any of the following signs and symptoms during your treatment with sunitinib malate capsules:. otiredness that gets worse and does not go away. oloss of appetite. oproblems with heat. ofeeling nervous or agitated, tremors. osweating. onausea or vomiting. odiarrhea. ofast heart rate. oweight gain or weight loss. ofeeling depressed. oirregular menstrual periods or no menstrual periods. oheadache. ohair loss. oLow blood sugar (hypoglycemia). Low blood sugar can happen with sunitinib malate capsules, and may cause you to become unconscious, or you may need to be hospitalized. Low blood sugar with sunitinib malate capsules may be worse in people who have diabetes and take antidiabetic medicines. Your healthcare provider should check your blood sugar levels regularly during treatment with sunitinib malate capsules and may need to adjust the dose of your antidiabetic medicines. Call your healthcare provider right away if you have any of the following signs or symptoms of low blood sugar during your treatment with sunitinib malate capsules:. oheadache. odrowsiness. oweakness. odizziness. oconfusion. oirritability. ohunger. ofast heart beat. osweating. ofeeling jittery. oJawbone problems (osteonecrosis). Severe jawbone problems have happened in some people who take sunitinib malate capsules. Certain risk factors such as taking bisphosphonate medicine or having dental disease may increase your risk of getting osteonecrosis. Your healthcare provider may tell you to see your dentist before you start taking sunitinib malate capsules. Your healthcare provider may tell you to avoid dental procedures, if possible, during your treatment with sunitinib malate capsules, especially if you are receiving bisphosphonate medicine into vein (intravenous). Tell your healthcare provider if you plan to have any dental procedures before or during treatment with sunitinib malate capsules.oYou should stop taking sunitinib malate capsules at least weeks before planned dental procedures.oYour healthcare provider should tell you when you may start taking sunitinib malate capsules again after dental procedures.. oYou should stop taking sunitinib malate capsules at least weeks before planned dental procedures.. oYour healthcare provider should tell you when you may start taking sunitinib malate capsules again after dental procedures.. oWound healing problems. Wound healing problems have happened in some people who take sunitinib malate capsules. Tell your healthcare provider if you plan to have any surgery before or during treatment with sunitinib malate capsules. oYou should stop taking sunitinib malate capsules at least weeks before planned surgery.oYour healthcare provider should tell you when you may start taking sunitinib malate capsules again after surgery.. oYou should stop taking sunitinib malate capsules at least weeks before planned surgery.. oYour healthcare provider should tell you when you may start taking sunitinib malate capsules again after surgery.. otiredness. oweakness. odiarrhea. opain, swelling or sores inside of your mouth. onausea. oloss of appetite. oindigestion. ovomiting. ostomach-area (abdominal) pain. oblisters or rash on the palms of your hands and soles of your feet. ohigh blood pressure. otaste changes. olow platelet counts. oStore sunitinib malate capsules at room temperature, between 20 to 25C (68 to 77F).

SPL UNCLASSIFIED SECTION.

1.1Gastrointestinal 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.

USE IN SPECIFIC POPULATIONS SECTION.

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