Sunitinib Drug Information

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in the Warnings and Precautions reflect exposure to sunitinib malate in 7,527 patients with GIST, RCC (advanced and adjuvant), or pNET. In this pooled safety population, the most common adverse reactions (≥25%) were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia. Gastrointestinal Stromal Tumor The safety of sunitinib malate was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received sunitinib malate 50 mg daily on Schedule 4/2 (n = 202) or placebo (n = 102). Median duration of blinded study treatment was 2 cycles for patients on sunitinib malate (mean: 3.0; range: 1 to 9) and 1 cycle (mean; 1.8; range: 1 to 6) for patients on placebo at the time of the interim analysis.

Permanent discontinuation due to an adverse reaction occurred in 7% of patients in the sunitinib malate arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received sunitinib malate. Table 3 summarizes the adverse reactions for Study 1. Table 3. Adverse Reactions Reported in ≥10% of GIST Patients Who Received Sunitinib Malate in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo* in Study 1 Adverse Reaction GIST Sunitinib Malate (N = 202) Placebo (N = 102) All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Any Adverse Reaction 94 56 97 51 Gastrointestinal Diarrhea 40 4 27 0 Mucositis/stomatitis 29 1 18 2 Constipation 20 0 14 2 Metabolism/Nutrition Anorexia a 33 1 29 5 Asthenia 22 5 11 3 Dermatology Skin discoloration 30 0 23 0 Rash 14 1 9 0 Hand-foot syndrome 14 4 10 3 Neurology Altered taste 21 0 12 0 Cardiac Hypertension 15 4 11 0 Musculoskeletal Myalgia/limb pain 14 1 9 1 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: GIST = gastrointestinal stromal tumor; N = number of patients. a Includes decreased appetite.

Other clinically relevant adverse reactions included oral pain other than mucositis/stomatitis in 6%; hair color changes in 7%; alopecia in 5% of patients who received sunitinib malate. Table 4 summarizes the laboratory abnormalities in Study 1. Table 4. Laboratory Abnormalities Reported in ≥10% of GIST Patients Who Received Sunitinib Malate or Placebo in the Double-Blind Treatment Phase* in Study 1 Laboratory Abnormality GIST Sunitinib Malate (N = 202) Placebo (N = 102) All Grades* % Grade 3 to 4*,a % All Grades* % Grade 3 to 4*,b % Any Laboratory Abnormality 34 22 Hematology Neutrophils decreased 53 10 4 0 Lymphocytes decreased 38 0 16 0 Platelets decreased 38 5 4 0 Hemoglobin decreased 26 3 22 2 Gastrointestinal AST/ALT increased 39 2 23 1 Lipase increased 25 10 17 7 Alkaline phosphatase increased 24 4 21 4 Amylase increased 17 5 12 3 Total bilirubin increased 16 1 8 0 Indirect bilirubin increased 10 0 4 0 Renal/Metabolic Creatinine increased 12 1 7 0 Potassium decreased 12 1 4 0 Sodium increased 10 0 4 1 Cardiac Decreased LVEF 11 1 3 0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GIST = gastrointestinal stromal tumor; LVEF = left ventricular ejection fraction; N = number of patients. a Grade 4 laboratory abnormalities in patients on sunitinib malate included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%). b Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%). After an interim analysis, the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label sunitinib malate . For 241 patients randomized to the sunitinib malate arm, including 139 who received sunitinib malate in both the double-blind and open-label phases, the median duration of sunitinib malate treatment was 6 cycles (mean: 8.5; range: 1 to 44). For the 255 patients who ultimately received open-label sunitinib malate treatment, median duration of treatment was 6 cycles (mean: 7.8; range: 1 to 37) from the time of the unblinding. Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received sunitinib malate.

Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received sunitinib malate. The most common Grade 3 or 4 adverse reactions in patients who received sunitinib malate in the open-label phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%). Advanced Renal Cell Carcinoma The safety of sunitinib malate was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received sunitinib malate 50 mg daily on Schedule 4/2 (n = 375) or interferon alfa 9 million International Units (MIU) (n = 360). The median duration of treatment was 11.1 months (range: 0.4 to 46.1) for sunitinib malate treatment and 4.1 months (range: 0.1 to 45.6) for interferon alfa treatment. Permanent discontinuation due to an adverse reaction occurred in 20% of patients in the sunitinib malate arm.

Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received sunitinib malate. Table 5 summarizes the adverse reactions for Study 3. Table 5. Adverse Reactions Reported in ≥10% of Patients with RCC Who Received Sunitinib Malate or Interferon Alfa* in Study 3 Adverse Reaction Treatment-Naïve RCC Sunitinib Malate (N = 375) Interferon Alfa (N = 360) All Grades % Grade 3 to 4 a % All Grades % Grade 3 to 4 b % Any Adverse Reaction 99 77 99 55 Gastrointestinal Diarrhea 66 10 21 <1 Nausea 58 6 41 2 Mucositis/stomatitis 47 3 5 <1 Vomiting 39 5 17 1 Dyspepsia 34 2 4 0 Abdominal pain c 30 5 12 1 Constipation 23 1 14 <1 Dry mouth 13 0 7 <1 Oral pain 14 <1 1 0 Flatulence 14 0 2 0 GERD/reflux esophagitis 12 <1 1 0 Glossodynia 11 0 1 0 Hemorrhoids 10 0 2 0 Constitutional Fatigue 62 15 56 15 Asthenia 26 11 22 6 Fever 22 1 37 <1 Weight decreased 16 <1 17 1 Chills 14 1 31 0 Chest Pain 13 2 7 1 Influenza like illness 5 0 15 <1 Metabolism/Nutrition Anorexia d 48 3 42 2 Neurology Altered taste e 47 <1 15 0 Headache 23 1 19 0 Dizziness 11 <1 14 1 Hemorrhage/Bleeding Bleeding, all sites 37 4 f 10 1 Cardiac Hypertension 34 13 4 <1 Edema peripheral 24 2 5 1 Ejection fraction decreased 16 3 5 2 Dermatology Rash 29 2 11 <1 Hand-foot syndrome 29 8 1 0 Skin discoloration/yellow skin 25 <1 0 0 Dry skin 23 <1 7 0 Hair color changes 20 0 <1 0 Alopecia 14 0 9 0 Erythema 12 <1 1 0 Pruritus 12 <1 7 <1 Musculoskeletal Pain in extremity/limb discomfort 40 5 30 2 Arthralgia 30 3 19 1 Back pain 28 5 14 2 Respiratory Cough 27 1 14 <1 Dyspnea 26 6 20 4 Nasopharyngitis 14 0 2 0 Oropharyngeal pain 14 <1 2 0 Upper respiratory tract infection 11 <1 2 0 Endocrine Hypothyroidism 16 2 1 0 Psychiatric Insomnia 15 <1 10 0 Depression g 11 0 14 1 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma. a Grade 4 ARs in patients on sunitinib malate included back pain (1%), arthralgia (<1%), dyspnea (<1%), asthenia (<1%), fatigue (<1%), limb pain (<1%), and rash (<1%). b Grade 4 ARs in patients on interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (<1%), and depression (<1%). c Includes flank pain. d Includes decreased appetite. e Includes ageusia, hypogeusia, and dysgeusia. f Includes 1 patient with Grade 5 gastric hemorrhage. g Includes depressed mood. Table 6 summarizes the laboratory abnormalities in Study 3. Table 6. Laboratory Abnormalities Reported in ≥10% of RCC Patients Who Received Sunitinib Malate or Interferon Alfa in Study 3 Laboratory Abnormality Treatment-Naïve RCC Sunitinib Malate (N = 375) Interferon Alfa (N = 360) All Grades* % Grade 3 to 4*,a % All Grades* % Grade 3 to 4*,b % Hematology Hemoglobin decreased 79 8 69 5 Neutrophils decreased 77 17 49 9 Platelets decreased 68 9 24 1 Lymphocytes decreased 68 18 68 26 Renal/Metabolic Creatinine increased 70 <1 51 <1 Creatine kinase increased 49 2 11 1 Uric acid increased 46 14 33 8 Calcium decreased 42 1 40 1 Phosphorus decreased 31 6 24 6 Albumin decreased 28 1 20 0 Glucose increased 23 6 15 6 Sodium decreased 20 8 15 4 Glucose decreased 17 0 12 <1 Potassium increased 16 3 17 4 Calcium increased 13 <1 10 1 Potassium decreased 13 1 2 <1 Sodium increased 13 0 10 0 Gastrointestinal AST increased 56 2 38 2 Lipase increased 56 18 46 8 ALT increased 51 3 40 2 Alkaline phosphatase increased 46 2 37 2 Amylase increased 35 6 32 3 Total bilirubin increased 20 1 2 0 Indirect bilirubin increased 13 1 1 0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; RCC = renal cell carcinoma. a Grade 4 laboratory abnormalities in patients on sunitinib malate included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (<1%), creatine kinase (<1%), creatinine (<1%), glucose increased (<1%), calcium decreased (<1%), phosphorous (<1%), potassium increased (<1%), and sodium decreased (<1%). b Grade 4 laboratory abnormalities in patients on interferon alfa included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (<1%), calcium increased (<1%), glucose decreased (<1%), potassium increased (<1%), and hemoglobin (<1%). Long-Term Safety in RCC The long-term safety of sunitinib malate in patients with metastatic RCC was analyzed across 9 completed clinical studies conducted in the first-line, bevacizumab-refractory, and cytokine-refractory treatment settings.

The analysis included 5,739 patients, of whom 807 (14%) were treated for at least 2 years and 365 (6%) for at least 3 years. Prolonged treatment with sunitinib malate did not appear to be associated with new types of adverse reactions. There appeared to be no increase in the yearly incidence of adverse reactions at later time points.

Hypothyroidism increased during the second year of treatment with new cases reported up to year 4. Adjuvant Treatment of RCC The safety of sunitinib malate was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who had undergone nephrectomy for RCC received sunitinib malate 50 mg daily on Schedule 4/2 (n = 306) or placebo (n = 304). The median duration of treatment was 12.4 months (range: 0.13 to 14.9) for sunitinib malate and 12.4 months (range: 0.03 to 13.7) for placebo. Permanent discontinuation due to an adverse reaction occurred in 28% of patients in the sunitinib malate arm. Adverse reactions leading to permanent discontinuation in >2% of patients include hand-foot syndrome and fatigue/asthenia.

Dosing interruptions occurred in 54% and dose reductions occurred in 46% of patients who received sunitinib malate. Table 7 summarizes the adverse reactions in S-TRAC. Table 7. Adverse Reactions Reported in ≥10% of Patients with RCC Who Received Sunitinib Malate and More Commonly Than in Patients Given Placebo* in S-TRAC Adverse Reaction Adjuvant Treatment of RCC Sunitinib Malate (N = 306) Placebo (N = 304) All Grades % Grade 3 to 4 % All Grades % Grade 3 to 4 % Any Adverse Reaction 99 60 88 15 Gastrointestinal Mucositis/Stomatitis a 61 6 15 0 Diarrhea 57 4 22 <1 Nausea 34 2 15 0 Dyspepsia 27 1 7 0 Abdominal pain b 25 2 9 <1 Vomiting 19 2 7 0 Constipation 12 0 11 0 Constitutional Fatigue/Asthenia 57 8 34 2 Localized edema c 18 <1 <1 0 Pyrexia 12 <1 6 0 Dermatology Hand-foot syndrome 50 16 10 <1 Rash d 24 2 12 0 Hair color changes 22 0 2 0 Skin discoloration/Yellow skin 18 0 1 0 Dry skin 14 0 6 0 Cardiac Hypertension e 39 8 14 1 Edema/Peripheral edema 10 <1 7 0 Neurology Altered taste f 38 <1 6 0 Headache 19 <1 12 0 Endocrine Hypothyroidism/TSH increased 24 <1 4 0 Hemorrhage/Bleeding Bleeding events, all sites g 24 <1 5 <1 Metabolism/Nutrition Anorexia/Decreased appetite 19 <1 5 0 Musculoskeletal Pain in extremity 15 <1 7 0 Arthralgia 11 <1 10 0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma. a Includes mucosal inflammation, stomatitis aphthous ulcer, mouth ulceration, tongue ulceration, oropharyngeal pain, and oral pain. b Includes abdominal pain, abdominal pain lower, and abdominal pain upper. c Includes edema localized, face edema, eyelid edema, periorbital edema, swelling face, and eye edema. d Includes dermatitis, dermatitis psoriasiform, exfoliative rash, genital rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic. e Includes hypertension, blood pressure increased, blood pressure systolic increased, blood pressure diastolic increased, and hypertensive crisis. f Includes ageusia, hypogeusia, and dysgeusia. g Includes epistaxis, gingival bleeding, rectal hemorrhage, hemoptysis, anal hemorrhage, upper gastrointestinal hemorrhage, and hematuria. Grade 4 adverse reactions in patients on sunitinib malate included hand-foot syndrome (1%), fatigue (<1%), abdominal pain (< 1%), stomatitis (<1%), and pyrexia (< 1%). Grade 3 to 4 laboratory abnormalities that occurred in ≥2% of patients receiving sunitinib malate include neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%). Advanced Pancreatic Neuroendocrine Tumors The safety of sunitinib malate was evaluated in Study 6, a randomized, double-blind, placebo-controlled trial in which patients with progressive pNET received sunitinib malate 37.5 mg once daily (n = 83) or placebo (n = 82). The median number of days on treatment was 139 days (range: 13 days to 532 days) for patients on sunitinib malate and 113 days (range: 1 day to 614 days) for patients on placebo.

Nineteen patients (23%) on sunitinib malate and 4 patients (5%) on placebo were on study for >1 year. Permanent discontinuation due to an adverse reaction occurred in 22% in the sunitinib malate arm. Dose interruptions occurred in 30% and dose reductions occurred in 31% of patients who received sunitinib malate.

Table 8 summarizes the adverse reactions in Study 6. Table 8. Adverse Reactions Reported in ≥10% of Patients with pNET Who Received Sunitinib Malate and More Commonly Than in Patients Given Placebo* in Study 6 Adverse Reaction pNET Sunitinib Malate (N = 83) Placebo (N = 82) All Grades % Grade 3 to 4 a % All Grades % Grade 3 to 4 % Any Adverse Reaction 99 54 95 50 Gastrointestinal Diarrhea 59 5 39 2 Stomatitis/oral syndromes b 48 6 18 0 Nausea 45 1 29 1 Abdominal pain c 39 5 34 10 Vomiting 34 0 31 2 Dyspepsia 15 0 6 0 Constitutional Asthenia 34 5 27 4 Fatigue 33 5 27 9 Weight decreased 16 1 11 0 Dermatology Hair color changes 29 1 1 0 Hand-foot syndrome 23 6 2 0 Rash 18 0 5 0 Dry skin 15 0 11 0 Cardiac Hypertension 27 10 5 1 Hemorrhage/Bleeding Bleeding events d 22 0 10 4 Epistaxis 21 1 5 0 Neurology Dysgeusia 21 0 5 0 Headache 18 0 13 1 Psychiatric Insomnia 18 0 12 0 Musculoskeletal Arthralgia 15 0 6 0 * Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: N = number of patients; pNET = pancreatic neuroendocrine tumors. a Grade 4 adverse reactions in patients on sunitinib malate included fatigue (1%). b Includes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth. c Includes abdominal discomfort, abdominal pain, and abdominal pain upper. d Includes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia. Table 9 summarizes the laboratory abnormalities in Study 6. Table 9. Laboratory Abnormalities Reported in ≥10% of Patients with pNET Who Received Sunitinib Malate in Study 6 Laboratory Abnormality pNET Sunitinib Malate Placebo All Grades* % Grade 3 to 4*,a % All Grades* % Grade 3 to 4*,b % Gastrointestinal AST increased 72 5 70 3 Alkaline phosphatase increased 63 10 70 11 ALT increased 61 4 55 3 Total bilirubin increased 37 1 28 4 Amylase increased 20 4 10 1 Lipase increased 17 5 11 4 Hematology Neutrophils decreased 71 16 16 0 Hemoglobin decreased 65 0 55 1 Platelets decreased 60 5 15 0 Lymphocytes decreased 56 7 35 4 Renal/Metabolic Glucose increased 71 12 78 18 Albumin decreased 41 1 37 1 Phosphorus decreased 36 7 22 5 Calcium decreased 34 0 19 0 Sodium decreased 29 2 34 3 Creatinine increased 27 5 28 5 Glucose decreased 22 2 15 4 Potassium decreased 21 4 14 0 Magnesium decreased 19 0 10 0 Potassium increased 18 1 11 1 * The denominator used to calculate the rate varied from 52 to 82 for sunitinib malate and 39 to 80 for Placebo based on the number of patients with a baseline value and at least one post-treatment value. Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; pNET = pancreatic neuroendocrine tumors. a Grade 4 laboratory abnormalities in patients on sunitinib malate included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%), and total bilirubin (1%). b Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%), and lipase (1%). Venous Thromboembolic Events In pooled safety population, 3.5% of patients experienced a venous thromboembolic event, including Grade 3 to 4 in 2.2% of patients.

Pancreatic Function Pancreatitis was observed in 1 patient (1%) in the pNET study, 5 patients (1%) in the treatment-naïve RCC study, and 1 patient (<1%) in the adjuvant treatment for RCC study on sunitinib malate.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of sunitinib malate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: hemorrhage associated with thrombocytopenia *. Gastrointestinal disorders: esophagitis.

Hepatobiliary disorders: cholecystitis, particularly acalculous cholecystitis. Immune system disorders: hypersensitivity reactions, including angioedema. Infections and infestations: serious infection (with or without neutropenia) *. The infections most commonly observed with sunitinib malate include respiratory, urinary tract, skin infections, and sepsis/septic shock.

Musculoskeletal and connective tissue disorders: fistula formation, sometimes associated with tumor necrosis and/or regression * ; myopathy and/or rhabdomyolysis with or without acute renal failure *. Renal and urinary disorders: renal impairment and/or failure *. Respiratory disorders: pulmonary embolism *, pleural effusion *. Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive de‑challenges. Vascular disorders: arterial (including aortic) aneurysms, dissections *, and rupture * ; arterial thromboembolic events *. The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral infarction. General disorders and administration site conditions: impaired wound healing. * including some fatalities

Effect of Other Drugs on Sunitinib Malate Strong

CYP3A4 Inhibitors Co-administration with strong CYP3A4 inhibitors may increase sunitinib plasma concentrations . Select an alternate concomitant medication with no or minimal enzyme inhibition potential. Consider a dose reduction for sunitinib malate when it is co‑administered with strong CYP3A4 inhibitors . Strong CYP3A4 Inducers Co-administration with strong CYP3A4 inducers may decrease sunitinib plasma concentrations . Select an alternate concomitant medication with no or minimal enzyme induction potential. Consider a dose increase for sunitinib malate when it must be co‑administered with CYP3A4 inducers .

Drugs that Prolong QT Interval Sunitinib malate is associated with QTc interval

prolongation . Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

Pregnancy Risk Summary Based on animal reproduction studies and its mechanism of action, sunitinib malate can cause fetal harm when administered to a pregnant woman . There are no available data in pregnant women to inform a drug-associated risk. In animal developmental and reproductive toxicology studies, oral administration of sunitinib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity (embryolethality, craniofacial and skeletal malformations) at 5.5 times and 0.3 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the recommended daily doses (RDD) of 50 mg, respectively (see Data). Advise females of reproductive potential of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5 mg/kg/day, 1.5 mg/kg/day, 5 mg/kg/day) for 21 days prior to mating and for 7 days after mating.

Embryolethality was observed at 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg). In embryo-fetal developmental toxicity studies, oral sunitinib was administered to pregnant rats (0.3 mg/kg/day, 1.5 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day) and rabbits (0.5 mg/kg/day, 1 mg/kg/day, 5 mg/kg/day, 20 mg/kg/day) during the period of organogenesis. In rats, embryolethality and skeletal malformations of the ribs and vertebrae were observed at the dose of 5 mg/kg/day (approximately 5.5 times the combined AUC in patients administered the RDD of 50 mg). No adverse fetal effects were observed in rats at doses ≤3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg). In rabbits, embryolethality was observed at 5 mg/kg/day (approximately 3 times the combined AUC in patients administered the RDD of 50 mg), and craniofacial malformations (cleft lip and cleft palate) were observed at ≥1 mg/kg/day (approximately 0.3 times the combined AUC in patients administered the RDD of 50 mg). Sunitinib (0.3 mg/kg/day, 1 mg/kg/day, 3 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses ≥1 mg/kg/day (approximately 0.5 times the combined AUC in patients administered the RDD of 50 mg). At 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg), reduced neonate body weights were observed at birth and persisted in the offspring of both sexes during the preweaning period and in males during postweaning period.

No adverse developmental effects were observed at doses ≤1 mg/kg/day.

Pediatric Use The safety and effectiveness of sunitinib malate in pediatric patients have not been established. Safety and pharmacokinetics of sunitinib were assessed in an open-label study (NCT00387920) in pediatric patients 2 years to <17 years of age (n = 29) with refractory solid tumors. In addition, efficacy, safety and pharmacokinetics of sunitinib was assessed in another open-label study (NCT01462695) in pediatric patients 2 years to <17 years of age (n = 27) with high-grade glioma or ependymoma.

The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults. Sunitinib was poorly tolerated in pediatric patients. The occurrence of dose-limiting cardiotoxicity prompted an amendment of the NCT00387920 study to exclude patients with previous exposure to anthracyclines or cardiac radiation.

No responses were reported in patients in either of the trials. Apparent clearance and volume of distribution normalized for BSA for sunitinib and its active major metabolite were lower in pediatrics as compared to adults. The effect on open tibial growth plates in pediatric patients who received sunitinib malate has not been adequately studied.

See Juvenile Animal Toxicity Data below. Juvenile Animal Toxicity Data Physeal dysplasia was present in cynomolgus monkeys with open growth plates treated with sunitinib for ≥3 months (3-month dosing 2 mg/kg/day, 6 mg/kg/day, 12 mg/kg/day; 8 cycles of dosing 0.3 mg/kg/day, 1.5 mg/kg/day, 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 8 cycles, but was not identified in monkeys treated continuously for 3 months.

In developing rats treated continuously for 3 months (1.5 mg/kg, 5.0 mg/kg, and 15.0 mg/kg) or 5 cycles (0.3 mg/kg/day, 1.5 mg/kg/day, 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 ≥5 mg/kg (approximately 10 times the combined AUC in patients administered the RDD of 50 mg). Additionally, tooth caries were present in rats at >5 mg/kg. The incidence and severity of physeal dysplasia were dose related and reversible upon cessation of treatment; however, findings in the teeth were not. In rats, the NOEL in bones was ≤2 mg/kg/day.

Treatment of overdose with sunitinib malate should consist of general supportive measures. There is no specific antidote for overdosage with sunitinib malate. 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, or without adverse reactions. In nonclinical studies, mortality was observed following as few as 5 daily doses of 500 mg/kg (3,000 mg/m 2 ) 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.