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warnings and cautions
5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Fatal liver failure has been observed. Monitor liver function tests at baseline, during each cycle, and as clinically indicated. Interrupt sunitinib for Grade 3 hepatotoxicity until resolution Grade ≤ 1 or baseline and resume sunitinib at a reduced dose; discontinue if no resolution. Discontinue sunitinib in patients with Grade 4 hepatoxicity, in patients who have subsequent severe changes in liver function tests or other signs and symptoms of liver failure. (2.4, 5.1) Cardiovascular Events : Myocardial ischemia, myocardial infarction, heart failure, cardiomyopathy, and decreased left ventricular ejection fraction (LVEF) to below the lower limit of normal including death have occurred. Monitor for signs and symptoms of congestive heart failure and consider monitoring LVEF at baseline and periodically during treatment. Discontinue sunitinib for clinical manifestations of congestive heart failure. Interrupt and/or dose reduce for decreased LVEF. (5.2) QT Interval Prolongation and Torsade de Pointes : Monitor patients at higher risk for developing QT interval prolongation. Consider monitoring of electrocardiograms and electrolytes. (5.3) Hypertension : Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. Interrupt sunitinib for Grade 3 hypertension until resolution to Grade ≤1 or baseline, then resume sunitinib at a reduced dose. Discontinue sunitinib in patients who develop Grade 4 hypertension. (5.4) Hemorrhagic Events : Tumor-related hemorrhage and viscus perforation (both with fatal events) have occurred. Perform serial complete blood counts and physical examinations. Interrupt sunitinib for Grade 3 or 4 hemorrhagic events until resolution to Grade ≤1 or baseline, then resume at a reduced dose; discontinue if no resolution. (5.5) Tumor Lysis Syndrome (TLS) : TLS (some fatal) has been reported primarily in patients with RCC and GIST. Monitor these patients and treat as clinically indicated. (5.6) Thrombotic microangiopathy (TMA) : TMA, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, has been reported. Discontinue sunitinib for TMA. (5.7) Proteinuria : Renal failure or a fatal outcome has occurred. Monitor urine protein. Interrupt treatment for 24-hour urine protein of 3 or more grams. Discontinue for repeat episodes of 24-hour urine protein of 3 or more grams despite dose reductions or nephrotic syndrome. (5.8) Dermatologic Toxicities : Necrotizing fasciitis, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (some fatal) have occurred. Discontinue sunitinib for these events. (5.9) Reversible Posterior Leukoencephalopathy Syndrome (RPLS) : RPLS (some fatal) has been reported. Monitor for signs and symptoms of RPLS. Withhold sunitinib until resolution. (5.10) Thyroid Dysfunction : Monitor thyroid function at baseline, periodically during treatment, and as clinically indicated. Initiate and/or adjust therapy for thyroid dysfunction as appropriate. (5.11) Hypoglycemia: Check blood glucose levels regularly and assess if antidiabetic drug dose modifications are required. (5.12) Osteonecrosis of the Jaw (ONJ) : Withhold sunitinib for at least 3 weeks prior to invasive dental procedure and development of ONJ until complete resolution. (5.13) Impaired Wound Healing : Withhold sunitinib for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of sunitinib after resolution of wound healing complications has not been established. (5.14) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.15, 8.1, 8.3) 5.1 Hepatotoxicity Sunitinib 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 for Grade 3 hepatotoxicity until resolution to Grade ≤ 1 or baseline, then resume sunitinib at a reduced dose. Discontinue sunitinib in patients with Grade 4 hepatotoxicity, in patients without resolution of Grade 3 hepatotoxicity, in patients who subsequently experience severe changes in liver function tests and in patients who have other signs and symptoms of liver failure. Safety in patients with ALT or AST > 2.5 times upper limit of normal (ULN) or with > 5.0 times ULN and liver metastases has not been established. 5.2 Cardiovascular Events Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been reported. In pooled safety population, 3% of patients experienced heart failure; 71% of the patients with heart failure were reported as recovered. Fatal cardiac failure was reported in < 1% of patients. In the adjuvant treatment of RCC study, 11 patients experienced Grade 2 decreased ejection fraction (left ventricular ejection fraction [LVEF] 40% to 50% and a 10% to 19% decrease from baseline). In 3 of these 11 patients, the ejection fractions arm did not return to ≥ 50% or baseline by the time of last measurement. No patients who received sunitinib were diagnosed with CHF. Patients who presented with cardiac events within 12 months prior to sunitinib 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 clinical studies. Patients with prior anthracycline use or cardiac radiation were also excluded from some studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing left ventricular dysfunction. Consider monitoring LVEF at baseline and periodically as clinically indicated. Carefully monitor patients for clinical signs and symptoms of congestive heart failure (CHF). Discontinue sunitinib in patients who experience clinical manifestations of CHF. Interrupt sunitinib and/or reduce the dose in patients without clinical evidence of CHF who have an ejection fraction of greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline ejection fraction was not obtained. 5.3 QT Interval Prolongation and Torsade de Pointes Sunitinib can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes was observed in < 0.1% of patients. Monitor patients who are at higher risk of developing QT interval prolongation, including patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Consider periodic monitoring of electrocardiograms and electrolytes (i.e., magnesium, potassium) during treatment with sunitinib. Monitor QT interval more frequently when sunitinib is concomitantly administered with strong CYP3A4 inhibitors or drugs known to prolong QT interval. Consider dose reducing sunitinib [see Dosage and Administration (2.5) , Drug Interactions (7.2)]. 5.4 Hypertension In the pooled safety population, 29% of patients experienced hypertension. Grade 3 hypertension was reported in 7% of patients, and Grade 4 hypertension was reported in 0.2%. Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. In cases of Grade 3 hypertension, withhold sunitinib until resolution to Grade ≤ 1 or baseline, then resume sunitinib at a reduced dose. Discontinue sunitinib in patients with who develop Grade 4 hypertension. 5.5 Hemorrhagic Events and Viscus Perforation Hemorrhagic events, some of which were fatal, have involved the gastrointestinal tract, respiratory tract, tumor, urinary tract, and brain. In the pooled safety population, 30% of patients experienced hemorrhagic events, including Grade 3 or 4 in 4.2% of patients. Epistaxis was the most common hemorrhagic event and gastrointestinal hemorrhage was the most common Grade 3-5 event. Tumor-related hemorrhage was observed in patients treated with sunitinib. These events may occur suddenly, and in the case of pulmonary tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Pulmonary hemorrhage, some with a fatal outcome, was observed in patients treated with sunitinib for metastatic RCC, GIST, and metastatic lung cancer. Sunitinib is not approved for use in patients with lung cancer. Serious, sometimes fatal, gastrointestinal complications including gastrointestinal perforation, have been reported in patients with intra-abdominal malignancies treated with sunitinib. Include serial complete blood counts (CBCs) and physical examinations with the clinical assessment of hemorrhagic events. Interrupt sunitinib for Grade 3 or 4 hemorrhagic events until resolution to Grade ≤ 1 or baseline, then resume sunitinib at a reduced dose. Discontinue sunitinib in patients without resolution of Grade 3 or 4 hemorrhagic events. 5.6 Tumor 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 a fatal outcome, occurred in clinical trials and in postmarketing experience of sunitinib as monotherapy and administered in combination with bevacizumab. Sunitinib is not approved for use in combination with bevacizumab. Discontinue sunitinib in patients developing TMA. Reversal of the effects of TMA has been observed after sunitinib was discontinued. 5.8 Proteinuria Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Monitor patients for the development or worsening of proteinuria. Perform baseline and periodic urinalyses during treatment, with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt sunitinib and dose reduce for 24-hour urine protein of 3 or more grams. Discontinue sunitinib for patients with nephrotic syndrome or repeat episodes of 24-hour urine protein 3 or more grams despite dose reductions. The safety of continued sunitinib treatment in patients with moderate to severe proteinuria has not been evaluated. 5.9 Dermatologic Toxicities Severe cutaneous adverse reactions have been reported, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. Permanently discontinue sunitinib for these severe cutaneous adverse reactions. Necrotizing fasciitis, including fatal cases, has been reported in patients treated with sunitinib, including of the perineum and secondary to fistula formation. Discontinue sunitinib in patients who develop necrotizing fasciitis. 5.10 Reversible 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 in patients developing RPLS. 5.11 Thyroid Dysfunction Hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through postmarketing experience of sunitinib. 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. Initiate and/or adjust therapies for thyroid dysfunction as appropriate. 5.12 Hypoglycemia Sunitinib 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. Hypoglycemia has occurred in clinical trials in 2% of the patients treated with sunitinib for advanced RCC (Study 3) and GIST (Study 1) (n = 577) and in approximately 10% of the patients treated with sunitinib for pNET (Study 6) (n = 83). For patients being treated with sunitinib 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. In patients with diabetes, assess if antidiabetic therapies need to be adjusted to minimize the risk of hypoglycemia. 5.13 Osteonecrosis of the Jaw Osteonecrosis of the Jaw (ONJ) occurred in patients treated with sunitinib. 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 and periodically during sunitinib therapy. Advise patients regarding good oral hygiene practices. Withhold sunitinib treatment for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold sunitinib for development of ONJ until complete resolution.The safety of resumption of sunitinib after resolution of osteonecrosis of the jaw has not been established. 5.14 Impaired Wound Healing Impaired wound healing has been reported in patients who received sunitinib [see Adverse Reactions (6.2)]. Withhold sunitinib for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of sunitinib after resolution of wound healing complications has not been established. 5.15 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, sunitinib can cause fetal harm when administered to pregnant woman. Administration of sunitinib to pregnant rats and rabbits during the period of organogenesis resulted in teratogenicity at approximately 5.5 and 0.3 times the combined systemic exposure [combined area under the curve (AUC) of sunitinib plus its active metabolite] in patients administered the recommended daily dose (RDD) of 50 mg, respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with sunitinib and for 4 weeks following the final dose [see Use in Specific Populations (8.1, 8.3)] .