5 WARNINGS AND PRECAUTIONS
SUTENT 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.
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 SUTENT were diagnosed with CHF.
Patients who presented with cardiac events within 12 months prior to SUTENT 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 SUTENT 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 SUTENT in patients who experience clinical manifestations of CHF. Interrupt SUTENT 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
SUTENT 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 SUTENT.
Monitor QT interval more frequently when SUTENT is concomitantly administered with strong CYP3A4 inhibitors or drugs known to prolong QT interval. Consider dose reducing SUTENT [see Dosage and Administration (2.5), Drug Interactions (7.2)].
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%.
5.5 Hemorrhagic Events and Viscus Perforation
Tumor-related hemorrhage was observed in patients treated with SUTENT. 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 SUTENT for metastatic RCC, GIST, and metastatic lung cancer. SUTENT 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 SUTENT.
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 SUTENT as monotherapy and administered in combination with bevacizumab. SUTENT is not approved for use in combination with bevacizumab.
Discontinue SUTENT in patients developing TMA. Reversal of the effects of TMA has been observed after SUTENT was discontinued.
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 SUTENT and dose reduce for 24-hour urine protein of 3 or more grams. Discontinue SUTENT for patients with nephrotic syndrome or repeat episodes of 24-hour urine protein of 3 or more grams despite dose reductions. The safety of continued SUTENT 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 SUTENT for these severe cutaneous adverse reactions.
Necrotizing fasciitis, including fatal cases, has been reported in patients treated with SUTENT, including of the perineum and secondary to fistula formation. Discontinue SUTENT in patients who develop necrotizing fasciitis.
5.11 Thyroid Dysfunction
Hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through postmarketing experience of SUTENT.
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 SUTENT. Initiate and/or adjust therapies for thyroid dysfunction as appropriate.
Check blood glucose levels at baseline, regularly during treatment, as clinically indicated and after discontinuation of SUTENT. In patients with diabetes, assess if antidiabetic therapies need to be adjusted to minimize the risk of hypoglycemia.
5.14 Impaired Wound Healing
Impaired wound healing has been reported in patients who received SUTENT [see Adverse Reactions (6.2)].
Withhold SUTENT for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of SUTENT after resolution of wound healing complications has not been established.
5.15 Embryo-Fetal Toxicity
Based on findings from animal studies and its mechanism of action, SUTENT 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 SUTENT and for 4 weeks following the final dose [see Use in Specific Populations (8.1, 8.3)].