Important Safety Information

Boxed Warning/
Hepatotoxicity
  • Hepatotoxicity may be severe, and in some cases fatal. Monitor hepatic function and interrupt, dose reduce, or discontinue SUTENT as recommended
  • Fatal liver failure has been observed. Monitor liver function tests at baseline, during each cycle, and as clinically indicated
  • Interrupt SUTENT for Grade 3 or 4 hepatotoxicity until resolution; discontinue if no resolution
  • Discontinue SUTENT for subsequent severe changes in liver function tests or other signs and symptoms of liver failure
  • Safety in patients with ALT or AST >2.5 x upper limit of normal (ULN) or with >5 x ULN and liver metastases has not been established
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, as clinically indicated
  • Discontinue SUTENT for clinical manifestations of congestive heart failure
  • Interrupt and/or dose reduce for decreased LVEF
QT prolongation and
Torsades de Pointes
  • SUTENT can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsades de Pointes
  • Monitor patients at higher risk of developing QT interval prolongation, including patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, and patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Consider periodic monitoring of electrocardiograms and electrolytes 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
Hypertension
  • Hypertension may occur
  • Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate
  • In cases of hypertension, withhold SUTENT until hypertension is controlled
Hemorrhagic events
  • Hemorrhagic events, including tumor-related hemorrhage and viscus perforation (both with fatal events) have occurred
  • Hemorrhagic events have involved the gastrointestinal tract, respiratory tract, tumor, urinary tract, and brain
  • These events may occur suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage
  • Perform serial complete blood counts (CBCs) and physical examinations with the clinical assessment of hemorrhagic events
Tumor lysis syndrome
(TLS)
  • Tumor lysis syndrome (TLS) (some fatal) has been reported
  • Patients generally at risk of TLS are those with high tumor burden prior to treatment
  • Monitor these patients and treat as clinically indicated
Thrombotic
microangiopathy (TMA)
  • Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, has been reported in patients who received SUTENT
  • Discontinue SUTENT for TMA
  • Reversal of the effects of TMA has been observed after treatment was discontinued
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 urinalysis during treatment, with follow-up measurement of 24-hour urine protein as clinically indicated
  • 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
Dermatologic toxicities
  • Severe cutaneous reactions have been reported, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal
  • Necrotizing fasciitis, including fatal cases, has been reported, including of the perineum and secondary to fistula formation
  • Permanently discontinue SUTENT for these severe cutaneous adverse reactions
Reversible Posterior
Leukoencephalopathy
Syndrome (RPLS)
  • Reversible Posterior
    Leukoencephalopathy Syndrome (RPLS)
    (some fatal) has been reported. Monitor for signs and symptoms of RPLS
  • Patients can present with hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness
  • Withhold SUTENT until resolution. The safety of reinitiating SUTENT in patients with RPLS is unknown
Thyroid dysfunction
  • Thyroid dysfunction may occur
  • Monitor thyroid function at baseline, periodically during treatment, and as clinically indicated
  • Monitor patients closely for signs and/or symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis during treatment with SUTENT
  • Initiate and/or adjust therapy for thyroid dysfunction as appropriate
Hypoglycemia
  • Hypoglycemia may occur
  • SUTENT can result in symptomatic hypoglycemia, which may lead to a loss of consciousness or require hospitalization
  • 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 SUTENT
  • In patients with diabetes, assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia
Osteonecrosis of the Jaw (ONJ)
  • Osteonecrosis of the Jaw (ONJ) occurred in patients treated with SUTENT. 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 SUTENT and periodically during SUTENT therapy
  • Advise patients regarding good oral hygiene practices
  • Withhold SUTENT treatment for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible
  • Withhold SUTENT for development of ONJ until complete resolution
Impaired wound healing
  • Impaired wound healing has been reported in patients who received SUTENT
  • 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
Embryofetal toxicity and reproductive potential
  • Females
    • SUTENT can cause fetal harm when administered to pregnant women
    • 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
  • Males
    • Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with SUTENT and for 7 weeks after the last dose
  • Male and female infertility
    • Based on findings in animals, male and female fertility may be compromised by treatment with SUTENT
Lactation
  • Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with SUTENT and for at least 4 weeks after the last dose
Venous thromboembolic
events
  • In pooled safety population, 3.5% of patients experienced a venous thromboembolic event, including Grade 3-4 in 2.2% of patients
Pancreatic function
  • Pancreatitis was observed in 5 patients (1%) receiving SUTENT for treatment-naïve RCC compared to 1 patient (<1%) receiving interferon alfa
  • In a trial of patients receiving adjuvant treatment for RCC, 1 patient (<1%) on SUTENT and none on placebo experienced pancreatitis
  • Pancreatitis was observed in 1 patient (1%) receiving SUTENT for pNET and 1 patient (1%) receiving placebo
CYP3A4 Inhibitors and Inducers
  • Dose adjustments are recommended when SUTENT is administered with CYP3A4 inhibitors or inducers
  • During treatment with SUTENT, patients should not drink grapefruit juice, eat grapefruit, or take St. John’s Wort
Most common ARs & most common grade 3/4 ARs (advanced pNET)
  • The most common ARs reported in ≥20% of patients with advanced pNET and more commonly with SUTENT than placebo (all grades, vs placebo) were diarrhea (59% vs 39%), stomatitis/oral syndromes (48% vs 18%), nausea (45% vs 29%), abdominal pain (39% vs 34%), vomiting (34% vs 31%), asthenia (34% vs 27%), fatigue (33% vs 27%), hair color changes (29% vs 1%), hypertension (27% vs 5%), hand-foot syndrome (23% vs 2%), bleeding events (22% vs 10%), epistaxis (21% vs 5%), and dysgeusia (21% vs 5%)
  • The most common grade 3/4 ARs reported in ≥5% of patients with advanced pNET receiving SUTENT (vs placebo) were hypertension (10% vs 1%), hand-foot syndrome (6% vs 0%), stomatitis/oral syndromes (6% vs 0%), abdominal pain (5% vs 10%), fatigue (5% vs 9%), asthenia (5% vs 4%), and diarrhea (5% vs 2%)
Most common grade
3/4 lab abnormalities (advanced pNET)
  • The most common grade 3/4 lab abnormalities (occurring in ≥5% of patients with advanced pNET receiving SUTENT vs placebo) included decreased neutrophils (16% vs 0%), increased glucose (12% vs 18%), increased alkaline phosphatase (10% vs 11%), decreased phosphorus (7% vs 5%), decreased lymphocytes (7% vs 4%), increased creatinine (5% vs 5%), increased lipase (5% vs 4%), increased AST (5% vs 3%), and decreased platelets (5% vs 0%)