Important Safety Info | Adjuvant RCC | SUTENT® (sunitinib malate)

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 hepatotoxicity until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose Discontinue SUTENT in patients with Grade 4 hepatotoxicity, in patients without resolution of Grade 3 hepatotoxicity, and in patients who subsequently experience 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 Grade 3 hypertension, withhold SUTENT until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose Discontinue SUTENT in patients who develop Grade 4 hypertension
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 Include serial complete blood counts (CBCs) and physical examinations with the clinical assessment of hemorrhagic events Interrupt SUTENT for Grade 3 or 4 hemorrhagic events until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose Discontinue SUTENT in patients without resolution of Grade 3 or 4 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 Discontinue SUTENT in patients developing RPLS
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 The safety of resumption of SUTENT after resolution of osteonecrosis of the jaw has not been established
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 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 SUTENT
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 (adjuvant RCC)	The most common ARs reported in ≥20% of patients receiving SUTENT for adjuvant treatment of RCC and more commonly than in patients given placebo (all grades, vs placebo) were mucositis/stomatitis (61% vs 15%), diarrhea (57% vs 22%), fatigue/asthenia (57% vs 34%), hand-foot syndrome (50% vs 10%), hypertension (39% vs 14%), altered taste (38% vs 6%), nausea (34% vs 15%), dyspepsia (27% vs 7%), abdominal pain (25% vs 9%), hypothyroidism/TSH increased (24% vs 4%), rash (24% vs 12%), bleeding events, all sites (24% vs 5%), and hair color changes (22% vs 2%) The most common grade 3/4 ARs reported in ≥5% of patients receiving SUTENT for adjuvant treatment of RCC and more commonly than in patients given placebo (vs placebo) were hand-foot syndrome (16% vs <1%), fatigue/asthenia (8% vs 2%), hypertension (8% vs 1%), and mucositis/stomatitis (6% vs 0%)
Most common grade 3/4 lab abnormalities (adjuvant RCC)	The most common grade 3/4 lab abnormalities (occurring in ≥2% of patients receiving SUTENT) included neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%)

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 hepatotoxicity until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose.

Discontinue SUTENT in patients with Grade 4 hepatotoxicity, in patients without resolution of Grade 3 hepatotoxicity, and in patients who subsequently experience 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.

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 may occur. Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. In cases of Grade 3 hypertension, withhold SUTENT until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose. Discontinue SUTENT in patients who develop Grade 4 hypertension.

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. Interrupt SUTENT for Grade 3 or 4 hemorrhagic events until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose. Discontinue SUTENT in patients without resolution of Grade 3 or 4 hemorrhagic events

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), 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 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) (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. Discontinue SUTENT in patients developing RPLS.

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 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) 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. The safety of resumption of SUTENT after resolution of osteonecrosis of the jaw has not been established.

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 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 SUTENT.

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 RCC): The most common ARs reported in ≥20% of patients receiving SUTENT for treatment-naïve metastatic RCC (all grades, vs interferon alfa) were diarrhea (66% vs 21%), fatigue (62% vs 56%), nausea (58% vs 41%), anorexia (48% vs 42%), altered taste (47% vs 15%), mucositis/stomatitis (47% vs 5%), pain in extremity/limb discomfort (40% vs 30%), vomiting (39% vs 17%), bleeding, all sites (37% vs 10%), hypertension (34% vs 4%), dyspepsia (34% vs 4%), arthralgia (30% vs 19%), abdominal pain (30% vs 12%), rash (29% vs 11%), hand-foot syndrome (29% vs 1%), back pain (28% vs 14%), cough (27% vs 14%), asthenia (26% vs 22%), dyspnea (26% vs 20%), skin discoloration/yellow skin (25% vs 0%), peripheral edema (24% vs 5%), headache (23% vs 19%), constipation (23% vs 14%), dry skin (23% vs 7%), fever (22% vs 37%), and hair color changes (20% vs <1%). The most common grade 3/4 ARs reported in ≥5% of patients with RCC receiving SUTENT (vs interferon alfa) were fatigue (15% vs 15%), hypertension (13% vs <1%), asthenia (11% vs 6%), diarrhea (10% vs <1%), hand-foot syndrome (8% vs 0%), dyspnea (6% vs 4%), nausea (6% vs 2%), back pain (5% vs 2%), pain in extremity/limb discomfort (5% vs 2%), vomiting (5% vs 1%), and abdominal pain (5% vs 1%).

Most common grade 3/4 lab abnormalities (advanced RCC): The most common grade 3/4 lab abnormalities (occurring in ≥5% of patients with RCC receiving SUTENT vs Interferon alfa) included lymphocytes (18% vs 26%), lipase (18% vs 8%), neutrophils (17% vs 9%), uric acid (14% vs 8%), platelets (9% vs 1%), hemoglobin (8% vs 5%), sodium decreased (8% vs 4%), glucose increased (6% vs 6%), phosphorus (6% vs 6%), and amylase (6% vs 3%).

Most common ARs & most common grade 3/4 ARs (adjuvant RCC): The most common ARs reported in ≥20% of patients receiving SUTENT for adjuvant treatment of RCC and more commonly than in patients given placebo (all grades, vs placebo) were mucositis/stomatitis (61% vs 15%), diarrhea (57% vs 22%), fatigue/asthenia (57% vs 34%), hand-foot syndrome (50% vs 10%), hypertension (39% vs 14%), altered taste (38% vs 6%), nausea (34% vs 15%), dyspepsia (27% vs 7%), abdominal pain (25% vs 9%), hypothyroidism/TSH increased (24% vs 4%), rash (24% vs 12%), bleeding events, all sites (24% vs 5%), and hair color changes (22% vs 2%). The most common grade 3/4 ARs reported in ≥5% of patients receiving SUTENT for adjuvant treatment of RCC and more commonly than in patients given placebo (vs placebo) were hand-foot syndrome (16% vs <1%), fatigue/asthenia (8% vs 2%), hypertension (8% vs 1%), and mucositis/stomatitis (6% vs 0%).

Most common grade 3/4 lab abnormalities (adjuvant RCC): The most common grade 3/4 lab abnormalities (occurring in ≥2% of patients receiving SUTENT) included neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%).

Most common ARs & most common grade 3/4 ARs (imatinib-resistant or -intolerant GIST): The most common ARs reported in ≥20% of patients with GIST and more commonly with SUTENT than placebo (all grades, vs placebo) were diarrhea (40% vs 27%), anorexia (33% vs 29%), skin discoloration (30% vs 23%), mucositis/stomatitis (29% vs 18%), asthenia (22% vs 11%), altered taste (21% vs 12%), and constipation (20% vs 14%). The most common grade 3/4 ARs reported in ≥4% of patients with GIST receiving SUTENT (vs placebo) were asthenia (5% vs 3%), hand-foot syndrome (4% vs 3%), diarrhea (4% vs 0%), and hypertension (4% vs 0%).

Most common grade 3/4 lab abnormalities (imatinib-resistant or -intolerant GIST): The most common grade 3/4 lab abnormalities (occurring in ≥5% of patients with GIST receiving SUTENT vs placebo) included lipase (10% vs 7%), neutrophils (10% vs 0%), amylase (5% vs 3%), and platelets (5% vs 0%).

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%).

Please see full Prescribing Information, including BOXED WARNING and Medication Guide, for SUTENT® (sunitinib malate).

INDICATIONS

SUTENT® (sunitinib malate) is indicated for:

the treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate
the treatment of adult patients with advanced renal cell carcinoma (RCC)
the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy
the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease