treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. ( 1.1 )
treatment of adult patients with advanced renal cell carcinoma (RCC). ( 1.2 )
adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy. ( 1.3 )
treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease. ( 1.4 )
1.1Gastrointestinal Stromal Tumor
SUTENT is indicated for the treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.
1.2Advanced Renal Cell Carcinoma
SUTENT is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC).
1.3Adjuvant Treatment of Renal Cell Carcinoma
SUTENT is indicated for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy.
1.4Advanced Pancreatic Neuroendocrine Tumors
SUTENT is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease.
Contraindications
None. None ( 4 )
Warnings and precautions
Hepatotoxicity : 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 and resume SUTENT at a reduced dose; discontinue if no resolution. Discontinue SUTENT 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 SUTENT 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 SUTENT for Grade 3 hypertension until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose. Discontinue SUTENT 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 SUTENT 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 SUTENT 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 SUTENT for these events. ( 5.9 )
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) : RPLS (some fatal) has been reported. Monitor for signs and symptoms of RPLS. Withhold SUTENT 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 SUTENT for at least 3 weeks prior to invasive dental procedure and for development of ONJ until complete resolution. ( 5.13 )
Impaired Wound Healing : 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. ( 5.14 )
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 )
5.1Hepatotoxicity
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. Monitor liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) 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, 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 × upper limit of normal (ULN) or with >5 × ULN and liver metastases has not been established.
5.2Cardiovascular 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) ] .
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 thera
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Interactions
CYP3A4 Inhibitors : Consider dose reduction of SUTENT when administered with strong CYP3A4 inhibitors. ( 7.1 )
CYP3A4 Inducers : Consider dose increase of SUTENT when administered with strong CYP3A4 inducers. ( 7.1 )
7.1Effect of Other Drugs on
SUTENT Strong CYP3A4 Inhibitors Co-administration with strong CYP3A4 inhibitors may increase sunitinib plasma concentrations [see Clinical Pharmacology (12.3) ] . Select an alternate concomitant medication with no or minimal enzyme inhibition potential. Consider a dose reduction for SUTENT when it is co-administered with strong CYP3A4 inhibitors [see Dosage and Administration (2.5) ] . Strong CYP3A4 Inducers Co-administration with strong CYP3A4 inducers may decrease sunitinib plasma concentrations [see Clinical Pharmacology (12.3) ] .
Select an alternate concomitant medication with no or minimal enzyme induction potential. Consider a dose increase for SUTENT when it must be co-administered with CYP3A4 inducers [see Dosage and Administration (2.5) ] .
7.2 Drugs that Prolong QT Interval SUTENT is associated with QTc interval prolongation [see Warnings and Precautions (5.3) , Clinical Pharmacology (12.2) ] . Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on animal reproduction studies and its mechanism of action, SUTENT can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . 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 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, 1.5, 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, 1.5, 3, 5 mg/kg/day) and rabbits (0.5, 1, 5, 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, 1, 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.
Adverse reactions
The following clinically significant adverse reactions are described elsewhere in the labeling.
Hepatotoxicity [see Warnings and Precautions (5.1) ]
Cardiovascular Events [see Warnings and Precautions (5.2) ]
QT Interval Prolongation and Torsade de Pointes [see Warnings and Precautions (5.3) ]
Hypertension [see Warnings and Precautions (5.4) ]
Hemorrhagic Events [see Warnings and Precautions (5.5) ]
Tumor Lysis Syndrome [see Warnings and Precautions (5.6) ]
Thrombotic Microangiopathy [see Warnings and Precautions (5.7) ]
Proteinuria [see Warnings and Precautions (5.8) ]
Dermatologic Toxicities [see Warnings and Precautions (5.9) ]
Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10) ]
Thyroid Dysfunction [see Warnings and Precautions (5.11) ]
Hypoglycemia [see Warnings and Precautions (5.12) ]
Osteonecrosis of the Jaw [see Warnings and Precautions (5.13) ]
Impaired Wound Healing [see Warnings and Precautions (5.14) ]
The most common adverse reactions (≥25%) are fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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 SUTENT in 7527 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 SUTENT was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received SUTENT 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 SUTENT (mean: 3.0; range: 1–9) and 1 cycle (mean; 1.8; range: 1–6) 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 SUTENT arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received SUTENT. Table 3 summarizes the adverse reactions for Study 1.
Table 3. Adverse Reactions Reported in ≥10% of GIST Patients Who Received SUTENT in the Double-Blind Treatment Phase and More Commonly Than in Patients Given Placebo Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 1 Adverse Reaction GIST SUTENT (N=202) Placebo (N=102) All Grades % Grade 3–4 % All Grades % Grade 3–4 % Abbreviations: GIST=gastrointestinal stromal tumor; N=number of patients.
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 Includes decreased appetite. 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 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 SUTENT.
Table 4 summarizes the laboratory abnormalities in Study 1. Table 4. Laboratory Abnormalities Reported in ≥10% of GIST Patients Who Received SUTENT or Placebo in the Double-Blind Treatment Phase Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 1 Laboratory Abnormality GIST SUTENT (N=202) Placebo (N=102) All Grades % Grade 3–4 , Grade 4 laboratory abnormalities in patients on SUTENT included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%). % All Grades % Grade 3–4 , Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%). % Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; GIST=gastrointestinal stromal tumor; LVEF=left ventricular ejection fraction; N=number of patients.
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 After an interim analysis , the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label SUTENT [see Clinical Studies (14.1) ] .
For 241 patients randomized to the SUTENT arm, including 139 who received SUTENT in both the double-blind and open-label phases, the median duration of SUTENT treatment was 6 cycles (mean: 8.5; range: 1–44). For the 255 patients who ultimately received open-label SUTENT treatment, median duration of treatment was 6 cycles (mean: 7.8; range: 1–37) from the time of the unblinding. Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received SUTENT.
Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received SUTENT. The most common Grade 3 or 4 adverse reactions in patients who received SUTENT 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 SUTENT was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received SUTENT 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 SUTENT 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 SUTENT arm. Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received SUTENT. Table 5 summarizes the adverse reactions for Study 3. Table 5.
Adverse Reactions Reported in ≥10% of Patients With RCC Who Received SUTENT or Interferon Alfa Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 3 Adverse Reaction Treatment-Naïve RCC SUTENT (N=375) Interferon Alfa (N=360) All Grades % Grade 3–4 Grade 4 ARs in patients on SUTENT included back pain (1%), arthralgia (<1%), dyspnea (<1%), asthenia (<1%), fatigue (<1%), limb pain (<1%), and rash (<1%). % All Grades % Grade 3–4 Grade 4 ARs in patients on interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (<1%), and depression (<1%). % Abbreviations: ARs=adverse reactions; N=number of patients; RCC=renal cell carcinoma.
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