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Boxed Warning/Hepatotoxicity: Hepatotoxicity has been observed in clinical trials and postmarketing experience. Hepatotoxicity may be severe, and in some cases fatal. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. Fatal liver failure has been observed. Monitor liver function tests before initiation of treatment, during each cycle of treatment, and as clinically indicated. Interrupt SUTENT for Grade 3 or 4 drug-related hepatic adverse reactions and discontinue if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have signs and symptoms of liver failure.

Cardiovascular events, including myocardial ischemia, myocardial infarction, left ventricular ejection fraction declines to below the lower limit of normal, and cardiac failure, including death, have occurred. Monitor patients for signs and symptoms of congestive heart failure. Discontinue SUTENT for clinical manifestations of congestive heart failure. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered. Baseline and periodic evaluations of left ventricular ejection fraction should also be considered while these patients are receiving SUTENT.

SUTENT can cause QT prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsades de Pointes, which has been seen in <0.1% of patients. Monitor patients who are at higher risk for developing QT interval prolongation, including those 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 monitoring electrocardiograms and electrolytes. Concomitant treatment with strong CYP3A4 inhibitors may increase sunitinib plasma concentrations and dose reduction of SUTENT should be considered.

Hypertension may occur. Monitor blood pressure and treat as needed with standard antihypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled.

Hemorrhagic events, including tumor-related hemorrhage, and viscus perforation (both with fatal events) have occurred. 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.

Cases of tumor lysis syndrome (TLS) (some fatal) have been reported. Patients generally at risk of TLS are those with high tumor burden prior to treatment. Monitor these patients closely 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 as monotherapy and in combination with bevacizumab. Discontinue SUTENT in patients developing 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 ≥3 grams. Discontinue for repeat episodes of protein ≥3 grams despite dose reductions or nephrotic syndrome.

Dermatologic toxicities: Severe cutaneous reactions have been reported, including cases of necrotizing fasciitis, erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of EM, SJS, or TEN are present, discontinue SUTENT treatment. If a diagnosis of SJS or TEN is suspected, treatment must not be restarted.

Necrotizing fasciitis, including fatal cases, has been reported, including of the perineum and secondary to fistula formation. Discontinue SUTENT in patients who develop necrotizing fasciitis.

Thyroid dysfunction may occur. Monitor thyroid function in patients with signs and/or symptoms suggestive of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, and treat per standard medical practice.

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 regularly during and after discontinuation of treatment with SUTENT. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

Osteonecrosis of the jaw (ONJ) has been reported. Consider preventive dentistry prior to treatment with SUTENT. If possible, avoid invasive dental procedures, particularly in patients receiving intravenous bisphosphonate therapy.

Impaired wound healing has occurred with SUTENT. Temporary interruption of therapy with SUTENT is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume SUTENT therapy following a major surgical intervention should be based on clinical judgment of recovery from surgery.

Embryo fetal 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 from SUTENT, advise a lactating woman not to breastfeed during treatment with SUTENT and for at least 4 weeks after the last dose.

Venous thromboembolic events: In patients treated with SUTENT (N=7527) for GIST, advanced RCC, pNET, and as adjuvant treatment for RCC, 3.5% of patients experienced a venous thromboembolic event; 2.2% were Grade 3-4.

There have been (<1%) reports, some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness, should be controlled with medical management including control of hypertension. Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating healthcare provider.

Pancreatic function: In a trial of patients receiving adjuvant treatment for RCC, 1 patient (<1%) on SUTENT and none on placebo experienced pancreatitis.

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%).

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 IFNα) 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 IFNα) 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 IFNα) 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%), leukocytes (8% vs 2%), glucose increased (6% vs 6%), phosphorus (6% vs 6%), and amylase (6% vs 3%).

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%).

Indications:
SUTENT® (sunitinib malate) is indicated for:
  • the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate
  • the treatment of 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 patients with unresectable locally advanced or metastatic disease

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

Clinical Overview

The only 2nd-line therapy for imatinib-resistant or -intolerant GIST


Results from the phase 3, randomized, double-blind, placebo-controlled trial for SUTENT in patients with imatinib-resistant or -intolerant GIST (N=312)...

SUTENT demonstrated a significant 4-fold increase in median time to progression (TTP)

Primary endpoint: TTP

All data are from the phase 3, multicenter, double-blind, placebo-controlled study, in which 312 patients with imatinib-resistant or -intolerant GIST were randomized 2:1 to receive either SUTENT (50 mg once daily in cycles of 4 weeks on/2 weeks off) or placebo. The primary endpoint was TTP. Secondary endpoints included OS, ORR, PFS, and safety.

Results from the phase 3, randomized, double-blind, placebo-controlled trial for SUTENT in patients with imatinib-resistant or -intolerant GIST (N=312)...

Duration of median PFS was consistent with median TTP

Secondary endpoint: PFS

  • 67% reduced risk of progression or death
  • Significant improvement in PFS (HR=0.33 [95% Cl: 0.24, 0.47; P<.0001])

    Median: 24 .1 weeks (5.6 months) for SUTENT vs 6 weeks (1.4 months) with placebo (95% Cl: 11.1, 28.3 and 4.4, 9.9, respectively)

  • PFS was assessed using RECIST criteria1

Results from the phase 3, randomized, double-blind, placebo-controlled trial for SUTENT in patients with imatinib-resistant or -intolerant GIST (N=312)...

SUTENT reached a median OS of more than 16 months

Secondary endpoint: OS

  • Median: 72.7 weeks (16.8 months) for SUTENT vs 64.9 weeks (15.0 months) with placebo (95% CI: 61.3, 83.0 and 45.7, 96.0, respectively; HR=0.876 [95% CI: 0.679, 1.129])
  • The majority of patients in the placebo arm (99/118) crossed over to SUTENT in an open-label treatment phase

According to the National Comprehensive Cancer Network® (NCCN®), sunitinib malate (SUTENT) is the category 1–recommended 2nd-line TKI for GIST treatment2

  • For patients with limited or widespread disease progression on the standard dose of imatinib, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Soft Tissue Sarcoma V.2.2014 recommend dose escalation of imatinib as tolerated or changing to sunitinib malate (SUTENT)2

 

SUTENT has a well-known safety profile

Results from the phase 3, randomized, double-blind, placebo-controlled trial for SUTENT in patients with imatinib-resistant or -intolerant GIST (N=312)...

Adverse reactions

*Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
Includes decreased appetite.

Lab abnormalities

LVEF=left ventricular ejection fraction.

*Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
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%).
Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%).

Results from the phase 3, randomized, double-blind, placebo-controlled trial for SUTENT in patients with imatinib-resistant or -intolerant GIST (N=312)...

Discontinuation rates due to ARs* were similar between the SUTENT and placebo groups (7% vs 6%, respectively)

  • Additional reasons for discontinuation of SUTENT (n=207) or placebo (n=105), respectively, in the phase 3 trial included withdrawal of consent (3% each) and absence of efficacy (25% vs 62%)3
  • Dose interruptions (29% with SUTENT vs 30% with placebo) and dose reductions (11% with SUTENT vs 0% with placebo) may have helped to prevent treatment discontinuations due to ARs

*Treatment-emergent, nonfatal ARs.

 

Dose recommendations for imatinib-resistant or -intolerant GIST

    One 50-mg capsule taken orally once daily (4 weeks on/2 weeks off)
  • SUTENT may be taken with or without food
  • Remind patients to disclose any prescription or nonprescription medications they are taking, including bisphosphonates, vitamins, and herbal supplements, which can interact with SUTENT in different ways

    No dose adjustment is recommended based on:
  • Age, race, gender, body weight, creatinine clearance, ECOG performance status score, or hepatic impairment (Child-Pugh Class A or B)

    Strong CYP3A4 inhibitors or inducers should be avoided
  • Dose adjustments should be considered if SUTENT must be coadministered with these medications

Coadministration with CYP3A4 inhibitors and inducers

    Avoid strong CYP3A4 inhibitors or inducers whenever possible
  • They can affect the metabolism and plasma concentrations of SUTENT
  • They may have an effect on efficacy and tolerability
  • Patients should not take St John's Wort, eat grapefruit, or drink grapefruit juice while taking SUTENT

Adjust the dose of SUTENT when prescribing a CYP3A4 inhibitor or inducer

Dose modifications may be made during treatment

Multiple dosage strengths may enable patients to take 1 capsule per day

The dose of SUTENT may be adjusted in 12.5-mg increments or decrements, based on individual patient safety and tolerability.