SUTENT

SUTENT- sunitinib malate capsule
U.S. Pharmaceuticals

WARNING: HEPATOTOXICITY

Hepatotoxicity may be severe, and in some cases, fatal. Monitor hepatic function and interrupt, dose reduce, or discontinue SUTENT as recommended [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

1.1 Gastrointestinal 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.

1.2 Advanced Renal Cell Carcinoma

SUTENT is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC).

1.3 Adjuvant Treatment of Renal Cell Carcinoma

SUTENT is indicated for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy.

1.4 Advanced 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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage for GIST and Advanced RCC

The recommended dosage of SUTENT for gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC) is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) until disease progression or unacceptable toxicity. SUTENT may be taken with or without food.

2.2 Recommended Dosage for Adjuvant Treatment of RCC

The recommended dosage of SUTENT for the adjuvant treatment of RCC is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2), for nine 6-week cycles. SUTENT may be taken with or without food.

2.3 Recommended Dosage for pNET

The recommended dosage of SUTENT for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily until disease progression or unacceptable toxicity. SUTENT may be taken with or without food.

2.4 Dosage Modifications for Adverse Reactions

Dose interruption and/or dose modification in 12.5 mg increments or decrements is recommended based on individual safety and tolerability. The maximum dose administered in the pNET study was 50 mg daily. The minimum dose administered in the adjuvant RCC study was 37.5 mg daily.

2.5 Dosage Modification for Drug Interactions

Strong CYP3A4 Inhibitors

Select an alternate concomitant medication with no or minimal enzyme inhibition potential. If coadministration of SUTENT with a strong CYP3A4 inducer cannot be avoided, consider a dose reduction for SUTENT to a minimum dosage as follows [see Drug Interactions (7.1)]:

  • GIST and RCC: 37.5 mg orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2)
  • pNET: 25 mg orally once daily

Strong CYP3A4 Inducers

Select an alternate concomitant medication with no or minimal enzyme induction potential. If coadministration of SUTENT with a strong CYP3A4 inducer cannot be avoided, consider a dose increase for SUTENT to a maximum dosage as follows:

  • GIST and RCC: 87.5 mg orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2)
  • pNET: 62.5 mg orally once daily

If the dose of SUTENT is increased, monitor patients carefully for adverse reactions [see Drug Interactions (7.1)].

2.6 Dosage Modification for End-Stage Renal Disease Patients on Hemodialysis

No starting dose adjustment is required in patients with end-stage renal disease (ESRD) on hemodialysis. However, given the decreased exposure compared to patients with normal renal function, subsequent doses may be increased gradually up to 2-fold based on safety and tolerability [see Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Capsules, hard gelatin:

  • 12.5 mg sunitinib: orange cap and orange body, printed with white ink “Pfizer” on the cap and “STN 12.5 mg” on the body.
  • 25 mg sunitinib: caramel cap and orange body, printed with white ink “Pfizer” on the cap and “STN 25 mg” on the body.
  • 37.5 mg sunitinib: yellow cap and yellow body, printed with black ink “Pfizer” on the cap and “STN 37.5 mg” on the body.
  • 50 mg sunitinib: caramel top and caramel body, printed with white ink “Pfizer” on the cap and “STN 50 mg” on the body.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

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 or 4 hepatotoxicity until resolution.

Discontinue SUTENT in patients without resolution of Grade 3 or 4 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.

5.2 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)].

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