SUTENT

2 DOSAGE AND ADMINISTRATION GIST and Advanced RCC : • The recommended dosage is 50 mg orally once daily for the first 4 weeks of each 6-week cycle (Schedule 4/2). ( 2.1 ) Adjuvant Treatment of RCC : • The recommended dosage is 50 mg orally once daily for the first 4 weeks of a 6-week cycle (Schedule 4/2) for a maximum of 9 cycles. ( 2.2 ) pNET : • The recommended dosage is 37.5 mg orally once daily. ( 2.3 ) 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 To manage adverse reactions, the recommended dosage modifications are provided in Table 1. Table 2 provides the recommended dosage reductions of SUTENT for adverse reactions. Table 1. Recommended Dosage Reductions of SUTENT for Adverse Reactions Indications GIST RCC pNET Advanced RCC Adjuvant RCC First dose reduction 37.5 mg once daily 37.5 mg once daily 37.5 mg once daily 25 mg once daily Second dose reduction 25 mg once daily 25 mg once daily NA NA Table 2. Recommended Dosage Modifications for SUTENT for Adverse Reactions Adverse Reaction Severity Dosage Modifications for SUTENT Hepatotoxicity [see Warnings and Precautions (5.1) ] Grade 3 • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose. • For recurring Grade 3 permanently discontinue. Grade 4 • Permanently discontinue. Cardiovascular events [see Warnings and Precautions (5.2) ] Asymptomatic cardiomyopathy (left ventricular ejection fraction greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline was not obtained) • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at reduced dose. Clinically manifested congestive heart failure (CHF) • Permanently discontinue. Hypertension [see Warnings and Precautions (5.4) ] Grade 3 • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose. Grade 4 • Permanently discontinue. Hemorrhagic events [see Warnings and Precautions (5.5) ] Grade 3 or 4 • Withhold until resolution to Grade 0 to 1 or baseline. • Either resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction. Thrombotic microangiopathy [see Warnings and Precautions (5.7) ] Any Grade • Permanently discontinue. Proteinuria or Nephrotic syndrome [see Warnings and Precautions (5.8) ] 3 or more grams proteinuria in 24 hours in the absence of nephrotic syndrome • Withhold until resolution to Grade 0 to 1 or baseline. • Resume at a reduced dose. Nephrotic syndrome or recurrent proteinuria of 3 or more grams per 24 hours despite dose reductions • Permanently discontinue. Dermatological toxicities Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Necrotizing fasciitis [see Warnings and Precautions (5.9) ] Any Grade • Permanently discontinue. Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10) ] Any Grade • Permanently discontinue. Osteonecrosis of the jaw [see Warnings and Precautions (5.13) ] Any Grade • The safety of resumption of SUTENT after osteonecrosis has not been established. • Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction. Impaired wound healing [see Warnings and Precautions (5.14) ] Any Grade • The safety of resumption of SUTENT after resolution of wound healing has not been established. • Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction. 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 inhibitor 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) ] .

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1 INDICATIONS AND USAGE SUTENT is a kinase inhibitor indicated for: • treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.