Dosage & Administration
GIST and Advanced RCC:
Adjuvant Treatment of RCC:
pNET:
Sutent Prescribing Information
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)].
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.
Advanced Renal Cell Carcinoma
SUTENT is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC).
Adjuvant Treatment of Renal Cell Carcinoma
SUTENT is indicated for the adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy.
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.
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.
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.
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.
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.
| 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 |
| Adverse Reaction | Severity | Dosage Modifications for SUTENT |
|---|---|---|
Hepatotoxicity [see Warnings and Precautions (5.1)] | Grade 3 |
|
Grade 4 |
| |
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) |
|
Clinically manifested congestive heart failure (CHF) |
| |
Hypertension [see Warnings and Precautions (5.4)] | Grade 3 |
|
Grade 4 |
| |
Hemorrhagic events [see Warnings and Precautions (5.5)] | Grade 3 or 4 |
|
Thrombotic microangiopathy [see Warnings and Precautions (5.7)] | Any Grade |
|
Proteinuria or Nephrotic syndrome [see Warnings and Precautions (5.8)] | 3 or more grams proteinuria in 24 hours in the absence of nephrotic syndrome |
|
Nephrotic syndrome or recurrent proteinuria of 3 or more grams per 24 hours despite dose reductions |
| |
Dermatological toxicities Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Necrotizing fasciitis [see Warnings and Precautions (5.9)] | Any Grade |
|
Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10)] | Any Grade |
|
Osteonecrosis of the jaw [see Warnings and Precautions (5.13)] | Any Grade |
|
Impaired wound healing [see Warnings and Precautions (5.14)] | Any Grade |
|
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)].
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)].
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.
Pregnancy
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.
Lactation
There is no information regarding the presence of sunitinib and its metabolites in human milk. Sunitinib and its metabolites were excreted in rat milk at concentrations up to 12-fold higher than in plasma (see Data). 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.
Data
Animal Data
In lactating female rats administered 15 mg/kg, sunitinib and its metabolites were excreted in milk at concentrations up to 12-fold higher than in plasma.
Females and Males of Reproductive Potential
SUTENT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating treatment with SUTENT.
Contraception
Females
Advise females of reproductive potential to use effective contraception during treatment with SUTENT and for at least 4 weeks after the last dose.
Males
Based on findings in animal reproduction studies, advise males with female partners of reproductive potential to use effective contraception during treatment with SUTENT and for 7 weeks after the last dose.
Infertility
Based on findings in animals, SUTENT may impair male and female fertility [see Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness of SUTENT in pediatric patients have not been established. Safety and pharmacokinetics of sunitinib were assessed in an open-label study (NCT00387920) in pediatric patients 2 years to <17 years of age (n=29) with refractory solid tumors. In addition, efficacy, safety and pharmacokinetics of sunitinib was assessed in another open-label study (NCT01462695) in pediatric patients 2 years to <17 years of age (n=27) with high-grade glioma or ependymoma. The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults. Sunitinib was poorly tolerated in pediatric patients. The occurrence of dose-limiting cardiotoxicity prompted an amendment of the NCT00387920 study to exclude patients with previous exposure to anthracyclines or cardiac radiation. No responses were reported in patients in either of the trials.
Apparent clearance and volume of distribution normalized for BSA for sunitinib and its active major metabolite were lower in pediatrics as compared to adults.
The effect on open tibial growth plates in pediatric patients who received SUTENT has not been adequately studied. See Juvenile Animal Toxicity Data below.
Juvenile Animal Toxicity Data
Physeal dysplasia was present in cynomolgus monkeys with open growth plates treated with sunitinib for ≥3 months (3 month dosing 2, 6, 12 mg/kg/day; 8 cycles of dosing 0.3, 1.5, 6.0 mg/kg/day) at doses that were >0.4 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the RDD of 50 mg. The no-effect level (NOEL) was 1.5 mg/kg/day in monkeys treated intermittently for 8 cycles, but was not identified in monkeys treated continuously for 3 months. In developing rats treated continuously for 3 months (1.5, 5.0, and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day), bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses ≥5 mg/kg (approximately 10 times the combined AUC in patients administered the RDD of 50 mg). Additionally, tooth caries were present in rats at >5 mg/kg. The incidence and severity of physeal dysplasia were dose related and reversible upon cessation of treatment; however, findings in the teeth were not. In rats, the NOEL in bones was ≤2 mg/kg/day.
Geriatric Use
Of the 7527 patients with GIST, RCC (advanced and adjuvant), or pNET who received SUTENT, 32% were 65 years and older, and 7% were 75 years and older. Patients aged 65 years of age and older had a higher incidence of Grade 3 or 4 adverse reactions (67%) than younger patients (60%).
In the GIST study, 73 (30%) of the patients who received SUTENT were 65 years and older. In the mRCC study, 152 (41%) of patients who received SUTENT were 65 years and older. No overall differences in safety or effectiveness were observed between these patients and younger patients.
In the pNET study, 22 (27%) of the patients who received SUTENT were 65 years and older. Clinical studies of SUTENT did not include sufficient numbers of patients with pNET to determine if patients 65 years of age and older respond differently than younger patients.
Hepatic Impairment
No dose adjustment is required in patients with mild or moderate (Child-Pugh Class A or B) hepatic impairment [see Clinical Pharmacology (12.3)]. SUTENT was not studied in patients with severe (Child-Pugh Class C) hepatic impairment.
Renal Impairment
No dose adjustment is recommended in patients with mild (CLcr 50 to 80 mL/min), moderate (CLcr 30 to <50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not on dialysis [see Clinical Pharmacology (12.3)].
No dose adjustment is recommended for patients with end-stage renal disease (ESRD) on hemodialysis [see Clinical Pharmacology (12.3)].
None.