tion of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort) may decrease sunitinib concentrations. St. John's Wort may decrease SUTENT plasma concentrations unpredictably. Patients receiving SUTENT should not take St. John's Wort concomitantly. A dose increase for SUTENT should be considered when it must be co-administered with CYP3A4 inducers (see 2.2 Dose Modification).
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
See 5 WARNINGS AND PRECAUTIONS.
8.3 Nursing Mothers
Sunitinib and/or its metabolites are excreted in rat milk. In lactating female rats administered 15 mg/kg, sunitinib and its metabolites were extensively excreted in milk at concentrations up to 12-fold higher than in plasma. It is not known whether SUTENT or its primary active metabolite are excreted in human milk. Because drugs are commonly excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breastfeeding while taking SUTENT.
8.4 Pediatric Use
The safety and efficacy of SUTENT in pediatric patients have not been studied in clinical trials.
Physeal dysplasia was observed in Cynomolgus monkeys with open growth plates treated 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) with sunitinib at doses that were > 0.4 times the RDD based on systemic exposure (AUC). 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 RDD based on AUC). Additionally, caries of the teeth were observed in rats at >5 mg/kg. The incidence and severity of physeal dysplasia were dose-related and were reversible upon cessation of treatment however findings in the teeth were not. A no effect level was not observed in monkeys treated continuously for 3 months, but was 1.5 mg/kg/day when treated intermittently for 8 cycles. In rats the no effect level in bones was ≤ 2 mg/kg/day.
8.5 Geriatric Use
Of the 825 GIST and MRCC patients who received SUTENT on pivotal clinical studies, 277 (34%) were 65 and over. No overall differences in safety or effectiveness were observed between younger and older patients.
8.7 Hepatic Impairment
Sunitinib and its primary metabolite are primarily metabolized by the liver. Systemic exposures after a single dose of SUTENT were similar in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to subjects with normal hepatic function. SUTENT was not studied in subjects with severe (Child-Pugh class C) hepatic impairment. Studies in cancer patients have excluded patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN. No dose adjustment is required when administering SUTENT to patients with Child Pugh Class A or B hepatic impairment.
10 OVERDOSAGE
No overdose of SUTENT was reported in completed clinical studies. In non-clinical studies mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection and gastrointestinal distress.
