Hypothyroidism

Treatment-emergent acquired hypothyroidism was noted in 8 GIST patients (4%) on SUTENT versus 1 (1%) on placebo. Hypothyroidism was reported as an adverse event in nine patients (2%) on SUTENT in the treatment-naïve MRCC study and one patient (<1%) in the IFN-α arm, and in 7 patients (4%) across the two cytokine-refractory MRCC studies. Additionally, TSH elevations were reported in 4 cytokine-refractory MRCC patients (2%). Overall, 7% of the cytokine-refractory MRCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism.

Patients with symptoms suggestive of hypothyroidism should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.

Gastrointestinal Function

Grade 3 and 4 increases in serum lipase were observed in 23 (14%) and 4 (2%), respectively, of 169 patients receiving SUTENT for cytokine-refractory MRCC and in 49 (13%) and 11 (3%), respectively, of patients receiving SUTENT for treatment-naïve MRCC. Grade 3 and 4 increases in serum amylase were observed in 8 (5%) and 1 (1%) cytokine-refractory MRCC patients, respectively and in 16 (4%) and 3 (1%), respectively, of patients receiving SUTENT for treatment-naïve MRCC. Increases in lipase levels were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects with either GIST or MRCC. Pancreatitis has been observed rarely (<1%) in patients receiving SUTENT for GIST or MRCC. Hepatic failure was observed in <1% of solid tumor patients treated with SUTENT. If symptoms of pancreatitis or hepatic failure are present, patients should have SUTENT discontinued and be provided with appropriate supportive care.

7 DRUG INTERACTIONS

7.1 In Vitro Studies of CYP Inhibition and Induction
In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.

7.2 CYP3A4 Inhibitors
Concurrent administration of sunitinib malate with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of sunitinib malate in healthy volunteers. Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconizole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of SUTENT. A dose reduction for SUTENT should be considered when it must be co-administered with strong CYP3A4 inhibitors (see 2.2 Dose Modification).

7.3 CYP3A4 Inducers
Concurrent administration of SUTENT with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Co-administra