5.5 Hypertension
Hypertension (all grades) was reported in 31/202 GIST patients on SUTENT (15%) and 11/102 GIST patients on placebo (11%); Grade 3 hypertension was reported in 9/202 GIST patients on SUTENT (4%), none of the GIST patients on placebo.  Of patients receiving SUTENT for treatment-naïve MRCC, 101/375 patients (27%) receiving SUTENT compared with 13/360 patients (4%) on IFN-α experienced hypertension, as did 48/169 cytokine-refractory MRCC patients (28%). Grade 3 hypertension was observed in  34/375 treatment-naïve MRCC patients (9%) on SUTENT compared to 1/360 patient (<1%) on IFN-α, and 10/169 cytokine-refractory MRCC patients (6%). No Grade 4 hypertension was reported. SUTENT dosing was reduced or temporarily delayed for hypertension in none of the patients in GIST Study A and 6/169 cytokine-refractory MRCC patients (4%). No patients were discontinued from treatment with SUTENT due to systemic hypertension. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 8/202 GIST patients on SUTENT (4%), 1/102 GIST patients on placebo (1%),  20/375 treatment-naïve patients (5%) on SUTENT and 2/360 patients (1%) on IFN-α, and 10/169 cytokine-refractory MRCC patients (6%).

Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled.

5.6 Adrenal Function
Adrenal toxicity was noted in non-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at plasma exposures as low as 0.7 times the AUC observed in clinical studies. Histological changes of the adrenal gland were characterized as hemorrhage, necrosis, congestion, hypertrophy and inflammation. In clinical studies, CT/MRI obtained in 336 patients after exposure to one or more cycles of SUTENT demonstrated no evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately 400 patients across multiple clinical trials of SUTENT. Among patients with normal baseline ACTH stimulation testing, one patient developed consistently abnormal test results during treatment that are unexplained and may be related to treatment with SUTENT. Eleven additional patients with normal baseline testing had abnormalities in the final test performed, with peak cortisol levels of 12–16.4 mcg/dL (normal >18 mcg/dL) following stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency.

Physicians prescribing SUTENT are advised to monitor for adrenal insufficiency in patients who experience stress such as surgery, trauma or severe infection.

5.7 Laboratory Tests
CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT.

6 ADVERSE REACTIONS

6.1 Overview
One thousand nine hundred twenty-four (1924) patients with solid tumors including 808 patients (42%) with GIST and 816 patients (42%) with MRCC have been treated with SUTENT in 20 completed and ongoing clinical trials. Most patients received SUTENT once daily as a 50-mg oral capsule on Schedule 4/2. One hundred t