mic exposure in patients administered the recommended daily doses [RDD]). Significantly increased embryolethality was observed in rabbits at 5 mg/kg/day while developmental effects were observed at ≥ 1 mg/kg/day (approximately 0.3 times the AUC in patients administered the RDD of 50 mg/day). Developmental effects consisted of fetal skeletal malformations of the ribs and vertebrae in rats. In rabbits, cleft lip was observed at 1 mg/kg/day and cleft lip and cleft palate were observed at 5 mg/kg/day (approximately 2.7 times the AUC in patients administered the RDD). Neither fetal loss nor malformations were observed in rats dosed at ≤ 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD).
As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of SUTENT should be expected to result in adverse effects on pregnancy. There are no adequate and well-controlled studies of SUTENT in pregnant women. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SUTENT.
5.2 Left Ventricular Dysfunction
In GIST Study A, 22/209 patients (11%) on SUTENT and 3/102 patients (3%) on placebo had treatment-emergent left ventricular ejection fraction (LVEF) values below the lower limit of normal (LLN). Nine of 22 GIST patients on SUTENT with LVEF changes recovered without intervention. Five patients had documented LVEF recovery following intervention (dose reduction - one patient; addition of antihypertensive or diuretic medications - four patients). Six patients went off study without documented recovery. Additionally, three patients (1%) on SUTENT had Grade 3 reductions in left ventricular systolic function to LVEF < 40%; two of these patients died without receiving further study drug. No GIST patients on placebo had Grade 3 decreased LVEF. In GIST Study A, 1 patient (<1%) on SUTENT and 1 patient (1%) on placebo died of diagnosed heart failure; 2 patients (1%) on SUTENT and 2 patients (2%) on placebo died of treatment-emergent cardiac arrest. In the treatment-naïve MRCC study, 78 (21%) and 44 (12%) patients on SUTENT and IFN-α, respectively, had an LVEF value below the LLN. One (<1%) patient who received SUTENT was diagnosed with congestive heart failure (CHF). In the two cytokine-refractory MRCC studies, 25 patients (15%) had decreases in LVEF to below the LLN.
Patients who presented with cardiac events within 12 months prior to SUTENT administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from SUTENT clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing drug-related left ventricular dysfunction. Physicians are advised to weigh this risk against the potential benefits of the drug. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving SUTENT. Baseline and periodic eva luations of LVEF should also be considered while the patient is receiving SUTENT. In patients without cardiac risk factors, a baseline eva luation of ejection fraction sho
