Sutent (Sunitinib Malate) - Warnings and Precautions

5.1 Pregnancy Category D

Sunitinib was evaluated in pregnant rats (0.3, 1.5, 3.0, 5.0 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) for effects on the embryo. Significant increases in the incidence of embryolethality and structural abnormalities were observed in rats at the dose of 5 mg/kg/day (approximately 5.5 times the systemic 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 evaluations of LVEF should also be considered while the patient is receiving SUTENT. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.

In the presence of clinical manifestations of CHF, discontinuation of SUTENT is recommended. The dose of SUTENT should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline.

5.3 QT Interval Prolongation

At approximately twice therapeutic concentrations, SUTENT has been shown to prolong the QTcF interval (see 12.4 Cardiac Electrophysiology). There were no patients on this study with greater than Grade 2 (CTCAE v3.0) QT/QTc interval prolongation. QT interval prolongation may lead to an increased risk for ventricular arrhythmias including torsade de pointes. Torsade de pointe has been observed in <0.1% of SUTENT-exposed patients. SUTENT should be used with caution in patients with a known history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Concomitant treatment with strong CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and dose reduction of SUTENT should be considered (see 2.2 Dose Modification).

5.4 Hemorrhagic Events

Bleeding events occurred in 37/202 patients (18%) receiving SUTENT in GIST Study A, compared to 17/102 patients (17%) receiving placebo. In patients receiving SUTENT for treatment-naïve MRCC, 104/375 patients (28%) had bleeding events compared with 25/360 patients (7%) receiving IFN-α; 44/169 patients (26%) receiving SUTENT for cytokine-refractory MRCC experienced bleeding. Epistaxis was the most common hemorrhagic adverse event reported. Less common bleeding events in GIST or MRCC patients included rectal, gingival, upper gastrointestinal, genital, and wound bleeding. In GIST Study A, 14/202 patients (7%) receiving SUTENT and 9/102 patients (9%) on placebo had Grade 3 or 4 bleeding events. In addition, one patient in Study A taking placebo had a fatal gastrointestinal bleeding event during cycle 2. Most events in MRCC patients were Grade 1 or 2; there was one Grade 3 event (bleeding foot wound) in a cytokine-refractory patient and one Grade 5 event of gastric bleed, unrelated to SUTENT treatment, in a treatment-naïve patient.

Tumor-related hemorrhage has been observed in patients treated with SUTENT. These events may occur suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Fatal pulmonary hemorrhage occurred in 2 patients receiving SUTENT on a clinical trial of patients with metastatic non-small cell lung cancer (NSCLC). Both patients had squamous cell histology. SUTENT is not approved for use in patients with NSCLC. Treatment-emergent Grade 3 and 4 tumor hemorrhage occurred in 5/202 patients (3%) with GIST receiving SUTENT on Study A. Tumor hemorrhages were observed as early as cycle 1 and as late as cycle 6. One of these five patients received no further drug following tumor hemorrhage. None of the other four patients discontinued treatment or experienced dose delay due to tumor hemorrhage. No patients with GIST in the Study A placebo arm were observed to undergo intratumoral hemorrhage. Tumor hemorrhage has not been observed in patients with MRCC. Clinical assessment of these events should include serial complete blood counts (CBCs) and physical examinations.

Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, have occurred rarely in patients with intra-abdominal malignancies treated with SUTENT.

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.

8 USE IN SPECIFIC POPULATIONS

• Nursing Mothers: It is not known whether sunitinib or its primary active metabolite is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, women should be advised against breastfeeding while taking SUTENT.

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

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.