Serious peripheral arterial events were reported in 2% (7/449) of Iclusig treated patients. Three patients developed digital or distal extremity necrosis; 2 of these patients had diabetes mellitus and peripheral arterial disease and required amputations.

Thirty of 34 Iclusig patients who experienced a serious arterial thrombosis event had one or more cardiovascular risk factors (e.g., myocardial infarction, coronary artery disease, angina, stroke, transient ischemic attack, hypertension, diabetes mellitus, hyperlipidemia, and smoking). Patients with cardiovascular risk factors are at increased risk for arterial thrombosis with Iclusig. Interrupt and consider discontinuation of Iclusig in patients who develop arterial thrombotic events [see Dosage and Administration (2.3)].

Venous Thromboembolism

Venous thromboembolic events occurred in 3% of Iclusig-treated patients, including deep venous thrombosis (9 patients), pulmonary embolism (4 patients), and 1 case each of portal vein thrombosis, and retinal vein thrombosis. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

Hepatotoxicity
Hepatotoxicity that has resulted in liver failure and death occurred in Iclusig-treated patients. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with BP-CML or Ph+ALL. Severe hepatotoxicity occurred in all disease cohorts.

The incidence of aspartate aminotransferase (ALT) or alanine aminotransferase (AST) elevation was 56% (all grades) and 8% (grade 3 or 4). Iclusig-treatment may result in elevation in ALT, AST, or both. ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Monitor liver function tests at baseline, at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

Congestive Heart Failure
Twenty patients treated with Iclusig (4%) experienced serious congestive heart failure or left ventricular dysfunction, with 4 fatalities. Thirty-three patients treated with Iclusig (7%) experienced any grade of congestive heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with congestive heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious congestive heart failure [see Dosage and Administration (2.3)].

Hypertension
Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis. These patients required urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.

Treatment-emergent hypertension occurred in 67% of patients (300/449) [see Adverse Reactions (6)]. In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90mm Hg, 78% (220/282) experienced treatment-emergent hypertension; 49% (139/282) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥9