iclusig

Important safety information

Hypertension : Monitor blood pressure and manage hypertension as clinically indicated. Interrupt, dose reduce or stop ICLUSIG if hypertension is not medically controlled. ( 2.2 , 5.5 ) Pancreatitis : Monitor serum lipase. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms. ( 2.2 , 5.6 ) Neuropathy : Monitor for symptoms of peripheral and cranial neuropathy. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. ( 2.2 , 5.8 ) Ocular Toxicity : Conduct comprehensive eye exams at baseline and periodically during treatment. ( 5.9 ) Hemorrhage : Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. ( 2.2 , 5.10 ) Fluid Retention : Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. ( 2.2 , 5.11 ) Cardiac Arrhythmias : Monitor for signs or symptoms of arrhythmias and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. ( 5.12 ) Myelosuppression : Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 × 10 9 /L or platelets less than 50 × 10 9 /L, interrupt ICLUSIG until ANC at least 1.5 × 10 9 /L and platelets at least 75 × 10 9 /L, then resume at same or reduced dose. ( 2.2 , 5.13 ) Tumor Lysis Syndrome : Ensure adequate hydration and correct elevated uric acid levels prior to initiating ICLUSIG. ( 5.14 ) Reversible Posterior Leukoencephalopathy Syndrome (RPLS) : Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG in patients upon resolution of RPLS is unknown. ( 5.15 ) Impaired Wound Healing and Gastrointestinal Perforation : Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. ( 5.16 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.17 , 8.1 , 8.3 ) 5.1 Arterial Occlusive Events Arterial occlusive events (AOEs), including fatalities, occurred in patients who received ICLUSIG [see Adverse Reactions (6.1) ] . In PhALLCON, 6% of 163 patients experienced AOEs, of which 3.1%, 1.8%, and 1.2% experienced cardiovascular, cerebrovascular, and peripheral vascular AOEs, respectively. The median time to onset of the first AOE was 11.3 months (range: 8 days to 2.8 years). Grade 3 or 4 AOEs occurred in 3.7% of patients; the most frequent Grade 3 or 4 AOEs were myocardial infarction (1.2%), peripheral arterial occlusive disease (1.2%), angina pectoris and cerebrovascular accident (0.6% each). Fatal AOE of sudden death occurred in 1 patient (0.6%). AOEs were more frequent with increasing age [see Use in Specific Populations (8.5) ] . In PhALLCON, patients with uncontrolled hypertension, hypertriglyceridemia, or diabetes were excluded. Patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, venous thromboembolism, clinically significant atrial/ventricular tachyarrhythmias, unstable angina, or congestive heart failure within the 6 months prior to the first dose of ICLUSIG, were also excluded. In OPTIC, of the 94 patients who received a starting dose of 45 mg (45 mg → 15 mg), 18% experienced AOEs, of which 11%, 4.3%, and 3.2% experienced cardiovascular, cerebrovascular or peripheral vascular AOEs, respectively. The median time to onset of the first cardiovascular, cerebrovascular, or peripheral vascular event was 9.4 months (range: 12 days to 5.7 years), 11.7 months (range: 15 days to 1.6 years), and 6.3 months (range: 23 days to 3.6 years), respectively. Grade 3 or 4 AOEs occurred in 7% of patients; the most frequent Grade 3 or 4 AOEs were myocardial infarction, acute coronary syndrome, arterial thrombosis, ischemic stroke, ischemic cerebral infarction, subclavian artery stenosis and unstable angina (1.1% each). Fatal AOEs occurred in 4 patients (4.3%); including sudden death (2.1%), myocardial ischemia (1.1%) and myocardial infarction (1.1%). AOEs were more frequent with increasing age [see Use in Specific Populations (8.5) ] . In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, congestive heart failure, venous thromboembolism, or clinically significant atrial/ventricular arrhythmias, were excluded. In PACE, 26% of 449 patients experienced AOEs, of which 15%, 7%, and 11% experienced cardiovascular, cerebrovascular, and peripheral vascular AOEs, respectively. Some patients experienced recurrent or multisite vascular occlusion. The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular AOEs was 1 year (range: 1 day to 4.1 years), 1.4 years (range: 2 days to 4.5 years), and 2 years (range: 10 days to 4.9 years), respectively. Grade 3 or 4 AOEs occurred in 14% of patients; the most frequent Grade 3 or 4 AOEs were peripheral arterial occlusive disease (3.1%), myocardial infarction (2%), coronary artery disease (1.6%), and cerebral infarction (1.6%). Fatal AOEs occurred in 9 patients (2%); the most frequent fatal AOE was cardiac arrest (0.9%). In PACE, fatal and life-threatening AOEs occurred within 2 weeks of starting treatment at 45 mg, and at dose levels as low as 15 mg per day. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced AOEs. AOEs were more frequent with increasing age [see Use in Specific Populations (8.5) ] and in patients with history of ischemia, hypertension, diabetes, or hypercholesterolemia. The most common risk factors in patients with AOEs were history of hypertension (67%; 77/115), hypercholesterolemia (59%; 68/115), and non-ischemic cardiac disease (43%; 49/115). In PACE, patients developed heart failure concurrent or subsequent to a myocardial ischemic event [see Warnings and Precautions (5.3) ] . Patients required revascularization procedures (coronary, cerebrovascular, and peripheral arterial). ICLUSIG caused stenosis over multiple segments in major arterial vessels that supply the brain (e.g., carotid, vertebral, middle cerebral artery). Patients developed digital or distal extremity necrosis and required amputations. Renal artery stenosis associated with worsening, labile or treatment-resistant hypertension occurred in some ICLUSIG-treated patients [see Warnings and Precautions (5.5) ] . In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease, including any history of clinically significant atrial/ventricular arrhythmias or history of myocardial infarction, unstable angina, or congestive heart failure within the 3 months prior to the first dose of ICLUSIG, were excluded [see Adverse Reactions (6.1) ] . Consider whether the benefits of ICLUSIG are expected to exceed the risks. Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity [see Dosage and Administration (2.2) ] . Consider benefit-risk to guide a decision to restart ICLUSIG. 5.2 Venous Thromboembolic Events Serious or severe VTEs have occurred in patients who received ICLUSIG. In…