Ponatinib Hydrochloride

5 WARNINGS AND PRECAUTIONS 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 PhALLCON, VTEs occurred in 12% of 163 patients, including serious or severe (Grade 3 or 4) in 3.1%. VTEs included deep vein thrombosis (6%), superficial vein thrombosis (2.5%), embolism (1.8%), pulmonary embolism and thrombosis (1.2% each), and jugular vein thrombosis and retinal vein occlusion (0.6% each). The median time to onset of the first VTE event was 2.5 months (range: 6 days to 1.8 years). In OPTIC, of the 94 patients who received a starting dose of 45 mg, 2 patients experienced a VTE (Grade 1 retinal vein occlusion and grade 2 phlebitis). In PACE, VTEs occurred in 6% of 449 patients, including serious or severe (Grade 3 or 4) in 5.8%. VTEs included deep venous thrombosis (2.2%), pulmonary embolism (1.8%), superficial thrombophlebitis (0.7%), retinal vein occlusion (0.7%), and retinal vein thrombosis (0.4%) with vision loss. VTEs occurred in 10% of the 62 patients with BP-CML, 9% of the 32 patients with Ph+ ALL, 6% of the 270 patients with CP-CML, and 3.5% of the 85 patients with AP-CML. Monitor for evidence of VTEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity [see Dosage and Administration (2.2) ] . 5.3 Heart Failure Fatal, serious or severe heart failure events have occurred in patients who received ICLUSIG. In PhALLCON, heart failure occurred in 6% of 163 patients; 1.2% experienced serious or severe (Grade 3 or 4) heart failure. The most frequently reported heart failure event (>1 patient) was increased brain natriuretic peptide (BNP) (2.5%). In OPTIC, of the 94 patients who received a starting dose of 45 mg, heart failure occurred in 20% of patients; 2.1% experienced serious or severe (Grade 3 or 4) heart failure. The most frequently reported heart failure events (>1 patient each) were left ventricular hypertrophy (5%), left ventricular dysfunction (5%), BNP increased (5%), cardiac failure (3.2%), left atrial dilatation (2.1%) and ejection fraction decreased (2.1%). Fatal or serious heart failure occurred in PACE. Heart failure occurred in 9% of 449 patients; 7% experienced serious or severe (Grade 3 or higher) heart failure. The most frequently reported heart failure events (≥2%) were congestive cardiac failure (3.1%), decreased ejection fraction (2.9%), and cardiac failure (2%). Monitor patients for signs or symptoms consistent with heart failure and manage heart failure as clinically indicated. Interrupt, then resume at reduced dose or discontinue ICLUSIG for new or worsening heart failure [see Dosage and Administration (2.2) ] . 5.4 Hepatotoxicity ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in 3 patients, with hepatic failure occurring within 1 week of starting ICLUSIG in one of these patients. These fatal cases occurred in patients with BP-CML or Ph+ ALL treated with monotherapy. In PhALLCON, hepatotoxicity occurred in 66% of 163 patients; 30% experienced Grade 3 or 4 hepatotoxicity. The median time to onset of hepatotoxicity was 15 days (range: 1 day to 10 months). The most frequent hepatotoxic events were elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin and alkaline phosphatase, decreased albumin and decreased blood fibrinogen. In 6% of the 73 patients who reported ALT or AST elevation, the elevations were not resolved by the date of the last follow-up. In OPTIC, of the 94 patients who received a starting dose of 45 mg, hepatotoxicity occurred in 34% of patients; 7% experienced Grade 3 or 4 hepatotoxicity. The median time to onset of hepatotoxicity was 4.1 months, with a range of 1 day to 4.8 years. The most frequent hepatotoxic events were elevations of ALT, AST, alkaline phosphatase, and GGT. In one of the 26 patients who reported ALT or AST elevation, the event was not resolved by the date of last follow-up. In PACE, hepatotoxicity occurred in 32% of 449 patients; 13% experienced Grade 3 or 4 hepatotoxicity. The median time to onset of hepatotoxicity was 3.1 months, with a range of 1 day to 4.9 years. The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. In 9% of the 88 patients who reported ALT or AST elevation, the event was not resolved by the date of last follow-up. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at reduced dose or discontinue ICLUSIG based on recurrence/severity [see Dosage and Administration (2.2) ] . 5.5 Hypertension Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received ICLUSIG. In PhALLCON, hypertension occurred in 34% of 163 patients; 14% experienced serious or severe hypertension. Based on vital signs data, Grade 1 blood pressure elevation occurred in 15 out of 60 (25%) patients with normal initial blood pressure, Grade 2 occurred in 67 out of 134 (50%) patients with initial blood pressure of less than Grade 2, and Grade 3 occurred in 63 out of 160 (39%) patients with an initial blood pressure of less than Grade 3. In OPTIC, of the 94 patients who received a starting dose of 45 mg, hypertension events were reported in 37% of patients; 14% experienced serious or severe hypertension. Based on vital signs data, Grade 1 blood pressure elevation occurred in 8 out of 18 (44%) patients with normal initial blood pressure, Grade 2 occurred in 30 out of 81 (37%) patients with initial blood pressure of less than Grade 2, and Grade 3 occurred in 20 out of 92 (22%) patients with initial blood pressure of less than Grade 3. Three patients (3.2%) experienced hypertensive crisis. In PACE, hypertension events were reported in 32% of 449 patients; 13% experienced serious or severe hypertension. Any post-baseline elevation of systolic or diastolic BP of Grade 2 or higher in patients with normal baseline blood pressure occurred in 44% of 449 patients. Grade 1 BP elevation occurred in 26%, Grade 2 in 45%, and Grade 3 in 26%. Two patients (<1%) experienced Grade 4 hypertension (hypertensive crisis). Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath [see Adverse Reactions (6.1) ] . Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled [see Dosage and Administration (2.2) ] . For significant worsening, labile or treatment-resistant hypertension, interrupt ICLUSIG and consider evaluating for renal artery stenosis. 5.6 Pancreatitis Serious or severe pancreatitis has occurred in patients who received ICLUSIG. In PhALLCON, pancreatitis occurred in 34% of 163 patients; 15% experienced serious or severe (Grade 3 or 4) pancreatitis. The median time to onset of pancreatitis was 8 days (range: 1 day to 2 years). In 7 patients with clinical pancreatitis that led to dose modification, pancreatitis resolved within 3 weeks. Laboratory abnormalities of amylase elevations occurred in 25% of patients, while lipase elevations occurred in 60% of patients. In OPTIC, of the 94 patients who received a starting dose of 45 mg, pancreatitis occurred in 29% of patients; 16% experienced serious or severe (Grade 3 or 4) pancreatitis. Pancreatitis resulted in discontinuation in 1.1% of patients and interruption and/or dose reduction in 23% of patients. The median time to onset of pancreatitis was 1 month (range: 3 days to 4.1 years). In two patients with clinical pancreatitis that led to dose modification or treatment discontinuation, pancreatitis resolved within 2 weeks. Laboratory abnormalities of amylase elevation occurred in 15% of patients, while lipase elevation occurred in 40% of patients. In PACE, pancreatitis occurred in 26% of 449 patients; 17% experienced serious or severe (Grade 3 or 4) pancreatitis. Pancreatitis resulted in discontinuation in 0.4% of patients and interruption and/or dose reduction in 17% of patients. The median time to onset of pancreatitis was 29 days (range: 1 day to 4 years). Nineteen of the 28 cases of clinical pancreatitis that led to dose modification or treatment discontinuation resolved within 2 weeks. Laboratory abnormalities of amylase elevations occurred in 18% of patients, while lipase elevations occurred in 39% of patients. Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on severity [see Dosage and Administration (2.2) ] . Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms. 5.7 Increased Toxicity in Newly Diagnosed Chronic Phase CML In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with CP-CML, single agent ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib-treated patients, ICLUSIG-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. 5.8 Neuropathy In PhALLCON, peripheral neuropathy occurred in 68% of 163 patients; 3.1% experienced Grade 3 or 4 peripheral neuropathy. The most frequent peripheral neuropathies were neuropathy peripheral (33%), paresthesia (22%), and peripheral sensory neuropathy (12%). The median time to onset of peripheral neuropathy was 1.1 month (range: 1 day to 17.2 months). Cranial neuropathy was reported in 0.6% of 163 patients. In OPTIC, of the 94 patients who received a starting dose of 45 mg, neuropathy occurred in 13% of patients. Peripheral neuropathy occurred in 11% of patients. The most frequently reported peripheral neuropathies were muscular weakness (3.2%), paresthesia (3.2%), hypoesthesia (2.1%) and neuropathy peripheral (2.1%). Cranial neuropathy developed in 2 patients. The median time to onset of peripheral neuropathy and cranial neuropathy was 1.1 years (range: 1 month to 4.1 years) and 3 years (range: 10.3 months to 5.2 years), respectively. In PACE, neuropathy occurred in 22% of patients; 2.4% experienced Grade 3 or 4 neuropathy. Peripheral neuropathy occurred in 20% of 449 patients; 1.8% experienced Grade 3 or 4 peripheral neuropathy. The most frequent peripheral neuropathies were paresthesia (5%), neuropathy peripheral (4.5%), and hypoesthesia (3.6%). Cranial neuropathy developed in 3% of patients; 0.7% were Grade 3 or 4. The median time to onset of peripheral neuropathy and cranial neuropathy was 5.3 months (range: 1 day to 4.6 years) and 1.2 years (range: 18 days to 4 years), respectively. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity [see Dosage and Administration (2.2) ] . 5.9 Ocular Toxicity Serious ocular toxicities leading to blindness or blurred vision have occurred in ICLUSIG-treated patients. In PhALLCON, ocular toxicities occurred in 33% of 163 patients; 1.8% experienced a serious or severe ocular toxicity. The most frequent ocular toxicities were blurred vision and dry eye. Retinal toxicities occurred in 4.3% of patients; 0.6% experienced a Grade 3 retinal vein occlusion. The most frequent retinal toxicity event (>1 patient) was retinal hemorrhage (1.8%). In OPTIC, of the 94 patients who received a starting dose of 45 mg, ocular toxicities occurred in 15% of patients; 1.1% experienced a serious or severe ocular toxicity. The most frequent ocular toxicities were dry eye, blurred vision and eye pain. Retinal toxicities occurred in 4.3% of patients, including age-related macular degeneration, arteriosclerotic retinopathy, retinal vascular disorder and retinal vein occlusion (1.1% each). In PACE, ocular toxicities occurred in 30% of 449 patients; 3.6% experienced a serious or severe ocular toxicity. The most frequent ocular toxicities were dry eye, blurred vision, and eye pain. Retinal toxicities occurred in 3.6% of patients. The most frequent retinal toxicities were macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floaters (0.7% each). Conduct comprehensive eye exams at baseline and periodically during treatment. 5.10 Hemorrhage Fatal and serious hemorrhage events have occurred in patients who received ICLUSIG. In PhALLCON, hemorrhage occurred in 31% of 163 patients; 2.5% experienced a serious hemorrhage. Intracranial hemorrhage was the most frequently reported serious hemorrhage, occurring in 1.2% of patients. In OPTIC, of the 94 patients who received a starting dose of 45 mg, hemorrhage occurred in 13% of patients; 1 patient experienced a serious subdural hematoma. In PACE, hemorrhage occurred in 28% of 449 patients; 6% experienced a serious hemorrhage and 1.3% experienced a fatal hemorrhage. The incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Gastrointestinal hemorrhage and subdural hematoma were the most frequently reported serious hemorrhages, each occurring in 0.9% of patients. Most hemorrhages occurred in patients with Grade 4 thrombocytopenia [see Warnings and Precautions (5.13) ] . 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 [see Dosage and Administration (2.2) ] . 5.11 Fluid Retention Fatal and serious fluid retention events have occurred in patients who received ICLUSIG. In PhALLCON, fluid retention occurred in 24% of 163 patients; 1.2% experienced serious fluid retention, including pericardial effusion (1.2%). The most frequent occurrences of fluid retention were peripheral edema (11%) and pleural effusion (6%). In OPTIC, of the 94 patients who received a starting dose of 45 mg, fluid retention occurred in 6% of patients. The most frequent fluid retention events were peripheral edema (3.2%), hydrothorax (2.1%) and pleural effusion (2.1%). In PACE, fluid retention events occurred in 33% of 449 patients; 4.5% experienced serious fluid retention. One instance of brain edema was fatal. Serious fluid retention included pleural effusion (1.6%), pericardial effusion (1.6%), and angioedema (0.4%). The most frequent fluid retention events were peripheral edema (17%), pleural effusion (9%), pericardial effusion (4.2%) and peripheral swelling (3.8%). 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 [see Dosage and Administration (2.2) ] . 5.12 Cardiac Arrhythmias In PhALLCON, cardiac arrhythmia events occurred in 22% of 163 patients; 2.5% experienced Grade 3 or 4 cardiac arrhythmias, including tachycardia, syncope, atrial fibrillation and supraventricular tachycardia (0.6%, each). In OPTIC, of the 94 patients who received a starting dose of 45 mg, cardiac arrhythmias occurred in 27% of patients; 5% experienced Grade 3 or 4 cardiac arrhythmias including atrial fibrillation, cardio-respiratory arrest, supraventricular extrasystoles, supraventricular tachycardia and syncope (1.1%, each). In PACE, cardiac arrhythmias occurred in 20% of 449 patients; 7% experienced Grade 3 or 4 cardiac arrhythmias. Ventricular arrhythmias occurred in 3.4% of the 89 patients who reported an arrhythmia, with one event being Grade 3 or 4. Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% of patients. Atrial fibrillation was the most frequent cardiac arrhythmia (8%), with 3.3% being Grade 3 or 4. Other Grade 3 or 4 arrhythmia events included syncope (2%), tachycardia and bradycardia (0.4% each), and QT interval prolongation, atrial flutter, sinus bradycardia, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (0.2% each). For 31 patients, the arrythmia led to hospitalization. Monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness) and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. 5.13 Myelosuppression In PhALLCON, neutropenia occurred in 66% (Grade 3 or 4 occurred in 63%), thrombocytopenia occurred in 65% (Grade 3 or 4 occurred in 62%) and anemia occurred in 53% (Grade 3 or 4 occurred in 38%) of 163 patients. The median time to onset of Grade 3 or 4 myelosuppression was 27 days (range: 1 day to 9.2 months). In OPTIC, of the 94 patients who received a starting dose of 45 mg, thrombocytopenia occurred in 66% (Grade 3 or 4 occurred in 31%), neutropenia occurred in 56% (Grade 3 or 4 occurred in 22%), and anemia occurred in 38% of patients (Grade 3 or 4 occurred in 14%). The median time to onset of Grade 3 or 4 myelosuppression was 1.3 months (range: 1 day to 1.2 years). In PACE, neutropenia occurred in 56% (Grade 3 or 4 occurred in 34%), thrombocytopenia occurred in 63% (Grade 3 or 4 occurred in 40%), and anemia occurred in 52% of patients (Grade 3 or 4 occurred in 20%). The incidence of myelosuppression was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML. Severe myelosuppression (Grade 3 or 4) was observed early in treatment, with a median onset time of 29 days (range: 1 day to 4.1 years). 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 [see Dosage and Administration (2.2) ] . 5.14 Tumor Lysis Syndrome In PhALLCON, serious tumor lysis syndrome (TLS) developed in 0.6% of 163 patients. Hyperuricemia occurred in 10% of patients. In OPTIC, of the 94 patients who received a starting dose of 45 mg, serious TLS developed in 1.1% of patients. Hyperuricemia occurred in 2.1% of patients. In PACE, serious TLS developed in 0.4% of 449 patients. One case occurred in a patient with advanced AP-CML and 1 case occurred in a patient with BP-CML. Hyperuricemia occurred in 7% of patients. Ensure adequate hydration and treat high uric acid levels prior to initiating ICLUSIG. 5.15 Reversible Posterior Leukoencephalopathy Syndrome Reversible posterior leukoencephalopathy syndrome (RPLS; also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received ICLUSIG. Patients can present with hypertension, seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis. Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG in patients upon resolution of RPLS is unknown. 5.16 Impaired Wound Healing and Gastrointestinal Perforation Impaired wound healing occurred in patients receiving ICLUSIG [see Adverse Reactions (6.2) ] . 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. Gastrointestinal perforation or fistula occurred in patients receiving ICLUSIG [see Adverse Reactions (6.2) ] . Permanently discontinue in patients with gastrointestinal perforation. 5.17 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at exposures lower than human exposures at the maximum recommended human dose of 45 mg/day. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .