Iclusig

WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITY

• Arterial occlusive events (AOEs), including fatalities, have occurred in ICLUSIG-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ICLUSIG based on severity. Consider benefit-risk to guide a decision to restart ICLUSIG. (

  2.2 Dosage Modifications for Adverse Reactions

  Recommended dosage modifications of ICLUSIG for adverse reactions are provided in Table 1 and recommended dose reductions of ICLUSIG for adverse reactions are presented in Table 2.

  Table 1: Recommended Dosage Modifications for ICLUSIG for Adverse Reactions

  Adverse Reaction	Severity	ICLUSIG Dosage Modifications
  Based on CTCAE v5.0: Grade 1 mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening ULN = Upper Limit of Normal for the lab; AOE = Arterial Occlusive Event; VTE = Venous Thromboembolic Event; ANC = absolute neutrophil count
  AOE: cardiovascular or cerebrovascular [see Warnings and Precautions (5.1)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 3 or 4	Discontinue ICLUSIG.
  AOE: peripheral vascular and other or VTE [see Warnings and Precautions (5.1, 5.2)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at same dose. If recurrence, interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	Grade 3	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 4	Discontinue ICLUSIG.
  Heart Failure [see Warnings and Precautions (5.3)]	Grade 2 or 3	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 4	Discontinue ICLUSIG.
  Hepatotoxicity [see Warnings and Precautions (5.4)]	AST or ALT greater than 3 times ULN	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	AST or ALT at least 3 times ULN concurrent with bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULN	Discontinue ICLUSIG.
  Pancreatitis and Elevated Lipase [see Warnings and Precautions (5.6)]	Serum lipase greater than 1 to 1.5 times ULN	Consider interrupting ICLUSIG until resolution, then resume at same dose.
  	Serum lipase greater than 1.5 to 2 times ULN, 2 to 5 times ULN and asymptomatic, or asymptomatic radiologic pancreatitis	Interrupt ICLUSIG until Grade 0 or 1 (less than 1.5 times ULN), then resume at next lower dose.
  	Serum lipase greater than 2 to 5 times ULN and symptomatic, symptomatic Grade 3 pancreatitis, or serum lipase greater than 5 times ULN and asymptomatic	Interrupt ICLUSIG until complete resolution of symptoms and after recovery of lipase elevation Grade 0 or 1, then resume at next lower dose.
  	Symptomatic pancreatitis and serum lipase greater than 5 times ULN	Discontinue ICLUSIG.
  Myelosuppression [see Warnings and Precautions (5.13)]	ANC less than 1 × 109/L or Platelets less than 50 × 109/L	Interrupt ICLUSIG until ANC at least 1.5 × 109/L and platelet at least 75 × 109/L, then resume at same dose. If recurrence, interrupt ICLUSIG until resolution, then resume at next lower dose.
  Other Non-hematologic Adverse Reactions [see Warnings and Precautions (5.5, 5.8, 5.10, 5.11, 5.12)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at same dose. If recurrence, interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	Grade 3 or 4	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.

  Table 2: Recommended Dose Reductions for ICLUSIG for Adverse Reactions

  Dose Reduction	Dosage for Patients with CP-CML	Dosage for Patients with AP-CML, BP-CML, and Ph+ ALL Monotherapy	Dosage for Patients with Newly Diagnosed Ph+ ALL
  First	30 mg orally once daily	30 mg orally once daily	15 mg orally once daily
  Second	15 mg orally once daily	15 mg orally once daily	10 mg orally once daily
  Third	10 mg orally once daily	Permanently discontinue ICLUSIG in patients unable to tolerate 15 mg orally once daily.	Permanently discontinue ICLUSIG in patients unable to tolerate 10 mg orally once daily.
  Subsequent Reduction	Permanently discontinue ICLUSIG in patients unable to tolerate 10 mg orally once daily.

  ,

  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.

  )
• Venous thromboembolic events (VTEs) have occurred in ICLUSIG-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue ICLUSIG based on severity. (

  2.2 Dosage Modifications for Adverse Reactions

  Recommended dosage modifications of ICLUSIG for adverse reactions are provided in Table 1 and recommended dose reductions of ICLUSIG for adverse reactions are presented in Table 2.

  Table 1: Recommended Dosage Modifications for ICLUSIG for Adverse Reactions

  Adverse Reaction	Severity	ICLUSIG Dosage Modifications
  Based on CTCAE v5.0: Grade 1 mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening ULN = Upper Limit of Normal for the lab; AOE = Arterial Occlusive Event; VTE = Venous Thromboembolic Event; ANC = absolute neutrophil count
  AOE: cardiovascular or cerebrovascular [see Warnings and Precautions (5.1)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 3 or 4	Discontinue ICLUSIG.
  AOE: peripheral vascular and other or VTE [see Warnings and Precautions (5.1, 5.2)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at same dose. If recurrence, interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	Grade 3	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 4	Discontinue ICLUSIG.
  Heart Failure [see Warnings and Precautions (5.3)]	Grade 2 or 3	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 4	Discontinue ICLUSIG.
  Hepatotoxicity [see Warnings and Precautions (5.4)]	AST or ALT greater than 3 times ULN	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	AST or ALT at least 3 times ULN concurrent with bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULN	Discontinue ICLUSIG.
  Pancreatitis and Elevated Lipase [see Warnings and Precautions (5.6)]	Serum lipase greater than 1 to 1.5 times ULN	Consider interrupting ICLUSIG until resolution, then resume at same dose.
  	Serum lipase greater than 1.5 to 2 times ULN, 2 to 5 times ULN and asymptomatic, or asymptomatic radiologic pancreatitis	Interrupt ICLUSIG until Grade 0 or 1 (less than 1.5 times ULN), then resume at next lower dose.
  	Serum lipase greater than 2 to 5 times ULN and symptomatic, symptomatic Grade 3 pancreatitis, or serum lipase greater than 5 times ULN and asymptomatic	Interrupt ICLUSIG until complete resolution of symptoms and after recovery of lipase elevation Grade 0 or 1, then resume at next lower dose.
  	Symptomatic pancreatitis and serum lipase greater than 5 times ULN	Discontinue ICLUSIG.
  Myelosuppression [see Warnings and Precautions (5.13)]	ANC less than 1 × 109/L or Platelets less than 50 × 109/L	Interrupt ICLUSIG until ANC at least 1.5 × 109/L and platelet at least 75 × 109/L, then resume at same dose. If recurrence, interrupt ICLUSIG until resolution, then resume at next lower dose.
  Other Non-hematologic Adverse Reactions [see Warnings and Precautions (5.5, 5.8, 5.10, 5.11, 5.12)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at same dose. If recurrence, interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	Grade 3 or 4	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.

  Table 2: Recommended Dose Reductions for ICLUSIG for Adverse Reactions

  Dose Reduction	Dosage for Patients with CP-CML	Dosage for Patients with AP-CML, BP-CML, and Ph+ ALL Monotherapy	Dosage for Patients with Newly Diagnosed Ph+ ALL
  First	30 mg orally once daily	30 mg orally once daily	15 mg orally once daily
  Second	15 mg orally once daily	15 mg orally once daily	10 mg orally once daily
  Third	10 mg orally once daily	Permanently discontinue ICLUSIG in patients unable to tolerate 15 mg orally once daily.	Permanently discontinue ICLUSIG in patients unable to tolerate 10 mg orally once daily.
  Subsequent Reduction	Permanently discontinue ICLUSIG in patients unable to tolerate 10 mg orally once daily.

  ,

  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)]

  .

  )
• Heart failure, including fatalities, occurred in ICLUSIG-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue ICLUSIG for new or worsening heart failure. (

  2.2 Dosage Modifications for Adverse Reactions

  Recommended dosage modifications of ICLUSIG for adverse reactions are provided in Table 1 and recommended dose reductions of ICLUSIG for adverse reactions are presented in Table 2.

  Table 1: Recommended Dosage Modifications for ICLUSIG for Adverse Reactions

  Adverse Reaction	Severity	ICLUSIG Dosage Modifications
  Based on CTCAE v5.0: Grade 1 mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening ULN = Upper Limit of Normal for the lab; AOE = Arterial Occlusive Event; VTE = Venous Thromboembolic Event; ANC = absolute neutrophil count
  AOE: cardiovascular or cerebrovascular [see Warnings and Precautions (5.1)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 3 or 4	Discontinue ICLUSIG.
  AOE: peripheral vascular and other or VTE [see Warnings and Precautions (5.1, 5.2)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at same dose. If recurrence, interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	Grade 3	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 4	Discontinue ICLUSIG.
  Heart Failure [see Warnings and Precautions (5.3)]	Grade 2 or 3	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 4	Discontinue ICLUSIG.
  Hepatotoxicity [see Warnings and Precautions (5.4)]	AST or ALT greater than 3 times ULN	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	AST or ALT at least 3 times ULN concurrent with bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULN	Discontinue ICLUSIG.
  Pancreatitis and Elevated Lipase [see Warnings and Precautions (5.6)]	Serum lipase greater than 1 to 1.5 times ULN	Consider interrupting ICLUSIG until resolution, then resume at same dose.
  	Serum lipase greater than 1.5 to 2 times ULN, 2 to 5 times ULN and asymptomatic, or asymptomatic radiologic pancreatitis	Interrupt ICLUSIG until Grade 0 or 1 (less than 1.5 times ULN), then resume at next lower dose.
  	Serum lipase greater than 2 to 5 times ULN and symptomatic, symptomatic Grade 3 pancreatitis, or serum lipase greater than 5 times ULN and asymptomatic	Interrupt ICLUSIG until complete resolution of symptoms and after recovery of lipase elevation Grade 0 or 1, then resume at next lower dose.
  	Symptomatic pancreatitis and serum lipase greater than 5 times ULN	Discontinue ICLUSIG.
  Myelosuppression [see Warnings and Precautions (5.13)]	ANC less than 1 × 109/L or Platelets less than 50 × 109/L	Interrupt ICLUSIG until ANC at least 1.5 × 109/L and platelet at least 75 × 109/L, then resume at same dose. If recurrence, interrupt ICLUSIG until resolution, then resume at next lower dose.
  Other Non-hematologic Adverse Reactions [see Warnings and Precautions (5.5, 5.8, 5.10, 5.11, 5.12)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at same dose. If recurrence, interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	Grade 3 or 4	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.

  Table 2: Recommended Dose Reductions for ICLUSIG for Adverse Reactions

  Dose Reduction	Dosage for Patients with CP-CML	Dosage for Patients with AP-CML, BP-CML, and Ph+ ALL Monotherapy	Dosage for Patients with Newly Diagnosed Ph+ ALL
  First	30 mg orally once daily	30 mg orally once daily	15 mg orally once daily
  Second	15 mg orally once daily	15 mg orally once daily	10 mg orally once daily
  Third	10 mg orally once daily	Permanently discontinue ICLUSIG in patients unable to tolerate 15 mg orally once daily.	Permanently discontinue ICLUSIG in patients unable to tolerate 10 mg orally once daily.
  Subsequent Reduction	Permanently discontinue ICLUSIG in patients unable to tolerate 10 mg orally once daily.

  ,

  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)]

  .

  )
• Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor liver function tests. Interrupt or discontinue ICLUSIG based on severity. (

  2.2 Dosage Modifications for Adverse Reactions

  Recommended dosage modifications of ICLUSIG for adverse reactions are provided in Table 1 and recommended dose reductions of ICLUSIG for adverse reactions are presented in Table 2.

  Table 1: Recommended Dosage Modifications for ICLUSIG for Adverse Reactions

  Adverse Reaction	Severity	ICLUSIG Dosage Modifications
  Based on CTCAE v5.0: Grade 1 mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening ULN = Upper Limit of Normal for the lab; AOE = Arterial Occlusive Event; VTE = Venous Thromboembolic Event; ANC = absolute neutrophil count
  AOE: cardiovascular or cerebrovascular [see Warnings and Precautions (5.1)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 3 or 4	Discontinue ICLUSIG.
  AOE: peripheral vascular and other or VTE [see Warnings and Precautions (5.1, 5.2)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at same dose. If recurrence, interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	Grade 3	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 4	Discontinue ICLUSIG.
  Heart Failure [see Warnings and Precautions (5.3)]	Grade 2 or 3	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.
  	Grade 4	Discontinue ICLUSIG.
  Hepatotoxicity [see Warnings and Precautions (5.4)]	AST or ALT greater than 3 times ULN	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	AST or ALT at least 3 times ULN concurrent with bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULN	Discontinue ICLUSIG.
  Pancreatitis and Elevated Lipase [see Warnings and Precautions (5.6)]	Serum lipase greater than 1 to 1.5 times ULN	Consider interrupting ICLUSIG until resolution, then resume at same dose.
  	Serum lipase greater than 1.5 to 2 times ULN, 2 to 5 times ULN and asymptomatic, or asymptomatic radiologic pancreatitis	Interrupt ICLUSIG until Grade 0 or 1 (less than 1.5 times ULN), then resume at next lower dose.
  	Serum lipase greater than 2 to 5 times ULN and symptomatic, symptomatic Grade 3 pancreatitis, or serum lipase greater than 5 times ULN and asymptomatic	Interrupt ICLUSIG until complete resolution of symptoms and after recovery of lipase elevation Grade 0 or 1, then resume at next lower dose.
  	Symptomatic pancreatitis and serum lipase greater than 5 times ULN	Discontinue ICLUSIG.
  Myelosuppression [see Warnings and Precautions (5.13)]	ANC less than 1 × 109/L or Platelets less than 50 × 109/L	Interrupt ICLUSIG until ANC at least 1.5 × 109/L and platelet at least 75 × 109/L, then resume at same dose. If recurrence, interrupt ICLUSIG until resolution, then resume at next lower dose.
  Other Non-hematologic Adverse Reactions [see Warnings and Precautions (5.5, 5.8, 5.10, 5.11, 5.12)]	Grade 1	Interrupt ICLUSIG until resolved, then resume at same dose.
  	Grade 2	Interrupt ICLUSIG until Grade 0 or 1, then resume at same dose. If recurrence, interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.
  	Grade 3 or 4	Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence.

  Table 2: Recommended Dose Reductions for ICLUSIG for Adverse Reactions

  Dose Reduction	Dosage for Patients with CP-CML	Dosage for Patients with AP-CML, BP-CML, and Ph+ ALL Monotherapy	Dosage for Patients with Newly Diagnosed Ph+ ALL
  First	30 mg orally once daily	30 mg orally once daily	15 mg orally once daily
  Second	15 mg orally once daily	15 mg orally once daily	10 mg orally once daily
  Third	10 mg orally once daily	Permanently discontinue ICLUSIG in patients unable to tolerate 15 mg orally once daily.	Permanently discontinue ICLUSIG in patients unable to tolerate 10 mg orally once daily.
  Subsequent Reduction	Permanently discontinue ICLUSIG in patients unable to tolerate 10 mg orally once daily.

  ,

  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)]

  .

  )

ICLUSIG^® is indicated for the treatment of adult patients with:

• Newly diagnosed Ph+ ALL in combination with chemotherapy.
  
  This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction
  [see

  14 CLINICAL STUDIES

  Newly Diagnosed Ph+ ALL

  The efficacy of ICLUSIG in combination with chemotherapy was evaluated in PhALLCON (NCT03589326), a randomized, active-controlled, multicenter, open-label trial of 245 patients with newly diagnosed Ph+ ALL. Randomization was stratified by age at the time of induction therapy (18 to <45 years; ≥45 to <60 years; and ≥60 years). Patients were randomized (2:1) to receive either ICLUSIG 30 mg orally once daily (n=164) or imatinib 600 mg orally once daily (n=81) in combination with chemotherapy (imatinib in combination with chemotherapy is an unapproved regimen in adult patients). The ICLUSIG dose was reduced to 15 mg once daily after completion of the induction phase and achievement of MRD-negative complete remission (CR). If a patient lost MRD negativity at any time after dose reduction to 15 mg, re-escalation to 30 mg once daily was allowed. Only patients who achieved CR or CR with incomplete hematologic recovery (CRi) with MRD-negativity at the end of induction could continue study treatment at the investigator’s discretion.

  Per protocol, patients were allowed to receive one cycle of optional prephase therapy excluding TKI prior to randomization to manage the acute disease during the screening period.

  Patients were randomized to receive either ICLUSIG or imatinib in combination with 20 cycles of chemotherapy, followed by ICLUSIG or imatinib as single-agent therapy (ICLUSIG or imatinib as single-agent after chemotherapy for newly diagnosed Ph+ ALL is not an approved regimen). Each cycle lasted 28 days.

  • Induction (Cycles 1 to 3):
    ICLUSIG 30 mg
    or
    imatinib 600 mg once daily in combination with:
    • Vincristine
      : 1.4 mg/m²IV on Days 1 and 14; capped at 2 mg
      and
    • Dexamethasone
      : <60 years old – 40 mg orally on Days 1 to 4 and Days 11 to 14; ≥60 years old: 20 mg orally on Days 1 to 4 and Days 11 to 14.

  • Consolidation (Cycles 4 to 9, alternating methotrexate and cytarabine):
    ICLUSIG 30 mg (or decreased to 15 mg if in MRD-negative CR)
    or
    imatinib 600 mg once daily in combination with:
    • Methotrexate
      (Cycles 4, 6, and 8): <60 years old – 1000 mg/m²IV on Day 1; ≥60 years old – 250 mg/m²IV, Day 1
      or
    • Cytarabine
      (Cycles 5, 7, and 9): <60 years old – 1000 mg/m²IV every 12 hours on Days 1, 3, and 5; ≥60 years old – 250 mg/m²IV every 12 hours on Days 1, 3, and 5.

  • Maintenance (Cycles 10 to 20):
    ICLUSIG 30 mg (or decreased to 15 mg if in MRD-negative CR)
    or
    imatinib 600 mg once daily in combination with:
    • Vincristine
      : 1.4 mg/m²IV on Day 1 of each cycle; capped at 2 mg
      and
    • Prednisone
      : <60 years old – 200 mg orally on Days 1 to 5; ≥60 to 69 years old – 100 mg orally on Days 1 to 5; ≥70 years old – 50 mg orally on Days 1 to 5.

  Following combination therapy, patients continued to receive ICLUSIG or imatinib as single-agent therapy until relapse from CR, progressive disease (PD), hematopoietic stem cell transplantation (HSCT), start of alternative therapy, or unacceptable toxicity.

  The demographics and baseline disease characteristics of the randomized population are described in Table 11.

  Table 11: Demographic and Disease Characteristics for PhALLCON

  Patient Characteristics at Entry	ICLUSIG 30 mg → 15 mg with Chemotherapy (N = 164)	Imatinib 600 mg with Chemotherapy (N = 81)
  Age (years)
  Median, years (range)	54 (19 to 82)	52 (19 to 75)
  Age Category, n (%)
  18 to <45 years	58 (35%)	29 (36%)
  45 to <60 years	45 (27%)	22 (27%)
  ≥60 years	61 (37%)	30 (37%)
  Sex, n (%)
  Female	90 (55%)	43 (53%)
  Race, n (%)
  White	104 (63%)	62 (77%)
  Not reported	28 (17%)	2 (3%)
  Asian	20 (12%)	11 (14%)
  Black or African American	9 (5%)	4 (5%)
  ECOG Performance Status, n (%)
  0	72 (44%)	33 (41%)
  1	85 (52%)	43 (53%)
  2	7 (4%)	5 (6%)
  Baseline BCR::ABL1 Dominant Variant
  p190	114 (70%)	53 (65%)
  p210	40 (24%)	25 (31%)
  Undetermined/not tested	10 (6%)	3 (4%)
  Prephase Therapy Per protocol, patients were allowed to receive one cycle of optional prephase therapy excluding TKI prior to randomization.	74 (45%)	41 (51%)
  Comorbidities, n (%)
  Hypertension	58 (35%)	30 (37%)
  Diabetes	39 (24%)	24 (30%)
  Dyslipidemia	29 (18%)	23 (28%)

  Among 244 treated patients, 96% completed induction (96% ICLUSIG, 95% imatinib), 84% received at least one cycle of consolidation (89% ICLUSIG, 75% imatinib), and 31% initiated maintenance (36% ICLUSIG, 21% imatinib). After completing combination therapy, 21% of patients received ICLUSIG and 9% received imatinib as single-agent therapy. The overall rate of HSCT was 34% (56/164) in the ICLUSIG arm versus 48% (39/81) in the imatinib arm.

  Efficacy was based on the MRD-negative CR rate at the end of induction. The analysis population for MRD-negative CR included 232 randomized patients who had a baseline BCR::ABL1 dominant variant of p190 or p210 as determined by central laboratory tests (154 patients in the ICLUSIG arm and 78 in the imatinib arm). Efficacy results are summarized in Table 12.

  Table 12: Efficacy Results in Patients with Ph+ ALL with Baseline BCR::ABL1 Dominant Variant of p190 or p210 in PhALLCON

  	ICLUSIG 30 mg → 15 mg with Chemotherapy (N = 154)	Imatinib 600 mg with Chemotherapy (N = 78)
  MRD: minimal residual disease; CR: complete remission (complete response); BCR::ABL1: breakpoint cluster region-Abelson.
  MRD-negative CRMRD-negative CR is defined as ≤0.01% BCR::ABL1/ABL1 or undetectable BCR::ABL1 transcripts in cDNA with ≥10,000 ABL1 transcripts, and meeting criteria for CRat End of Induction
  Achieved at the end of induction % (n/N)	30% (46/154)	12% (9/78)
  Risk difference (95% CI)Difference, 95% CI and two-sided p-value are based on Cochran-Mantel-Haenszel (CMH) method stratified by the randomization stratification factor.	0.18 (0.08, 0.28)
  p-value	0.0004
  CRCR is defined as no circulating blasts and <5% blasts in the bone marrow with normal maturation of all cellular components; no evidence of extramedullary disease (i.e., CNS involvement, lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass); and hematologic recovery of absolute neutrophil count >1.0 × 109/L and platelets >100 × 109/L for at least 4 weeks.at End of Induction % (n/N)	79% (122/154)	63% (49/78)

  The median duration of follow-up for overall survival was 20.4 months (95% CI: 18.4, 23.9) in the ICLUSIG arm and 18.1 months (95% CI: 13.9, 24.3) in the imatinib arm.

  In the subset of patients who did not receive prephase therapy, MRD-negative CR at the end of induction was achieved by 31% of patients in the ICLUSIG arm compared to 16% of patients in the imatinib arm and CR at the end of induction was achieved by 84% and 61%, respectively.

  Chronic Phase (CP) CML

  The efficacy of ICLUSIG was evaluated in OPTIC (NCT02467270), a dose-optimization trial. Eligible patients had CP-CML whose disease was considered to be resistant or resistant/intolerant to at least 2 prior kinase inhibitors or who have the T315I mutation. T315I mutation testing was performed on peripheral blood by Sanger Sequencing of the p190 or p210 BCR::ABL region. Resistance in CP-CML while on a prior kinase inhibitor was defined as failure to achieve either a complete hematologic response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months), or development of a new BCR::ABL1 kinase domain mutation or new clonal evolution. Patients were required to have >1% BCR::ABL1^IS(by real-time polymerase chain reaction) at trial entry. Patients received one of three starting dosages: 45 mg orally once daily, 30 mg orally once daily, or 15 mg orally once daily. Patients who received a starting dose of 45 mg or 30 mg had a dose reduction to 15 mg once daily upon achieving ≤1% BCR::ABL1^IS. The major efficacy outcome measure was ≤1% BCR::ABL1^ISat 12 months. Only the efficacy results for the recommended starting dose of 45 mg are described below.

  The median duration of follow-up for the 45 mg cohort (N=94) was 72.9 months (range: 0.5 months to 106.3 months).

  A total of 282 patients received ICLUSIG: 94 received a starting dose of 45 mg, 94 received a starting dose of 30 mg, and 94 received a starting dose of 15 mg. Baseline demographic characteristics are described in Table 13 for patients who received a starting dose of 45 mg.

  Table 13: Demographic and Disease Characteristics for OPTIC

  Patient Characteristics at Entry	ICLUSIG 45 mg → 15 mg (N = 94)
  Age
  Median years (range)	46 (19 to 81)
  Sex, n (%)
  Male	50 (53%)
  Race, n (%)
  White	73 (78%)
  Asian	16 (17%)
  Other/Unknown	4 (4%)
  Black or African American	1 (1%)
  ECOG Performance Status, n (%)
  ECOG 0 or 1	93 (99%)
  Disease History
  Median time from diagnosis to first dose, years (range)	5.5 (1 to 21)
  Resistant to Prior Kinase Inhibitor, n (%)	92 (98%)
  Presence of one or more BCR::ABL kinase domain mutations, n (%)	41 (44%)
  Number of Prior Kinase Inhibitors, n (%)
  1	1 (1%)
  2	43 (46%)
  ≥3	50 (53%)
  T315I mutation at baseline	25 (27%)
  Comorbidities
  Hypertension	29 (31%)
  Diabetes	5 (5%)
  Hypercholesterolemia	3 (3%)
  History of ischemic heart disease	3 (3%)

  Efficacy results are summarized in Table 14.

  Table 14: Efficacy Results in Patients with CP-CML Who Received ICLUSIG at Starting Dose of 45 mg in OPTIC

  	ICLUSIG 45 mg → 15 mg (N = 93)ITT population (N=93) defined as patients who had the b2a2/b3a2 (p210) transcript.
  Molecular Response at 12 months Primary endpoint was ≤1% BCR::ABL1ISrate at 12 months. Defined as a ≤1% ratio of BCR::ABL to ABL transcripts on the International Scale (IS) (i.e., ≤1% BCR::ABLIS; patients must have the b2a2/b3a2 (p210) transcript), in peripheral blood measured by quantitative reverse transcriptase polymerase chain reaction (qRT PCR).
  Overall ≤1% BCR::ABL1ISRate
  % (n/N)	44% (41/93)
  (95% CI)95% CI is calculated using the binomial exact (Clopper-Pearson) method.	(34%, 55%)
  Patients with T315I mutation
  % (n/N)	44% (11/25)
  (95% CI)	(24%, 65%)
  Patients without T315I mutation
  % (n/N)	44% (29/66)Of the 93 patients, two patients did not have a baseline mutation assessment and were excluded from the response by mutation analysis.
  (95% CI)	(32%, 57%)
  Cytogenetic Response by 12 months
  Major (MCyR)Secondary endpoint was MCyR by 12 months which combines both complete (no detectable Ph+ cells) and partial (1% to 35% Ph+ cells in at least 20 metaphases) cytogenetic responses.
  % (n/N)	48% (44/91)Analysis is based on ITT cytogenetic population (N=91) defined as patients who had a cytogenetic assessment at baseline with at least 20 metaphases examined. One patient who had a complete cytogenetic response at baseline was excluded from the analysis.
  (95% CI)	(38%, 59%)
  Patients with T315I mutation
  % (n/N)	52% (13/25)
  (95% CI)	(31%, 72%)
  Patients without T315I mutation
  % (n/N)	46% (30/65)Of the 91 patients, one patient did not have a baseline mutation assessment and was excluded from the response by mutation analysis.
  (95% CI)	(34%, 59%)

  The rate of molecular response (≤1% BCR::ABL1^IS) by 60 months was 60.2% (95% CI 49.5, 70.0). In patients with T3151 mutation, it was 64.0% (95% CI 42.5, 82.0) and in patients without T3151 mutation, it was 59.1% (95% CI, 46.3, 71.0).

  Of the 45 patients who had a dose reduction to 15 mg after achieving ≤1% BCR::ABL1^IS, 25 patients (56%) maintained their response at the reduced dose for at least one year. Of these 25 patients, 16 patients (64%) maintained response for greater than 60 months. With a minimum follow-up of 60 months, median duration of molecular response (≤1% BCR::ABL1^IS) was not reached.

  Chronic Phase (CP), Accelerated Phase (AP), Blast Phase (BP) CML and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

  The efficacy of ICLUSIG was evaluated in PACE (NCT01207440), a single-arm, open-label, international, multicenter trial. Eligible patients had CML and Ph+ ALL whose disease was considered to be resistant or intolerant to a prior kinase inhibitor. Patients were assigned to one of six cohorts based on disease phase (CP-CML, AP-CML, or BP-CML/Ph+ ALL), resistance or intolerance (R/I) to prior kinase inhibitors, and the presence of the T315I mutation. T315I mutation testing was performed on peripheral blood by Sanger Sequencing of the p190 or p210 BCR::ABL region.

  Resistance in CP-CML while on a prior kinase inhibitor was defined as failure to achieve either a complete hematologic response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months). Patients with CP-CML who experienced a loss of response or development of a kinase domain mutation in the absence of a complete cytogenetic response or progression to AP-CML or BP-CML at any time on a prior kinase inhibitor were also considered resistant.

  Resistance in AP-CML, BP-CML, and Ph+ ALL was defined as failure to achieve either a major hematologic response (by 3 months in AP-CML, and by 1 month in BP-CML and Ph+ ALL), loss of major hematologic response (at any time), or development of a kinase domain mutation in the absence of a complete major hematologic response while on a prior kinase inhibitor. Intolerance was defined as the discontinuation of a prior kinase inhibitor due to toxicities despite optimal management in the absence of a complete cytogenetic response in patients with CP-CML or major hematologic response for patients with AP-CML, BP-CML, or Ph+ ALL.

  Patients were administered a starting dose of ICLUSIG 45 mg orally once daily.

  The major efficacy outcome measure for patients with CP-CML was major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PCyR). The major efficacy outcome measure for patients with AP-CML, BP-CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL).

  The trial enrolled 449 patients, of which 444 were eligible for efficacy analysis: 267 patients with CP-CML (R/I Cohort: N=203, T315I: N=64), 83 patients with AP-CML, 62 patients with BP-CML, and 32 patients with Ph+ ALL. Five patients were not eligible for efficacy analysis due to lack of confirmation of T315I mutation status, and these patients had not received prior dasatinib or nilotinib.

  At study completion, the median duration of follow-up for the trial (all cohorts) was 40.5 months (range: 0.1 months to 79.5 months). The median duration of treatment was 35 months for patients with CP-CML, 21.1 months for patients with AP-CML, 3.2 months for patients with BP-CML and 2.9 months for patients with Ph+ ALL. Baseline demographic characteristics are described in Table 15.

  Table 15: Demographic and Disease Characteristics for PACE

  Patient Characteristics at Entry	Efficacy Population (N = 444)
  Age
  Median, years (range)	59 (18 to 94)
  Sex, n (%)
  Male	236 (53%)
  Race, n (%)
  White	349 (79%)
  Asian	57 (13%)
  Black or African American	25 (6%)
  Other/Unknown	13 (3%)
  ECOG Performance Status, n (%)
  ECOG = 0 or 1	409 (92%)
  Disease History
  Median time from diagnosis to first dose, years (range)	6.1 (0.3 to 29)
  Resistant to Prior Kinase Inhibitor, n (%)	374 (88%)
  Presence of one or more BCR::ABL kinase domain mutationsOf the patients with one or more BCR::ABL kinase domain mutations detected at entry, 37 unique mutations were detected., n (%)	244 (55%)
  Number of Prior Kinase Inhibitor, n (%)
  1	29 (7%)
  2	166 (37%)
  ≥3	249 (56%)
  T315I mutation at baseline	128 (29%)
  Comorbidities
  Hypertension	159 (35%)
  Diabetes	57 (13%)
  Hypercholesterolemia	100 (22%)
  History of ischemic disease	67 (15%)

  Efficacy results are summarized in Table 16 and Table 17.

  Table 16: Efficacy of ICLUSIG in Patients with Resistant or Intolerant CP-CML in PACE

  	Overall (N = 267)	Cohort
  		R/I Cohort (N = 203)	T315I Cohort (N = 64)
  Cytogenetic Response
  MajorPrimary endpoint for CP-CML cohorts was MCyR by 12 months, which combines both complete (no detectable Ph+ cells) and partial (1% to 35% Ph+ cells in at least 20 metaphases) cytogenetic responses.(MCyR) (95% CI)	55% (49%, 62%)	51% (44%, 58%)	70% (58%, 81%)
  Complete (CCyR) (95% CI)	46% (40%, 52%)	40% (33%, 47%)	66% (53%, 77%)
  Major Molecular Response Secondary endpoint for CP-CML cohorts was MMR (proportion of patients who met the criteria for MMR at least once after the initiation of study treatment) measured in peripheral blood. Defined as a ≤0.1% ratio of BCR::ABL to ABL transcripts on the International Scale (IS) (i.e., ≤0.1% BCR::ABLIS; patients must have the b2a2/b3a2 (p210) transcript), in peripheral blood measured by quantitative reverse transcriptase polymerase chain reaction (qRT PCR). (95% CI)	40% (35%, 47%)	35% (28%, 42%)	58% (45%, 70%)

  In patients with CP-CML who achieved MCyR or MMR, the median time to response was 3 months (range: 1.8 to 12.3 months) and 6 months (range: 2 to 60.2 months), respectively. With a minimum follow-up of 60 months, the median durations of MCyR (range: 1 day to 70.1 months) and MMR (range: 1 day to 67.8 months) had not yet been reached.

  Table 17: Efficacy of ICLUSIG in Patients with Resistant or Intolerant Advanced Disease (includes R/I and T315I Cohorts) in PACE

  	AP-CML Overall (N = 83)	BP-CML Overall (N = 62)	Ph+ ALL Overall (N = 32)
  Hematologic Response
  MajorPrimary endpoint for patients with AP-CML, BP-CML, and Ph+ ALL was MaHR by 6 months, which combines complete hematologic responses and no evidence of leukemia.(MaHR)	57%	31%	41%
  (95% CI)	(45%, 68%)	(20%, 44%)	(24%, 59%)
  CompleteCHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils <5% in peripheral blood, no extramedullary involvement (including no hepatomegaly or splenomegaly) .(CHR)	51%	21%	34%
  (95% CI)	(39%, 62%)	(12%, 33%)	(19%, 53%)

  The median time to MaHR in patients with AP-CML, BP-CML, and Ph+ ALL was 0.8 months (range: 0.4 to 6.3 months), 1.0 month (range: 0.4 to 4 months), and 0.7 months (range: 0.4 to 6 months), respectively. The median duration of MaHR for patients with AP-CML, BP-CML, and Ph+ ALL was 14 months (range: 1.3 to 74.3 months), 6.5 months (range: 1.9 to 64.7 months), and 3.5 months (range: 1.9 to 13.7 months), respectively.

  ]
  . Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s).
  
• As monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL.

• Chronic phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors.
• Accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated.
• T315I-positive CML (chronic phase, accelerated phase, or blast phase).

• Recommended Dosage in Newly Diagnosed Ph+ ALL
  : Starting dose is 30 mg orally once daily in combination with chemotherapy, with a reduction to 15 mg once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction. (
  2.1 Recommended Dosage

  Newly Diagnosed Ph+ ALL

  The recommended starting dosage of ICLUSIG in combination with chemotherapy is 30 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction. Continue ICLUSIG in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity

  [see Clinical Studies (14)]

  .

  For a description of dosing of agents administered in combination with ICLUSIG,

  [see Clinical Studies (14)]

  .

  Monotherapy for Ph+ ALL for Whom No Other Kinase Inhibitors Are Indicated or T315I-positive Ph+ ALL

  The optimal dose of ICLUSIG has not been identified.

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Continue ICLUSIG until loss of response or unacceptable toxicity.

  Consider discontinuing ICLUSIG if response has not occurred by 3 months.

  CP-CML

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of ≤1% BCR::ABL1^IS. Patients with loss of response can re-escalate the dose of ICLUSIG to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue ICLUSIG until loss of response at the re-escalated dose or unacceptable toxicity.

  Consider discontinuing ICLUSIG if hematologic response has not occurred by 3 months.

  AP-CML and BP-CML

  The optimal dose of ICLUSIG has not been identified.

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Consider reducing the dose of ICLUSIG for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response. Continue ICLUSIG until loss of response or unacceptable toxicity.

  Consider discontinuing ICLUSIG if response has not occurred by 3 months.

  Administration

  Advise patients of the following:

  • ICLUSIG may be taken with or without food.
  • Swallow tablets whole. Do not crush, break, cut or chew tablets.
  • If a dose is missed, take the next dose at the regularly scheduled time the next day.
  )
• Recommended Dosage in Monotherapy for Ph+ ALL for Whom No Other Kinase Inhibitors are Indicated or T315I-positive Ph+ ALL
  : Starting dose is 45 mg orally once daily. (
  2.1 Recommended Dosage

  Newly Diagnosed Ph+ ALL

  The recommended starting dosage of ICLUSIG in combination with chemotherapy is 30 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction. Continue ICLUSIG in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity

  [see Clinical Studies (14)]

  .

  For a description of dosing of agents administered in combination with ICLUSIG,

  [see Clinical Studies (14)]

  .

  Monotherapy for Ph+ ALL for Whom No Other Kinase Inhibitors Are Indicated or T315I-positive Ph+ ALL

  The optimal dose of ICLUSIG has not been identified.

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Continue ICLUSIG until loss of response or unacceptable toxicity.

  Consider discontinuing ICLUSIG if response has not occurred by 3 months.

  CP-CML

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of ≤1% BCR::ABL1^IS. Patients with loss of response can re-escalate the dose of ICLUSIG to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue ICLUSIG until loss of response at the re-escalated dose or unacceptable toxicity.

  Consider discontinuing ICLUSIG if hematologic response has not occurred by 3 months.

  AP-CML and BP-CML

  The optimal dose of ICLUSIG has not been identified.

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Consider reducing the dose of ICLUSIG for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response. Continue ICLUSIG until loss of response or unacceptable toxicity.

  Consider discontinuing ICLUSIG if response has not occurred by 3 months.

  Administration

  Advise patients of the following:

  • ICLUSIG may be taken with or without food.
  • Swallow tablets whole. Do not crush, break, cut or chew tablets.
  • If a dose is missed, take the next dose at the regularly scheduled time the next day.
  )
• Recommended Dosage in CP-CML
  : Starting dose is 45 mg orally once daily with a reduction to 15 mg once daily upon achievement of ≤1% BCR::ABL1^IS. (
  2.1 Recommended Dosage

  Newly Diagnosed Ph+ ALL

  The recommended starting dosage of ICLUSIG in combination with chemotherapy is 30 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction. Continue ICLUSIG in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity

  [see Clinical Studies (14)]

  .

  For a description of dosing of agents administered in combination with ICLUSIG,

  [see Clinical Studies (14)]

  .

  Monotherapy for Ph+ ALL for Whom No Other Kinase Inhibitors Are Indicated or T315I-positive Ph+ ALL

  The optimal dose of ICLUSIG has not been identified.

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Continue ICLUSIG until loss of response or unacceptable toxicity.

  Consider discontinuing ICLUSIG if response has not occurred by 3 months.

  CP-CML

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of ≤1% BCR::ABL1^IS. Patients with loss of response can re-escalate the dose of ICLUSIG to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue ICLUSIG until loss of response at the re-escalated dose or unacceptable toxicity.

  Consider discontinuing ICLUSIG if hematologic response has not occurred by 3 months.

  AP-CML and BP-CML

  The optimal dose of ICLUSIG has not been identified.

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Consider reducing the dose of ICLUSIG for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response. Continue ICLUSIG until loss of response or unacceptable toxicity.

  Consider discontinuing ICLUSIG if response has not occurred by 3 months.

  Administration

  Advise patients of the following:

  • ICLUSIG may be taken with or without food.
  • Swallow tablets whole. Do not crush, break, cut or chew tablets.
  • If a dose is missed, take the next dose at the regularly scheduled time the next day.
  )
• Recommended Dosage in AP-CML and BP-CML
  : Starting dose is 45 mg orally once daily. (
  2.1 Recommended Dosage

  Newly Diagnosed Ph+ ALL

  The recommended starting dosage of ICLUSIG in combination with chemotherapy is 30 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction. Continue ICLUSIG in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity

  [see Clinical Studies (14)]

  .

  For a description of dosing of agents administered in combination with ICLUSIG,

  [see Clinical Studies (14)]

  .

  Monotherapy for Ph+ ALL for Whom No Other Kinase Inhibitors Are Indicated or T315I-positive Ph+ ALL

  The optimal dose of ICLUSIG has not been identified.

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Continue ICLUSIG until loss of response or unacceptable toxicity.

  Consider discontinuing ICLUSIG if response has not occurred by 3 months.

  CP-CML

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of ≤1% BCR::ABL1^IS. Patients with loss of response can re-escalate the dose of ICLUSIG to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue ICLUSIG until loss of response at the re-escalated dose or unacceptable toxicity.

  Consider discontinuing ICLUSIG if hematologic response has not occurred by 3 months.

  AP-CML and BP-CML

  The optimal dose of ICLUSIG has not been identified.

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Consider reducing the dose of ICLUSIG for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response. Continue ICLUSIG until loss of response or unacceptable toxicity.

  Consider discontinuing ICLUSIG if response has not occurred by 3 months.

  Administration

  Advise patients of the following:

  • ICLUSIG may be taken with or without food.
  • Swallow tablets whole. Do not crush, break, cut or chew tablets.
  • If a dose is missed, take the next dose at the regularly scheduled time the next day.
  )
• Hepatic Impairment
  : See the Full Prescribing Information for dosage modifications for hepatic impairment. (
  2.4 Dosage for Patients with Hepatic Impairment

  For patients with CP-CML, AP-CML, BP-CML, and Ph+ ALL receiving monotherapy, reduce the starting dose of ICLUSIG from 45 mg orally once daily to 30 mg orally once daily in patients with pre-existing hepatic impairment (Child-Pugh A, B, or C).

  For patients with newly diagnosed Ph+ ALL, no dosage adjustment is recommended when administering ICLUSIG to patients with mild hepatic impairment (Child-Pugh A). Closely monitor patients with moderate or severe hepatic impairment (Child-Pugh B or C) and modify the ICLUSIG dosage in the event of adverse reactions

  [see Dosage and Administration (2.2), Use in Specific Populations (8.6)]

  .
  )
• ICLUSIG may be taken with or without food. (
  2.1 Recommended Dosage

  Newly Diagnosed Ph+ ALL

  The recommended starting dosage of ICLUSIG in combination with chemotherapy is 30 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction. Continue ICLUSIG in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity

  [see Clinical Studies (14)]

  .

  For a description of dosing of agents administered in combination with ICLUSIG,

  [see Clinical Studies (14)]

  .

  Monotherapy for Ph+ ALL for Whom No Other Kinase Inhibitors Are Indicated or T315I-positive Ph+ ALL

  The optimal dose of ICLUSIG has not been identified.

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Continue ICLUSIG until loss of response or unacceptable toxicity.

  Consider discontinuing ICLUSIG if response has not occurred by 3 months.

  CP-CML

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of ≤1% BCR::ABL1^IS. Patients with loss of response can re-escalate the dose of ICLUSIG to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue ICLUSIG until loss of response at the re-escalated dose or unacceptable toxicity.

  Consider discontinuing ICLUSIG if hematologic response has not occurred by 3 months.

  AP-CML and BP-CML

  The optimal dose of ICLUSIG has not been identified.

  The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Consider reducing the dose of ICLUSIG for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response. Continue ICLUSIG until loss of response or unacceptable toxicity.

  Consider discontinuing ICLUSIG if response has not occurred by 3 months.

  Administration

  Advise patients of the following:

  • ICLUSIG may be taken with or without food.
  • Swallow tablets whole. Do not crush, break, cut or chew tablets.
  • If a dose is missed, take the next dose at the regularly scheduled time the next day.
  )

Tablets, film-coated:

• 10 mg of ponatinib: Oval, white to off-white, biconvex, debossed "NZ" on one side and plain on the other side
• 15 mg of ponatinib: Round, white, biconvex, debossed "A5" on one side and plain on the other side
• 30 mg of ponatinib: Round, white, biconvex, debossed "C7" on one side and plain on the other side
• 45 mg of ponatinib: Round, white, biconvex, debossed "AP4" on one side and plain on the other side