Iclusig (ponatinib hydrochloride 15 mg) Dailymed

2 Dosage And Administration

• 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 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 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 in AP-CML and BP-CML: Starting dose is 45 mg orally once daily. (2.1)
• Hepatic Impairment: See the Full Prescribing Information for dosage modifications for hepatic impairment. (2.4)
• ICLUSIG may be taken with or without food. (2.1)

2.1Recommended 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.

2.2Dosage 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-threateningULN = 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 otherorVTE [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/LorPlatelets 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.

2.3Dosage Modification for Coadministration of Strong CYP3A Inhibitors

Avoid coadministration of ICLUSIG with strong CYP3A inhibitors. If coadministration of a strong CYP3A inhibitor cannot be avoided, reduce the dosage of ICLUSIG as recommended in Table 3.

After the strong CYP3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the ICLUSIG dosage that was tolerated prior to initiating the strong CYP3A inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Table 3: Recommended ICLUSIG Dosage for Coadministration of Strong CYP3A Inhibitors

Current ICLUSIG Dosage	Recommended ICLUSIG Dosage with a Strong CYP3A Inhibitor
45 mg orally once daily	30 mg orally once daily
30 mg orally once daily	15 mg orally once daily
15 mg orally once daily	10 mg orally once daily
10 mg orally once daily	Avoid coadministration of ICLUSIG with a strong CYP3A inhibitor

2.4Dosage 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)].

• 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 × 10⁹/L or platelets less than 50 × 10⁹/L, interrupt ICLUSIG until ANC at least 1.5 × 10⁹/L and platelets at least 75 × 10⁹/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)

5.1Arterial 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, 94 patients who received a starting dose of 45 mg (45 mg → 15 mg), 14% experienced AOEs, of which 7%, 4.3%, and 2.1% experienced cardiovascular, cerebrovascular or peripheral vascular AOEs, respectively. The median time to onset of the first cardiovascular, cerebrovascular, or peripheral vascular event was 4.7 months (range: 12 days to 2.1 years), 11.7 months (range: 15 days to 1.6 years), and 3.6 months (range: 23 days to 6.3 months), respectively. Grade 3 or 4 AOEs occurred in 6% of patients; the most frequent Grade 3 or 4 AOEs were myocardial infarction, acute coronary syndrome, arterial thrombosis, ischemic stroke, ischemic cerebral infarction, and unstable angina (1.1% each). Fatal AOEs occurred in 2 patients (2.1%); both of which were sudden death. 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, 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.

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)].

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.

5.2Venous 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, 1 patient experienced a VTE (Grade 1 retinal vein occlusion).

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)].

5.3Heart 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 13% of patients; 1.1% experienced serious or severe (Grade 3 or 4) heart failure. The most frequently reported heart failure events (>1 patient each) were left ventricular hypertrophy (3.2%) and BNP increased (3.2%).

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)].

5.4Hepatotoxicity

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 28% of patients; 6% experienced Grade 3 or 4 hepatotoxicity. The median time to onset of hepatotoxicity was 1.9 months, with a range of 3 days to 4.1 years. The most frequent hepatotoxic events were elevations of ALT, AST, alkaline phosphatase, and GGT. In 29% of the 21 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)].

5.5Hypertension

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 32% of patients; 12% 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 28 out of 81 (35%) patients with initial blood pressure of less than Grade 2, and Grade 3 occurred in 18 out of 92 (20%) 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.

5.6Pancreatitis

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 23% of patients; 15% 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 20% of patients. The median time to onset of pancreatitis was 23 days (range: 3 days to 5.6 months). 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 11% of patients, while lipase elevation occurred in 34% 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 9% of patients. Peripheral neuropathy occurred in 6% of patients. The most frequently reported peripheral neuropathies were hypoesthesia (2.1%), muscular weakness (2.1%), and paresthesia (2.1%). Cranial neuropathy developed in 2 patients. The median time to onset of peripheral neuropathy and cranial neuropathy was 7.7 months (range: 1.5 months to 1.4 years) and 2.1 years (range: Day 1 to 4.2 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 11% of patients; 1.1% experienced a serious or severe ocular toxicity. The most frequent ocular toxicities were blurred vision and eye pain. Retinal toxicities, including age-related macular degeneration and retinal vein occlusion, occurred in 2.1% of patients.

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 12% 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)].

5.11Fluid 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 5% of patients. The most frequent fluid retention events were peripheral edema (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)].

5.12Cardiac 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 16% of patients; 4.3% experienced Grade 3 or 4 cardiac arrhythmias. Grade 3 or 4 cardiac arrhythmias included atrial fibrillation, cardio-respiratory arrest, supraventricular extrasystoles, and syncope.

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, neutropenia occurred in 55% (Grade 3 or 4 occurred in 22%), thrombocytopenia occurred in 65% (Grade 3 or 4 occurred in 31%), and anemia occurred in 35% of patients (Grade 3 or 4 occurred in 14%). The median time to onset of Grade 3 or 4 myelosuppression was 1.4 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 × 10⁹/L or platelets less than 50 × 10⁹/L, interrupt ICLUSIG until ANC at least 1.5 × 10⁹/L and platelets at least 75 × 10⁹/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.

5.15Reversible 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.

5.17Embryo-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)].

6 Adverse Reactions

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Arterial Occlusive Events [see Warnings and Precautions (5.1)]
• Venous Thromboembolic Events [see Warnings and Precautions (5.2)]
• Heart Failure [see Warnings and Precautions (5.3)]
• Hepatotoxicity [see Warnings and Precautions (5.4)]
• Hypertension [see Warnings and Precautions (5.5)]
• Pancreatitis [see Warnings and Precautions (5.6)]
• Neuropathy [see Warnings and Precautions (5.8)]
• Ocular Toxicity [see Warnings and Precautions (5.9)]
• Hemorrhage [see Warnings and Precautions (5.10)]
• Fluid Retention [see Warnings and Precautions (5.11)]
• Cardiac Arrhythmias [see Warnings and Precautions (5.12)]
• Myelosuppression [see Warnings and Precautions (5.13)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.14)]
• Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.15)]
• Impaired Wound Healing and Gastrointestinal Perforation [see Warnings and Precautions (5.16)]

Most common adverse reactions (occurring in >20% of patients) are:

• ICLUSIG as a single agent: rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased. (6.1)
• ICLUSIG in combination with chemotherapy: hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias. The most common Grade 3 or 4 laboratory abnormalities (>20%) are decreased white blood cell count, decreased neutrophil cell count, decreased platelet count, decreased lymphocyte cell count, decreased hemoglobin, increased lipase, and increased alanine aminotransferase. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-817-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most common adverse reactions identified in the Highlights of the Prescribing Information are based on two safety populations. The first is from a pooled safety population of 543 patients with CML or resistant or intolerant Ph+ ALL (OPTIC and PACE studies) who received ICLUSIG as a single agent at a starting dose of 45 mg orally once daily. In this pooled safety population, the most common (>20%) adverse reactions were rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction, and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) were platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.

The second safety population is from163 patients with newly diagnosed Ph+ ALL (PhALLCON study) who received ICLUSIG in combination with chemotherapy at a starting dose of 30 mg orally once daily. The most common adverse reactions (>20%) included hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias. The most common Grade 3 or 4 laboratory abnormalities (>20%) included decreased white blood cell count, decreased neutrophil cell count, decreased platelet count, decreased lymphocyte cell count, decreased hemoglobin, increased lipase, and increased ALT.

Newly Diagnosed Ph+ ALL

The safety of ICLUSIG was evaluated in PhALLCON, a randomized, active-controlled, multicenter trial conducted in patients with newly diagnosed Ph+ ALL [see Clinical Studies (14)]. Patients received ICLUSIG (n=163) or imatinib 600 mg (n=81) in combination with reduced-intensity chemotherapy followed by continued treatment with ICLUSIG or imatinib as a single agent (imatinib in combination with chemotherapy is not an approved regimen in adult patients). In the ICLUSIG arm, patients received a starting dosage of ICLUSIG 30 mg orally once daily in combination with chemotherapy, with a reduction to 15 mg orally once daily upon achievement of MRD-negative CR at the end of induction. The median duration of exposure was 9.0 months (range: <1 month to 4.2 years) in the ICLUSIG arm and 5.2 months (range: <1 month to 4.4 years) in the imatinib arm.

Patients with uncontrolled hypertension, hypertriglyceridemia, or diabetes and 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, history of myocardial infarction, unstable angina, or congestive heart failure within the 6 months prior to the first dose of ICLUSIG, were excluded.

Serious adverse reactions occurred in 63% of patients receiving ICLUSIG in combination with chemotherapy. Serious adverse reactions in >2% of patients included febrile neutropenia (18%), pyrexia (6%), thrombocytopenia (4.3%), sepsis (3.7%), septic shock (3.7%), anemia (2.5%), hemorrhage (2.5%), neutropenia (2.5%), pancreatitis (2.5%), peripheral neuropathy (2.5%), pneumonia (2.5%) and acute kidney injury (2.5%). Fatal adverse reactions occurred in 6% of patients who received ICLUSIG in combination with chemotherapy, including sepsis (3.7%), sudden death, pneumonitis and respiratory failure (0.6%, each).

Permanent discontinuation of ICLUSIG due to adverse reactions occurred in 13% of patients. Adverse reactions resulting in permanent discontinuation of ICLUSIG in >2% of patients included arterial occlusive events and sepsis.

Dosage modifications (dose interruption or reduction) of ICLUSIG due to adverse reactions occurred in 71% of patients. Adverse reactions leading to dose interruption or reduction of ICLUSIG in >5% of patients included increased ALT, neutropenia, increased lipase, thrombocytopenia, increased AST, febrile neutropenia, and abdominal pain.

Table 4 summarizes the adverse reactions in patients receiving ICLUSIG or imatinib in combination with chemotherapy in PhALLCON.

Table 4: Adverse Reactions (>10%) in Patients with Newly Diagnosed Ph+ ALL in PhALLCON

Adverse Reaction	ICLUSIG30 mg → 15 mgwith Chemotherapy(n = 163)		Imatinib600 mgwith Chemotherapy(n = 81)
	All Grades(%)	Grade 3 or 4(%)	All Grades(%)	Grade 3 or 4(%)
Graded using CTCAE v5.0
Hepatobiliary Disorders
  Hepatotoxicity	66	30	57	14
Musculoskeletal and Connective Tissue Disorders
  ArthralgiaIncludes arthralgia, arthritis, back pain, flank pain, intervertebral disc degeneration, joint swelling, osteoarthritis, neck pain, pain, pain in extremity, pain of skin, sciatica, spinal pain, tendonitis, and tenosynovitis.	47	4.3	35	1.2
  Myalgia	13	1.2	10	1.2
Nervous System Disorders
  Headache	45	1.8	43	1.2
  Neuropathy peripheral	33	1.2	24	1.2
  Paresthesia	22	0	10	0
  Peripheral sensory neuropathy	12	0	12	0
Skin and Subcutaneous Tissue Disorders
  Rash and related conditions	47	1.2	33	1.2
Gastrointestinal Disorders
  Abdominal painIncludes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, chronic gastritis, colitis, enteritis, enterocolitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal pain, gastroesophageal reflux disease, and helicobacter gastritis.	43	4.9	28	0
  Constipation	41	0.6	21	1.2
  Nausea	37	3.1	52	7
  Oral mucositis	35	4.9	30	10
  Pancreatitis/lipase elevation	34	15	37	20
  Vomiting	24	1.2	40	2.5
  Diarrhea	20	0	35	2.5
General Disorders
  Pyrexia	44	4.3	26	2.5
  Fatigue or asthenia	40	2.5	38	3.7
  Fluid retention and edema	24	0.6	48	3.7
Vascular Disorders
  Hypertension	34	14	15	7
  Hemorrhage	31	1.8	30	7
  Venous thromboembolic events	12	3.1	10	2.5
Blood and Lymphatic System Disorders
  Febrile neutropenia	28	25	22	20
Metabolism and Nutrition Disorders
  Impaired glucose tolerance	20	4.9	20	9
  Hyperlipidemia	16	1.2	15	1.2
  Decreased appetite	10	0	19	3.7
Cardiac Disorders
  Cardiac arrhythmias	22	2.5	17	6
Infections
  SepsisIncludes abdominal sepsis, bacteremia, bacterial sepsis, device-related sepsis, escherichia bacteremia, fungemia, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, pseudomonal sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal sepsis, streptococcal bacteremia, and urosepsis.	17	12	15	11
  Pneumonia	11	7	11	6
Respiratory, Thoracic, and Mediastinal Disorders
  Cough	17	0	6	0
  Dyspnea	13	1.2	4.9	2.5

Clinically relevant adverse reactions in ≤10% of patients receiving ICLUSIG with chemotherapy: urinary tract infection (10%), arterial occlusive events (6%), cardiac failure (6%), and acute kidney injury (4.3%).

Table 5 summarizes the laboratory abnormalities in PhALLCON for patients who received ICLUSIG or imatinib in combination with chemotherapy.

Table 5: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Newly Diagnosed Ph+ ALL in PhALLCON

Laboratory Abnormality	ICLUSIG30 mg → 15 mgwith Chemotherapy(n = 163)		Imatinib600 mgwith Chemotherapy(n = 81)
	All Grades(%)	Grade 3 or 4(%)	All Grades(%)	Grade 3 or 4(%)
ALT = alanine aminotransferase, AST = aspartate aminotransferaseGraded using CTCAE v5.0
Hematologic Laboratory Tests
  White blood cell decreased	79	71	78	70
  Lymphocyte cell count decreased	77	61	94	89
  Neutrophil cell count decreased	66	63	57	53
  Platelet count decreased	65	62	64	53
  Hemoglobin decreased	53	38	59	49
Liver Function Tests
  ALT increased	69	21	62	7
  AST increased	53	7	48	6
  Alkaline phosphatase increased	44	1.2	24	0
  Total bilirubin increased	25	0.6	24	0
  Direct bilirubin increased	24	4.3	24	1.2
Pancreatic Enzymes
  Lipase increased	60	24	78	38
  Amylase increased	25	6	35	7
Chemistry
  Calcium decreased	67	3.1	69	4.9
  Phosphate decreased	58	16	85	36
  Potassium decreased	44	10	74	25
  Albumin decreased	42	1.8	56	0
  Glucose increased	34	2.5	38	2.5
  Creatinine increased	34	3.7	48	4.9
  Sodium decreased	32	3.1	35	3.7
  Potassium increased	31	3.7	12	0
  Magnesium decreased	15	0.6	31	2.5

Previously Treated CP-CML

The safety of ICLUSIG was evaluated in OPTIC [see Clinical Studies (14)]. Patients received one of three starting doses of ICLUSIG: 45 mg orally once daily (n=94), 30 mg orally once daily (n=94), or 15 mg orally once daily (n=94). 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. Only the safety information for the recommended starting dosage (45 mg) is described below. Patients who received a starting dose of ICLUSIG 45 mg orally once daily had a mandatory dose reduction to 15 mg once daily upon achievement of ≤1% BCR::ABL^IS. Of these patients, 76% were exposed for 1 year or longer and 38% were exposed for greater than two years. The median time to the response-based dose reduction to 15 mg was 6.4 months (range: 3.1 months to 1.8 years).

Serious adverse reactions occurred in 34% of patients who received ICLUSIG at a starting dose of 45 mg. Serious adverse reactions in >2% of patients included AOEs (9%; of which 2.1% were sudden death), cardiac arrhythmias (6%), thrombocytopenia (5%), pyrexia (4.3%), anemia (3.2%), abdominal pain (3.2%), atrial fibrillation (2.1%), pancreatitis/lipase elevation (2.1%), neutropenia (2.1%), and hypertension (2.1%). Fatal adverse reactions occurred in 2 patients (2.1%), both of which were sudden death.

Permanent discontinuation of ICLUSIG due to an adverse reaction occurred in 19% of patients who received ICLUSIG at a starting dose of 45 mg. Adverse reactions which resulted in permanent discontinuation in >2% of patients included AOEs, thrombocytopenia, hypertension, and sudden death.

Dose modifications (dose interruption or reductions) of ICLUSIG due to an adverse reaction occurred in 71% of patients who received ICLUSIG at a starting dose of 45 mg. Adverse reactions which required dose interruptions or reductions in >5% of patients included thrombocytopenia, pancreatitis/lipase elevation, neutropenia, hepatic dysfunction, rash and related conditions, and anemia.

The most common (>20%) adverse reactions were rash and related conditions, hypertension, arthralgia, hyperlipidemia, hepatic dysfunction, pancreatitis/lipase elevation, and abdominal pain. The most common (>20%) Grade 3 or 4 laboratory abnormalities were platelet count decreased and neutrophil cell count decreased.

Table 6 summarizes the adverse reactions in OPTIC for patients who received ICLUSIG at a starting dose of 45 mg.

Table 6: Adverse Reactions (≥10%) in Patients with CP-CML Who Received ICLUSIG at Starting Dose of 45 mg Followed by Reduction to 15 mg After Achievement of ≤1% BCR::ABL1^IS in OPTIC

Adverse Reaction	ICLUSIG 45 mg → 15 mg(N = 94)
	All Grades(%)	Grade 3 or 4(%)
Graded using CTCAE v5.0
Skin and Subcutaneous Tissue Disorders
  Rash and related conditions	51	3.2
  Dry skin	12	0
Vascular Disorders
  Hypertension	32	12
  Arterial occlusive events	14	6
  Hemorrhage	12	2.1
Musculoskeletal and Connective Tissue Disorders
  ArthralgiaArthralgia includes arthralgia, arthritis, back pain, intervertebral disc degeneration, osteoarthritis, pain, neck pain, pain in extremity, pain of skin, sciatica, spinal pain, tendonitis, tenosynovitis	30	0
Metabolism and Nutrition Disorders
  HyperlipidemiaHyperlipidemia includes blood cholesterol increased, blood triglycerides increased, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, low density lipoprotein increased	28	2.1
Gastrointestinal Disorders
  Abdominal painAbdominal pain includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, chronic gastritis, colitis, enteritis, enterocolitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal pain, gastroesophageal reflux disease, Helicobacter gastritis	25	3.2
  Pancreatitis/lipase elevation	23	15
  Constipation	11	0
Hepatobiliary Disorders
  Hepatotoxicity	28	6
Nervous System Disorders
  Headache	17	0
General Disorders and Administration Site Conditions
  Pyrexia	16	1.1
  Fatigue or asthenia	10	1.1
Cardiac Disorders
  Cardiac arrhythmias	16	4.3
  Cardiac failure	13	1.1

Clinically relevant adverse reactions in <10% of patients who received ICLUSIG at a starting dose of 45 mg: neuropathy (9%), fluid retention and edema (5%), and hypothyroidism (3.2%).

Table 7 summarizes the laboratory abnormalities in OPTIC for patients who received ICLUSIG at a starting dose of 45 mg.

Table 7: Select Laboratory Abnormalities (>20%) that Worsened from Baseline in Patients with CP-CML Who Received ICLUSIG at Starting Dose of 45 mg in OPTIC

Laboratory Abnormality	ICLUSIG 45 mg → 15 mg(N = 94)
	All Grades(%)	Grade 3 or 4(%)
ALT = alanine aminotransferase, AST = aspartate aminotransferaseGraded using CTCAE v5.0 (except glucose increased which is graded using CTCAE v4.03)
Hematologic Laboratory Tests
  Platelet count decreased	65	31
  White blood cell decreased	56	13
  Neutrophil cell count decreased	55	22
  Lymphocyte decreased	42	7
  Hemoglobin decreased	35	14
Liver Function Tests
  ALT increased	49	1.1
  AST increased	40	0
  Alkaline phosphatase increased	23	1.1
Chemistry
  Glucose increased	48	1.1
  Triglycerides increased	44	3.2
  Phosphate decreased	27	3.2
  Bicarbonate decreased	27	0
Pancreatic Enzymes
  Lipase increased	34	12

Previously Treated CML or Ph+ ALL

The safety of ICLUSIG was evaluated in PACE [see Clinical Studies (14)]. Eligible patients had CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior kinase inhibitor, including those with the BCR::ABL T315I mutation. 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. Patients received a starting dose of ICLUSIG 45 mg orally once daily (N=449). Dose reductions to 30 mg orally once daily or 15 mg orally once daily were allowed for the management of adverse reactions. After approximately 2 years of follow-up, patients who were still taking a 45 mg orally once daily dose were recommended to undergo a dose reduction in response to the continued occurrence of AOEs and VTEs in the clinical trial [see Warnings and Precautions (5.1)]. At study completion (60 months of follow-up), the median duration of treatment with ICLUSIG was 32 months in patients with CP-CML, 19 months in patients with AP-CML, 2.9 months in patients with BP-CML, and 2.7 months in patients with Ph+ ALL.

Serious adverse reactions occurred in 69% of patients who received ICLUSIG. Serious adverse reactions in >2% of patients included AOEs (20%), pneumonia (10%), cardiac arrhythmias (8%), pancreatitis/lipase elevation (7%), abdominal pain (6%), cardiac failure (6%), hemorrhage (6%), sepsis (5%), VTEs (5%), fluid retention and edema (4.5%), pyrexia (4.5%), secondary malignancies (5%), anemia (3.3%), hypertension (3.1%), thrombocytopenia (3.1%), febrile neutropenia (2.9%), cellulitis (2.7%), and arthralgia (2.2%). Fatal adverse reactions occurred in 9% of patients who received ICLUSIG; the most frequent fatal adverse reactions were AOEs (2%), sepsis (1.6%), and hemorrhage (1.3%).

Permanent discontinuation of ICLUSIG due to an adverse reaction occurred in 21% of CP-CML, 12% of AP-CML, 15% of BP-CML, and 9% of Ph+ ALL patients. The most frequent adverse reactions that led to treatment discontinuation were thrombocytopenia (4.5%) and AOEs (4%).

Dose interruption of ICLUSIG for more than 3 days due to an adverse reaction occurred in 71% of patients and dose reduction of ICLUSIG due to an adverse reaction occurred in 68% of patients. Adverse reactions which required a dosage interruption or dose reduction in >5% of patients included thrombocytopenia (31%), pancreatitis/lipase elevation (17%), abdominal pain (14%), rash and related conditions (14%), neutropenia (14%), hepatic dysfunction (12%), AOEs (10%), arthralgia (8%), anemia (7%), ALT increased (6%), and AST increased (5%).

The most common (>20%) non-hematologic adverse reactions were rash and related conditions, arthralgia, abdominal pain, fatigue, constipation, headache, dry skin, fluid retention and edema, hepatic dysfunction, hypertension, pyrexia, nausea, hemorrhage, pancreatitis/lipase elevation, AOEs, diarrhea, vomiting, and myalgia.

Table 8 summarizes the adverse reactions in PACE.

Table 8: Adverse Reactions (>10%) in Patients with CML or Ph+ ALL Who Received ICLUSIG in PACE

Adverse Reaction	CP-CML(N = 270)		AP-CML(N = 85)		BP-CML(N = 62)		Ph+ ALL(N = 32)
	All Grades(%)	Grade 3 or 4(%)	All Grades(%)	Grade 3 or 4(%)	All Grades(%)	Grade 3 or 4(%)	All Grades(%)	Grade 3 or 4(%)
Graded using CTCAE v4.03.
Skin and Subcutaneous Tissue Disorders
  Rash and related conditions	75	9	68	12	55	7	50	3.1
  Dry skin	42	3.3	32	1.2	26	1.6	25	0
  Alopecia	8	0	11	0	8	0	6	0
Musculoskeletal and Connective Tissue Disorders
  Arthralgia	61	9	58	6	52	4.8	41	0
  Myalgia	24	1.1	21	0	18	0	6	0
  Muscle spasms	14	0	7	0	4.8	0	13	0
  Bone pain	14	0.4	13	1.2	11	3	9	3
  Musculoskeletal pain	11	1.5	7	0	8.1	0	6	3
Gastrointestinal Disorders
  Abdominal pain	54	11	49	9	45	13	34	6
  Constipation	42	2.6	29	2.4	27	0	53	3.1
  Pancreatitis/lipase elevation	32	19	21	15	19	16	9	6
  Nausea	29	0.7	32	0	34	1.6	22	0
  Diarrhea	20	0.7	29	2.4	24	3.2	13	3.1
  Vomiting	19	1.5	27	0	27	1.6	25	0
  Oral mucositisOral mucositis includes aphthous ulcer, gingival pain, lip buler, lip pain, lip swelling, mouth ulceration, oropharyngeal pain, oral mucosal bulering, oral mucosal eruption, oral pain, pharyngeal ulceration, stomatitis, and tongue ulceration	16	1.1	20	1.2	24	0	9	3.1
General Disorders
  Fatigue or asthenia	44	3.7	47	8	36	4.8	34	3.1
  Fluid retention and edema	31	3.7	37	3.5	32	4.8	41	6
  Pyrexia	26	1.1	40	7	37	3.2	25	0
  Chills	8	0	12	0	13	1.6	9	0
Nervous System Disorders
  Headache	43	3.3	31	1.2	31	3.2	25	0
  Neuropathy	26	3.3	18	2.4	13	0	13	0
  Dizziness	17	0.4	11	0	4.8	0	3.1	0
Vascular Disorders
  HypertensionDerived from blood pressure (BP) measurement	42	30	53	28	48	6	31	25
  Arterial occlusive events	31	17	22	12	13	10	13	6
  Hemorrhage	23	3	38	12	37	8	31	13
Hepatobiliary Disorders
  Hepatotoxicity	32	10	39	14	34	19	16	13
Cardiac Disorders
  Cardiac arrhythmias	19	7	17	4.7	24	8	25	6
  Cardiac failure	9	5	8	4.7	16	10	6	3.1
Respiratory, Thoracic, and Mediastinal Disorders
  CoughCough includes cough, productive cough, and upper airway cough syndrome	19	0	24	0	21	0	6	0
  DyspneaDyspnea includes dyspnea and dyspnea exertional	19	3	20	3.5	23	6	16	0
Infections
  Upper respiratory tract infectionUpper respiratory tract infection includes upper respiratory tract infection and viral upper respiratory tract infection	14	1.1	13	0	13	1.6	3.1	0
  Urinary tract infectionUrinary tract infection includes escherichia urinary tract infection, urinary tract infection, and urinary tract infection bacterial	12	2.2	14	3.5	1.6	1.6	9	0
  Nasopharyngitis	12	0	18	0	3.2	0	3.1	0
  Pneumonia	8	4.8	18	11	18	13	22	16
  Cellulitis	4.4	1.9	8	3.5	13	4.8	0	0
  SepsisSepsis includes abdominal sepsis, bacteremia, device-related sepsis, escherichia bacteremia, fungemia, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal sepsis, streptococcal bacteremia, and urosepsis	2.6	1.9	11	6	18	6	28	25
Metabolism and Nutrition Disorders
  Decreased appetite	13	0.4	14	1.2	8	0	31	0
  Hyperlipidemia	13	0.7	7	0	3.2	0	3.1	0
Investigations
  Weight decreased	10	0.4	9	0	4.8	0	13	0
Psychiatric Disorders
  Insomnia	11	0	13	0	11	0	13	0
  Anxiety	4.8	0	18	0	8	0	6	0
Blood and Lymphatic System Disorders
  Febrile neutropenia	1.1	1.1	4.7	4.7	13	13	25	25

Clinically relevant adverse reactions occurring in ≤10% of patients: impaired glucose tolerance (9%)Grouped terms: secondary malignancies includes basal cell carcinoma, squamous cell carcinoma of the skin, melanoma, chronic myelomonocytic leukemia, colon cancer, epithelioid mesothelioma, large cell lung cancer recurrent, lung neoplasm, malignant ascites, myelodysplastic syndrome, neuroendocrine carcinoma metastatic, non-Hodgkin lymphoma, pancreatic cancer, thyroid neoplasm, vulval cancer; venous thromboembolic events includes deep vein thrombosis, pulmonary embolism, retinal vein occlusion, retinal vein thrombosis, superficial thrombophlebitis, venous embolism, veno-occlusive liver disease, portal vein thrombosis; impaired glucose tolerance includes blood glucose increased, diabetes mellitus, glucose tolerance impaired, glycosylated hemoglobin increased, hyperglycemia, insulin resistance, and type 2 diabetes mellitus, venous thromboembolic events (6%), secondary malignancies (6%), and hypothyroidism (3%).

Tables 9 and 10 summarize the Grade 3 or 4 hematologic laboratory abnormalities or all grades non-hematologic abnormalities in PACE.

Table 9: Select Grade 3 or 4Graded using CTCAE v4.03 Hematologic Laboratory Abnormalities in Patients Who Received ICLUSIG in PACE

Laboratory Abnormality	CP-CML(N = 270)(%)	AP-CML(N = 85)(%)	BP-CML(N = 62)(%)	Ph+ ALL(N = 32)(%)
Hematology
Platelet count decreased	35	49	45	47
Neutrophil cell count decreased	23	52	48	59
White blood cell decreased	12	37	48	63
Lymphocyte decreased	10	25	32	19
Hemoglobin decreased	8	31	52	34

Table 10: Select Non-Hematologic Laboratory Abnormalities (≥20%) in Patients Who Received ICLUSIG in PACE

Laboratory Abnormality	Pooled Safety Population(N = 449)
	All GradesGraded using CTCAE v4.03 (%)	Grade 3 or 4(%)
ALT = alanine aminotransferase, AST = aspartate aminotransferase
Chemistry
  Glucose increased	54	7
  Phosphate decreased	34	10
  Calcium decreased	30	0.9
  Sodium decreased	27	4.9
  Creatinine increased	21	0.2
  Potassium increased	20	2.2
  Bicarbonate decreased	20	0.2
Liver Function Tests
  ALT increased	41	6
  Alkaline phosphatase increased	40	2
  AST increased	35	3.6
  Albumin decreased	28	0.2
  Bilirubin increased	13	0.9
Pancreatic Enzymes
  Lipase increased	40	14
  Amylase increased	18	3.6

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ICLUSIG. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Blood and Lymphatic System Disorders: Thrombotic microangiopathy

Endocrine Disorders: Hyperthyroidism

Gastrointestinal Disorders: Gastrointestinal perforation, fistula

Metabolism and Nutrition Disorders: Dehydration

Nervous System Disorders: Reversible posterior leukoencephalopathy syndrome (RPLS)

Skin and Subcutaneous Tissue Disorders: Severe cutaneous reaction (e.g., Erythema multiforme, Stevens-Johnson syndrome), impaired wound healing, panniculitis (including erythema nodosum)

Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture