Drug Safety-related Labeling Changes (SrLC)

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ICLUSIG (NDA-203469)

(PONATINIB HYDROCHLORIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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02/15/2022 (SUPPL-35)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Arterial Occlusive Events

Additions and/or revisions underlined:

Arterial occlusive events (AOEs), including fatalities, occurred in patients who received Iclusig in OPTIC and PACE [see Adverse Reactions (6.1)].

Of the 94 patients who received a starting dose of 45 mg (45 mg ‘arrow right’ 15 mg) in OPTIC, 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)].

5.3 Heart Failure

Additions and/or revisions underlined:

Fatal, serious or severe heart failure events have occurred in patients who received Iclusig.

Of the 94 patients who received a starting dose of 45 mg in OPTIC, heart failure events 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%).

5.4 Hepatic Toxicity

Additions and/or revisions underlined:

… Of the 94 patients who received a starting dose of 45 mg in OPTIC, 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 alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and gamma-glutamyl transferase (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.

5.5 Hypertension

Additions and/or revisions underlined:

… Of the 94 patients who received a starting dose of 45 mg in OPTIC, hypertension events were reported in 32% of patients: 12% experienced serious or severe hypertension. Based on vital sign 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.

5.6 Pancreatitis

Additions and/or revisions underlined:

… 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.

5.8 Neuropathy

Additions and/or revisions underlined:

Of the 94 patients who received a starting dose of 45 mg in OPTIC, 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.

5.12 Cardiac Arrhythmias

Additions and/or revisions underlined:

Of the 94 patients who received a starting dose of 45 mg in OPTIC, 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.

5.13 Myelosuppression

Additions and/or revisions underlined:

Of the 94 patients who received a starting dose of 45 mg in OPTIC, 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%) …

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

Previously Treated CP-CML

… 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.

Table 4: Adverse Reactions (greater than or equal to 10%) in Patients with CP-CML Who Received Iclusig at Starting Dose of 45 mg Followed by Reduction to 15 mg After Achievement of less than or equal to 1% BCR-ABL1IS in OPTIC

Clinically relevant adverse reactions in less than or equal to 10% of patients who received Iclusig at a starting dose of 45 mg: neuropathy (9%), fluid retention and edema (5%), and hypothyroidism (3.2%).

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 94 patients with CP-CML who received Iclusig at a starting dose of 45 mg in OPTIC, 17% were 65 years and older and 2.1% were 75 years and older. Patients aged 65 years and older had a lower less than or equal to 1% BCR-ABL1IS rate at 12 months (27%) as compared with patients less than 65 years of age (47%). AOEs occurred in 38% (6/16) of patients 65 years and older and 9% (7/78) of patients less than 65 years of age [see Warnings and Precautions (5.1)].

12/18/2020 (SUPPL-34)

Approved Drug Label (PDF)

Boxed Warning

(Effective December 2020, Box Warning has been revised; see underlined text)

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

See full prescribing information for complete boxed warning.

• 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, 5.1).

• Venous thromboembolic events (VTEs) have occurred in Iclusig-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue Iclusig based on severity (2.2, 5.2).

• 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, 5.3).

• Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor liver function tests. Interrupt or discontinue Iclusig based on severity (2.2, 5.4).

5 Warnings and Precautions

5.1 Arterial Occlusive Events

(Extensive changes; please refer to label)

5.10 Hemorrhage

(Additions and/or revisions underlined)

Fatal and serious hemorrhage events have occurred in patients who received Iclusig.

Of the 94 patients who received a starting dose of 45 mg in OPTIC, 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)].

5.11 Fluid Retention

(Additions and/or revisions underlined)

Fatal and serious fluid retention events have occurred in patients who received Iclusig.

Of the 94 patients who received a starting dose of 45 mg in OPTIC, 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)].

5.12 Cardiac Arrhythmias

(Additions and/or revisions underlined)

Of the 94 patients who received a starting dose of 45 mg in OPTIC, cardiac arrhythmias occurred in 15% 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

(Additions and/or revisions underlined)

Of the 94 patients who received a starting dose of 45 mg in OPTIC, neutropenia occurred in 53% (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 x 109/L or platelets less than 50 x 109/L, interrupt Iclusig until ANC at least 1.5 x 109/L and platelets at least 75 x 109/L, then resume at same or reduced dose [see Dosage and Administration (2.2)].

5.14 Tumor Lysis Syndrome

(Additions and/or revisions underlined)

Of the 94 patients who received a starting dose of 45 mg in OPTIC, serious tumor lysis syndrome (TLS) developed in 1.1% of patients. Hyperuricemia occurred in 2.1% of patients.

In PACE, serious TLS developed in 0.4% of 449 patients. One case occurred in a patient with advanced AP-CML and 1 case occurred in a patient with BP-CML. Hyperuricemia occurred in 7% of patients.

Ensure adequate hydration and treat high uric acid levels prior to initiating Iclusig.

5.15 Reversible Posterior Leukoencephalopathy Syndrome

(Additions and/or revisions underlined)

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.

5.2 Venous Thromboembolic Events

(Additions and/or revisions underlined)

Serious or severe VTEs have occurred in patients who received Iclusig.

Of the 94 patients who received a starting dose of 45 mg in OPTIC, 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)].

5.3 Heart Failure

(Additions and/or revisions underlined)

Fatal, serious or severe heart failure events have occurred in patients who received Iclusig.

Of the 94 patients who received a starting dose of 45 mg in OPTIC, heart failure events occurred in 12% 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 (2.1%) and BNP increased (2.1%).

Fatal or serious heart failure occurred in PACE. Heart failure events 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%) and decreased ejection fraction (2.9%), and cardiac failure (2%).

Monitor patients for signs or symptoms consistent with heart failure and manage heart failure as clinically indicated. Interrupt, then resume at reduced dose or discontinue Iclusig for new or worsening heart failure [see Dosage and Administration (2.2)].

5.4 Hepatotoxicity

(Additions and/or revisions underlined)

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.

Of the 94 patients who received a starting dose of 45 mg in OPTIC, hepatotoxicity occurred in 25% 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 1.9 years. The most frequent hepatotoxic events were elevations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and gamma-glutamyl transferase (GGT). In 22% of the 18 patients who reported ALT or AST elevation, the event was not resolved by the date of last follow-up.

In PACE, hepatotoxicity occurred in 32% of 449 patients; 13% experienced Grade 3 or 4 hepatotoxicity. The median time to onset of hepatotoxicity was 3.1 months, with a range of 1 day to

4.9 years. The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. In 9% of the 88 patients who reported ALT or AST elevation, the event was not resolved by the date of last follow-up.

Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at reduced dose or discontinue Iclusig based on recurrence/severity [see Dosage and Administration (2.2)].

5.5 Hypertension

(Additions and/or revisions underlined)

Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received Iclusig.

Of the 94 patients who received a starting dose of 45 mg in OPTIC, hypertension events were reported in 32% of patients; 10% experienced serious or severe hypertension. Any post-baseline elevation of systolic or diastolic blood pressure (defined as an increase in systolic BP from less than or equal to 120 mmHg to greater than or equal to 140 mmHg or in diastolic BP from less than or equal to 80 mmHg to greater than or equal to 90 mmHg or development of Grade 2 or higher blood pressure elevation in patients with normal baseline blood pressure) occurred in 26% of 94 patients. Grade 1 BP elevation occurred in 57%, Grade 2 occurred in 35%, and Grade 3 occurred in 15%.

Two patients (2.1%) experienced Grade 4 hypertension (hypertensive crisis).

In PACE, hypertension events were reported in 32% of 449 patients; 13% experienced serious or severe hypertension. Any post-baseline elevation of systolic or diastolic BP of Grade 2 or higher in patients with normal baseline blood pressure occurred in 44% of 449 patients. Grade 1 BP elevation occurred in 26%, Grade 2 in 45%, and Grade 3 in 26%. Two patients (<1%) experienced Grade 4 hypertension (hypertensive crisis).

Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath [see Adverse Reactions (6.1)]. Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled [see Dosage and Administration (2.2)]. For significant worsening, labile or treatment-resistant hypertension, interrupt Iclusig and consider evaluating for renal artery stenosis.

5.6 Pancreatitis

(Additions and/or revisions underlined)

Serious or severe pancreatitis has occurred in patients who received Iclusig.

Of the 94 patients who received a starting dose of 45 mg in OPTIC, 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). Three of the 4 cases of clinical pancreatitis that led to dose modification or treatment discontinuation 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.

5.8 Neuropathy

(Additions and/or revisions underlined)

Of the 94 patients who received a starting dose of 45 mg in OPTIC, neuropathy occurred in 7% 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 1 patient. The median time to onset of peripheral neuropathy was

7.7 months (range: 1.5 months to 1.4 years).

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

(Additions and/or revisions underlined)

Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients.

Of the 94 patients who received a starting dose of 45 mg in OPTIC, 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.

6 Adverse Reactions

(Additions and/or revisions underlined)

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)]

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

7 Drug Interactions

7.1 Effects of Other Drugs on Iclusig

(Subsection title revised; Additions and/or revisions underlined)

Strong CYP3A Inhibitors

Coadministration of Iclusig with a strong CYP3A inhibitor increases ponatinib plasma concentrations [see Clinical Pharmacology (12.3)], which may increase the risk of Iclusig adverse reactions. Avoid coadministration of Iclusig with strong CYP3A inhibitors. If coadministration of Iclusig with strong CYP3A inhibitors cannot be avoided, reduce the Iclusig dosage [see Dosage and Administration (2.3)].

Strong CYP3A Inducers

Coadministration of Iclusig with a strong CYP3A inducer decreases ponatinib plasma concentrations [see Clinical Pharmacology (12.3)]. Avoid coadministration of Iclusig with strong CYP3A inducers unless the benefit outweighs the risk of decreased ponatinib exposure. Monitor patients for reduced efficacy. Selection of concomitant medication with no or minimal CYP3A induction potential is recommended.

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the 94 patients with CP-CML who received Iclusig at a starting dose of 45 mg in OPTIC, 17% were 65 years and older and 2.1% were 75 years and older. Patients aged 65 years and older had a lower ?1% BCR-ABL1IS rate at 12 months (29%) as compared with patients less than 65 years of age (45%). AOEs occurred in 38% (6/16) of patients 65 years and older and 8% (6/78) of patients less than 65 years of age [see Warnings and Precautions (5.1)].

Of the 449 patients who received Iclusig in PACE, 35% were 65 years and older and 8% were

75 years and older. In patients with CP-CML, patients aged 65 years and older had a lower major cytogenetic response rate (40%) as compared with patients less than 65 years of age (65%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients aged 65 years and older had a similar hematologic response rate (45%) as compared with patients less than 65 years of age (44%). AOEs occurred in 35% (54/155) of patients 65 years and older and in 21% (61/294) of patients less than 65 years of age [see Warnings and Precautions (5.1)].

Patients aged 65 years or older are more likely to experience adverse reactions including vascular occlusion, decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

(Additions and/or revisions underlined)

Patients with hepatic impairment are more likely to experience adverse reactions compared to patients with normal hepatic function. Reduce the starting dose of Iclusig for patients with pre- existing hepatic impairment (Child-Pugh A, B, or C) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. The safety of multiple doses, or doses higher than 30 mg, has not been studied in patients with hepatic impairment.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Extensive changes; please refer to label)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).  

Arterial Occlusive Events and Venous Thromboembolic Events

Inform patients that serious arterial thromboses (including arterial stenosis sometimes requiring revascularization) and VTEs have occurred. Advise patients to immediately contact their healthcare provider with any symptoms suggestive of a blood clot such as chest pain, shortness of breath, weakness on one side of the body, speech problems, leg pain, or leg swelling [see Warnings and Precautions (5.1, 5.2)].

…

Tumor Lysis Syndrome

Inform patients of the possibility of developing TLS and to immediately contact their healthcare provider for any signs or symptoms associated with TLS [see Warnings and Precautions (5.14)]. Advise patients to be adequately hydrated when taking Iclusig to reduce the risk of TLS.

…

Instructions for Taking Iclusig

Advise patients to take Iclusig exactly as prescribed and not to change their dose or to stop taking Iclusig unless they are told to do so by their healthcare provider. Iclusig may be taken with or without food. Iclusig tablets should be swallowed whole. Patients should not cut, crush or dissolve the tablets.

Patients should not take two doses at the same time to make up for a missed dose.

Advise patients not to drink grapefruit juice or eat grapefruit as it may increase the amount of Iclusig in their blood and therefore increase their risk of adverse reactions.

07/10/2020 (SUPPL-33)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions underlined)

…

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

06/17/2020 (SUPPL-32)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(Newly added information)

Other clinically significant adverse reactions occurring in ?10% of patients included: hypothyroidism (3%).

6.2 Postmarketing Experience

(Newly added information)

Endocrine Disorders: Hyperthyroidism

01/10/2020 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

Additions and/or revisions underlined:

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.

6 Adverse Reactions

Additions and/or revisions underlined:

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

• 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)]

  6.2 Postmarketing Experience

  Additions and/or revisions underlined:

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

  Gastrointestinal Disorders: Gastrointestinal perforation, fistula

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

Before you take Iclusig, tell your healthcare provider about all of your medical conditions, including if you:

• Plan to have surgery or have had a recent surgery. You should stop taking Iclusig at least 1 week before planned surgery.  See “What are the possible side effects of Iclusig?”

What are the possible side effects of Iclusig? Iclusig may cause serious side effects, including:

• Wound healing problems. Wound healing problems have happened in some people who take Iclusig. Tell your healthcare provider if you plan to have any surgery before or during treatment with Iclusig.

  • You should stop taking Iclusig at least 1 week before any planned surgery.

  • Your healthcare provider should tell you when you may start taking Iclusig again after surgery.

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Impaired Wound Healing and Gastrointestinal Perforation

Inform patients that impaired wound healing and gastrointestinal fistula or perforation have been reported. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.16)].

10/18/2018 (SUPPL-30)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

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

12/20/2017 (SUPPL-28)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trial Experience

(additions underlined)

…

Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 5. Overall, the most common non-hematologic adverse reactions (greater than or equal to 20%) were abdominal pain, rash, constipation, headache, dry skin, arterial occlusion, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity.

...

6.2 Postmarketing Experience

(additions underlined)

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:

Nervous system disorders: Reversible posterior leukoencephalopathy syndrome (RPLS) – also known as Posterior Reversible Encephalopathy Syndrome (PRES)

Metabolism and nutrition disorders: Dehydration

Skin and subcutaneous tissue disorders: Severe cutaneous reaction (e.g. Erythema multiforme, Stevens-Johnson syndrome)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Reversible Posterior Leukoencephalopathy Syndrome (RPLS – also known as Posterior Reversible Encephalopathy Syndrome - PRES)

Inform patients of the possibility of developing Reversible Posterior Leukoencephalopathy Syndrome while being treated with Iclusig. Advise patients to report symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances.

11/28/2016 (SUPPL-22)

Approved Drug Label (PDF)

Boxed Warning

(additions and/or revisions are underlined)

WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

Arterial Occlusion:

• Arterial occlusions have occurred in at least 35% of Iclusig-treated patients. Some patients experienced more than 1 type of event. Events observed 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 arterial occlusion. Interrupt or stop Iclusig immediately for arterial occlusion...

Venous Thromboembolism

• Venous occlusive events have occurred in 6% of Iclusig-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure:

• Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients...

5 Warnings and Precautions

5.1 Arterial Occlusion

(additions and/or revisions are underlined)

Arterial occlusions, including fatal myocardial infarction...severe peripheral vascular disease have occurred in at least 35% of Iclusig-treated patients from the phase 1 and phase 2 trials. With a minimum of 48 months follow-up for ongoing patients (N=133) in the phase 2 trial, 33% (150/449) of Iclusig- treated patients experienced a cardiac vascular (21%), peripheral vascular (12%), or cerebrovascular (9%) arterial occlusive event; some patients experienced more than 1 type of arterial occlusive event.

Iclusig can cause fatal and life-threatening arterial occlusion within 2 weeks of starting treatment, and at dose levels as low as 15 mg per day. Iclusig can also cause recurrent or multi-site vascular occlusion. Patients have required revascularization procedures (coronary, cerebrovascular, and peripheral arterial).

In the phase 2 trial, the median time to onset of the first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events was 193 (range: 1 - 1355), 526 (range: 5 - 1339), and 478 (range: 3 - 1344) days, respectively.

Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. The most common risk factors observed in patients with arterial occlusive events were hypertension (62%; 93/150), hyperlipidemia (61%; 91/150), and history of cardiac disease (48%; 72/150). Arterial occlusion adverse events were more frequent with increasing age...

Table 4: Arterial Occlusion Incidence in Iclusig-Treated Patients in Phase 2 Trial According to Risk Categories: 4 year follow-up (Table title has been revised as has data; please refer to label)

5.10 Hemorrhage

(additions and/or revisions are underlined)

Serious hemorrhage events including fatalities, occurred in 6% (28/449) of patients treated with Iclusig in the phase 2 trial, with 48 months follow-up. Hemorrhage occurred in 28% (124/449) of patients… Gastrointestinal hemorrhage and subdural hematoma were the most commonly reported serious bleeding events occurring in 1% (4/449 and 4/449, respectively).

5.11 Fluid Retention

(additions and/or revisions are underlined)

Fluid retention events judged as serious occurred in 4% (18/449) of patients treated with Iclusig in the phase 2 trial (48 months follow-up). One instance of brain edema was fatal. For fluid retention events occurring in more than 2% of the patients (treatment-emergent), serious cases included: pleural effusion (7/449, 2%), pericardial effusion (4/449, 1%), and edema peripheral (2/449, less than 1%).

In total, fluid retention occurred in 31% of the patients. The most common fluid retention events were peripheral edema (17%), pleural effusion (8%), pericardial effusion (4%) and peripheral swelling (3%).

5.12 Cardiac Arrhythmias

(additions and/or revisions are underlined)

Arrhythmias occurred in 19% (86/449) of Iclusig-treated patients, of which 7% (33/449) were grade 3 or greater. Arrhythmia of ventricular origin was reported in 3% (3/86) of all arrhythmias, with one case being grade 3 or greater.

Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. Atrial fibrillation was the most common arrhythmia and occurred in 7% (31/449) of patients, approximately half of which were grade 3 or 4. Other grade 3 or 4 arrhythmia events included syncope (9 patients; 2.0%), tachycardia and bradycardia (2 patients each 0.4%), and electrocardiogram QT prolonged, atrial flutter , supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (1 patient each 0.2%).  For 27 patients, the event led to hospitalization.

In patients with signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness), interrupt Iclusig and evaluate.

5.13 Myelosuppression

(additions and/or revisions are underlined)

Myelosuppression was reported as an adverse reaction in 59% (266/449) of patients, and severe (grade 3 or 4) myelosuppression occurred in 50% (226/449) of patients treated with Iclusig. With 48 months of follow-up, the incidence of these events...

Severe myelosuppression (Grade 3 or 4) was observed early in treatment, with a median onset time of 1 month (range less than 1–40 months)...

5.14 Tumor Lysis Syndrome

(additions and/or revisions are underlined)

One case occurred in a patient with advanced AP-CML and one case occurred in a patient with BP-CML.  Hyperuricemia occurred in 7% (31/449) of patients...

5.15 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

(Newly added subsection)

Post marketing cases of reversible posterior leukoencephalopathy syndrome (RPLS – also known as Posterior Reversible Encephalopathy Syndrome - PRES) have been reported in Iclusig-treated patients. RPLS is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Hypertension is often present and diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. If RPLS is diagnosed, interrupt Iclusig treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of RPLS.

5.17 Embryo-Fetal Toxicity

(additions and/or revisions are underlined)

Based on its mechanism of action and findings from animals 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 recommended human dose. 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.

5.2 Venous Thromboembolism

(additions and/or revisions are underlined)

Venous thromboembolic events occurred in 6% (25/449) of Iclusig-treated patients, including deep venous thrombosis (10 patients), pulmonary embolism (7 patients), superficial thrombophlebitis (3 patients), and retinal vein thrombosis (2 patients) with vision loss.

In the phase 2 trial, the incidence of venous thromboembolism was 9% (3/32) in patients with Ph+ ALL, 10% (6/62) in patients with blast phase (BP) CML, 4% (3/85) in patients with AP-CML, and 5% (13/270) in patients with CP-CML.

5.3 Heart Failure

(additions and/or revisions are underlined)

Fatal or serious heart failure or left ventricular dysfunction occurred in 6% of Iclusig-treated patients (N=29/449) in the phase 2 trial (48 months follow-up). Nine percent of patients (N=39) experienced any grade of heart failure or left ventricular dysfunction. The most frequently reported heart failure events were congestive cardiac failure and decreased ejection fraction (in 14 patients each; 3%)...

5.4 Hepatotoxicity

(additions and/or revisions are underlined)

Two additional fatal cases of acute liver failure also occurred...The fatal cases occurred in patients with blast phase (BP) CML or Ph+ ALL. Severe (grade 3 or 4) hepatotoxicity occurred in all disease cohorts.

With 48 months follow-up, 11% (50/449) of Iclusig-treated patients experienced grade 3 or 4 hepatotoxicity in the phase 2 trial. The most common forms of hepatotoxicity were elevations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), bilirubin, and alkaline phosphatase. The incidence of AST or ALT elevation was 54% (all grades) and 8% (grade 3 or 4)...

Hepatotoxic events were observed in 29% of patients. The median time to onset of hepatotoxicity event was 3 months, with a range of less than 1 month to 47 months...

5.5 Hypertension

(additions and/or revisions are underlined)

Treatment-emergent elevation of systolic or diastolic blood pressure (BP) occurred in 68% (306/449) of patients in the phase 2 clinical trial (48 months of follow-up). Fifty three patients (12%) treated with Iclusig in this clinical trial experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including hypertensive crisis…In patients with baseline systolic BP less than 140 mm Hg and baseline diastolic BP less than 90 mm Hg, 80% (229/285) experienced treatment-emergent hypertension; 44% (124/285) developed Stage 1 hypertension (defined as systolic BP greater than or equal to 140 mm Hg or diastolic BP greater than or equal to 90 mm Hg) while 37% developed Stage 2 hypertension (defined as systolic BP greater than or equal to 160 mm Hg or diastolic BP greater than or equal to 100 mm Hg). In 132 patients with Stage 1 hypertension at baseline, 67% (88/132) developed Stage 2 hypertension.

5.6 Pancreatitis

(additions and/or revisions are underlined)

Pancreatitis occurred in 7% (31/449, 6% serious or grade 3/4) of Iclusig-treated patients with 48 months of follow-up in the phase 2 trial. The incidence of treatment-emergent lipase elevation was 42% (16% grade 3 or greater).

Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (26/449).   The median time to onset of pancreatitis was 14 days (range: 3 - 1452). Twenty-three of the 31 cases of pancreatitis resolved within 2 weeks with dose interruption or reduction...

5.8 Neuropathy

(additions and/or revisions are underlined)

Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 20% (90/449) of Iclusig-treated patients in the pivotal phase 2 trial experienced a peripheral neuropathy event of any grade (2%, grade 3/4) (48 months follow-up).  The most common peripheral neuropathies reported were paresthesia (5%, 23/449), neuropathy peripheral (4%,19/449), hypoesthesia (3%, 15/449), dysgeusia (2%, (10/449), muscular weakness (2% (10/449) and hyperesthesia (1%,5/449). Cranial neuropathy developed in 2% (10/449) of Iclusig-treated patients (less than 1%, 3/449 - grade 3/4).

Of the patients who developed neuropathy, 26% (23/90) developed neuropathy during the first month of treatment...

5.9 Ocular Toxicity

(additions and/or revisions are underlined)

Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients in the phase 2 trial (48 months follow-up). Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 2% of Iclusig-treated patients. Conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema or eye pain occurred in 14% of patients. Visual blurring occurred in 6% of patients. Other ocular toxicities include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis...

6 Adverse Reactions

(Additions and/or revisions to the adverse reactions discussed in greater detail in other sections listing as below; previously located in section 6.1)

• Arterial replaces Vascular Occlusion

• Addition of Venous Thromboembolism

6.1 Clinical Trial Experience

(Additions and/or revisions are underlined)

All patients received a starting dose of 45 mg Iclusig once daily ...  Interruptions and dose adjustments to 30 mg once daily or 15 mg once daily were allowed for the management of treatment toxicity. Additionally, after approximately 2 years of follow-up, patients who were still taking a 45 mg daily dose were recommended to undergo a dose reduction, in response to the continued occurrence of arterial occlusive events and venous thromboembolic events in the clinical trial.

At the time of analysis (48 months of follow-up), 133 patients (30%) were ongoing (110 CP-CML; 20 AP-CML; 3 BP- CML; 0 Ph+ ALL), and the median duration of treatment with Iclusig was 32.2 months in patients with CP-CML, 19.4 months in patients with AP-CML, 2.9 months in patients with BP-CML, and 2.7 months in patients with Ph+ ALL. The median dose intensity in patients with CP-CML was 29 mg /day or 64% of the 45 mg starting dose; median dose intensity was greater in patients with advanced disease patients. Seventy one percent (318/449) of patients experienced a dose interruption of more than three days and 68% (304/449) experienced a dose reduction.

The most common adverse reactions (greater than or equal to 5%) that led to dose modifications (interruption or dose reduction) include thrombocytopenia (31%), neutropenia (14%), lipase increased (13%), arterial occlusive events (13%), abdominal pain (12%), rash (9%), anemia (6%), pancreatitis (6%), ALT increased (5%) and hypertension (5%).

At the time of the analysis, 69% of the ongoing patients (92/133 patients) were reported to be receiving 15 mg; with 26% (35/133) and 5% (6/133) of Iclusig-treated patients receiving 30 mg and 45 mg, respectively.

… Overall, the most common non-hematologic adverse reactions (greater than or equal to 20%) were abdominal pain, rash, constipation, headache, dry skin, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity. The rates of treatment-emergent adverse reactions resulting in discontinuation were 19% in CP-CML, 12% in AP-CML … The most common adverse reactions that led to treatment …

Table 5: Adverse Reactions in greater than 10% of Patients in the Phase 2 Trial (N=449) (Revision to table title and table data; please refer to label)

Table 6: Serious Adverse Reactions Occurring in > 2% of Patients from the Phase 2 Trial (N=449) (Revision to table title and data text and data; please refer to label)

Table 7: Clinically Relevant Grade 3/4* Hematologic Laboratory Abnormalities in Patients from the Phase 2 Trial (N=449) (Revision to table title and table data; please refer to label)

Table 8: Clinically Relevant Non-Hematologic Laboratory Abnormalities (Data revised in table; please refer to label)

6.2 Postmarketing Experience

(Newly added subsection)

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:

Reversible posterior leukoencephalopathy syndrome (RPLS) – also known as Posterior Reversible Encephalopathy Syndrome - PRES)

7 Drug Interactions

7.4 Drugs that are Substrates of the P-gp or ABCG2 Transporter Systems

(Newly added subsection)

Ponatinib inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro.

8 Use in Specific Populations

8. 3 Females and Males of Reproductive Potential

(PLLR conversion)

Iclusig can cause fetal harm when administered to pregnant women.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating Iclusig treatment.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after the last dose.

Infertility

Based on animal data, ponatinib may impair fertility in females of reproductive potential. It is not known whether these effects on fertility are reversible.

8.1 Pregnancy

(PLLR conversion)

...There are no available data on Iclusig use in pregnant women. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the recommended human dose. Advise pregnant women of the potential risk to a fetus.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data

Animal Data

Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis (25 rats per group)...

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no data on the presence of ponatinib in human milk, the effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from ponatinib including arterial occlusion, venous thromboembolism, heart failure, and hepatotoxicity, advise women not to breastfeed during treatment with Iclusig and for 6 days following the last dose.

8.4 Pediatric Use

(additions and/or revisions are underlined)

Safety and effectiveness have not been established in pediatric patients.

Juvenile Animal Toxicity Data

A juvenile toxicity study in 15-day-old rats was conducted with daily oral gavage administration of ponatinib at 0.75, 1.5, or 3 mg/kg/day for 21 days. There were no adverse effects of ponatinib on juvenile rat developmental parameters (vaginal opening, preputial separation or bone measurements) observed in this study. Once daily oral administration of 3 mg/kg/day ponatinib to juvenile rats beginning on Day 15 postpartum (pp) resulted in mortality related to inflammatory effects after 6 to 7 days following initiation of treatment. The dose of 3 mg/kg/day is approximately 0.32 times the clinical dose on a mg/m2 basis for a child.

8.5 Geriatric Use

(additions and/or revisions are underlined)

In patients with CP-CML, patients of age greater than or equal to 65 years had a lower major cytogenetic response rate (40%) as compared with patients less than 65 years of age (65%).  In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age greater than or equal to 65 years had a similar hematologic response rate (45%) as compared with patients less than 65 years of age (44%).  Forty percent of patients greater than or equal to 65 years had arterial occlusion events...

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(additions and/or revisions are underlined)

Arterial Occlusions and Venous Thromboembolism

Inform patients that serious arterial thromboses…

Hypertension

...Advise patients to contact their health care provider for elevated blood pressure or if symptoms of hypertension occur including confusion, headache...

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

Inform patients of the possibility of developing Reversible Posterior Leukoencephalopathy Syndrome while being treated with Iclusig. Advise patients to report symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances.

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy.

Lactation

Advise women not to breastfeed during treatment with Iclusig and for 6 days after the last dose.

Infertility

Advise females of reproductive potential of the potential for reduced fertility from Iclusig.

MEDICATION GUIDE

(additions and/or revisions are underlined)

What is the most important information I should know about Iclusig? Iclusig can cause serious side effects, including:

Liver problems

Get medical help right away if you get any of these symptoms of liver problems during treatment:

• yellowing of your skin or the white part of your eyes (jaundice)

• dark “tea-colored” urine

• sleepiness

• loss of appetite

• bleeding or bruising

What should I tell my healthcare provider before taking Iclusig? Before you take Iclusig, tell your healthcare provider if you:

• have high blood pressure

• are pregnant or plan to become pregnant. Iclusig can harm your unborn baby.

  • Your healthcare provider will do a pregnancy test before you start taking Iclusig.

  • You should not become pregnant during treatment with Iclusig.

  • For females who can become pregnant :

    • Use an effective form of birth control during treatment and for 3 weeks after your last dose of Iclusig.

    • Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with Iclusig.

    • Iclusig may affect your ability to have children. Tell your healthcare provider if this is a concern for you.

• are breastfeeding or plan to breastfeed. It is not known if Iclusig passes into your breast milk. Do not breastfeed during treatment and for 6 days after your last dose of Iclusig.

What are the possible side effects of Iclusig? Iclusig may cause serious side effects, including:

• Neuropathy.

  • double vision and other problems with eyesight, trouble moving the eye, drooping of part of the face, sagging or drooping eyelids, change in taste

• Effects on the eye. Serious eye problems that can lead to blindness or blurred vision may happen with Iclusig. Tell your healthcare provider if you get any of the following symptoms: bleeding in the eye, perceived flashes of light, light sensitivity, floaters, dry inflamed, swollen, or itchy eyes, and eye pain.

The most common side effects of Iclusig include:

• high blood pressure

• diarrhea

• increase of a serum protein known as lipase

• vomiting

• muscle pain

• pain in arms, hands, legs, and feet

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with Iclusig if you have certain side effects.

06/02/2016 (SUPPL-21)

Approved Drug Label (PDF)

5 Warnings and Precautions

Increased Toxicity in Newly Diagnosed Chronic Phase CML

• In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with chronic phase (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 in October 2013.
• 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.

6 Adverse Reactions

(addition of subheadings)

• Clinical Trial Experience
• Previously Treated CML or Ph+ ALL
• The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation…

(addition to bulleted list)

• Increased Toxicity in Newly Diagnosed Chronic Phase CML

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MG - What is Iclusig?

• Iclusig is not for use to treat people with newly diagnosed chronic phase CML