Iclusig (ponatinib hydrochloride 45 mg) Dailymed

Iclusig (ponatinib) is a kinase inhibitor indicated for the:

• Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
• Treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

Iclusig is a kinase inhibitor indicated for the:

• Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
• Treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). (1)

Limitations of use:

Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML (5.7).

Limitations of use:

Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML [see Warnings and Precautions (5.7)].

2dosage And Administration

• Recommended dose: 45 mg taken orally once daily with or without food (2.1)
• Hepatic Impairment: 30 mg orally once daily (2.5)
• Modify or interrupt dosing for hematologic and non-hematologic toxicity (2.2, 2.3)

2.1Recommended Dosage

The optimal dose of Iclusig has not been identified. In clinical trials, the starting dose of Iclusig was 45 mg administered orally once daily. However, in the phase 2 trial, 68% of the patients required dose reductions to 30 mg or 15 mg once daily during the course of therapy.

Start dosing with 45 mg once daily. Consider reducing the dose of Iclusig for patients with chronic phase (CP) CML and accelerated phase (AP) CML who have achieved a major cytogenetic response.

Consider discontinuing Iclusig if response has not occurred by 3 months (90 days).

Iclusig may be taken with or without food. Tablets should be swallowed whole.

2.2Dose Modifications for Myelosuppression

Suggested dose modifications for neutropenia (ANC* less than 1.0 × 10⁹/L) and thrombocytopenia (platelet less than 50 × 10⁹/L) that are unrelated to leukemia are summarized in Table 1.

Table 1: Suggested Dose Modifications for Myelosuppression

ANCANC = absolute neutrophil count < 1 × 109/Lorplatelet < 50 × 109/L	First occurrence: Interrupt Iclusig and resume initial 45 mg dose after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L
	Second occurrence: Interrupt Iclusig and resume at 30 mg after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L
	Third occurrence: Interrupt Iclusig and resume at 15 mg after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L

2.3Dose Modifications for Non-Hematologic Adverse Reactions

If a serious non-hematologic adverse reaction occurs, modify the dose or interrupt treatment. Do not restart Iclusig in patients with arterial or venous occlusive reactions unless the potential benefit outweighs the risk of recurrent arterial or venous occlusions and the patient has no other treatment options. For serious reactions other than arterial or venous occlusion, do not restart Iclusig until the serious event has resolved or the potential benefit of resuming therapy is judged to outweigh the risk.

Hepatotoxicity

Recommended modifications for hepatotoxicity are summarized in Table 2.

Table 2: Recommended Dose Modifications for Hepatotoxicity

Elevation of liver transaminase > 3 × ULNULN = Upper Limit of Normal for the lab (Grade 2 or higher)	Occurrence at 45 mg: Interrupt Iclusig and monitor hepatic function Resume Iclusig at 30 mg after recovery to ≤ Grade 1 (< 3 × ULN) Occurrence at 30 mg: Interrupt Iclusig and resume at 15 mg after recovery to ≤ Grade 1 Occurrence at 15 mg: Discontinue Iclusig
Elevation of AST or ALT ≥ 3 × ULN concurrent with an elevation of bilirubin > 2 × ULN and alkaline phosphatase < 2 × ULN	Discontinue Iclusig

Pancreatitis and Elevation of Lipase

Recommended modifications for pancreatic adverse reactions are summarized in Table 3.

Table 3: Recommended Dose Modifications for Pancreatitis and Elevation of Lipase

Asymptomatic Grade 1 or 2 elevation of serum lipase	Consider interruption or dose reduction of Iclusig
Asymptomatic Grade 3 or 4 elevation of lipase (> 2 × ULNULN = Upper Limit of Normal for the lab) or asymptomatic radiologic pancreatitis (Grade 2 pancreatitis)	Occurrence at 45 mg: Interrupt Iclusig and resume at 30 mg after recovery to ≤ Grade 1 (< 1.5 × ULN) Occurrence at 30 mg: Interrupt Iclusig and resume at 15 mg after recovery to ≤ Grade 1 Occurrence at 15 mg: Discontinue Iclusig
Symptomatic Grade 3 pancreatitis	Occurrence at 45 mg: Interrupt Iclusig and resume at 30 mg after complete resolution of symptoms and after recovery of lipase elevation to ≤ Grade 1 Occurrence at 30 mg: Interrupt Iclusig and resume at 15 mg after complete resolution of symptoms and after recovery of lipase elevation to ≤ Grade 1 Occurrence at 15 mg: Discontinue Iclusig
Grade 4 pancreatitis	Discontinue Iclusig

2.4Dose Modification for Use With Strong CYP3A Inhibitors

The recommended dose should be reduced to 30 mg once daily when administering Iclusig with strong CYP3A inhibitors [see Drug Interactions (7.1)].

2.5Dose Modification for Use in Patients with Hepatic Impairment

The recommended starting dose is 30 mg once daily in patients with hepatic impairment (Child-Pugh A, B, or C) [see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

3dosage Forms And Strengths

15 mg, 30 mg and 45 mg round, white, film-coated tablets.


Tablets: 15 mg, 30 mg and 45 mg (3)

4contraindications

None.


None (4)

5warnings And Precautions

• Hypertension: Monitor for high blood pressure and manage as clinically indicated (5.5).
• Pancreatitis: Monitor serum lipase monthly; interrupt or discontinue Iclusig (2.3, 5.6).
• Neuropathy: Monitor for symptoms of peripheral and cranial neuropathy (5.8).
• Ocular Toxicity: Conduct comprehensive eye exams at baseline and periodically during treatment (5.9).
• Hemorrhage: Interrupt Iclusig for serious or severe hemorrhage (5.10).
• Fluid Retention: Monitor patients for fluid retention; interrupt, reduce, or discontinue Iclusig (5.11).
• Cardiac Arrhythmias: Monitor for symptoms of arrhythmias (5.12, 6).
• Myelosuppression: Thrombocytopenia, neutropenia, and anemia may require dose interruption or reduction. Monitor complete blood counts every 2 weeks for 3 months and then monthly and as clinically indicated. Interrupt Iclusig for ANC < 1000/mm³ or thrombocytopenia < 50,000/ mm³ (2.2, 5.13).
• Tumor Lysis Syndrome: Ensure adequate hydration and correct elevated uric acid levels prior to initiating therapy with Iclusig (5.14).
• Reversible posterior leukoencephalopathy syndrome (RPLS): Interrupt Iclusig and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of RPLS (5.15)
• Compromised Wound Healing and Gastrointestinal Perforation: Temporarily interrupt therapy in patients undergoing major surgical procedures (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 Occlusion

Arterial occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, 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 and in patients with history of ischemia, hypertension, diabetes, or hyperlipidemia (see Table 4).

Table 4: Arterial Occlusion Incidence in Iclusig-Treated Patients in Phase 2 Trial According to Risk Categories: 4 year follow-up

Age(At time of study entry)	History of ischemia, hypertension, diabetes, or hyperlipidemiaN=218	No history of ischemia, hypertension, diabetes, or hyperlipidemiaN=231
49 or younger	31%(11/36)	19%(21/108)
50 to 74 years	40%(64/158)	30%(32/109)
75 and older	58%(14/24)	57%(8/14)
All age groups	41%(89/218)	26%(61/231)
Total	33%(150/449)

Cardiac vascular occlusion, including fatal and life-threatening myocardial infarction and coronary artery occlusion has occurred in 21% (94/449) of Iclusig-treated patients. Patients have developed heart failure concurrent or subsequent to the myocardial ischemic event [see Warnings and Precautions (5.3)].

Cerebrovascular occlusion, including fatal stroke, has occurred in 9% (40/449) of Iclusig-treated patients. Iclusig can cause stenosis over multiple segments in major arterial vessels that supply the brain (e.g., carotid, vertebral, middle cerebral artery).

Peripheral arterial occlusion, including fatal mesenteric artery occlusion and life-threatening peripheral arterial disease, have occurred in 12% (52/449) of Iclusig-treated patients. Patients have developed digital or distal extremity necrosis and have required amputations. Renal artery stenosis, associated with worsening, labile or treatment-resistant hypertension, has occurred in some Iclusig-treated patients [see Warnings and Precautions (5.5)].

Clinicians should consider whether the benefits of Iclusig treatment are expected to exceed the risks of therapy. In patients suspected of developing arterial occlusive events, interrupt or stop Iclusig. A benefit-risk consideration should guide a decision to restart Iclusig therapy [see Dosage and Administration (2.3)].

5.2Venous Thromboembolism

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. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism [see Dosage and Administration (2.3)].

5.3Heart Failure

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%).

Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure [see Dosage and Administration (2.3)].

5.4Hepatotoxicity

Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. 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). ALT or AST elevation was not reversed by the date of last follow-up in 5% of patients.

Hepatotoxic events were observed in 29% of patients. The median time to onset of hepatotoxicity event was 3 months, with a range of <1 month to 47 months. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

5.5Hypertension

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. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath [see Adverse Reactions (6)].

In patients with baseline systolic BP<140 mm Hg and baseline diastolic BP<90 mm Hg, 80% (229/285) experienced treatment-emergent hypertension; 44% (124/285) developed Stage 1 hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg) while 37% developed Stage 2 hypertension (defined as systolic BP≥160 mm Hg or diastolic BP≥100 mm Hg). In 132 patients with Stage 1 hypertension at baseline, 67% (88/132) developed Stage 2 hypertension.

Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled. In the event of significant worsening, labile or treatment-resistant hypertension, interrupt treatment and consider evaluating for renal artery stenosis.

5.6Pancreatitis

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.

Check 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. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis [see Dosage and Administration (2.3)]. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 × ULN.

5.7Increased 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.

5.8Neuropathy

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 (<1%, 3/449 - grade 3/4).

Of the patients who developed neuropathy, 26% (23/90) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

5.9Ocular Toxicity

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. Conduct comprehensive eye exams at baseline and periodically during treatment [see Adverse Reactions (6)].

5.10Hemorrhage

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. 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 commonly reported serious bleeding events occurring in 1% (4/449 and 4/449, respectively). Most hemorrhagic events, but not all, occurred in patients with grade 4 thrombocytopenia [see Warnings and Precautions (5.13)]. Interrupt Iclusig for serious or severe hemorrhage and evaluate [see Dosage and Administration (2.3)].

5.11Fluid Retention

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, <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%).

Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated [see Dosage and Administration (2.3)].

5.12Cardiac Arrhythmias

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.

5.13Myelosuppression

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 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 1 month (range <1– 40 months). Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended [see Dosage and Administration (2.2)].

5.14Tumor Lysis Syndrome

Two patients (<1%) treated with Iclusig developed serious tumor lysis syndrome. 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. Due to the potential for tumor lysis syndrome in patients with advanced disease (AP-CML, BP-CML, or Ph+ ALL), ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

5.15Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

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.

5.16Compromised Wound Healing and Gastrointestinal Perforation

No formal studies of the effect of Iclusig on wound healing have been conducted. Based on the mechanism of action [see Clinical Pharmacology (12.1)], Iclusig could compromise wound healing. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Interrupt Iclusig for at least 1 week prior to major surgery. The decision when to resume Iclusig after surgery should be based on clinical judgment of adequate wound healing.

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 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 [see Use in Specific Populations (8.1 ,8.3) and Clinical Pharmacology (12.1) ].

6adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the prescribing information:

• Arterial Occlusion [see Warnings and Precautions (5.1)]
• Venous Thromboembolism [see Warnings and Precautions (5.2)]
• Heart Failure [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)]
• Hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)]
• Hypertension [see Warnings and Precautions (5.5)]
• Pancreatitis [see Dosage and Administration (2.3) and Warnings and Precautions (5.6)]
• Increased Toxicity in Newly Diagnosed Chronic Phase CML [see Warnings and Precautions (5.7)]
• 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 Dosage and Administration (2.2) and Warnings and Precautions (5.13)]

The most common non-hematologic adverse reactions (≥ 20%) were abdominal pain, rash, constipation, headache, dry skin, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity (6).

To report SUSPECTED ADVERSE REACTIONS, contact ARIAD Pharmaceuticals, Inc. at 1-855-55-ARIAD or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trial 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.

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.

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 (≥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.

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 (≥ 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, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse reactions that led to treatment discontinuation was thrombocytopenia (4%).

Table 5: Adverse Reactions in > 10% of Patients in the Phase 2 Trial (N=449)

	CP-CML(N=270)		AP-CML(N=85)		BP-CML(N=62)		Ph+ ALL(N=32)
Body System	Any Grade(%)	Grade 3 / 4(%)	Any Grade(%)	Grade 3 / 4(%)	Any Grade(%)	Grade 3 / 4(%)	Any Grade(%)	Grade 3 / 4(%)
Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity.
Treatment-emergent, all causality events
Cardiac or Vascular disorders
  Hypertension derived from blood pressure (BP) measurement recorded monthly while on trial	69	42	74	42	60	23	53	28
  Arterial ischemia cardiovascular, cerebrovascular, and peripheral vascular ischemia	42	17	28	14	11	8	22	6
  Cardiac Failure includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure	8	5	7	5	15	8	6	3
Gastrointestinal disorders
  Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort	48	10	42	9	35	8	34	6
  Constipation	41	3	27	2	27	0	53	3
  Nausea	28	1	31	0	34	2	22	0
  Diarrhea	20	1	29	2	24	3	13	3
  Vomiting	18	2	26	0	27	2	25	0
  Oral mucositis includes aphthous stomatitis, lip buler, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration	14	1	19	1	23	0	9	3
  GI hemorrhage includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage	1	<1	8	1	6	3	9	6
Blood and lymphatic system disorders
  Febrile neutropenia	1	1	5	5	13	13	25	25
Infections and infestations
  Sepsis	2	1	4	4	3	0	13	13
  Pneumonia	6	5	13	9	16	11	9	3
  Urinary tract infection	11	2	14	2	2	2	9	0
  Upper respiratory tract infection	14	1	13	0	13	2	3	0
  Nasopharyngitis	12	0	18	0	3	0	3	0
  Cellulitis	3	2	6	2	11	3	0	0
Nervous system disorders
  Headache	43	3	29	0	31	3	25	0
  Peripheral neuropathy includes burning sensation, skin burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, polyneuropathy, dysgeusia, muscular weakness, gait disturbance, nerve compression, areflexia, hypotonia, restless legs syndrome	24	3	14	1	11	0	16	0
  Dizziness	16	0	9	0	5	0	3	0
Respiratory, thoracic, and mediastinal disorders
  Pleural effusion	5	2	12	2	13	0	19	3
  Cough	16	0	22	0	19	0	6	0
  Dyspnea	17	3	20	4	19	5	6	0
Skin and subcutaneous tissue disorders
  Rash and related conditions	63	4	59	7	39	5	28	3
  Dry skin	42	3	32	1	26	2	25	0
  Pruritus	13	<1	8	0	5	2	0	0
  Erythema	10	1	8	0	8	0	6	0
  Alopecia	7	0	11	0	8	0	6	0
Musculoskeletal and connective tissue disorders
  Arthralgia	32	3	33	2	19	0	13	0
  Myalgia	24	1	20	0	18	0	6	0
  Pain in extremity	23	3	19	0	13	0	13	0
  Back pain	21	1	14	2	19	2	13	0
  Muscle spasms	14	0	6	0	5	0	13	0
  Bone pain	14	<1	13	1	11	3	9	3
  Musculoskeletal pain	11	2	7	0	8	0	6	3
General disorders and administration site conditions
  Fatigue or asthenia	47	4	49	8	40	6	34	3
  Pyrexia	26	1	40	7	36	3	25	0
  Edema, peripheral	16	<1	18	0	15	0	25	0
  Pain	10	<1	13	0	16	3	6	0
  Chills	8	0	11	0	13	2	9	0
Metabolism and nutrition disorders
  Decreased appetite	13	<1	14	1	8	0	31	0
Investigations
  Weight decreased	10	<1	9	0	5	0	13	0
Psychiatric disorders
  Insomnia	11	0	13	0	11	0	13	0

Table 6: Serious Adverse Reactions Occurring in > 2% of Patients from the Phase 2 Trial (N=449)

System Organ Class	N (%)
Cardiovascular disorders
  Arterial Occlusion	99 (22%)
    Cardiac vascular	53 (12%)
    Cerebrovascular	31 (7%)
    Peripheral vascular	34 (8%)
  Venous thromboembolism	22 (5%)
  Hemorrhage	28 (6%)
    CNS hemorrhage	6 (1%)
    Gastrointestinal hemorrhage	11 (2%)
  Heart failure	28(6%)
  Effusionsincludes pericardial effusion, pleural effusion, and ascites	15 (3%)
  Atrial fibrillation	18 (4%)
  Hypertension	12 (3%)
Gastrointestinal disorders
  Pancreatitis	26(6%)
  Abdominal pain	20 (5%)
Blood and lymphatic system disorders
  Febrile neutropenia	13 (3%)
  Anemia	16(3%)
  Thrombocytopenia	14 (3%)
Infections
  Pneumonia	32 (7%)
  Sepsis	10 (2%)
General
  Pyrexia	20 (5%)

Laboratory Abnormalities

Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 7).

Table 7: Clinically Relevant Grade 3/4Reported using NCI-CTC-AE v 4.0 Hematologic Laboratory Abnormalities in Patients from the Phase 2 Trial (N=449)

Laboratory Test	CP-CML(N=270)(%)	AP-CML(N=85)(%)	BP-CML(N=62)(%)	Ph+ ALL(N=32)(%)
Hematology
ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count
  Thrombocytopenia (platelet count decreased)	35	49	45	47
  Neutropenia (ANC decreased)	23	52	48	59
  Leukopenia (WBC decreased)	12	36	48	63
  Anemia (Hgb decreased)	8	31	52	34
  Lymphopenia	10	25	32	19

Table 8: Clinically Relevant Non-Hematologic Laboratory Abnormalities

Laboratory Test	Safety PopulationN=449
	Any GradeGraded using NCI-CTC-AE v 4.0 (%)	CTCAE Grade 3 / 4(%)
ALT=alanine aminotransferase, AST=aspartate aminotransferase.
Liver function tests
  ALT increased	41	6
  AST increased	35	4
  Alkaline phosphatase increased	40	2
  Albumin decreased	27	<1
  Bilirubin increased	13	<1
Pancreatic enzymes
  Lipase increased	38	13
  Amylase increased	18	3
Chemistry
  Glucose increased	54	7
  Phosphorus decreased	33	10
  Calcium decreased	30	<1
  Sodium decreased	27	5
  Glucose decreased	13	0
  Potassium decreased	18	2
  Potassium increased	19	2
  Sodium increased	10	<1
  Bicarbonate decreased	19	<1
  Creatinine increased	21	<1
  Calcium increased	12	0
  Triglycerides increased	3	<1

6.2Postmarketing 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:

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

7drug Interactions

• Strong CYP3A Inhibitors: Avoid concurrent use, or reduce Iclusig dose if co-administration cannot be avoided (2.4, 7.1)
• Strong CYP3A Inducers: Avoid concurrent use (7.2)

7.1Drugs That Are Strong Inhibitors of CYP3A Enzymes

Based on in vitro studies, ponatinib is a substrate of CYP3A and to a lesser extent CYP2C8 and CYP2D6. In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC_0-inf and C_max by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced [see Dosage and Administration (2.4)]. Patients taking concomitant strong CYP3A inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)].

7.2Drugs That Are Strong Inducers of CYP3A Enzymes

Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John's Wort) with Iclusig should be avoided 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. In a drug interaction study in healthy volunteers, co-administration of Iclusig following multiple doses of rifampin resulted in decreased ponatinib AUC_0-inf and C_max values by 62% and 42%, respectively [see Clinical Pharmacology (12.3)].

7.3Drugs That Elevate Gastric pH

Iclusig may be co-administered with gastric pH-elevating medications. In a drug interaction study in healthy volunteers, co-administration of Iclusig following multiple doses of lansoprazole resulted in a minimal (6%) decrease in ponatinib exposure [see Clinical Pharmacology (12.3)].

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

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 [see Clinical Pharmacology (12.3)].

8use In Specific Populations

• Lactation: Advise women not to breastfeed (8.2).

8.1Pregnancy

Risk Summary

Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman [see Data]. 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 [see Data]. 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). At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

8.2Lactation

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.

8.3Females and Males of Reproductive Potential

Iclusig can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)].

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 [see Nonclinical Toxicology (13.1)].

8.4Pediatric Use

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.

8.5Geriatric Use

One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (40%) as compared with patients < 65 years of age (65%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a similar hematologic response rate (45%) as compared with patients < 65 years of age (44%). Forty percent of patients ≥ 65 years had arterial occlusion events. Patients of age ≥ 65 years 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.

8.6Hepatic Impairment

Administer Iclusig at a dose of 30 mg once daily in patients with hepatic impairment (Child-Pugh A, B, or C) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

In a single-dose (30 mg) pharmacokinetic (PK) study; compared to subjects with normal liver function, no major differences in ponatinib PK were observed in subjects with hepatic impairment (Child-Pugh A, B, or C). However, there was an increased overall incidence of adverse reactions (e.g., gastrointestinal disorders, including a case of severe pancreatitis) in the subjects with hepatic impairment following the single 30 mg dose compared to subjects with normal liver function. The safety of multiple ponatinib doses, or doses higher than 30 mg have not been studied in patients with hepatic impairment.