Iclusig is a kinase inhibitor indicated for the treatment of adult patients with:
 Chronic phase (CP) chronic myeloid leukemia (CML) with resistance or intolerance to at least two prior kinase inhibitors.
 Accelerated phase (AP) or blast phase (BP) CML or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other kinase inhibitors are indicated.
 T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL.
Limitations of Use:
Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. (see section 4.4).

Posology
 Recommended Dosage in CP-CML: Starting dose is 45 mg orally once daily with a reduction to 15 mg once daily upon achievement of ≤1% BCR-ABL1IS.
 Recommended Dosage in AP-CML, BP-CML, and Ph+ ALL: Starting dose is 45 mg orally once daily.
Hepatic Impairment: Reduce the starting dose to 30 mg orally once daily.
Administration
Advise patients of the following:
 Iclusig may be taken with or without food.
 Swallow tablets whole. Do not crush, break, cut or chew tablets.
 If a dose is missed, take the next dose at the regularly scheduled time the next day.

Dose Modifications for Adverse Reactions

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

Based on CTCAE v5.0: Grade 1 mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening
ULN = Upper Limit of Normal for the lab; AOE = Arterial Occlusive Event; VTE = Venous Thromboembolic Event; ANC = absolute neutrophil count

Dosage Modification for Coadministration of Strong CYP3A Inhibitors
Avoid coadministration of Iclusig with strong CYP3A inhibitors. If coadministration of a strong CYP3A inhibitor cannot be avoided, reduce the dosage of Iclusig as recommended in Table 3.
After the strong CYP3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the Iclusig dosage that was tolerated prior to initiating the strong CYP3A inhibitor.

Dosage for Patients with Hepatic Impairment
Reduce the starting dose of Iclusig from 45 mg orally once daily to 30 mg orally once daily in patients with pre-existing hepatic impairment (Child-Pugh A, B, or C)
Elderly population
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 Special warnings and precautions for use (4.4)].
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 Special warnings and precautions for use (4.4)].

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.

Hepatic impairment
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 Posology and method of administration (4.2), Pharmacokinetic Properties (5.2)]. The safety of multiple doses, or doses higher than 30 mg, has not been studied in patients with hepatic impairment.

Renal impairment
Iclusig has not been studied in patients with renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined.

Pediatric population
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 mg/kg/day, 1.5 mg/kg/day, 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.

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

Arterial Occlusive Events
Arterial occlusive events (AOEs), including fatalities, occurred in patients who received Iclusig in OPTIC and PACE.
Of the 94 patients who received a starting dose of 45 mg (45 mg  15 mg) in OPTIC, 13% experienced AOEs, of which 9%, 2.1%, 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 4.5 months (range: 12 days to 2.1 years), 1 year (range: 5.9 months to 1.6 years), and 3.6 months (range: 23 days to 6.3 months), respectively. Grade 3 or 4 AOEs occurred in 5% of patients; the most frequent Grade 3 or 4 AOEs were myocardial infarction, acute coronary syndrome, arterial thrombosis, ischemic stroke, and ischemic cerebral infarction (1.1% each). Fatal AOEs occurred in 2 patients (2.1%); both of which were sudden death. AOEs were more frequent with increasing age.
In PACE, 26% of 449 patients experienced AOEs, of which 15%, 7%, and 11% experienced cardiovascular, cerebrovascular, and peripheral vascular AOEs, respectively. Some patients experienced recurrent or multisite vascular occlusion. The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular AOEs was 1 year (range: 1 day to 4.1 years),

1.4 years (range: 2 days to 4.5 years), and 2 years (range: 10 days to 4.9 years), respectively. Grade 3 or 4 AOEs occurred in 14% of patients; the most frequent Grade 3 or 4 AOEs were peripheral arterial occlusive disease (3.1%), myocardial infarction (2%), coronary artery disease (1.6%), and cerebral infarction (1.6%). Fatal AOEs occurred in 9 patients (2%); the most frequent fatal AOE was cardiac arrest (0.9%).
In PACE, fatal and life-threatening AOEs occurred within 2 weeks of starting treatment at 45 mg, and at dose levels as low as 15 mg per day. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced AOEs. AOEs were more frequent with increasing age and in patients with history of ischemia, hypertension, diabetes, or hypercholesterolemia. The most common risk factors in patients with AOEs were history of hypertension (67%; 77/115), hypercholesterolemia (59%; 68/115), and non-ischemic cardiac disease (43%; 49/115).
In PACE, patients developed heart failure concurrent or subsequent to a myocardial ischemic event [see Special warnings and precautions for use (4.4)]. Patients required revascularization procedures (coronary, cerebrovascular, and peripheral arterial). Iclusig caused stenosis over multiple segments in major arterial vessels that supply the brain (e.g., carotid, vertebral, middle cerebral artery). Patients developed digital or distal extremity necrosis and required amputations. Renal artery stenosis associated with worsening, labile or treatment-resistant hypertension occurred in some Iclusig-treated patients [see Special warnings and precautions for use ].
In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, congestive heart failure, venous thromboembolism, or clinically significant atrial/ventricular arrhythmias, were excluded. In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease, including any history of clinically significant atrial/ventricular arrhythmias or history of myocardial infarction, unstable angina, or congestive heart failure within the 3 months prior to the first dose of Iclusig, were excluded. Consider whether the benefits of Iclusig are expected to exceed the risks.
Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue Iclusig based on recurrence/severity [see Posology and method of administration (4.2)]. Consider benefit-risk to guide a decision to restart Iclusig.

Venous Thromboembolic Events
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 Posology and method of administration (4.2)].

Heart failure
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 Posology and method of administration (4.2)].

Hepatotoxicity
Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in 3 patients, with hepatic failure occurring within 1 week of starting Iclusig in one of these patients. These fatal cases occurred in patients with BP-CML or Ph+ ALL.
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 Posology and method of administration (4.2)]

Hypertension
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. 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 Posology and method of administration (4.2)]. For significant worsening, labile or treatment-resistant hypertension, interrupt Iclusig and consider evaluating for renal artery stenosis.

Pancreatitis
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 Posology and method of administration (4.2)]. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms.

Increased Toxicity in Newly Diagnosed Chronic Phase CML
In a prospective randomized clinical trial in the first line treatment of newly diagnosed patients with CP-CML, single agent Iclusig 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety.

Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the Iclusig arm compared to the imatinib arm. Compared to imatinib-treated patients, Iclusig-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML.

Neuropathy
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 Posology and method of administration (4.2)].

Ocular Toxicity
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.

Hemorrhage
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 Special warnings and precautions for use].
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 Posology and method of administration (4.2)]

Fluid Retention
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 [Posology and method of administration (4.2)]

Cardiac Arrhythmias
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.

Myelosuppression
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 Posology and method of administration (4.2)]

Tumor Lysis Syndrome
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.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
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.

Impaired Wound Healing and Gastrointestinal Perforation
Impaired wound healing occurred in patients receiving Iclusig. 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. Permanently discontinue in patients with gastrointestinal perforation.

Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, Iclusig can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at exposures lower than human exposures at the 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.

Strong CYP3A Inhibitors
Coadministration of Iclusig with a strong CYP3A inhibitor increases ponatinib plasma concentrations, 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 Posology and method of administration (4.2)].

Strong CYP3A Inducers
Coadministration of Iclusig with a strong CYP3A inducer decreases ponatinib plasma concentrations [see Pharmacological properties (5)]. 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.

Pregnancy
Based on findings in animals and 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.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 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 mg/kg/day, 1 mg/kg/day, 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.

Breast-feeding
There is no data on the presence of ponatinib in human milk or the effects on the breastfed chid or on milk production.

Because of the potential for serious adverse reactions in the breastfed child from ponatinib, advise women not to breastfeed during treatment with Iclusig and for 6 days following the last dose.

Females and Males of childbearing potential/contraception
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.

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Summary of the safety profile
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most common adverse reactions identified in the Highlights of the Prescribing Information are from a pooled safety population of 543 patients with CML or Ph+ ALL who received Iclusig at a starting dose of 45 mg orally once daily. In this pooled safety population, the most common (>20%) adverse reactions were rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction, and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) were platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.

Previously Treated CP-CML
The safety of Iclusig was evaluated in OPTIC [see Clinical efficacy and safety]. Patients received one of three starting doses of Iclusig: 45 mg orally once daily (n=94), 30 mg orally once daily (n=94) or 15 mg orally once daily (n=94). Patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, congestive heart failure, venous thromboembolism, or clinically significant atrial/ventricular arrhythmias, were excluded. Only the safety information for the recommended starting dosage (45 mg) is described below. Patients who received a starting dose of Iclusig 45 mg orally once daily had a mandatory dose reduction to 15 mg once daily upon achievement of ≤1% BCR-ABL1IS. Of these patients, 70% were exposed for 1 year or longer and 37% 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 32% of patients who received Iclusig at a starting dose of 45 mg. Serious adverse reactions in >2% of patients included AOEs (7%; of which 2.1% were sudden death), cardiac arrhythmias (6%), thrombocytopenia (5%), pyrexia (4.3%), anemia (3.2%), abdominal pain (3.2%), 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 18% 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 69% 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, and abdominal pain. The most common (>20%) Grade 3 or 4 laboratory abnormalities were platelet count decreased and neutrophil cell count decreased.

Table 4 summarizes the adverse reactions in OPTIC for patients who received Iclusig at a starting dose of 45 mg.

Iclusig 45 mg  15 mg (N = 94)

Graded using CTCAE v5.0
(a) Arthralgia includes arthralgia, arthritis, back pain, intervertebral disc degeneration, osteoarthritis, pain, neck pain, pain in extremity, pain of skin, sciatica, spinal pain, tendonitis, tenosynovitis
(b) Hyperlipidemia includes blood cholesterol increased, blood triglycerides increased, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, low density lipoprotein increased
(c) Abdominal pain includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, chronic gastritis, colitis, enteritis, enterocolitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal pain, gastroesophageal reflux disease, Helicobacter gastritis

Clinically relevant adverse reactions in ≤10% of patients who received Iclusig at a starting dose of 45 mg: neuropathy (7%), fluid retention and edema (5%), and hypothyroidism (3.2%)
Table 5 summarizes the laboratory abnormalities in OPTIC for patients who received Iclusig at a starting dose of 45 mg

ALT = alanine aminotransferase, AST = aspartate aminotransferase
Graded using CTCAE v5.0 (except glucose increased which is graded using CTCAE v4.03)
Previously Treated CML or Ph+ ALL
The safety of Iclusig was evaluated in PACE [see Clinical efficacy and safety ]. Eligible patients had CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior kinase inhibitor, including those with the BCR-ABL T315I mutation. Patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease, including any history of clinically significant atrial/ventricular arrhythmias or history of myocardial infarction, unstable angina, or congestive heart failure within the 3 months prior to the first dose of Iclusig, were excluded. Patients received a starting dose of Iclusig 45 mg orally once daily (N=449). Dose reductions to 30 mg orally once daily or 15 mg orally once daily were allowed for the management of adverse reactions. After approximately 2 years of follow-up, patients who were still taking a 45 mg orally once daily dose were recommended to undergo a dose reduction in response to the continued occurrence of AOEs and VTEs in the clinical trial [see Special warnings and precautions for use (4.4)]. At study completion (60 months of follow-up), the median duration of treatment with Iclusig was 32 months in patients with CP-CML, 19 months in patients with AP-CML, 2.9 months in patients with BP-CML, and 2.7 months in patients with Ph+ ALL.
Serious adverse reactions occurred in 69% of patients who received Iclusig. Serious adverse reactions in >2% of patients included AOEs (20%), pneumonia (10%), cardiac arrhythmias (8%), pancreatitis/lipase elevation (7%), abdominal pain (6%), cardiac failure (6%), hemorrhage (6%), sepsis (5%), VTEs (5%), fluid retention and edema (4.5%), pyrexia (4.5%), secondary malignancies (5%), anemia (3.3%), hypertension (3.1%), thrombocytopenia (3.1%), febrile neutropenia (2.9%), cellulitis (2.7%), and arthralgia (2.2%). Fatal adverse reactions occurred in 9% of patients who received Iclusig; the most frequent fatal adverse reactions were AOEs (2%), sepsis (1.6%), and hemorrhage (1.3%).
Permanent discontinuation of Iclusig due to an adverse reaction occurred in 21% of CP-CML, 12% of AP-CML, 15% of BP-CML, and 9% of Ph+ ALL patients. The most frequent adverse reactions that led to treatment discontinuation were thrombocytopenia (4.5%) and AOEs (4%).
Dose interruption of Iclusig for more than 3 days due to an adverse reaction occurred in 71% of patients and dose reduction of Iclusig due to an adverse reaction occurred in 68% of patients. Adverse reactions which required a dosage interruption or dose reduction in >5% of patients included thrombocytopenia (31%), pancreatitis/lipase elevation (17%), abdominal pain (14%), rash and related conditions (14%), neutropenia (14%), hepatic dysfunction (12%), AOEs (10%), arthralgia (8%), anemia (7%), ALT increased (6%), and AST increased (5%).
The most common (>20%) non-hematologic adverse reactions were rash and related conditions, arthralgia, abdominal pain, fatigue, constipation, headache, dry skin, fluid retention and edema, hepatic dysfunction, hypertension, pyrexia, nausea, hemorrhage, pancreatitis/lipase elevation, AOEs, diarrhea, vomiting, and myalgia.

Table 6 summarizes the adverse reactions in PACE.

Graded using CTCAE v4.03.
(a) Oral mucositis includes aphthous ulcer, gingival pain, lip blister, lip pain, lip swelling, mouth ulceration, oropharyngeal pain, oral mucosal blistering, oral mucosal eruption, oral pain, pharyngeal ulceration, stomatitis, and tongue ulceration
(b) Derived from blood pressure (BP) measurement
(c) Cough includes cough, productive cough, and upper airway cough syndrome
(d) Dyspnea includes dyspnea and dyspnea exertional
(e) Upper respiratory tract infection includes upper respiratory tract infection and viral upper respiratory tract infection
(f) Urinary tract infection includes escherichia urinary tract infection, urinary tract infection, and urinary tract infection bacterial
(g) Sepsis includes abdominal sepsis, bacteremia, device-related sepsis, escherichia bacteremia, fungemia, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal sepsis, streptococcal bacteremia, and urosepsis
Clinically relevant adverse reactions occurring in ≤10% of patients: impaired glucose tolerance (9%)*, venous thromboembolic events (6%)*, secondary malignancies* (6%), and hypothyroidism (3%).
* Grouped terms: secondary malignancies includes basal cell carcinoma, squamous cell carcinoma of the skin, melanoma, chronic myelomonocytic leukemia, colon cancer, epithelioid mesothelioma, large cell lung cancer recurrent, lung neoplasm, malignant ascites, myelodysplastic syndrome, neuroendocrine carcinoma metastatic, non-Hodgkin lymphoma, pancreatic cancer, thyroid neoplasm, vulval cancer; venous thromboembolic events includes deep vein thrombosis, pulmonary embolism, retinal vein occlusion, retinal vein thrombosis, superficial thrombophlebitis, venous embolism, venoocclusive liver disease, portal vein thrombosis; impaired glucose tolerance includes blood glucose increased, diabetes mellitus, glucose tolerance impaired, glycosylated hemoglobin increased, hyperglycemia, insulin resistance, and type 2 diabetes mellitus

Tables 7 and 8 summarize the Grade 3 or 4 hematologic laboratory abnormalities or all grades non-hematologic abnormalities in PACE.

* Graded using CTCAE v4.03

ALT = alanine aminotransferase, AST = aspartate aminotransferase
* Graded using CTCAE v4.03

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

Blood and Lymphatic System Disorders: Thrombotic microangiopathy
Endocrine Disorders: Hyperthyroidism
Gastrointestinal Disorders: Gastrointestinal perforation, fistula
Metabolism and nutrition disorders: Dehydration
Nervous system disorders: Reversible posterior leukoencephalopathy syndrome (RPLS) – also known as Posterior Reversible Encephalopathy Syndrome (PRES)
Skin and subcutaneous tissue disorders: Severe cutaneous reaction (e.g. Erythema multiforme, Stevens-Johnson syndrome), impaired wound healing
Vascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

To Report Any Side Effect(s):

Overdoses with Iclusig were reported in clinical trials. One patient was estimated to have been administered 540mg via nasogastric tube. Two hours after the overdose, the patient had an uncorrected QT interval of 520 ms. Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 ms and 400 ms. The patient died 9 days after the overdose from pneumonia and sepsis. Another patient self-administered 165 mg on Cycle 1 Day 2. The patient experienced fatigue and non-cardiac chest pain on Day 3. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion.
In the event of an overdose, stop Iclusig, observe the patient and provide supportive treatment as appropriate.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01XE24
Mechanism of Action:
Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 nM and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 nM and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I. In mice, treatment with ponatinib reduced the size of tumors expressing native or T315I mutant BCR-ABL when compared to controls.

Pharmacodynamic effects
In PACE, the dose intensity-safety relationship indicated that there are significant increases in Grade ≥3 adverse reactions (hypertension, thrombocytopenia, pancreatitis, neutropenia, rash, ALT increase, AST increase, lipase increase, myelosuppression) over the dose range of 15 mg to 45 mg. In addition to dose, increased age and history of ischemia, hypertension, diabetes, or hypercholesterolemia were also contributory factors to a higher incidence of AOEs.
In OPTIC, an exposure-response relationship between ponatinib exposure and molecular response rate at 12 months was observed. A relationship between higher ponatinib exposures and higher incidence of adverse reactions, including thrombocytopenia (Grade ≥3) and AOEs, was observed.
In vitro, there was no significant inhibition of platelet aggregation with ponatinib at concentrations seen clinically and up to 0.7 mcg/mL (1.23 μM).

Cardiac Electrophysiology
The QT interval prolongation potential of Iclusig was assessed in 39 patients with cancer who received Iclusig 30 mg, 45 mg, or 60 mg (0.67 to 1.33 times the approved recommended starting dose) orally once daily. No large mean increase (i.e., >20 msec) in QTc interval was detected.

Clinical efficacy and safety
Chronic Phase (CP) CML The efficacy of Iclusig was evaluated in OPTIC (NCT02467270), a dose-optimization trial. Eligible patients had CP-CML whose disease was considered to be resistant or resistant/intolerant to at least 2 prior kinase inhibitors or who have the T315I mutation. Resistance in CP-CML while on a prior kinase inhibitor was defined as failure to achieve either a complete hematologic response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months), or development of a new BCR-ABL1 kinase domain mutation or new clonal evolution. Patients were required to have >1% BCR-ABL1IS (by real-time polymerase chain reaction) at trial entry. Patients

received one of three starting dosages: 45 mg orally once daily, 30 mg orally once daily, or 15 mg orally once daily. Patients who received a starting dose of 45 mg or 30 mg had a dose reduction to 15 mg once daily upon achieving ≤1% BCR-ABL1IS. The major efficacy outcome measure was ≤1% BCR-ABL1IS at 12 months. At the time of analysis, the median duration of follow-up for the 45 mg cohort was 28.5 months. Only the efficacy results for the recommended starting dose of 45 mg are described below.
A total of 282 patients received Iclusig: 94 received a starting dose of 45 mg, 94 received a starting dose of 30 mg, and 94 received a starting dose of 15 mg. Baseline demographic characteristics are described in Table 9 for patients who received a starting dose of 45 mg.

Efficacy results are summarized in Table 10.

(a) ITT population (N=93) defined as patients who had b2a2/b3a2 BCR ABL1 transcripts.
(b) Primary endpoint was ≤1% BCR-ABL1IS rate at 12 months. Defined as a ≤1% ratio of BCR ABL to ABL transcripts on the International Scale (IS) (i.e., ≤1% BCR-ABLIS; patients must have the b2a2/b3a2 (p210) transcript), in peripheral blood measured by quantitative reverse transcriptase polymerase chain reaction (qRT PCR).
(c) 95% CI is calculated using the binomial exact (Clopper-Pearson) method.
(d) Five patients were excluded from the analysis as they had not reached the 12 month timepoint in the study.
(e) Of the 88 patients, two patients did not have a baseline mutation assessment and were excluded from the response by mutation analysis.
(f) Secondary endpoint was MCyR by 12 months which combines both complete (no detectable Ph+ cells) and partial (1% to 35% Ph+ cells in at least 20 metaphases) cytogenetic responses.
(g) Analysis is based on ITT cytogenetic population (N = 92) defined as patients who had a cytogenetic assessment at baseline with at least 20 metaphases examined. Five patients who had not reached 12 month timepoint in the study and one patient who had a complete cytogenetic response at baseline were excluded from the analysis.
(h) Of the 86 patients, one patient did not have a baseline mutation assessment and was excluded from the response by mutation analysis.

At the time of analysis, 73% of patients maintained response at the reduced dose of 15 mg. Median duration of response (MR2) was not reached.
Chronic Phase (CP), Accelerated Phase (AP), Blast Phase (BP) CML and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
The efficacy of Iclusig was evaluated in PACE (NCT01207440), a single-arm, open-label, international, multicenter trial. Eligible patients had CML and Ph+ ALL whose disease was considered to be resistant or intolerant to a prior kinase inhibitor. Patients were assigned to one of six cohorts based on disease phase (CP-CML, AP-CML, or BP-CML/Ph+ ALL), resistance or intolerance (R/I) to prior kinase inhibitors, and the presence of the T315I mutation.

Resistance in CP-CML while on a prior kinase inhibitor was defined as failure to achieve either a complete hematologic response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months). Patients with CP-CML who experienced a loss of response or development of a kinase domain mutation in the absence of a complete cytogenetic response or progression to AP-CML or BP-CML at any time on a prior kinase inhibitor were also considered resistant.
Resistance in AP-CML, BP-CML, and Ph+ ALL was defined as failure to achieve either a major hematologic response (by 3 months in AP-CML, and by 1 month in BP-CML and Ph+ ALL), loss of major hematologic response (at any time), or development of a kinase domain mutation in the absence of a complete major hematologic response while on a prior kinase inhibitor. Intolerance was defined as the discontinuation of a prior kinase inhibitor due to toxicities despite optimal management in the absence of a complete cytogenetic response in patients with CP-CML or major hematologic response for patients with AP-CML, BP-CML, or Ph+ ALL.
Patients were administered a starting dose of Iclusig 45 mg orally once daily.
The major efficacy outcome measure for patients with CP-CML was major cytogenetic response (MCyR), which included complete and partial cytogenetic responses (CCyR and PCyR). The major efficacy outcome measure for patients with AP-CML, BP-CML, and Ph+ ALL was major hematologic response (MaHR), defined as either a complete hematologic response (CHR) or no evidence of leukemia (NEL).
The trial enrolled 449 patients, of which 444 were eligible for efficacy analysis: 267 patients with CP-CML (R/I Cohort: N = 203, T315I: N = 64), 83 patients with AP-CML, 62 patients with BP-CML, and 32 patients with Ph+ ALL. Five patients were not eligible for efficacy analysis due to lack of confirmation of T315I mutation status, and these patients had not received prior dasatinib or nilotinib.
At study completion, the median duration of follow-up for the trial (all cohorts) was 40.5 months (range: 0.1 months to 79.5 months). The median duration of treatment was 35 months for patients with CP-CML, 21.1 months for patients with AP-CML, 3.2 months for patients with BP-CML and 2.9 months for patients with Ph+ ALL. Baseline demographic characteristics are described in Table 11.

* Of the patients with one or more BCR-ABL kinase domain mutations detected at entry, 37 unique mutations were detected.
Efficacy results are summarized in Table 12 and Table 13.

(a) Primary endpoint for CP-CML cohorts was MCyR by 12 months, which combines both complete (no detectable Ph+ cells) and partial (1% to 35% Ph+ cells in at least 20 metaphases) cytogenetic responses.

(b) Secondary endpoint for CP-CML cohorts was MMR (proportion of patients who met the criteria for MMR at least once after the initiation of study treatment) measured in peripheral blood. Defined as a ≤0.1% ratio of BCR-ABL to ABL transcripts on the International Scale (IS) (i.e., ≤0.1% BCR-ABLIS; patients must have the b2a2/b3a2 (p210) transcript), in peripheral blood measured by quantitative reverse transcriptase polymerase chain reaction (qRT PCR).
In patients with CP-CML who achieved MCyR or MMR, the median time to response was 3 months (range: 1.8 to 12.3 months) and 6 months (range: 2 to 60.2 months), respectively. With a minimum follow-up of 60 months, the median durations of MCyR (range: 1 day to 70.1 months) and MMR (range: 1 day to 67.8 months) had not yet been reached.

(a) Primary endpoint for patients with AP-CML, BP-CML, and Ph+ ALL was MaHR by 6 months, which combines complete hematologic responses and no evidence of leukemia.
(b) CHR: WBC ≤ institutional ULN, ANC ≥1000/mm3, platelets ≥100,000/mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils <5% in peripheral blood, no extramedullary involvement (including no hepatomegaly or splenomegaly)

The median time to MaHR in patients with AP-CML, BP-CML, and Ph+ ALL was 0.7 months (range: 0.4 to 5.8 months), 1.0 month (range 0.4 to 3.7 months), and 0.7 months (range: 0.4 to 5.5 months), respectively. The median duration of MaHR for patients with AP-CML, BP-CML, and Ph+ ALL was 12.9 months (range: 1.2 to 52+ months), 6.0 months (range: 1.8 to 47.4+ months), and 3.2 months (range: 1.8 to 12.8+ months), respectively.

Ponatinib administered to patients with cancer exhibited approximately dose proportional increases in both steady-state Cmax and AUC over the dose range of 2 mg to 60 mg (0.04 to 1.33 times the approved recommended starting dose). The mean (CV%) Cmax and AUC(0-24) of Iclusig 45 mg orally once daily at presumed steady-state in patients with advanced hematologic malignancies were 73 ng/mL (74%) and 1253 ng•hr/mL (73%), respectively. Exposure increased by approximately 90% (median) [range: 20% to 440%] between the first dose and presumed steady-state.
Absorption
The absolute bioavailability of ponatinib is unknown. Peak concentrations of ponatinib are observed within 6 hours after Iclusig oral administration.
Effect of Food: Following ingestion of either a high-fat (approximately 900 to 1000 calories with approximately 150, 250, and 500 to 600 calories derived from protein, carbohydrate, and fat, respectively) or low-fat meal (approximately 547 calories with approximately 56, 428 and 63 calories derived from protein, carbohydrate, and fat, respectively) by 22 healthy volunteers, plasma ponatinib exposures (AUC and Cmax) were not different when compared to fasting conditions.
Distribution
Ponatinib is greater than 99% bound to plasma proteins in vitro. There was no plasma protein binding displacement of ponatinib (145 nM) in vitro by other highly protein bound medications (ibuprofen, nifedipine, propranolol, salicylic acid, and warfarin). The mean (CV%) apparent steady-state volume of distribution is 1,223 liters (102%) following oral administration of Iclusig 45 mg orally once daily for 28 days in patients with cancer.
Elimination
The mean (range) terminal elimination half-life of ponatinib was approximately 24 (12 to 66) hours following Iclusig 45 mg orally once daily for 28 days in patients with cancer.

Metabolism
At least 64% of a dose undergoes Phase I and Phase II metabolism. CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the Phase I metabolism of ponatinib in vitro. Ponatinib is also metabolized by esterases and/or amidases.
Excretion
Following a single oral dose of radiolabeled ponatinib, approximately 87% of the radioactive dose was recovered in the feces and approximately 5% in the urine.
Specific Populations
No clinically significant differences in the pharmacokinetics of ponatinib were observed based on age (19 to 85 years), body weight (41 to 152 kg), and mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min, estimated by the Cockcroft-Gault equation).
Hepatic Impairment
A single 30 mg oral dose of Iclusig was administered to subjects with normal hepatic function and to subjects with mild [Child-Pugh A], moderate [Child-Pugh B], and severe [Child-Pugh C] hepatic impairment. Compared to subjects with normal hepatic function, there was no trend of increased ponatinib exposure in subjects with hepatic impairment. There was an increased incidence of adverse reactions (e.g., gastrointestinal disorders, including a case of severe pancreatitis) in subjects with hepatic impairment compared to subjects with normal hepatic function.
Renal Impairment
Iclusig has not been studied in patients with severe renal impairment. Although renal excretion is not a major route of ponatinib elimination, the potential for severe renal impairment to affect hepatic elimination has not been determined.

Drug Interaction Studies
Clinical Studies
Strong CYP3A Inhibitors: Coadministration of ponatinib with multiple doses of ketoconazole (strong CYP3A inhibitor) increased the ponatinib AUC0-INF by 78% and Cmax by 47%.
Strong CYP3A Inducers: Coadministration of ponatinib with multiple doses of rifampin (strong CYP3A inducer) decreased the ponatinib AUC0-INF by 62% and Cmax by 42%.
Gastric Acid Reducing Agents: Coadministration of ponatinib with multiple doses of lansoprazole (proton pump inhibitor) decreased the ponatinib AUC0-INF by 6% and Cmax by 25%.
In Vitro Studies
CYP Enzymes: Ponatinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, or CYP2D6 and does not induce CYP1A2, CYP2B6, or CYP3A.
Transporter Systems: Ponatinib is a weak substrate for both P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Ponatinib is not a substrate for organic anion transporting polypeptides (OATP1B1, OATP1B3) and organic cation transporter 1 (OCT1).
Ponatinib inhibits P-gp, BCRP, and bile salt export pump (BSEP). Ponatinib does not inhibit OATP1B1, OATP1B3, OCT1, OCT2, or the organic anion transporters OAT1 and OAT3.

In a 2-year carcinogenicity study, male and female rats were administered daily oral doses of ponatinib of 0.05 mg/kg/day, 0.1 mg/kg/day, 0.2 mg/kg/day and 0.2 mg/kg/day, 0.4 mg/kg/day, and 0.8 mg/kg/day, respectively. Exposures in animals at the highest dose tested were 0.3- to 0.8-fold the human exposure (based on AUC) at doses of 15 mg and 45 mg daily. Ponatinib induced a statistically

significant increase in malignant squamous neoplasms of the clitoral gland in females at 0.8 mg/kg/day.
Ponatinib was not mutagenic in a bacterial mutagenesis (Ames) assay, was not clastogenic in a chromosome aberration assay in human lymphocytes, nor was it clastogenic in an in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg.
Ponatinib may impair female fertility. In a fertility study in male and female rats, female fertility parameters were reduced at 1.5 mg/kg/day with exposure equivalent to 0.43 times and 1.23 times, of human daily steady state AUC at the recommended dose of 45 mg/day (AUC = 1296 h·ng/mL) and 15 mg/day (451.8 h·ng/mL), respectively. Evidence of pre- and postimplantation loss of embryos was observed in female rats. Although there were no effects on male fertility parameters in the rat fertility study, repeat dose toxicology studies in monkeys showed degeneration of epithelium of the testes in monkeys at exposures approximately 3.3 times the plasma drug exposure (AUC) in patients receiving the recommended dose of 45 mg/day.

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 mg/kg/day, 1.5 mg/kg/day, 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.

Tablet core
Lactose monohydrate
Microcrystalline cellulose
Sodium starch glycolate (type B)
Colloidal silicon dioxide
Magnesium stearate
Tablet coating
Talc
Polyethylene glycol
Polyvinyl alcohol
Titanium dioxide

Not applicable

Do not store above 30° C. Keep away from children.

Iclusig 15 mg film-coated tablets
30 tablets in a wide-mouth white, high density polyethylene (HDPE) bottle with a dessicant canister and induction sealed child resistant closure.
Iclusig 45 mg film-coated tablets
30 tablets in a wide-mouth white, high density polyethylene (HDPE) bottle with a dessicant canister and induction sealed child resistant closure.
Not all pack sizes may be marketed

Disposal
No special requirements for disposal.