Limitations of Use: Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML [see Warnings and Precautions (5.7)].

2.1 Recommended Dosage

2.2 Dosage Modifications for Adverse Reactions

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

2.3 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 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

2.4 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) [see Use in Specific Populations (8.6)].

5.1 Arterial Occlusive Events

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

Of the 94 patients who received a starting dose of 45 mg (45 mg → 15 mg) in OPTIC, 14% experienced AOEs, of which 7%, 4.3%, and 2.1% experienced cardiovascular, cerebrovascular or peripheral vascular AOEs, respectively. The median time to onset of the first cardiovascular, cerebrovascular, or peripheral vascular event was 4.7 months (range: 12 days to 2.1 years), 11.7 months (range 15 days to 1.6 years), and 3.6 months (range: 23 days to 6.3 months), respectively. Grade 3 or 4 AOEs occurred in 6% of patients; the most frequent Grade 3 or 4 AOEs were myocardial infarction, acute coronary syndrome, arterial thrombosis, ischemic stroke, ischemic cerebral infarction, and unstable angina (1.1% each). Fatal AOEs occurred in 2 patients (2.1%); both of which were sudden death. AOEs were more frequent with increasing age [see Use in Specific Populations (8.5)].

In PACE, 26% of 449 patients experienced AOEs, of which 15%, 7%, and 11% experienced cardiovascular, cerebrovascular, and peripheral vascular AOEs, respectively. Some patients experienced recurrent or multisite vascular occlusion. The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular AOEs was 1 year (range: 1 day to 4.1 years), 1.4 years (range: 2 days to 4.5 years), and 2 years (range: 10 days to 4.9 years), respectively. Grade 3 or 4 AOEs occurred in 14% of patients; the most frequent Grade 3 or 4 AOEs were peripheral arterial occlusive disease (3.1%), myocardial infarction (2%), coronary artery disease (1.6%), and cerebral infarction (1.6%). Fatal AOEs occurred in 9 patients (2%); the most frequent fatal AOE was cardiac arrest (0.9%).

In PACE, fatal and life-threatening AOEs occurred within 2 weeks of starting treatment at 45 mg, and at dose levels as low as 15 mg per day. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced AOEs. AOEs were more frequent with increasing age [see Use in Specific Populations (8.5)] and in patients with history of ischemia, hypertension, diabetes, or hypercholesterolemia. The most common risk factors in patients with AOEs were history of hypertension (67%; 77/115), hypercholesterolemia (59%; 68/115), and non-ischemic cardiac disease (43%; 49/115).

In PACE, patients developed heart failure concurrent or subsequent to a myocardial ischemic event [see Warnings and Precautions (5.3)]. Patients required revascularization procedures (coronary, cerebrovascular, and peripheral arterial). Iclusig caused stenosis over multiple segments in major arterial vessels that supply the brain (e.g., carotid, vertebral, middle cerebral artery). Patients developed digital or distal extremity necrosis and required amputations. Renal artery stenosis associated with worsening, labile or treatment-resistant hypertension occurred in some Iclusig-treated patients [see Warnings and Precautions (5.5)].

In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, congestive heart failure, venous thromboembolism, or clinically significant atrial/ventricular arrhythmias, were excluded. In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease, including any history of clinically significant atrial/ventricular arrhythmias or history of myocardial infarction, unstable angina, or congestive heart failure within the 3 months prior to the first dose of Iclusig, were excluded [see Adverse Reactions (6.1)]. Consider whether the benefits of Iclusig are expected to exceed the risks.

Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue Iclusig based on recurrence/severity [see Dosage and Administration (2.2)]. Consider benefit-risk to guide a decision to restart Iclusig.

5.2 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 Dosage and Administration (2.2)].

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

Fatal or serious heart failure occurred in PACE. Heart failure events occurred in 9% of 449 patients; 7% experienced serious or severe (Grade 3 or higher) heart failure. The most frequently reported heart failure events (≥2%) were congestive cardiac failure (3.1%) and decreased ejection fraction (2.9%), and cardiac failure (2%).

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

5.4 Hepatotoxicity

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 28% of patients; 6% experienced Grade 3 or 4 hepatotoxicity. The median time to onset of hepatotoxicity was 1.9 months, with a range of 3 days to 4.1 years. The most frequent hepatotoxic events were elevations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and gamma-glutamyl transferase (GGT). In 29% of the 21 patients who reported ALT or AST elevation, the event was not resolved by the date of last follow-up.

In PACE, hepatotoxicity occurred in 32% of 449 patients; 13% experienced Grade 3 or 4 hepatotoxicity. The median time to onset of hepatotoxicity was 3.1 months, with a range of 1 day to 4.9 years. The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. In 9% of the 88 patients who reported ALT or AST elevation, the event was not resolved by the date of last follow-up.

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

5.5 Hypertension

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; 12% experienced serious or severe hypertension. Based on vital sign data, Grade 1 blood pressure elevation occurred in 8 out of 18 (44%) patients with normal initial blood pressure, Grade 2 occurred in 28 out of 81 (35%) patients with initial blood pressure of less than Grade 2, and Grade 3 occurred in 18 out of 92 (20%) patients with initial blood pressure of less than Grade 3. Three patients (3.2%) experienced hypertensive crisis.

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

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

5.6 Pancreatitis

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). In two patients with clinical pancreatitis that led to dose modification or treatment discontinuation, pancreatitis resolved within 2 weeks. Laboratory abnormalities of amylase elevation occurred in 11% of patients, while lipase elevation occurred in 34% of patients.

In PACE, pancreatitis occurred in 26% of 449 patients; 17% experienced serious or severe (Grade 3 or 4) pancreatitis. Pancreatitis resulted in discontinuation in 0.4% of patients and interruption and/or dose reduction in 17% of patients. The median time to onset of pancreatitis was 29 days (range: 1 day to 4 years). Nineteen of the 28 cases of clinical pancreatitis that led to dose modification or treatment discontinuation resolved within 2 weeks. Laboratory abnormalities of amylase elevations occurred in 18% of patients, while lipase elevations occurred in 39% of patients.

Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on severity [see Dosage and Administration (2.2)]. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms.

5.7 Increased Toxicity in Newly Diagnosed Chronic Phase CML

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

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

5.8 Neuropathy

Of the 94 patients who received a starting dose of 45 mg in OPTIC, neuropathy occurred in 9% of patients. Peripheral neuropathy occurred in 6% of patients. The most frequently reported peripheral neuropathies were hypoesthesia (2.1%), muscular weakness (2.1%), and paresthesia (2.1%). Cranial neuropathy developed in 2 patients. The median time to onset of peripheral neuropathy and cranial neuropathy was 7.7 months (range: 1.5 months to 1.4 years) and 2.1 years (range: Day 1 to 4.2 years), respectively.

In PACE, neuropathy occurred in 22% of patients; 2.4% experienced Grade 3 or 4 neuropathy. Peripheral neuropathy occurred in 20% of 449 patients; 1.8% experienced Grade 3 or 4 peripheral neuropathy. The most frequent peripheral neuropathies were paresthesia (5%), neuropathy peripheral (4.5%), and hypoesthesia (3.6%). Cranial neuropathy developed in 3% of patients; 0.7% were Grade 3 or 4. The median time to onset of peripheral neuropathy and cranial neuropathy was 5.3 months (range: 1 day to 4.6 years) and 1.2 years (range: 18 days to 4 years), respectively.

Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity [see Dosage and Administration (2.2)].

5.9 Ocular Toxicity

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

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.

5.10 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 Warnings and Precautions (5.13)].

Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity [see Dosage and Administration (2.2)].

5.11 Fluid Retention

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

Of the 94 patients who received a starting dose of 45 mg in OPTIC, fluid retention occurred in 5% of patients. The most frequent fluid retention events were peripheral edema (2.1%) and pleural effusion (2.1%).

In PACE, fluid retention events occurred in 33% of 449 patients; 4.5% experienced serious fluid retention. One instance of brain edema was fatal. Serious fluid retention included pleural effusion (1.6%), pericardial effusion (1.6%), and angioedema (0.4%). The most frequent fluid retention events were peripheral edema (17%), pleural effusion (9%), pericardial effusion (4.2%) and peripheral swelling (3.8%).

Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity [see Dosage and Administration (2.2)].

5.12 Cardiac Arrhythmias

Of the 94 patients who received a starting dose of 45 mg in OPTIC, cardiac arrhythmias occurred in 16% of patients; 4.3% experienced Grade 3 or 4 cardiac arrhythmias. Grade 3 or 4 cardiac arrhythmias included atrial fibrillation, cardio-respiratory arrest, supraventricular extrasystoles, and syncope.

In PACE, cardiac arrhythmias occurred in 20% of 449 patients; 7% experienced Grade 3 or 4 cardiac arrhythmias. Ventricular arrhythmias occurred in 3.4% of the 89 patients who reported an arrhythmia, with one event being Grade 3 or 4. Symptomatic bradyarrhythmias that led to pacemaker implantation occurred in 1% of patients. Atrial fibrillation was the most frequent cardiac arrhythmia (8%), with 3.3% being Grade 3 or 4. Other Grade 3 or 4 arrhythmia events included syncope (2%), tachycardia and bradycardia (0.4% each), and QT interval prolongation, atrial flutter, sinus bradycardia, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, atrioventricular block complete, cardio-respiratory arrest, loss of consciousness, and sinus node dysfunction (0.2% each). For 31 patients, the arrythmia led to hospitalization.

Monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness) and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity.

5.13 Myelosuppression

Of the 94 patients who received a starting dose of 45 mg in OPTIC, neutropenia occurred in 55% (Grade 3 or 4 occurred in 22%), thrombocytopenia occurred in 65% (Grade 3 or 4 occurred in 31%), and anemia occurred in 35% of patients (Grade 3 or 4 occurred in 14%). The median time to onset of Grade 3 or 4 myelosuppression was 1.4 months (range: 1 day to 1.2 years).

In PACE, neutropenia occurred in 56% (Grade 3 or 4 occurred in 34%), thrombocytopenia occurred in 63% (Grade 3 or 4 occurred in 40%), and anemia occurred in 52% of patients (Grade 3 or 4 occurred in 20%). The incidence of myelosuppression was greater in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML. Severe myelosuppression (Grade 3 or 4) was observed early in treatment, with a median onset time of 29 days (range: 1 day to 4.1 years).

Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 × 109/L or platelets less than 50 × 109/L, interrupt Iclusig until ANC at least 1.5 × 109/L and platelets at least 75 × 109/L, then resume at same or reduced dose [see Dosage and Administration (2.2)].

5.14 Tumor Lysis Syndrome

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

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

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

5.15 Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS; also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received Iclusig. Patients can present with hypertension, seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis. Interrupt Iclusig until resolution. The safety of resumption of Iclusig in patients upon resolution of RPLS is unknown.

5.16 Impaired Wound Healing and Gastrointestinal Perforation

Impaired wound healing occurred in patients receiving Iclusig [see Adverse Reactions (6.2)]. Withhold Iclusig for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Iclusig after resolution of wound healing complications has not been established.

Gastrointestinal perforation or fistula occurred in patients receiving Iclusig [see Adverse Reactions (6.2)]. Permanently discontinue in patients with gastrointestinal perforation.

5.17 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 [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

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

The most common adverse reactions identified in the Highlights of the Prescribing Information are 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.

6.2 Postmarketing Experience

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

Blood and Lymphatic System Disorders: Thrombotic microangiopathy

Endocrine Disorders: Hyperthyroidism

Gastrointestinal Disorders: Gastrointestinal perforation, fistula

Metabolism and Nutrition Disorders: Dehydration

Nervous System Disorders: Reversible posterior leukoencephalopathy syndrome (RPLS)

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

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

7.1 Effects of Other Drugs on Iclusig

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

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

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

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 (27%) as compared with patients less than 65 years of age (47%). AOEs occurred in 38% (6/16) of patients 65 years and older and 9% (7/78) of patients less than 65 years of age [see Warnings and Precautions (5.1)].

Of the 449 patients who received Iclusig in PACE, 35% were 65 years and older and 8% were 75 years and older. In patients with CP-CML, patients aged 65 years and older had a lower major cytogenetic response rate (40%) as compared with patients less than 65 years of age (65%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients aged 65 years and older had a similar hematologic response rate (45%) as compared with patients less than 65 years of age (44%). AOEs occurred in 35% (54/155) of patients 65 years and older and in 21% (61/294) of patients less than 65 years of age [see Warnings and Precautions (5.1)].

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

8.6 Hepatic Impairment

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

12.1 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.

12.2 Pharmacodynamics

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).

12.3 Pharmacokinetics

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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 post-implantation 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.

Chronic Phase (CP) CML

The efficacy of Iclusig was evaluated in OPTIC (NCT02467270), a dose-optimization trial. Eligible patients had CP-CML whose disease was considered to be resistant or resistant/intolerant to at least 2 prior kinase inhibitors or who have the T315I mutation. T315I mutation testing was performed on peripheral blood by Sanger Sequencing of the p190 or p210 BCR-ABL region. Resistance in CP-CML while on a prior kinase inhibitor was defined as failure to achieve either a complete hematologic response (by 3 months), a minor cytogenetic response (by 6 months), or a major cytogenetic response (by 12 months), or development of a new BCR-ABL1 kinase domain mutation or new clonal evolution. Patients were required to have >1% BCR-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. The median duration of follow-up for the 45 mg cohort (N=94) was 27.0 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.

Of the 45 patients who had a dose reduction after achieving ≤1% BCR-ABL1IS, 28 patients (62%) maintained their response at the reduced dose for at least 90 days. Of these 28 patients, 18 patients (64%) maintained the response for at least one year. 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. T315I mutation testing was performed on peripheral blood by Sanger Sequencing of the p190 or p210 BCR-ABL region.

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

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

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

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

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

At study completion, the median duration of follow-up for the trial (all cohorts) was 40.5 months (range: 0.1 months to 79.5 months). The median duration of treatment was 35 months for patients with CP-CML, 21.1 months for patients with AP-CML, 3.2 months for patients with BP-CML and 2.9 months for patients with Ph+ ALL. Baseline demographic characteristics are described in Table 11.

Efficacy results are summarized in Table 12 and Table 13.

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.

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

Store Iclusig tablets at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Arterial Occlusive Events and Venous Thromboembolic Events

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

Heart Failure and Cardiac Arrhythmias

Inform patients of the possibility of heart failure, and abnormally slow or fast heart rates. Advise patients to contact their healthcare provider if they experience symptoms such as shortness of breath, chest pain, palpitations, dizziness, or fainting [see Warnings and Precautions (5.3, 5.12)].

Hepatotoxicity

Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their healthcare provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see Warnings and Precautions (5.4)].

Hypertension

Inform patients of the possibility of new or worsening of existing hypertension. Advise patients to contact their healthcare provider for elevated blood pressure or if symptoms of hypertension occur including confusion, headache, dizziness, chest pain, or shortness of breath [see Warnings and Precautions (5.5)].

Pancreatitis

Inform patients of the possibility of developing pancreatitis that may be accompanied by nausea, vomiting, abdominal pain, or abdominal discomfort, and to promptly report these symptoms [see Warnings and Precautions (5.6)].

Neuropathy

Inform patients of the possibility of developing peripheral or cranial neuropathy while being treated with Iclusig. Advise patients to report symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness [see Warnings and Precautions (5.8)].

Ocular Toxicity

Inform patients of the possibility of ocular toxicity while being treated with Iclusig. Advise patients to report symptoms of ocular toxicity, such as blurred vision, dry eye, or eye pain [see Warnings and Precautions (5.9)].

Hemorrhage

Inform patients of the possibility of serious bleeding and to immediately contact their healthcare provider with any signs or symptoms suggestive of hemorrhage such as unusual bleeding or easy bruising [see Warnings and Precautions (5.10)].

Fluid Retention

Inform patients of the possibility of developing fluid retention and to contact their healthcare provider for symptoms such as leg swelling, abdominal swelling, weight gain, or shortness of breath [see Warnings and Precautions (5.11)].

Myelosuppression

Inform patients of the possibility of developing low blood cell counts; inform patients to report immediately should fever develop, particularly in association with any suggestion of infection [see Warnings and Precautions (5.13)].

Tumor Lysis Syndrome

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

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

Inform patients of the possibility of developing Reversible Posterior Leukoencephalopathy Syndrome while being treated with Iclusig. Advise patients to report symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances [see Warnings and Precautions (5.15)].

Impaired Wound Healing and Gastrointestinal Perforation

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

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after the last dose [see Warnings and Precautions (5.17), Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during treatment with Iclusig and for 6 days after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise females of reproductive potential of the potential for reduced fertility from Iclusig [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Instructions for Taking Iclusig

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

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

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

Lactose

Inform patients that Iclusig tablets contain lactose monohydrate.