ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Arterial Occlusive Events [see Warnings and Precautions (5.1)] Venous Thromboembolic Events [see Warnings and Precautions (5.2)] Heart Failure [see Warnings and Precautions (5.3)] Hepatotoxicity [see Warnings and Precautions (5.4)] Hypertension [see Warnings and Precautions (5.5)] Pancreatitis [see Warnings and Precautions (5.6)] Neuropathy [see Warnings and Precautions (5.8)] Ocular Toxicity [see Warnings and Precautions (5.9)] Hemorrhage [see Warnings and Precautions (5.10)] Fluid Retention [see Warnings and Precautions (5.11)] Cardiac Arrhythmias [see Warnings and Precautions (5.12)] Myelosuppression [see Warnings and Precautions (5.13)] Tumor Lysis Syndrome [see Warnings and Precautions (5.14)] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.15)] Impaired Wound Healing and Gastrointestinal Perforation [see Warnings and Precautions (5.16)] Arterial Occlusive Events [see Warnings and Precautions (5.1)] Venous Thromboembolic Events [see Warnings and Precautions (5.2)] Heart Failure [see Warnings and Precautions (5.3)] Hepatotoxicity [see Warnings and Precautions (5.4)] Hypertension [see Warnings and Precautions (5.5)] Pancreatitis [see Warnings and Precautions (5.6)] Neuropathy [see Warnings and Precautions (5.8)] Ocular Toxicity [see Warnings and Precautions (5.9)] Hemorrhage [see Warnings and Precautions (5.10)] Fluid Retention [see Warnings and Precautions (5.11)] Cardiac Arrhythmias [see Warnings and Precautions (5.12)] Myelosuppression [see Warnings and Precautions (5.13)] Tumor Lysis Syndrome [see Warnings and Precautions (5.14)] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.15)] Impaired Wound Healing and Gastrointestinal Perforation [see Warnings and Precautions (5.16)] The most common (>20%) adverse reactions are 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 or laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-817-6468 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 pooled safety population of 543 patients with CML or Ph+ ALL who received Iclusig at 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 or laboratory abnormalities (>20%) were platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.. Previously Treated CP-CMLThe safety of Iclusig was evaluated in OPTIC [see Clinical Studies (14)]. Patients received one of three starting doses of Iclusig: 45 mg orally once daily (n=94), 30 mg orally once daily (n=94) or 15 mg orally once daily (n=94). Patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, congestive heart failure, venous thromboembolism, or clinically significant atrial/ventricular arrhythmias, were excluded. Only the safety information for the recommended starting dosage (45 mg) is described below. Patients who received starting dose of Iclusig 45 mg orally once daily had mandatory dose reduction to 15 mg once daily upon achievement of <=1% BCR-ABL1IS. Of these patients, 70% were exposed for 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 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 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 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 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 or laboratory abnormalities were platelet count decreased and neutrophil cell count decreased.Table summarizes the adverse reactions in OPTIC for patients who received Iclusig at starting dose of 45 mg.Table 4: Adverse Reactions (>=10%) in Patients with CP-CML Who Received Iclusig at Starting Dose of 45 mg Followed by Reduction to 15 mg After Achievement of <=1% BCR-ABL1IS in OPTICAdverse ReactionIclusig 45 mg -> 15 mg(N 94)All Grades(%)Grade or 4(%)Graded using CTCAE v5.0Skin and Subcutaneous Tissue Disorders Rash and related conditions513.2 Dry Skin120Vascular Disorders Hypertension3210 Arterial occlusive events135 Hemorrhage122.1Musculoskeletal and Connective Tissue Disorders ArthralgiaArthralgia includes arthralgia, arthritis, back pain, intervertebral disc degeneration, osteoarthritis, pain, neck pain, pain in extremity, pain of skin, sciatica, spinal pain, tendonitis, tenosynovitis 280Metabolism and Nutrition Disorders HyperlipidemiaHyperlipidemia includes blood cholesterol increased, blood triglycerides increased, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, low density lipoprotein increased 282.1Gastrointestinal Disorders Abdominal PainAbdominal pain includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, chronic gastritis, colitis, enteritis, enterocolitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal pain, gastroesophageal reflux disease, Helicobacter gastritis 253.2 Pancreatitis/lipase elevation2315 Constipation110Hepatobiliary Disorders Hepatotoxicity256Nervous System Disorders Headache170General Disorders and Administration Site Conditions Pyrexia161.1 Fatigue or asthenia101.1Cardiac Disorders Cardiac arrhythmias154.3 Cardiac Failure121.1Clinically relevant adverse reactions in <=10% of patients who received Iclusig at starting dose of 45 mg: neuropathy (7%), fluid retention and edema (5%), and hypothyroidism (3.2%)Table summarizes the laboratory abnormalities in OPTIC for patients who received Iclusig at starting dose of 45 mg.Table 5: Select Laboratory Abnormalities (>20%) that Worsened from Baseline in Patients with CP-CML Who Received Iclusig at Starting Dose of 45 mg in OPTICLaboratory AbnormalityIclusig 45 mg -> 15 mg(N 94)All Grades(%)Grade or 4(%)ALT alanine aminotransferase, AST aspartate aminotransferaseGraded using CTCAE v5.0 (except glucose increased which is graded using CTCAE v4.03)Hematologic Laboratory Tests Platelet count decreased6531 White blood cell decreased5613 Neutrophil cell count decreased5322 Lymphocyte decreased427 Hemoglobin decreased3514Liver Function Tests ALT increased491.1 AST increased400 Alkaline phosphatase increased231.1Chemistry Glucose increased461.1 Triglycerides increased423.2 Phosphate decreased273.2 Bicarbonate decreased270Pancreatic Enzymes Lipase increased3412. Previously Treated CML or Ph+ ALLThe safety of Iclusig was evaluated in PACE [see Clinical Studies (14)]. Eligible patients had CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior kinase inhibitor, including those with the BCR-ABL T315I mutation. Patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease, including any history of clinically significant atrial/ventricular arrhythmias or history of myocardial infarction, unstable angina, or congestive heart failure within the months prior to the first dose of Iclusig, were excluded. Patients received 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 years of follow-up, patients who were still taking 45 mg orally once daily dose were recommended to undergo dose reduction in response to the continued occurrence of AOEs and VTEs in the clinical trial [see Warnings and Precautions (5.1)]. At study completion (60 months of follow-up), the median duration of treatment with Iclusig was 32 months in patients with CP-CML, 19 months in patients with AP-CML, 2.9 months in patients with BP-CML, and 2.7 months in patients with Ph+ ALL.Serious adverse reactions occurred in 69% of patients who received Iclusig. Serious adverse reactions in >2% of patients included AOEs (20%), pneumonia (10%), cardiac arrhythmias (8%), pancreatitis/lipase elevation (7%), abdominal pain (6%), cardiac failure (6%), hemorrhage (6%), sepsis (5%), VTEs (5%), fluid retention and edema (4.5%), pyrexia (4.5%), secondary malignancies (5%), anemia (3.3%), hypertension (3.1%), thrombocytopenia (3.1%), febrile neutropenia (2.9%), cellulitis (2.7%), and arthralgia (2.2%). Fatal adverse reactions occurred in 9% of patients who received Iclusig; the most frequent fatal adverse reactions were AOEs (2%), sepsis (1.6%), and hemorrhage (1.3%).Permanent discontinuation of Iclusig due to an adverse reaction occurred in 21% of CP-CML, 12% of AP-CML, 15% of BP-CML, and 9% of Ph+ ALL patients. The most frequent adverse reactions that led to treatment discontinuation were thrombocytopenia (4.5%) and AOEs (4%).Dose interruption of Iclusig for more than 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 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 summarizes the adverse reactions in PACE.Table 6: Adverse Reactions (>10%) in Patients with CML or Ph+ ALL Who Received Iclusig in PACE Adverse ReactionCP-CML(N 270)AP-CML(N 85)BP-CML(N 62)Ph+ ALL(N 32)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Graded using CTCAE v4.03.Skin and Subcutaneous Tissue Disorders Rash and related conditions7596812557503.1 Dry skin423.3321.2261.6250 Alopecia801108060Musculoskeletal and Connective Tissue Disorders Arthralgia619586524.8410 Myalgia241.121018060 Muscle spasms140704.80130 Bone pain140.4131.211393 Musculoskeletal pain111.5708.1063Gastrointestinal Disorders Abdominal pain54114994513346 Constipation422.6292.4270533.1 Pancreatitis/lipase elevation32192115191696 Nausea290.7320341.6220 Diarrhea200.7292.4243.2133.1 Vomiting191.5270271.6250 Oral mucositisOral 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 161.1201.224093.1General Disorders Fatigue or asthenia443.7478364.8343.1 Fluid retention and edema313.7373.5324.8416 Pyrexia261.1407373.2250 Chills80120131.690Nervous System Disorders Headache433.3311.2313.2250 Neuropathy263.3182.4130130 Dizziness170.41104.803.10Vascular Disorders HypertensionDerived from blood pressure (BP) measurement 423053284863125 Arterial occlusive events311722121310136 Hemorrhage23338123783113Hepatobiliary Disorders Hepatotoxicity3210391434191613Cardiac Disorders Cardiac arrhythmias197174.7248256 Cardiac failure9584.7161063.1Respiratory, Thoracic, and Mediastinal Disorders CoughCough includes cough, productive cough, and upper airway cough syndrome 19024021060 DyspneaDyspnea includes dyspnea and dyspnea exertional 193203.5236160Infections Upper respiratory tract infectionUpper respiratory tract infection includes upper respiratory tract infection and viral upper respiratory tract infection 141.1130131.63.10 Urinary tract infectionUrinary tract infection includes escherichia urinary tract infection, urinary tract infection, and urinary tract infection bacterial 122.2143.51.61.690 Nasopharyngitis1201803.203.10 Pneumonia84.8181118132216 Cellulitis4.41.983.5134.800 SepsisSepsis includes abdominal sepsis, bacteremia, device-related sepsis, escherichia bacteremia, fungemia, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal sepsis, streptococcal bacteremia, and urosepsis 2.61.91161862825Metabolism and Nutrition Disorders Decreased appetite130.4141.280310 Hyperlipidemia130.7703.203.10Investigations Weight decreased100.4904.80130Psychiatric Disorders Insomnia110130110130 Anxiety4.801808060Blood and Lymphatic System Disorders Febrile neutropenia1.11.14.74.713132525Clinically relevant adverse reactions occurring in <=10% of patients: impaired glucose tolerance (9%)Grouped terms: secondary malignancies includes basal cell carcinoma, squamous cell carcinoma of the skin, melanoma, chronic myelomonocytic leukemia, colon cancer, epithelioid mesothelioma, large cell lung cancer recurrent, lung neoplasm, malignant ascites, myelodysplastic syndrome, neuroendocrine carcinoma metastatic, non-Hodgkin lymphoma, pancreatic cancer, thyroid neoplasm, vulval cancer; venous thromboembolic events includes deep vein thrombosis, pulmonary embolism, retinal vein occlusion, retinal vein thrombosis, superficial thrombophlebitis, venous embolism, 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 diabetes mellitus, venous thromboembolic events (6%), secondary malignancies (6%), and hypothyroidism (3%).Tables and summarize the Grade or hematologic laboratory abnormalities or all grades non-hematologic abnormalities in PACE.Table 7: Select Grade or 4Graded using CTCAE v4.03 Hematologic Laboratory Abnormalities in Patients Who Received Iclusig in PACE Laboratory AbnormalityCP-CML(N 270)(%)AP-CML(N 85)(%)BP-CML(N 62)(%)Ph+ ALL(N 32)(%)HematologyPlatelet count decreased35494547Neutrophil cell count decreased23524859White blood cell decreased12374863Lymphocyte decreased10253219Hemoglobin decreased8315234Table 8: Select Non-Hematologic Laboratory Abnormalities (>=20%) in Patients Who Received Iclusig in PACELaboratory AbnormalityPooled Safety Population(N 449)All GradesGraded using CTCAE v4.03 (%)Grade or 4(%)ALT alanine aminotransferase, AST aspartate aminotransferaseChemistry Glucose increased547 Phosphate decreased3410 Calcium decreased300.9 Sodium decreased274.9 Creatinine increased210.2 Potassium increased202.2 Bicarbonate decreased200.2Liver Function Tests ALT increased416 Alkaline phosphatase increased402 AST increased353.6 Albumin decreased280.2 Bilirubin increased130.9Pancreatic Enzymes Lipase increased4014 Amylase increased183.6. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of Iclusig. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure:Blood and Lymphatic System Disorders: Thrombotic microangiopathyEndocrine Disorders: HyperthyroidismGastrointestinal Disorders: Gastrointestinal perforation, fistulaMetabolism and Nutrition Disorders: DehydrationNervous System Disorders: Reversible posterior leukoencephalopathy syndrome (RPLS) Skin and Subcutaneous Tissue Disorders: Severe cutaneous reaction (e.g., Erythema multiforme, Stevens-Johnson syndrome), impaired wound healingVascular Disorders: Arterial (including aortic) aneurysms, dissections, and rupture.

BOXED WARNING SECTION.

WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITY. WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITYSee full prescribing information for complete boxed warning.Arterial occlusive events (AOEs), including fatalities, have occurred in Iclusig-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue Iclusig based on severity. Consider benefit-risk to guide decision to restart Iclusig (2.2, 5.1).Venous thromboembolic events (VTEs) have occurred in Iclusig-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue Iclusig based on severity (2.2, 5.2).Heart failure, including fatalities, occurred in Iclusig-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue Iclusig for new or worsening heart failure (2.2, 5.3).Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor liver function tests. Interrupt or discontinue Iclusig based on severity (2.2, 5.4).. Arterial occlusive events (AOEs), including fatalities, have occurred in Iclusig-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue Iclusig based on severity. Consider benefit-risk to guide decision to restart Iclusig (2.2, 5.1).. Venous thromboembolic events (VTEs) have occurred in Iclusig-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue Iclusig based on severity (2.2, 5.2).. Heart failure, including fatalities, occurred in Iclusig-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue Iclusig for new or worsening heart failure (2.2, 5.3).. Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor liver function tests. Interrupt or discontinue Iclusig based on severity (2.2, 5.4).. Arterial Occlusive Events: Arterial occlusive events (AOEs), including fatalities, have occurred in Iclusig-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue Iclusig based on severity. Consider benefit-risk to guide decision to restart Iclusig [see Dosage and Administration (2.2) Warnings and Precautions (5.1)].. Arterial occlusive events (AOEs), including fatalities, have occurred in Iclusig-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue Iclusig based on severity. Consider benefit-risk to guide decision to restart Iclusig [see Dosage and Administration (2.2) Warnings and Precautions (5.1)].. Venous Thromboembolic Events:Venous thromboembolic events (VTEs) have occurred in Iclusig-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue Iclusig based on severity [see Dosage and Administration (2.2) Warnings and Precautions (5.2)].. Venous thromboembolic events (VTEs) have occurred in Iclusig-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue Iclusig based on severity [see Dosage and Administration (2.2) Warnings and Precautions (5.2)].. Heart Failure:Heart failure, including fatalities, occurred in Iclusig-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue Iclusig for new or worsening heart failure [see Dosage and Administration (2.2) Warnings and Precautions (5.3)].. Heart failure, including fatalities, occurred in Iclusig-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue Iclusig for new or worsening heart failure [see Dosage and Administration (2.2) Warnings and Precautions (5.3)].. Hepatotoxicity:Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor liver function tests. Interrupt or discontinue Iclusig based on severity [see Dosage and Administration (2.2) Warnings and Precautions (5.4)].. Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor liver function tests. Interrupt or discontinue Iclusig based on severity [see Dosage and Administration (2.2) Warnings and Precautions (5.4)].

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ponatinib is 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 higher incidence of AOEs.In OPTIC, an exposure-response relationship between ponatinib exposure and molecular response rate at 12 months was observed. 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 uM).. Cardiac ElectrophysiologyThe 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.. 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 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 nghr/mL (73%), respectively. Exposure increased by approximately 90% (median) [range: 20% to 440%] between the first dose and presumed steady-state.. AbsorptionThe absolute bioavailability of ponatinib is unknown. Peak concentrations of ponatinib are observed within hours after Iclusig oral administration.. Effect of Food: Following ingestion of either 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.. DistributionPonatinib 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.. EliminationThe 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.. MetabolismAt least 64% of dose undergoes Phase and Phase II metabolism. CYP3A4 and to lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the Phase metabolism of ponatinib in vitro. Ponatinib is also metabolized by esterases and/or amidases.. ExcretionFollowing single oral dose of radiolabeled ponatinib, approximately 87% of the radioactive dose was recovered in the feces and approximately 5% in the urine.. Specific PopulationsNo 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 ImpairmentA 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 case of severe pancreatitis) in subjects with hepatic impairment compared to subjects with normal hepatic function.. Renal ImpairmentIclusig has not been studied in patients with severe renal impairment. Although renal excretion is not 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 weak substrate for both P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Ponatinib is not substrate for organic anion transporting polypeptides (OATP1B1, OATP1B3) and organic cation transporter (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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Chronic Phase (CP) CMLThe efficacy of Iclusig was evaluated in OPTIC (NCT02467270), dose-optimization trial. Eligible patients had CP-CML whose disease was considered to be resistant or resistant/intolerant to at least prior kinase inhibitors or who have the T315I mutation. Resistance in CP-CML while on prior kinase inhibitor was defined as failure to achieve either complete hematologic response (by months), minor cytogenetic response (by months), or major cytogenetic response (by 12 months), or development of 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 starting dose of 45 mg or 30 mg had 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 starting dose of 45 mg, 94 received starting dose of 30 mg, and 94 received starting dose of 15 mg. Baseline demographic characteristics are described in Table for patients who received starting dose of 45 mg.Table 9: Demographic and Disease Characteristics for OPTICPatient Characteristics at EntryIclusig 45 mg -> 15 mg(N 94)Age Median years (range)46 (19 to 81)Sex, (%) Male50 (53%)Race, (%) White73 (78%) Asian16 (17%) Other/Unknown4 (4%) Black or African American1 (1%)ECOG Performance Status, (%) ECOG or 193 (99%)Disease History Median time from diagnosis to first dose, years (range)5.5 (1 to 21) Resistant to Prior Kinase Inhibitor, (%)92 (98%) Presence of one or more BCR-ABL kinase domain mutations, (%)41 (44%) Number of Prior Kinase Inhibitors, (%) 11 (1%) 243 (46%) >=350 (53%) T315I mutation at baseline25 (27%)Comorbidities Hypertension29 (31%) Diabetes5 (5%) Hypercholesterolemia3 (3%) History of ischemic heart disease3 (3%)Efficacy results are summarized in Table 10.Table 10: Efficacy Results in Patients with CP-CML Who Received Iclusig at Starting Dose of 45 mg in OPTICIclusig45 mg -> 15 mg(N 93)ITT population (N=93) defined as patients who had b2a2/b3a2 BCR ABL1 transcripts. Molecular Response at 12 monthsPrimary endpoint was <=1% BCR-ABL1IS rate at 12 months. Defined as <=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).Overall <=1% BCR-ABL1IS Rate% (n/N)42% (37/88)Five patients were excluded from the analysis as they had not reached the 12 month timepoint in the study. (95% CI)95% CI is calculated using the binomial exact (Clopper-Pearson) method. (32%, 53%) Patients with T315I mutation (n/N)42% (10/24) (95% CI)(22%, 63%) Patients without T315I mutation (n/N)42% (26/62)Of the 88 patients, two patients did not have baseline mutation assessment and were excluded from the response by mutation analysis. (95% CI)(30%, 55%)Cytogenetic Response by 12 monthsMajor (MCyR)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. (n/N)49% (42/86)Analysis is based on ITT cytogenetic population (N 92) defined as patients who had 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 complete cytogenetic response at baseline were excluded from the analysis. (95% CI)(38%, 60%) Patients with T315I mutation (n/N)50% (12/24) (95% CI)(29%, 71%) Patients without T315I mutation (n/N)48% (29/61)Of the 86 patients, one patient did not have baseline mutation assessment and was excluded from the response by mutation analysis. (95% CI)(36%, 61%)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), single-arm, open-label, international, multicenter trial. Eligible patients had CML and Ph+ ALL whose disease was considered to be resistant or intolerant to 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 prior kinase inhibitor was defined as failure to achieve either complete hematologic response (by months), minor cytogenetic response (by months), or major cytogenetic response (by 12 months). Patients with CP-CML who experienced loss of response or development of kinase domain mutation in the absence of complete cytogenetic response or progression to AP-CML or BP-CML at any time on prior kinase inhibitor were also considered resistant.Resistance in AP-CML, BP-CML, and Ph+ ALL was defined as failure to achieve either major hematologic response (by months in AP-CML, and by month in BP-CML and Ph+ ALL), loss of major hematologic response (at any time), or development of kinase domain mutation in the absence of complete major hematologic response while on prior kinase inhibitor. Intolerance was defined as the discontinuation of prior kinase inhibitor due to toxicities despite optimal management in the absence of 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 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 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: = 203, T315I: = 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.Table 11: Demographic and Disease Characteristics for PACEPatient Characteristics at EntryEfficacy Population(N 444)Age Median, years (range)59 (18 to 94)Sex, (%) Male236 (53%)Race, (%) White349 (79%) Asian57 (13%) Black or African American25 (6%) Other/Unknown13 (3%)ECOG Performance Status, (%) ECOG 0 or 1409 (92%)Disease History Median time from diagnosis to first dose, years (range)6.1 (0.3 to 29) Resistant to Prior Kinase Inhibitor, (%)374 (88%) Presence of one or more BCR-ABL kinase domain mutationsOf the patients with one or more BCR-ABL kinase domain mutations detected at entry, 37 unique mutations were detected., (%)244 (55%) Number of Prior Kinase Inhibitor, (%) 129 (7%) 2166 (37%) >=3249 (56%) T315I mutation at baseline128 (29%)Comorbidities Hypertension159 (35%) Diabetes57 (13%) Hypercholesterolemia100 (22%) History of ischemic disease67 (15%)Efficacy results are summarized in Table 12 and Table 13.Table 12: Efficacy of Iclusig in Patients with Resistant or Intolerant CP-CML in PACEOverall(N 267)CohortR/I Cohort(N 203)T315I Cohort(N 64)Cytogenetic Response Major 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. (MCyR) (95% CI)55%(49%, 62%)51%(44%, 58%)70%(58%, 81%) Complete (CCyR) (95% CI)46%(40%, 52%)40%(33%, 47%)66%(53%, 77%)Major Molecular Response 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 <=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). (95% CI)40%(35%, 47%)35%(28%, 42%)58%(45%, 70%)In patients with CP-CML who achieved MCyR or MMR, the median time to response was months (range: 1.8 to 12.3 months) and months (range: to 60.2 months), respectively. With minimum follow-up of 60 months, the median durations of MCyR (range: day to 70.1 months) and MMR (range: day to 67.8 months) had not yet been reached.Table 13: Efficacy of Iclusig in Patients with Resistant or Intolerant Advanced Disease (includes R/I and T315I Cohorts) in PACEAP-CML Overall(N 83)BP-CML Overall(N 62)Ph+ ALL Overall(N 32)Hematologic Response Major Primary endpoint for patients with AP-CML, BP-CML, and Ph+ ALL was MaHR by months, which combines complete hematologic responses and no evidence of leukemia. (MaHR)57%31%41% (95% CI)(45%, 68%)(20%, 44%)(24%, 59%) Complete 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) (CHR)51%21%34% (95% CI)(39%, 62%)(12%, 33%)(19%, 53%)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 months), and 0.7 months (range: 0.4 to 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.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 pooled safety population of 543 patients with CML or Ph+ ALL who received Iclusig at 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 or laboratory abnormalities (>20%) were platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.. Previously Treated CP-CMLThe safety of Iclusig was evaluated in OPTIC [see Clinical Studies (14)]. Patients received one of three starting doses of Iclusig: 45 mg orally once daily (n=94), 30 mg orally once daily (n=94) or 15 mg orally once daily (n=94). Patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, congestive heart failure, venous thromboembolism, or clinically significant atrial/ventricular arrhythmias, were excluded. Only the safety information for the recommended starting dosage (45 mg) is described below. Patients who received starting dose of Iclusig 45 mg orally once daily had mandatory dose reduction to 15 mg once daily upon achievement of <=1% BCR-ABL1IS. Of these patients, 70% were exposed for 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 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 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 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 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 or laboratory abnormalities were platelet count decreased and neutrophil cell count decreased.Table summarizes the adverse reactions in OPTIC for patients who received Iclusig at starting dose of 45 mg.Table 4: Adverse Reactions (>=10%) in Patients with CP-CML Who Received Iclusig at Starting Dose of 45 mg Followed by Reduction to 15 mg After Achievement of <=1% BCR-ABL1IS in OPTICAdverse ReactionIclusig 45 mg -> 15 mg(N 94)All Grades(%)Grade or 4(%)Graded using CTCAE v5.0Skin and Subcutaneous Tissue Disorders Rash and related conditions513.2 Dry Skin120Vascular Disorders Hypertension3210 Arterial occlusive events135 Hemorrhage122.1Musculoskeletal and Connective Tissue Disorders ArthralgiaArthralgia includes arthralgia, arthritis, back pain, intervertebral disc degeneration, osteoarthritis, pain, neck pain, pain in extremity, pain of skin, sciatica, spinal pain, tendonitis, tenosynovitis 280Metabolism and Nutrition Disorders HyperlipidemiaHyperlipidemia includes blood cholesterol increased, blood triglycerides increased, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, low density lipoprotein increased 282.1Gastrointestinal Disorders Abdominal PainAbdominal pain includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, chronic gastritis, colitis, enteritis, enterocolitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal pain, gastroesophageal reflux disease, Helicobacter gastritis 253.2 Pancreatitis/lipase elevation2315 Constipation110Hepatobiliary Disorders Hepatotoxicity256Nervous System Disorders Headache170General Disorders and Administration Site Conditions Pyrexia161.1 Fatigue or asthenia101.1Cardiac Disorders Cardiac arrhythmias154.3 Cardiac Failure121.1Clinically relevant adverse reactions in <=10% of patients who received Iclusig at starting dose of 45 mg: neuropathy (7%), fluid retention and edema (5%), and hypothyroidism (3.2%)Table summarizes the laboratory abnormalities in OPTIC for patients who received Iclusig at starting dose of 45 mg.Table 5: Select Laboratory Abnormalities (>20%) that Worsened from Baseline in Patients with CP-CML Who Received Iclusig at Starting Dose of 45 mg in OPTICLaboratory AbnormalityIclusig 45 mg -> 15 mg(N 94)All Grades(%)Grade or 4(%)ALT alanine aminotransferase, AST aspartate aminotransferaseGraded using CTCAE v5.0 (except glucose increased which is graded using CTCAE v4.03)Hematologic Laboratory Tests Platelet count decreased6531 White blood cell decreased5613 Neutrophil cell count decreased5322 Lymphocyte decreased427 Hemoglobin decreased3514Liver Function Tests ALT increased491.1 AST increased400 Alkaline phosphatase increased231.1Chemistry Glucose increased461.1 Triglycerides increased423.2 Phosphate decreased273.2 Bicarbonate decreased270Pancreatic Enzymes Lipase increased3412. Previously Treated CML or Ph+ ALLThe safety of Iclusig was evaluated in PACE [see Clinical Studies (14)]. Eligible patients had CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior kinase inhibitor, including those with the BCR-ABL T315I mutation. Patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease, including any history of clinically significant atrial/ventricular arrhythmias or history of myocardial infarction, unstable angina, or congestive heart failure within the months prior to the first dose of Iclusig, were excluded. Patients received 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 years of follow-up, patients who were still taking 45 mg orally once daily dose were recommended to undergo dose reduction in response to the continued occurrence of AOEs and VTEs in the clinical trial [see Warnings and Precautions (5.1)]. At study completion (60 months of follow-up), the median duration of treatment with Iclusig was 32 months in patients with CP-CML, 19 months in patients with AP-CML, 2.9 months in patients with BP-CML, and 2.7 months in patients with Ph+ ALL.Serious adverse reactions occurred in 69% of patients who received Iclusig. Serious adverse reactions in >2% of patients included AOEs (20%), pneumonia (10%), cardiac arrhythmias (8%), pancreatitis/lipase elevation (7%), abdominal pain (6%), cardiac failure (6%), hemorrhage (6%), sepsis (5%), VTEs (5%), fluid retention and edema (4.5%), pyrexia (4.5%), secondary malignancies (5%), anemia (3.3%), hypertension (3.1%), thrombocytopenia (3.1%), febrile neutropenia (2.9%), cellulitis (2.7%), and arthralgia (2.2%). Fatal adverse reactions occurred in 9% of patients who received Iclusig; the most frequent fatal adverse reactions were AOEs (2%), sepsis (1.6%), and hemorrhage (1.3%).Permanent discontinuation of Iclusig due to an adverse reaction occurred in 21% of CP-CML, 12% of AP-CML, 15% of BP-CML, and 9% of Ph+ ALL patients. The most frequent adverse reactions that led to treatment discontinuation were thrombocytopenia (4.5%) and AOEs (4%).Dose interruption of Iclusig for more than 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 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 summarizes the adverse reactions in PACE.Table 6: Adverse Reactions (>10%) in Patients with CML or Ph+ ALL Who Received Iclusig in PACE Adverse ReactionCP-CML(N 270)AP-CML(N 85)BP-CML(N 62)Ph+ ALL(N 32)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)All Grades(%)Grade or 4(%)Graded using CTCAE v4.03.Skin and Subcutaneous Tissue Disorders Rash and related conditions7596812557503.1 Dry skin423.3321.2261.6250 Alopecia801108060Musculoskeletal and Connective Tissue Disorders Arthralgia619586524.8410 Myalgia241.121018060 Muscle spasms140704.80130 Bone pain140.4131.211393 Musculoskeletal pain111.5708.1063Gastrointestinal Disorders Abdominal pain54114994513346 Constipation422.6292.4270533.1 Pancreatitis/lipase elevation32192115191696 Nausea290.7320341.6220 Diarrhea200.7292.4243.2133.1 Vomiting191.5270271.6250 Oral mucositisOral 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 161.1201.224093.1General Disorders Fatigue or asthenia443.7478364.8343.1 Fluid retention and edema313.7373.5324.8416 Pyrexia261.1407373.2250 Chills80120131.690Nervous System Disorders Headache433.3311.2313.2250 Neuropathy263.3182.4130130 Dizziness170.41104.803.10Vascular Disorders HypertensionDerived from blood pressure (BP) measurement 423053284863125 Arterial occlusive events311722121310136 Hemorrhage23338123783113Hepatobiliary Disorders Hepatotoxicity3210391434191613Cardiac Disorders Cardiac arrhythmias197174.7248256 Cardiac failure9584.7161063.1Respiratory, Thoracic, and Mediastinal Disorders CoughCough includes cough, productive cough, and upper airway cough syndrome 19024021060 DyspneaDyspnea includes dyspnea and dyspnea exertional 193203.5236160Infections Upper respiratory tract infectionUpper respiratory tract infection includes upper respiratory tract infection and viral upper respiratory tract infection 141.1130131.63.10 Urinary tract infectionUrinary tract infection includes escherichia urinary tract infection, urinary tract infection, and urinary tract infection bacterial 122.2143.51.61.690 Nasopharyngitis1201803.203.10 Pneumonia84.8181118132216 Cellulitis4.41.983.5134.800 SepsisSepsis includes abdominal sepsis, bacteremia, device-related sepsis, escherichia bacteremia, fungemia, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal sepsis, streptococcal bacteremia, and urosepsis 2.61.91161862825Metabolism and Nutrition Disorders Decreased appetite130.4141.280310 Hyperlipidemia130.7703.203.10Investigations Weight decreased100.4904.80130Psychiatric Disorders Insomnia110130110130 Anxiety4.801808060Blood and Lymphatic System Disorders Febrile neutropenia1.11.14.74.713132525Clinically relevant adverse reactions occurring in <=10% of patients: impaired glucose tolerance (9%)Grouped terms: secondary malignancies includes basal cell carcinoma, squamous cell carcinoma of the skin, melanoma, chronic myelomonocytic leukemia, colon cancer, epithelioid mesothelioma, large cell lung cancer recurrent, lung neoplasm, malignant ascites, myelodysplastic syndrome, neuroendocrine carcinoma metastatic, non-Hodgkin lymphoma, pancreatic cancer, thyroid neoplasm, vulval cancer; venous thromboembolic events includes deep vein thrombosis, pulmonary embolism, retinal vein occlusion, retinal vein thrombosis, superficial thrombophlebitis, venous embolism, 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 diabetes mellitus, venous thromboembolic events (6%), secondary malignancies (6%), and hypothyroidism (3%).Tables and summarize the Grade or hematologic laboratory abnormalities or all grades non-hematologic abnormalities in PACE.Table 7: Select Grade or 4Graded using CTCAE v4.03 Hematologic Laboratory Abnormalities in Patients Who Received Iclusig in PACE Laboratory AbnormalityCP-CML(N 270)(%)AP-CML(N 85)(%)BP-CML(N 62)(%)Ph+ ALL(N 32)(%)HematologyPlatelet count decreased35494547Neutrophil cell count decreased23524859White blood cell decreased12374863Lymphocyte decreased10253219Hemoglobin decreased8315234Table 8: Select Non-Hematologic Laboratory Abnormalities (>=20%) in Patients Who Received Iclusig in PACELaboratory AbnormalityPooled Safety Population(N 449)All GradesGraded using CTCAE v4.03 (%)Grade or 4(%)ALT alanine aminotransferase, AST aspartate aminotransferaseChemistry Glucose increased547 Phosphate decreased3410 Calcium decreased300.9 Sodium decreased274.9 Creatinine increased210.2 Potassium increased202.2 Bicarbonate decreased200.2Liver Function Tests ALT increased416 Alkaline phosphatase increased402 AST increased353.6 Albumin decreased280.2 Bilirubin increased130.9Pancreatic Enzymes Lipase increased4014 Amylase increased183.6.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended Dosage in CP-CML: Starting dose is 45 mg orally once daily with reduction to 15 mg once daily upon achievement of <=1% BCR-ABL1IS. (2.1)Recommended Dosage in AP-CML, BP-CML, and Ph+ ALL: Starting dose is 45 mg orally once daily. (2.1)Hepatic Impairment: Reduce the starting dose to 30 mg orally once daily. (2.4)Iclusig may be taken with or without food. (2.1). Recommended Dosage in CP-CML: Starting dose is 45 mg orally once daily with reduction to 15 mg once daily upon achievement of <=1% BCR-ABL1IS. (2.1). Recommended Dosage in AP-CML, BP-CML, and Ph+ ALL: Starting dose is 45 mg orally once daily. (2.1). Hepatic Impairment: Reduce the starting dose to 30 mg orally once daily. (2.4). Iclusig may be taken with or without food. (2.1). 2.1Recommended Dosage. CP-CMLThe recommended starting dosage is 45 mg orally once daily with reduction to 15 mg orally once daily upon achievement of <=1% BCR-ABL1IS. Patients with loss of response can re-escalate the dose of Iclusig to previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue Iclusig until loss of response at the re-escalated dose or unacceptable toxicity. Consider discontinuing Iclusig if hematologic response has not occurred by months. AP-CML, BP-CML, and Ph+ ALLThe optimal dose of Iclusig has not been identified. The recommended starting dosage of Iclusig is 45 mg orally once daily. Consider reducing the dose of Iclusig for patients with accelerated phase (AP) CML who have achieved major cytogenetic response. Continue Iclusig until loss of response or unacceptable toxicity.Consider discontinuing Iclusig if response has not occurred by months.. AdministrationAdvise patients of the following:Iclusig may be taken with or without food. Swallow tablets whole. Do not crush, break, cut or chew tablets.If dose is missed, take the next dose at the regularly scheduled time the next day.. Iclusig may be taken with or without food. Swallow tablets whole. Do not crush, break, cut or chew tablets.. If dose is missed, take the next dose at the regularly scheduled time the next day.. 2.2Dosage Modifications for Adverse Reactions. Recommended dosage modifications of Iclusig for adverse reactions are provided in Table and recommended dose reductions of Iclusig for adverse reactions are presented in Table 2.Table 1: Recommended Dosage Modifications for Iclusig for Adverse ReactionsAdverse ReactionSeverityIclusig Dosage ModificationsBased on CTCAE v5.0: Grade mild, Grade moderate, Grade severe, Grade life-threateningULN Upper Limit of Normal for the lab; AOE Arterial Occlusive Event; VTE Venous Thromboembolic Event; ANC absolute neutrophil countAOE: cardiovascular or cerebrovascular [see Warnings and Precautions (5.1)] Grade 1Interrupt Iclusig until resolved, then resume at same dose. Grade 2Interrupt Iclusig until Grade or 1, then resume at next lower dose.Discontinue Iclusig if recurrence.Grade or 4Discontinue Iclusig.AOE: peripheral vascular and otherorVTE [see Warnings and Precautions (5.1, 5.2)] Grade 1Interrupt Iclusig until resolved, then resume at same dose.Grade 2Interrupt Iclusig until Grade or 1, then resume at same dose.If recurrence, interrupt Iclusig until Grade or 1, then resume at next lower dose.Grade 3Interrupt Iclusig until Grade or 1, then resume at next lower dose.Discontinue Iclusig if recurrence.Grade 4Discontinue Iclusig.Heart Failure [see Warnings and Precautions (5.3)] Grade or 3Interrupt Iclusig until Grade or 1, then resume at next lower dose.Discontinue Iclusig if recurrence.Grade 4Discontinue Iclusig.Hepatotoxicity [see Warnings and Precautions (5.4)] AST or ALT greater than times ULNInterrupt Iclusig until Grade or 1, then resume at next lower dose.AST or ALT at least times ULN concurrent with bilirubin greater than times ULN and alkaline phosphatase less than times ULNDiscontinue Iclusig.Pancreatitis and Elevated Lipase [see Warnings and Precautions (5.6)] Serum lipase greater than to 1.5 times ULNConsider interrupting Iclusig until resolution then resume at same dose.Serum lipase greater than 1.5 to times ULN, to times ULN and asymptomatic, or asymptomatic radiologic pancreatitis Interrupt Iclusig until Grade or (less than 1.5 times ULN) then resume at next lower dose.Serum lipase greater than to times ULN and symptomatic, symptomatic Grade pancreatitis, or serum lipase greater than times ULN and asymptomatic Interrupt Iclusig until complete resolution of symptoms and after recovery of lipase elevation Grade or 1, then resume at next lower dose.Symptomatic pancreatitis and serum lipase greater than times ULN Discontinue Iclusig.Myelosuppression [see Warnings and Precautions (5.13)] ANC less than x 109/LorPlatelets less than 50 109/LInterrupt Iclusig until ANC at least 1.5 109/L and platelet at least 75 109/L, then resume at same dose.If recurrence, interrupt Iclusig until resolution, then resume at next lower dose. Other Non-hematologic Adverse Reactions [see Warnings and Precautions (5.5, 5.8, 5.10, 5.11, 5.12)] Grade 1Interrupt Iclusig until resolved, then resume at same dose.Grade 2Interrupt Iclusig until Grade or 1, then resume at same dose.If recurrence, interrupt Iclusig until Grade or 1, then resume at next lower dose.Grade or 4Interrupt Iclusig until Grade or 1, then resume at next lower dose.Discontinue Iclusig if recurrence.Table 2: Recommended Dose Reductions for Iclusig for Adverse ReactionsDose ReductionDosage for Patients with CP-CMLDosage for Patients with AP-CML, BP-CML, and Ph+ ALLFirst30 mg orally once daily30 mg orally once dailySecond15 mg orally once daily15 mg orally once dailyThird10 mg orally once dailyPermanently discontinue Iclusig in patients unable to tolerate 15 mg orally once daily.Subsequent ReductionPermanently discontinue Iclusig in patients unable to tolerate 10 mg orally once daily.. 2.3Dosage Modification for Coadministration of Strong CYP3A Inhibitors. Avoid coadministration of Iclusig with strong CYP3A inhibitors. If coadministration of 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 to elimination half-lives, resume the Iclusig dosage that was tolerated prior to initiating the strong CYP3A inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].Table 3: Recommended Iclusig Dosage for Coadministration of Strong CYP3A InhibitorsCurrent Iclusig DosageRecommended Iclusig Dosage with Strong CYP3A Inhibitor45 mg orally once daily30 mg orally once daily30 mg orally once daily15 mg orally once daily15 mg orally once daily10 mg orally once daily10 mg orally once dailyAvoid coadministration of Iclusig with strong CYP3A inhibitor. 2.4Dosage 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)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. Arterial Occlusive Events and Venous Thromboembolic EventsInform 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 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 ArrhythmiasInform 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)].. HepatotoxicityInform 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)].. HypertensionInform 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)].. PancreatitisInform 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)].. NeuropathyInform 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, burning sensation, neuropathic pain, or weakness [see Warnings and Precautions (5.8)].. Ocular ToxicityInform 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)].. HemorrhageInform 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 RetentionInform 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)].. MyelosuppressionInform 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 SyndromeInform 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 PerforationInform 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 ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for weeks after the last dose [see Warnings and Precautions (5.17), Use in Specific Populations (8.1, 8.3)].. LactationAdvise women not to breastfeed during treatment with Iclusig and for days after the last dose [see Use in Specific Populations (8.2)].. InfertilityAdvise 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 IclusigAdvise 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 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.. LactoseInform patients that Iclusig tablets contain lactose monohydrate.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on findings in animals and its mechanism of action [see Clinical Pharmacology (12.1)], Iclusig can cause fetal harm when administered to pregnant woman. 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 fetus.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. The background risk in the U.S. general population of major birth defects is to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.. Data. Animal DataPonatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3 mg/kg/day, mg/kg/day, and mg/kg/day during organogenesis (25 rats per group). At the maternally toxic dose of 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 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.. 8.2 Lactation. Risk SummaryThere is no data on the presence of ponatinib in human milk or the effects on the breastfed child 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 days following the last dose.. 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)].. Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating Iclusig.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with Iclusig and for weeks after the last dose.. InfertilityBased on animal data, ponatinib may impair fertility in females of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. Safety and effectiveness have not been established in pediatric patients.. Juvenile Animal Toxicity DataA 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 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 mg/kg/day ponatinib to juvenile rats beginning on Day 15 postpartum (pp) resulted in mortality related to inflammatory effects after to days following initiation of treatment. The dose of mg/kg/day is approximately 0.32 times the clinical dose on mg/m2 basis for child.. 8.5 Geriatric Use. Of the 94 patients with CP-CML who received Iclusig at 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 lower <=1% BCR-ABL1IS rate at 12 months (29%) as compared with patients less than 65 years of age (45%). AOEs occurred in 38% (6/16) of patients 65 years and older and 8% (6/78) of patients less than 65 years of age [see Warnings and Precautions (5.1)].Of the 449 patients who received Iclusig in PACE, 35% were 65 years and older and 8% were 75 years and older. In patients with CP-CML, patients aged 65 years and older had 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 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.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: July 2021MEDICATION GUIDEICLUSIG(R) (eye-CLUE-sig)(ponatinib)tabletsWhat is the most important information should know about IclusigIclusig can cause serious side effects, including:Blood clots or blockage in your blood vessels (arteries and veins). Blood clots or blockage in your blood vessels may lead to heart attack, stroke, or death. blood clot or blockage in your blood vessels can prevent proper blood flow to your heart, brain, bowels (intestines), legs, eyes, and other parts of your body. You may need emergency surgery or treatment in hospital. Get medical help right away if you get any of the following symptoms:chest pain or pressurepain in your arms, legs, back, neck or jawshortness of breathnumbness or weakness on one side of your bodyleg swellingtrouble talkingheadachedizzinesssevere stomach area paindecreased vision or loss of visionBlood clots or blockage in your blood vessels can happen in people with or without risk factors for heart and blood vessel disease, including people 50 years of age or younger. The most common risk factors for these problems are history of high blood pressure (hypertension), high cholesterol, and heart disease. Blood clots or blockages in your blood vessels happen more often in people as they get older, and in people with history of decreased blood flow, high blood pressure, diabetes, or high cholesterol. Heart problems. Iclusig can cause heart problems, including heart failure which can be serious and may lead to death. Heart failure means your heart does not pump blood well enough. Iclusig can also cause irregular, slow, or fast heartbeats and heart attack. Your healthcare provider will check you for heart problems during your treatment with Iclusig. Get medical help right away if you get any of the following symptoms: shortness of breath, chest pain, fast or irregular heartbeats, dizziness, or feel faint. Liver problems. Iclusig can cause liver problems, including liver failure, which can be severe and may lead to death. Your healthcare provider will do blood tests before and during your treatment with Iclusig to check for liver problems. Get medical help right away if you get any of these symptoms of liver problems during treatment:yellowing of your skin or the white part of your eyes dark tea-colored urinesleepinessloss of appetitebleeding or bruisingSee What are the possible side effects of Iclusig for information about side effects.What is IclusigIclusig is prescription medicine used to treat adults who have:chronic phase chronic myeloid leukemia (CML) who did not tolerate or no longer benefit from treatment with at least prior kinase inhibitor medicines accelerated phase or blast phase CML, or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who cannot receive any other kinase inhibitor medicinesa specific type of abnormal gene (T315I-positive) chronic phase, accelerated phase, or blast phase CML, or T315I-positive Ph+ ALL Iclusig is not for use to treat people with newly diagnosed chronic phase CML.It is not known if Iclusig is safe and effective in children.Before you take Iclusig, tell your healthcare provider about all of your medical conditions, including if you:have history of blood clots in your blood vessels (arteries or veins)have heart problems, including heart failure, irregular heartbeats, and QT prolongationhave diabeteshave history of high cholesterolhave liver problemshave had inflammation of your pancreas (pancreatitis)have high blood pressurehave bleeding problemsplan to have surgery or have had recent surgery. You should stop taking Iclusig at least week before planned surgery. See What are the possible side effects of Iclusig.are lactose (milk sugar) intolerant. Iclusig tablets contain lactose.eat grapefruit or drink grapefruit juice. See How should take Iclusig.are pregnant or plan to become pregnant. Iclusig can harm your unborn baby.Your healthcare provider will do pregnancy test before you start taking Iclusig.You should not become pregnant during treatment with Iclusig.For females who can become pregnant:Use an effective form of birth control during treatment and for weeks after your last dose of Iclusig.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with Iclusig.Iclusig may affect your ability to have children. Tell your healthcare provider if this is concern for you. are breastfeeding or plan to breastfeed. It is not known if Iclusig passes into your breast milk. Do not breastfeed during treatment and for days after your last dose of Iclusig.Tell your healthcare provider about all the medicines you take, including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements. Iclusig and other medicines may affect each other causing side effects.Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicine.How should take IclusigTake Iclusig exactly as your healthcare provider tells you to take it.Do not change your dose or stop taking Iclusig unless your healthcare provider tells you.Swallow Iclusig tablets whole. Do not crush, break, cut, chew or dissolve Iclusig tablets.Take Iclusig with or without food.Do not eat grapefruit or drink grapefruit juice during treatment with Iclusig. If you miss dose of Iclusig, take your next dose at your regularly scheduled time the next day. Do not take doses at the same time to make up for missed dose.If you take too much Iclusig, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of IclusigIclusig may cause serious side effects, including:See What is the most important information should know about Iclusig.High blood pressure (hypertension). Iclusig can cause new or worsening high blood pressure. Your blood pressure should be checked regularly, and any high blood pressure should be treated during treatment with Iclusig. Tell your healthcare provider right away if you get confusion, headaches, dizziness, chest pain or shortness of breath.Inflammation of the pancreas (pancreatitis). Tell your healthcare provider right away if you get any of the following symptoms: sudden stomach-area pain or discomfort, nausea, and vomiting. Your healthcare provider should do blood tests to check for pancreatitis during treatment with Iclusig.Neuropathy. Iclusig may cause damage to the nerves in your arms, brain, hands, legs, or feet (neuropathy). Tell your healthcare provider right away if you get any of these symptoms during treatment with Iclusig:muscle weakness, tingling, burning, pain, discomfort or loss of feeling in your hands and feetdouble vision and other problems with eyesight, trouble moving the eye, drooping of part of the face, sagging or drooping eyelids, or change in taste Eye problems. Serious eye problems that can lead to blindness or blurred vision may happen with Iclusig. Tell your healthcare provider right away if you get any of the following symptoms: bleeding in the eye, perceived flashes of light, light sensitivity, floaters, blurred vision, dry, inflamed, swollen, or itchy eyes, or eye pain. Your healthcare provider will monitor your vision before and during your treatment with Iclusig.Serious bleeding. Iclusig can cause bleeding which can be serious and may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during treatment with Iclusig including:vomiting blood or if your vomit looks like coffee-groundspink or brown urinered or black (looks like tar) stoolscoughing up blood or blood clotsunusual bleeding or bruising of your skinmenstrual bleeding that is heavier than normalunusual vaginal bleedingnose bleeds that happen oftendrowsiness or difficulty being awakenedconfusionheadachechange in speechFluid retention. Your body may hold too much fluid (fluid retention) which can be serious and may lead to death. Tell your healthcare provider right away if you get any of these symptoms during treatment with Iclusig:swelling of your hands, ankles, feet, face, or all over your bodyweight gainshortness of breath and cough Irregular heartbeat. Iclusig may cause an irregular heartbeat. Tell your healthcare provider right away if you experience loss of consciousness, fainting, dizziness, chest pain or palpitations.Low blood cell counts. Iclusig may cause low blood cell counts, which can be severe. Your healthcare provider will check your blood counts regularly during treatment with Iclusig. Tell your healthcare provider right away if you have fever or any signs of an infection while taking Iclusig.Tumor Lysis Syndrome (TLS). TLS is caused by fast breakdown of cancer cells. TLS can cause you to have:kidney failure and the need for dialysis treatmentan abnormal heartbeatYour healthcare provider may do blood tests to check for TLS. Drink plenty of water during treatment with Iclusig to help reduce your risk of getting TLS.Reversible Posterior Leukoencephalopathy Syndrome (RPLS also known as Posterior Reversible Encephalopathy Syndrome). Iclusig may trigger condition called RPLS. Call your healthcare provider right away if you get headaches, seizures, confusion, changes in vision or problems thinking.Wound healing problems. Wound healing problems have happened in some people who take Iclusig. Tell your healthcare provider if you plan to have any surgery before or during treatment with Iclusig.You should stop taking Iclusig at least week before planned surgery. Your healthcare provider should tell you when you may start taking Iclusig again after surgery. tear in your stomach or intestinal wall (perforation). Tell your healthcare provider right away if you get:severe pain in your stomach-area (abdomen)swelling of the abdomenhigh fever The most common side effects of Iclusig include:skin rashjoint painstomach-area (abdomen) painheadacheconstipationdry skinhigh blood pressuretirednessswelling of your hands, ankles, feet, face, or all of your body (fluid retention and edema) fevernauseainflammation of the pancreasincrease in lipase levels (a blood test done to check your pancreas)bleedinglow hemoglobin in the blood (anemia)liver problemsblood clots or blockage in blood vessels (arteries)low blood platelet countslow blood levels of white blood cells (including neutrophils)Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with Iclusig if you have certain side effects.Tell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all of the possible side effects of Iclusig. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store IclusigStore Iclusig at room temperature between 68F to 77F (20C to 25C). Keep Iclusig and all medicines out of the reach of children. General information about the safe and effective use of IclusigMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use Iclusig for condition for which it was not prescribed. Do not give Iclusig to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about Iclusig that is written for health professionals.What are the ingredients in IclusigActive ingredient: ponatinib Inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type B), colloidal silicon dioxide and magnesium stearate. The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol and titanium dioxide.For more information, go to www.iclusig.com or call 1-844-817-6468.Distributed by: Takeda Pharmaceuticals America, Inc. Lexington, MA 02421ICLUSIG(R) is registered trademark of ARIAD Pharmaceuticals, Inc. TAKEDA(R) and the TAKEDA Logo(R) are registered trademarks of Takeda Pharmaceutical Company Limited.(C)2021 ARIAD Pharmaceuticals, Inc. All rights reserved.ICL348 R8. chest pain or pressure. pain in your arms, legs, back, neck or jaw. shortness of breath. numbness or weakness on one side of your body. leg swelling. trouble talking. headache. dizziness. severe stomach area pain. decreased vision or loss of vision. yellowing of your skin or the white part of your eyes dark tea-colored urine. sleepiness. loss of appetite. bleeding or bruising. chronic phase chronic myeloid leukemia (CML) who did not tolerate or no longer benefit from treatment with at least prior kinase inhibitor medicines accelerated phase or blast phase CML, or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who cannot receive any other kinase inhibitor medicines. specific type of abnormal gene (T315I-positive) chronic phase, accelerated phase, or blast phase CML, or T315I-positive Ph+ ALL have history of blood clots in your blood vessels (arteries or veins). have heart problems, including heart failure, irregular heartbeats, and QT prolongation. have diabetes. have history of high cholesterol. have liver problems. have had inflammation of your pancreas (pancreatitis). have high blood pressure. have bleeding problems. plan to have surgery or have had recent surgery. You should stop taking Iclusig at least week before planned surgery. See What are the possible side effects of Iclusig.. are lactose (milk sugar) intolerant. Iclusig tablets contain lactose.. eat grapefruit or drink grapefruit juice. See How should take Iclusig.. are pregnant or plan to become pregnant. Iclusig can harm your unborn baby.Your healthcare provider will do pregnancy test before you start taking Iclusig.You should not become pregnant during treatment with Iclusig.For females who can become pregnant:Use an effective form of birth control during treatment and for weeks after your last dose of Iclusig.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with Iclusig.Iclusig may affect your ability to have children. Tell your healthcare provider if this is concern for you. Your healthcare provider will do pregnancy test before you start taking Iclusig.. You should not become pregnant during treatment with Iclusig.. For females who can become pregnant:Use an effective form of birth control during treatment and for weeks after your last dose of Iclusig.Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with Iclusig.Iclusig may affect your ability to have children. Tell your healthcare provider if this is concern for you.. Use an effective form of birth control during treatment and for weeks after your last dose of Iclusig.. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with Iclusig.. Iclusig may affect your ability to have children. Tell your healthcare provider if this is concern for you.. are breastfeeding or plan to breastfeed. It is not known if Iclusig passes into your breast milk. Do not breastfeed during treatment and for days after your last dose of Iclusig.. Take Iclusig exactly as your healthcare provider tells you to take it.. Do not change your dose or stop taking Iclusig unless your healthcare provider tells you.. Swallow Iclusig tablets whole. Do not crush, break, cut, chew or dissolve Iclusig tablets.. Take Iclusig with or without food.. Do not eat grapefruit or drink grapefruit juice during treatment with Iclusig. If you miss dose of Iclusig, take your next dose at your regularly scheduled time the next day. Do not take doses at the same time to make up for missed dose.. If you take too much Iclusig, call your healthcare provider or go to the nearest hospital emergency room right away.. See What is the most important information should know about Iclusig.. High blood pressure (hypertension). Iclusig can cause new or worsening high blood pressure. Your blood pressure should be checked regularly, and any high blood pressure should be treated during treatment with Iclusig. Tell your healthcare provider right away if you get confusion, headaches, dizziness, chest pain or shortness of breath.. Inflammation of the pancreas (pancreatitis). Tell your healthcare provider right away if you get any of the following symptoms: sudden stomach-area pain or discomfort, nausea, and vomiting. Your healthcare provider should do blood tests to check for pancreatitis during treatment with Iclusig.. Neuropathy. Iclusig may cause damage to the nerves in your arms, brain, hands, legs, or feet (neuropathy). Tell your healthcare provider right away if you get any of these symptoms during treatment with Iclusig:muscle weakness, tingling, burning, pain, discomfort or loss of feeling in your hands and feetdouble vision and other problems with eyesight, trouble moving the eye, drooping of part of the face, sagging or drooping eyelids, or change in taste muscle weakness, tingling, burning, pain, discomfort or loss of feeling in your hands and feet. double vision and other problems with eyesight, trouble moving the eye, drooping of part of the face, sagging or drooping eyelids, or change in taste. Eye problems. Serious eye problems that can lead to blindness or blurred vision may happen with Iclusig. Tell your healthcare provider right away if you get any of the following symptoms: bleeding in the eye, perceived flashes of light, light sensitivity, floaters, blurred vision, dry, inflamed, swollen, or itchy eyes, or eye pain. Your healthcare provider will monitor your vision before and during your treatment with Iclusig.. Serious bleeding. Iclusig can cause bleeding which can be serious and may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during treatment with Iclusig including:. vomiting blood or if your vomit looks like coffee-grounds. pink or brown urine. red or black (looks like tar) stools. coughing up blood or blood clots. unusual bleeding or bruising of your skin. menstrual bleeding that is heavier than normal. unusual vaginal bleeding. nose bleeds that happen often. drowsiness or difficulty being awakened. confusion. headache. change in speech. Fluid retention. Your body may hold too much fluid (fluid retention) which can be serious and may lead to death. Tell your healthcare provider right away if you get any of these symptoms during treatment with Iclusig:swelling of your hands, ankles, feet, face, or all over your bodyweight gainshortness of breath and cough swelling of your hands, ankles, feet, face, or all over your body. weight gain. shortness of breath and cough. Irregular heartbeat. Iclusig may cause an irregular heartbeat. Tell your healthcare provider right away if you experience loss of consciousness, fainting, dizziness, chest pain or palpitations.. Low blood cell counts. Iclusig may cause low blood cell counts, which can be severe. Your healthcare provider will check your blood counts regularly during treatment with Iclusig. Tell your healthcare provider right away if you have fever or any signs of an infection while taking Iclusig.. Tumor Lysis Syndrome (TLS). TLS is caused by fast breakdown of cancer cells. TLS can cause you to have:kidney failure and the need for dialysis treatmentan abnormal heartbeatYour healthcare provider may do blood tests to check for TLS. Drink plenty of water during treatment with Iclusig to help reduce your risk of getting TLS.. kidney failure and the need for dialysis treatment. an abnormal heartbeat. Reversible Posterior Leukoencephalopathy Syndrome (RPLS also known as Posterior Reversible Encephalopathy Syndrome). Iclusig may trigger condition called RPLS. Call your healthcare provider right away if you get headaches, seizures, confusion, changes in vision or problems thinking.. Wound healing problems. Wound healing problems have happened in some people who take Iclusig. Tell your healthcare provider if you plan to have any surgery before or during treatment with Iclusig.You should stop taking Iclusig at least week before planned surgery. Your healthcare provider should tell you when you may start taking Iclusig again after surgery. You should stop taking Iclusig at least week before planned surgery. Your healthcare provider should tell you when you may start taking Iclusig again after surgery.. tear in your stomach or intestinal wall (perforation). Tell your healthcare provider right away if you get:severe pain in your stomach-area (abdomen)swelling of the abdomenhigh fever severe pain in your stomach-area (abdomen). swelling of the abdomen. high fever. skin rash. joint pain. stomach-area (abdomen) pain. headache. constipation. dry skin. high blood pressure. tiredness. swelling of your hands, ankles, feet, face, or all of your body (fluid retention and edema) fever. nausea. inflammation of the pancreas. increase in lipase levels (a blood test done to check your pancreas). bleeding. low hemoglobin in the blood (anemia). liver problems. blood clots or blockage in blood vessels (arteries). low blood platelet counts. low blood levels of white blood cells (including neutrophils).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypertension: Monitor blood pressure and manage hypertension as clinically indicated. Interrupt, dose reduce or stop Iclusig if hypertension is not medically controlled. (2.2, 5.5)Pancreatitis: Monitor serum lipase. Interrupt then resume at the same or reduced dose or discontinue Iclusig based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms. (2.2, 5.6)Neuropathy: Monitor for symptoms of peripheral and cranial neuropathy. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity (2.2, 5.8)Ocular Toxicity: Conduct comprehensive eye exams at baseline and periodically during treatment. (5.9)Hemorrhage: Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity. (2.2, 5.10)Fluid Retention: Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity. (2.2, 5.11)Cardiac Arrhythmias: Monitor for signs or symptoms of arrhythmias and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity. (5.12)Myelosuppression: Obtain complete blood counts every weeks for the first months and then monthly or as clinically indicated. If ANC less than x 109/L or platelets less than 50 109/L, interrupt Iclusig until ANC at least 1.5 109/L and platelets at least 75 109/L, then resume at same or reduced dose. (2.2, 5.13)Tumor Lysis Syndrome: Ensure adequate hydration and correct elevated uric acid levels prior to initiating Iclusig. (5.14)Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Interrupt Iclusig until resolution. The safety of resumption of Iclusig in patients upon resolution of RPLS is unknown. (5.15)Impaired Wound Healing and Gastrointestinal Perforation: Withhold Iclusig for at least week prior to elective surgery. Do not administer for at least weeks following major surgery and until adequate wound healing. The safety of resumption of Iclusig after resolution of wound healing complications has not been established. (5.16)Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.17, 8.1, 8.3). Hypertension: Monitor blood pressure and manage hypertension as clinically indicated. Interrupt, dose reduce or stop Iclusig if hypertension is not medically controlled. (2.2, 5.5). Pancreatitis: Monitor serum lipase. Interrupt then resume at the same or reduced dose or discontinue Iclusig based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms. (2.2, 5.6). Neuropathy: Monitor for symptoms of peripheral and cranial neuropathy. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity (2.2, 5.8). Ocular Toxicity: Conduct comprehensive eye exams at baseline and periodically during treatment. (5.9). Hemorrhage: Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity. (2.2, 5.10). Fluid Retention: Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity. (2.2, 5.11). Cardiac Arrhythmias: Monitor for signs or symptoms of arrhythmias and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity. (5.12). Myelosuppression: Obtain complete blood counts every weeks for the first months and then monthly or as clinically indicated. If ANC less than x 109/L or platelets less than 50 109/L, interrupt Iclusig until ANC at least 1.5 109/L and platelets at least 75 109/L, then resume at same or reduced dose. (2.2, 5.13). Tumor Lysis Syndrome: Ensure adequate hydration and correct elevated uric acid levels prior to initiating Iclusig. (5.14). Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Interrupt Iclusig until resolution. The safety of resumption of Iclusig in patients upon resolution of RPLS is unknown. (5.15). Impaired Wound Healing and Gastrointestinal Perforation: Withhold Iclusig for at least week prior to elective surgery. Do not administer for at least weeks following major surgery and until adequate wound healing. The safety of resumption of Iclusig after resolution of wound healing complications has not been established. (5.16). Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to fetus and to use effective contraception. (5.17, 8.1, 8.3). 5.1Arterial Occlusive Events. Arterial occlusive events (AOEs), including fatalities, occurred in patients who received Iclusig in OPTIC and PACE [see Adverse Reactions (6.1)].Of the 94 patients who received 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), year (range: 5.9 months to 1.6 years), and 3.6 months (range: 23 days to 6.3 months), respectively. Grade or AOEs occurred in 5% of patients; the most frequent Grade or AOEs were myocardial infarction, acute coronary syndrome, arterial thrombosis, ischemic stroke, and ischemic cerebral infarction (1.1% each). Fatal AOEs occurred in 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 year (range: day to 4.1 years), 1.4 years (range: days to 4.5 years), and years (range: 10 days to 4.9 years), respectively. Grade or AOEs occurred in 14% of patients; the most frequent Grade or 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 patients (2%); the most frequent fatal AOE was cardiac arrest (0.9%).In PACE, fatal and life-threatening AOEs occurred within 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 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 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 decision to restart Iclusig.. 5.2Venous Thromboembolic Events. Serious or severe VTEs have occurred in patients who received Iclusig.Of the 94 patients who received starting dose of 45 mg in OPTIC, patient experienced VTE (Grade retinal vein occlusion).In PACE, VTEs occurred in 6% of 449 patients, including serious or severe (Grade or 4) in 5.8%. VTEs included deep venous thrombosis (2.2%), pulmonary embolism (1.8%), superficial thrombophlebitis (0.7%), retinal vein occlusion (0.7%), and retinal vein thrombosis (0.4%) with vision loss. VTEs occurred in 10% of the 62 patients with BP-CML, 9% of the 32 patients with Ph+ ALL, 6% of the 270 patients with CP-CML, and 3.5% of the 85 patients with AP-CML.Monitor for evidence of VTEs. Interrupt, then resume at the same or decreased dose or discontinue Iclusig based on recurrence/severity [see Dosage and Administration (2.2)].. 5.3Heart Failure. Fatal, serious or severe heart failure events have occurred in patients who received Iclusig.Of the 94 patients who received starting dose of 45 mg in OPTIC, heart failure events occurred in 12% of patients; 1.1% experienced serious or severe (Grade 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 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)].. 5.4Hepatotoxicity. Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in patients, with hepatic failure occurring within 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 starting dose of 45 mg in OPTIC, hepatotoxicity occurred in 25% of patients; 6% experienced Grade or hepatotoxicity. The median time to onset of hepatotoxicity was 1.9 months, with range of 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 or hepatotoxicity. The median time to onset of hepatotoxicity was 3.1 months, with range of day to 4.9 years. The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. In 9% of the 88 patients who reported ALT or AST elevation, the event was not resolved by the date of last follow-up.Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at reduced dose or discontinue Iclusig based on recurrence/severity [see Dosage and Administration (2.2)].. 5.5Hypertension. Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received Iclusig.Of the 94 patients who received 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 or higher blood pressure elevation in patients with normal baseline blood pressure) occurred in 26% of 94 patients. Grade BP elevation occurred in 57%, Grade occurred in 35%, and Grade occurred in 15%. Two patients (2.1%) experienced Grade 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 or higher in patients with normal baseline blood pressure occurred in 44% of 449 patients. Grade BP elevation occurred in 26%, Grade in 45%, and Grade in 26%. Two patients (<1%) experienced Grade hypertension (hypertensive crisis).Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath [see Adverse Reactions (6.1)]. Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled [see Dosage and Administration (2.2)]. For significant worsening, labile or treatment-resistant hypertension, interrupt Iclusig and consider evaluating for renal artery stenosis.. 5.6Pancreatitis. Serious or severe pancreatitis has occurred in patients who received Iclusig.Of the 94 patients who received starting dose of 45 mg in OPTIC, pancreatitis occurred in 23% of patients; 15% experienced serious or severe (Grade 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: days to 5.6 months). Three of the cases of clinical pancreatitis that led to dose modification or treatment discontinuation resolved within 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 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: day to years). Nineteen of the 28 cases of clinical pancreatitis that led to dose modification or treatment discontinuation resolved within weeks. Laboratory abnormalities of amylase elevations occurred in 18% of patients, while lipase elevations occurred in 39% of patients.Monitor serum lipase every weeks for the first months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with 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 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 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 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 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 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 or neuropathy. Peripheral neuropathy occurred in 20% of 449 patients; 1.8% experienced Grade or 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 or 4. The median time to onset of peripheral neuropathy and cranial neuropathy was 5.3 months (range: day to 4.6 years) and 1.2 years (range: 18 days to years), respectively.Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, 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 starting dose of 45 mg in OPTIC, ocular toxicities occurred in 11% of patients; 1.1% experienced 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 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 starting dose of 45 mg in OPTIC, hemorrhage occurred in 12% of patients; patient experienced serious subdural hematoma.In PACE, hemorrhage occurred in 28% of 449 patients; 6% experienced serious hemorrhage and 1.3% experienced 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 thrombocytopenia [see Warnings and Precautions (5.13)].Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity [see Dosage and Administration (2.2)].. 5.11Fluid Retention. Fatal and serious fluid retention events have occurred in patients who received Iclusig.Of the 94 patients who received 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)].. 5.12Cardiac Arrhythmias. Of the 94 patients who received starting dose of 45 mg in OPTIC, cardiac arrhythmias occurred in 15% of patients; 4.3% experienced Grade or cardiac arrhythmias. Grade or 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 or cardiac arrhythmias. Ventricular arrhythmias occurred in 3.4% of the 89 patients who reported an arrhythmia, with one event being Grade 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 or 4. Other Grade or 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 starting dose of 45 mg in OPTIC, neutropenia occurred in 53% (Grade or occurred in 22%), thrombocytopenia occurred in 65% (Grade or occurred in 31%), and anemia occurred in 35% of patients (Grade or occurred in 14%). The median time to onset of Grade or myelosuppression was 1.4 months (range: day to 1.2 years).In PACE, neutropenia occurred in 56% (Grade or occurred in 34%), thrombocytopenia occurred in 63% (Grade or occurred in 40%), and anemia occurred in 52% of patients (Grade or 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 or 4) was observed early in treatment, with median onset time of 29 days (range: day to 4.1 years).Obtain complete blood counts every weeks for the first months and then monthly or as clinically indicated. If ANC less than x 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 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 patient with advanced AP-CML and case occurred in patient with BP-CML. Hyperuricemia occurred in 7% of patients.Ensure adequate hydration and treat high uric acid levels prior to initiating Iclusig.. 5.15Reversible Posterior Leukoencephalopathy Syndrome. Reversible posterior leukoencephalopathy syndrome (RPLS; also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received Iclusig. Patients can present with hypertension, seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis. Interrupt Iclusig until resolution. The safety of resumption of Iclusig in patients upon resolution of RPLS is unknown.. 5.16 Impaired Wound Healing and Gastrointestinal Perforation. Impaired wound healing occurred in patients receiving Iclusig [see Adverse Reactions (6.2)]. Withhold Iclusig for at least week prior to elective surgery. Do not administer for at least weeks following major surgery and until adequate wound healing. The safety of resumption of Iclusig after resolution of wound healing complications has not been established.Gastrointestinal perforation or fistula occurred in patients receiving Iclusig [see Adverse Reactions (6.2)]. Permanently discontinue in patients with gastrointestinal perforation.. 5.17Embryo-Fetal Toxicity. Based on its mechanism of action and findings from animal studies, Iclusig can cause fetal harm when administered to 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 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].