Data from FDA - Curated by Marshall Pearce - Last updated 06 December 2017

Indication(s)

1 INDICATIONS AND USAGE Iclusig (ponatinib) is a kinase inhibitor indicated for the: Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. Treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig is a kinase inhibitor indicated for the: Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. Treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). (1) Limitations of use: Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML (5.7). Limitations of use: Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML [see Warnings and Precautions (5.7)].

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the prescribing information: Arterial Occlusion [see Warnings and Precautions (5.1)] Venous Thromboembolism [see Warnings and Precautions (5.2)] Heart Failure [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)] Hepatotoxicity [see Dosage and Administration (2.3) and Warnings and Precautions (5.4)] Hypertension [see Warnings and Precautions (5.5)] Pancreatitis [see Dosage and Administration (2.3) and Warnings and Precautions (5.6)] Increased Toxicity in Newly Diagnosed Chronic Phase CML [see Warnings and Precautions (5.7)] Neuropathy [see Warnings and Precautions (5.8)] Ocular Toxicity [see Warnings and Precautions (5.9)] Hemorrhage [see Warnings and Precautions (5.10)] Fluid Retention [see Warnings and Precautions (5.11)] Cardiac Arrhythmias [see Warnings and Precautions (5.12)] Myelosuppression [see Dosage and Administration (2.2) and Warnings and Precautions (5.13)] The most common non-hematologic adverse reactions (≥ 20%) were abdominal pain, rash, constipation, headache, dry skin, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity (6). To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals, Co. Ltd. at 1-844-T-1POINT (1-844-817-6468) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Previously Treated CML or Ph+ ALL The adverse reactions described in this section were identified in a single-arm, open-label, international, multicenter trial in 449 patients with CML or Ph+ ALL whose disease was considered to be resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy including those with the BCR-ABL T315I mutation. All patients received a starting dose of 45 mg Iclusig once daily. Interruptions and dose adjustments to 30 mg once daily or 15 mg once daily were allowed for the management of treatment toxicity. Additionally, after approximately 2 years of follow-up, patients who were still taking a 45 mg daily dose were recommended to undergo a dose reduction, in response to the continued occurrence of arterial occlusive events and venous thromboembolic events in the clinical trial. At the time of analysis (48 months of follow-up), 133 patients (30%) were ongoing (110 CP-CML; 20 AP-CML; 3 BP-CML; 0 Ph+ ALL), and the median duration of treatment with Iclusig was 32.2 months in patients with CP-CML, 19.4 months in patients with AP-CML, 2.9 months in patients with BP-CML, and 2.7 months in patients with Ph+ ALL. The median dose intensity in patients with CP-CML was 29 mg /day or 64% of the 45 mg starting dose; median dose intensity was greater in patients with advanced disease patients. Seventy one percent (318/449) of patients experienced a dose interruption of more than three days and 68% (304/449) experienced a dose reduction. The most common adverse reactions (≥5%) that led to dose modifications (interruption or dose reduction) include thrombocytopenia (31%), neutropenia (14%), lipase increased (13%), arterial occlusive events (13%), abdominal pain (12%), rash (9%), anemia (6%), pancreatitis (6%), ALT increased (5%) and hypertension (5%). At the time of the analysis, 69% of the ongoing patients (92/133 patients) were reported to be receiving 15 mg; with 26% (35/133) and 5% (6/133) of Iclusig-treated patients receiving 30 mg and 45 mg, respectively. Adverse reactions reported in more than 10% of all patients treated with Iclusig in this trial are presented in Table 5. Overall, the most common non-hematologic adverse reactions (≥ 20%) were abdominal pain, rash, constipation, headache, dry skin, fatigue, hypertension, pyrexia, arthralgia, nausea, diarrhea, lipase increased, vomiting, myalgia and pain in extremity. The rates of treatment-emergent adverse reactions resulting in discontinuation were 19% in CP-CML, 12% in AP-CML, 15% in BP-CML, and 9% in Ph+ ALL. The most common adverse reactions that led to treatment discontinuation was thrombocytopenia (4%). Table 5: Adverse Reactions in > 10% of Patients in the Phase 2 Trial (N=449) CP-CML (N=270) AP-CML (N=85) BP-CML (N=62) Ph+ ALL (N=32) Body System Any Grade (%) Grade 3 / 4 (%) Any Grade (%) Grade 3 / 4 (%) Any Grade (%) Grade 3 / 4 (%) Any Grade (%) Grade 3 / 4 (%) Adverse drug reactions, reported using MedDRA and graded using NCI-CTC-AE v 4.0 (NCI Common Terminology Criteria for Adverse Events) for assessment of toxicity. Treatment-emergent, all causality events Cardiac or Vascular disorders Hypertension derived from blood pressure (BP) measurement recorded monthly while on trial 69 42 74 42 60 23 53 28 Arterial ischemia cardiovascular, cerebrovascular, and peripheral vascular ischemia 42 17 28 14 11 8 22 6 Cardiac Failure includes cardiac failure, cardiac failure congestive, cardiogenic shock, cardiopulmonary failure, ejection fraction decreased, pulmonary edema, right ventricular failure 8 5 7 5 15 8 6 3 Gastrointestinal disorders Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort 48 10 42 9 35 8 34 6 Constipation 41 3 27 2 27 0 53 3 Nausea 28 1 31 0 34 2 22 0 Diarrhea 20 1 29 2 24 3 13 3 Vomiting 18 2 26 0 27 2 25 0 Oral mucositis includes aphthous stomatitis, lip blister, mouth ulceration, oral mucosal eruption, oral pain, oropharyngeal pain, pharyngeal ulceration, stomatitis, tongue ulceration 14 1 19 1 23 0 9 3 GI hemorrhage includes gastric hemorrhage, gastric ulcer hemorrhage, hemorrhagic gastritis, gastrointestinal hemorrhage, hematemesis, hematochezia, hemorrhoidal hemorrhage, intra-abdominal hemorrhage, melena, rectal hemorrhage, and upper gastrointestinal hemorrhage 1 <1 8 1 6 3 9 6 Blood and lymphatic system disorders Febrile neutropenia 1 1 5 5 13 13 25 25 Infections and infestations Sepsis 2 1 4 4 3 0 13 13 Pneumonia 6 5 13 9 16 11 9 3 Urinary tract infection 11 2 14 2 2 2 9 0 Upper respiratory tract infection 14 1 13 0 13 2 3 0 Nasopharyngitis 12 0 18 0 3 0 3 0 Cellulitis 3 2 6 2 11 3 0 0 Nervous system disorders Headache 43 3 29 0 31 3 25 0 Peripheral neuropathy includes burning sensation, skin burning sensation, hyperesthesia, hypoesthesia, neuralgia, neuropathy peripheral, paresthesia, peripheral sensorimotor neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, polyneuropathy, dysgeusia, muscular weakness, gait disturbance, nerve compression, areflexia, hypotonia, restless legs syndrome 24 3 14 1 11 0 16 0 Dizziness 16 0 9 0 5 0 3 0 Respiratory, thoracic, and mediastinal disorders Pleural effusion 5 2 12 2 13 0 19 3 Cough 16 0 22 0 19 0 6 0 Dyspnea 17 3 20 4 19 5 6 0 Skin and subcutaneous tissue disorders Rash and related conditions 63 4 59 7 39 5 28 3 Dry skin 42 3 32 1 26 2 25 0 Pruritus 13 <1 8 0 5 2 0 0 Erythema 10 1 8 0 8 0 6 0 Alopecia 7 0 11 0 8 0 6 0 Musculoskeletal and connective tissue disorders Arthralgia 32 3 33 2 19 0 13 0 Myalgia 24 1 20 0 18 0 6 0 Pain in extremity 23 3 19 0 13 0 13 0 Back pain 21 1 14 2 19 2 13 0 Muscle spasms 14 0 6 0 5 0 13 0 Bone pain 14 <1 13 1 11 3 9 3 Musculoskeletal pain 11 2 7 0 8 0 6 3 General disorders and administration site conditions Fatigue or asthenia 47 4 49 8 40 6 34 3 Pyrexia 26 1 40 7 36 3 25 0 Edema, peripheral 16 <1 18 0 15 0 25 0 Pain 10 <1 13 0 16 3 6 0 Chills 8 0 11 0 13 2 9 0 Metabolism and nutrition disorders Decreased appetite 13 <1 14 1 8 0 31 0 Investigations Weight decreased 10 <1 9 0 5 0 13 0 Psychiatric disorders Insomnia 11 0 13 0 11 0 13 0 Table 6: Serious Adverse Reactions Occurring in > 2% of Patients from the Phase 2 Trial (N=449) System Organ Class N (%) Cardiovascular disorders Arterial Occlusion 99 (22%) Cardiac vascular 53 (12%) Cerebrovascular 31 (7%) Peripheral vascular 34 (8%) Venous thromboembolism 22 (5%) Hemorrhage 28 (6%) CNS hemorrhage 6 (1%) Gastrointestinal hemorrhage 11 (2%) Heart failure 28(6%) Effusionsincludes pericardial effusion, pleural effusion, and ascites 15 (3%) Atrial fibrillation 18 (4%) Hypertension 12 (3%) Gastrointestinal disorders Pancreatitis 26(6%) Abdominal pain 20 (5%) Blood and lymphatic system disorders Febrile neutropenia 13 (3%) Anemia 16(3%) Thrombocytopenia 14 (3%) Infections Pneumonia 32 (7%) Sepsis 10 (2%) General Pyrexia 20 (5%) Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of grade 3 or 4 thrombocytopenia, neutropenia, and anemia was higher in patients with AP-CML, BP-CML, and Ph+ ALL than in patients with CP-CML (see Table 7). Table 7: Clinically Relevant Grade 3/4Reported using NCI-CTC-AE v 4.0 Hematologic Laboratory Abnormalities in Patients from the Phase 2 Trial (N=449) Laboratory Test CP-CML (N=270) (%) AP-CML (N=85) (%) BP-CML (N=62) (%) Ph+ ALL (N=32) (%) Hematology ANC=absolute neutrophil count, Hgb=hemoglobin, WBC=white blood cell count Thrombocytopenia (platelet count decreased) 35 49 45 47 Neutropenia (ANC decreased) 23 52 48 59 Leukopenia (WBC decreased) 12 36 48 63 Anemia (Hgb decreased) 8 31 52 34 Lymphopenia 10 25 32 19 Table 8: Clinically Relevant Non-Hematologic Laboratory Abnormalities Laboratory Test Safety Population N=449 Any GradeGraded using NCI-CTC-AE v 4.0 (%) CTCAE Grade 3 / 4 (%) ALT=alanine aminotransferase, AST=aspartate aminotransferase. Liver function tests ALT increased 41 6 AST increased 35 4 Alkaline phosphatase increased 40 2 Albumin decreased 27 <1 Bilirubin increased 13 <1 Pancreatic enzymes Lipase increased 38 13 Amylase increased 18 3 Chemistry Glucose increased 54 7 Phosphorus decreased 33 10 Calcium decreased 30 <1 Sodium decreased 27 5 Glucose decreased 13 0 Potassium decreased 18 2 Potassium increased 19 2 Sodium increased 10 <1 Bicarbonate decreased 19 <1 Creatinine increased 21 <1 Calcium increased 12 0 Triglycerides increased 3 <1 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Iclusig. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Reversible posterior leukoencephalopathy syndrome (RPLS) – also known as Posterior Reversible Encephalopathy Syndrome - PRES)

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Recommended dose: 45 mg taken orally once daily with or without food (2.1) Hepatic Impairment: 30 mg orally once daily (2.5) Modify or interrupt dosing for hematologic and non-hematologic toxicity (2.2, 2.3) 2.1 Recommended Dosage The optimal dose of Iclusig has not been identified. In clinical trials, the starting dose of Iclusig was 45 mg administered orally once daily. However, in the phase 2 trial, 68% of the patients required dose reductions to 30 mg or 15 mg once daily during the course of therapy. Start dosing with 45 mg once daily. Consider reducing the dose of Iclusig for patients with chronic phase (CP) CML and accelerated phase (AP) CML who have achieved a major cytogenetic response. Consider discontinuing Iclusig if response has not occurred by 3 months (90 days). Iclusig may be taken with or without food. Tablets should be swallowed whole. 2.2 Dose Modifications for Myelosuppression Suggested dose modifications for neutropenia (ANC* less than 1.0 × 109/L) and thrombocytopenia (platelet less than 50 × 109/L) that are unrelated to leukemia are summarized in Table 1. Table 1: Suggested Dose Modifications for Myelosuppression ANCANC = absolute neutrophil count < 1 × 109/L or platelet < 50 × 109/L First occurrence: Interrupt Iclusig and resume initial 45 mg dose after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L Second occurrence: Interrupt Iclusig and resume at 30 mg after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L Third occurrence: Interrupt Iclusig and resume at 15 mg after recovery to ANC ≥ 1.5 × 109/L and platelet ≥ 75 × 109/L 2.3 Dose Modifications for Non-Hematologic Adverse Reactions If a serious non-hematologic adverse reaction occurs, modify the dose or interrupt treatment. Do not restart Iclusig in patients with arterial or venous occlusive reactions unless the potential benefit outweighs the risk of recurrent arterial or venous occlusions and the patient has no other treatment options. For serious reactions other than arterial or venous occlusion, do not restart Iclusig until the serious event has resolved or the potential benefit of resuming therapy is judged to outweigh the risk. Hepatotoxicity Recommended modifications for hepatotoxicity are summarized in Table 2. Table 2: Recommended Dose Modifications for Hepatotoxicity Elevation of liver transaminase > 3 × ULNULN = Upper Limit of Normal for the lab (Grade 2 or higher) Occurrence at 45 mg: Interrupt Iclusig and monitor hepatic function Resume Iclusig at 30 mg after recovery to ≤ Grade 1 (< 3 × ULN) Occurrence at 30 mg: Interrupt Iclusig and resume at 15 mg after recovery to ≤ Grade 1 Occurrence at 15 mg: Discontinue Iclusig Elevation of AST or ALT ≥ 3 × ULN concurrent with an elevation of bilirubin > 2 × ULN and alkaline phosphatase < 2 × ULN Discontinue Iclusig Pancreatitis and Elevation of Lipase Recommended modifications for pancreatic adverse reactions are summarized in Table 3. Table 3: Recommended Dose Modifications for Pancreatitis and Elevation of Lipase Asymptomatic Grade 1 or 2 elevation of serum lipase Consider interruption or dose reduction of Iclusig Asymptomatic Grade 3 or 4 elevation of lipase (> 2 × ULNULN = Upper Limit of Normal for the lab) or asymptomatic radiologic pancreatitis (Grade 2 pancreatitis) Occurrence at 45 mg: Interrupt Iclusig and resume at 30 mg after recovery to ≤ Grade 1 (< 1.5 × ULN) Occurrence at 30 mg: Interrupt Iclusig and resume at 15 mg after recovery to ≤ Grade 1 Occurrence at 15 mg: Discontinue Iclusig Symptomatic Grade 3 pancreatitis Occurrence at 45 mg: Interrupt Iclusig and resume at 30 mg after complete resolution of symptoms and after recovery of lipase elevation to ≤ Grade 1 Occurrence at 30 mg: Interrupt Iclusig and resume at 15 mg after complete resolution of symptoms and after recovery of lipase elevation to ≤ Grade 1 Occurrence at 15 mg: Discontinue Iclusig Grade 4 pancreatitis Discontinue Iclusig 2.4 Dose Modification for Use With Strong CYP3A Inhibitors The recommended dose should be reduced to 30 mg once daily when administering Iclusig with strong CYP3A inhibitors [see Drug Interactions (7.1)]. 2.5 Dose Modification for Use in Patients with Hepatic Impairment The recommended starting dose is 30 mg once daily in patients with hepatic impairment (Child-Pugh A, B, or C) [see Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed (8.2). 8.1 Pregnancy Risk Summary Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman [see Data]. There are no available data on Iclusig use in pregnant women. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the recommended human dose [see Data]. Advise pregnant women of the potential risk to a fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Data Animal Data Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3, 1, and 3 mg/kg/day during organogenesis (25 rats per group). At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification. Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the recommended dose) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification. 8.2 Lactation Risk Summary There is no data on the presence of ponatinib in human milk, the effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in breastfed infants from ponatinib including arterial occlusion, venous thromboembolism, heart failure, and hepatotoxicity, advise women not to breastfeed during treatment with Iclusig and for 6 days following the last dose. 8.3 Females and Males of Reproductive Potential Iclusig can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.1)]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Iclusig treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with Iclusig and for 3 weeks after the last dose. Infertility Based on animal data, ponatinib may impair fertility in females of reproductive potential. It is not known whether these effects on fertility are reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. Juvenile Animal Toxicity Data A juvenile toxicity study in 15-day-old rats was conducted with daily oral gavage administration of ponatinib at 0.75, 1.5, or 3 mg/kg/day for 21 days. There were no adverse effects of ponatinib on juvenile rat developmental parameters (vaginal opening, preputial separation or bone measurements) observed in this study. Once daily oral administration of 3 mg/kg/day ponatinib to juvenile rats beginning on Day 15 postpartum (pp) resulted in mortality related to inflammatory effects after 6 to 7 days following initiation of treatment. The dose of 3 mg/kg/day is approximately 0.32 times the clinical dose on a mg/m2 basis for a child. 8.5 Geriatric Use One hundred and fifty-five of 449 patients (35%) in the clinical trial of Iclusig were 65 years of age and over. In patients with CP-CML, patients of age ≥ 65 years had a lower major cytogenetic response rate (40%) as compared with patients < 65 years of age (65%). In patients with AP-CML, BP-CML, and Ph+ ALL, patients of age ≥ 65 years had a similar hematologic response rate (45%) as compared with patients < 65 years of age (44%). Forty percent of patients ≥ 65 years had arterial occlusion events. Patients of age ≥ 65 years are more likely to experience adverse reactions including vascular occlusion, decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment Administer Iclusig at a dose of 30 mg once daily in patients with hepatic impairment (Child-Pugh A, B, or C) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. In a single-dose (30 mg) pharmacokinetic (PK) study; compared to subjects with normal liver function, no major differences in ponatinib PK were observed in subjects with hepatic impairment (Child-Pugh A, B, or C). However, there was an increased overall incidence of adverse reactions (e.g., gastrointestinal disorders, including a case of severe pancreatitis) in the subjects with hepatic impairment following the single 30 mg dose compared to subjects with normal liver function. The safety of multiple ponatinib doses, or doses higher than 30 mg have not been studied in patients with hepatic impairment.

Interactions

7 DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid concurrent use, or reduce Iclusig dose if co-administration cannot be avoided (2.4, 7.1) Strong CYP3A Inducers: Avoid concurrent use (7.2) 7.1 Drugs That Are Strong Inhibitors of CYP3A Enzymes Based on in vitro studies, ponatinib is a substrate of CYP3A and to a lesser extent CYP2C8 and CYP2D6. In a drug interaction study in healthy volunteers, co-administration of Iclusig with ketoconazole increased plasma ponatinib AUC0-inf and Cmax by 78% and 47%, respectively [see Clinical Pharmacology (12.3)]. When administering Iclusig with strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose should be reduced [see Dosage and Administration (2.4)]. Patients taking concomitant strong CYP3A inhibitors may be at increased risk for adverse reactions [see Clinical Pharmacology (12.3)]. 7.2 Drugs That Are Strong Inducers of CYP3A Enzymes Coadministration of strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John's Wort) with Iclusig should be avoided unless the benefit outweighs the risk of decreased ponatinib exposure. Monitor patients for reduced efficacy. Selection of concomitant medication with no or minimal CYP3A induction potential is recommended. In a drug interaction study in healthy volunteers, co-administration of Iclusig following multiple doses of rifampin resulted in decreased ponatinib AUC0-inf and Cmax values by 62% and 42%, respectively [see Clinical Pharmacology (12.3)]. 7.3 Drugs That Elevate Gastric pH Iclusig may be co-administered with gastric pH-elevating medications. In a drug interaction study in healthy volunteers, co-administration of Iclusig following multiple doses of lansoprazole resulted in a minimal (6%) decrease in ponatinib exposure [see Clinical Pharmacology (12.3)]. 7.4 Drugs that are Substrates of the P-gp or ABCG2 Transporter Systems Ponatinib inhibits the P-glycoprotein (P-gp), ATP-binding cassette G2 (ABCG2) [also known as BCRP], and bile salt export pump (BSEP) transporter systems in vitro [see Clinical Pharmacology (12.3)].

More information

Category Value
Authorisation number NDA203469
Agency product number 96R6PU3D8J
Orphan designation No
Product NDC 63020-533,63020-535,63020-534
Date Last Revised 27-07-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1364352
Storage and handling Store Iclusig tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature]. Keep away from children.
Marketing authorisation holder Millenium Pharmaceuticals Inc.
Warnings WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY WARNING: ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY See full prescribing information for complete boxed warning. Arterial occlusion has occurred in at least 35% of Iclusig-treated patients including 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 less than 50 years old, experienced these events. Interrupt or stop Iclusig immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart Iclusig (5.1). Venous thromboembolism has occurred in 6% of Iclusig-treated patients. Monitor for evidence of thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism (5.2). Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure (5.3). Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected (2.3, 5.4). Arterial Occlusion: Arterial occlusions have occurred in at least 35% of Iclusig-treated patients. Some patients experienced more than 1 type of event. Events observed included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop Iclusig immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart Iclusig therapy (5.1). Venous Thromboembolism Venous occlusive events have occurred in 6% of Iclusig-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism (5.2). Heart Failure: Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure (5.3). Hepatotoxicity: Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected (2.3, 5.4).