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  • CLASSES

    Protein Kinase Inhibitors

    BOXED WARNING

    Cardiac disease, diabetes mellitus, hyperlipidemia, myocardial infarction or stroke, peripheral vascular disease

    Arterial occlusions (e.g., myocardial infarction or stroke, coronary artery occlusion, stenosis of large arterial vessels of the brain, mesenteric artery occlusion, and severe peripheral vascular disease) have occurred with ponatinib therapy. Digital or distal extremity necrosis requiring amputation has also occurred. Carefully consider the potential benefits compared with the risk of serious arterial occlusions prior to starting ponatinib. Hold or discontinue therapy in patients with a suspected or confirmed arterial occlusive event; perform a benefit-risk evaluation to determine whether to restart ponatinib therapy. Fatal and life-threatening arterial occlusions have been reported within 2 weeks of starting ponatinib and at doses as low as 15 mg/day. Patients with advanced age, cardiac disease or ischemia, diabetes mellitus, hyperlipidemia, and high blood pressure may be at increased risk for developing arterial occlusions. Recurrent or multi-site vascular occlusion has also been reported with ponatinib therapy; in some cases, occlusion occurred in patients without cardiac risk factors and in patients aged 50 years and younger. In a phase II trial, the time to onset of first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events ranged from 1 to 1,355 days.

    Thromboembolic disease, thrombophlebitis

    Venous thromboembolic disease (e.g., deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis) has occurred with ponatinib therapy. A dose reduction or therapy discontinuation may be necessary in patients who develop a serious venous thromboembolism.

    Hepatic disease, hepatotoxicity

    Severe hepatotoxicity, including fatal liver failure, has been reported with ponatinib therapy. Cases of irreversible elevated hepatic enzymes (e.g., increased AST and ALT levels) have also occurred with ponatinib use. Use ponatinib with caution in patients with hepatic disease; reduce the initial dose in patients with hepatic impairment. Monitor liver function tests at baseline and then at least monthly or as clinically indicated during therapy. Therapy interruption, dosage adjustment, or discontinuation may be necessary in patients who develop hepatotoxicity. The median time to onset of hepatotoxicity was 3 months (range, <1 to 47 months).

    Heart failure

    Congestive heart failure (CHF) or left ventricular dysfunction has been reported with ponatinib therapy; some cases were fatal. Monitor patients for signs and symptoms of CHF and treat as clinically indicated. Therapy interruption or discontinuation may be necessary in patients who develop new or worsening CHF.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral multi-tyrosine kinase inhibitor
    Approved for use in T315I-positive chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML) or T315I-positive Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL), or CP, AP, or BP CML or Ph+ALL where no other tyrosine kinase inhibitor is indicated; not recommended for use in patients with newly diagnosed, chronic phase CML
    Arterial occlusions and venous thrombosis have been reported; monitor for evidence of thromboembolism and arterial occlusions

    COMMON BRAND NAMES

    Iclusig

    HOW SUPPLIED

    Iclusig Oral Tab: 15mg, 45mg

    DOSAGE & INDICATIONS

    For the treatment of chronic myelogenous leukemia (CML).
    For the treatment of T315I-positive CML in chronic phase, accelerated phase, or blast phase.
    Oral dosage
    Adults

    45 mg by mouth once daily. The optimal dose of ponatinib is not established with 68% of patients requiring dose reductions to 30 mg or 15 mg once daily during clinical trials. Consider a dosage reduction for patients with CML in chronic phase or accelerated phase who have achieved a major cytogenetic response. Avoid the concomitant use of strong CYP 3A4 inducers if possible; a dose reduction is necessary if ponatinib is co-administered with a strong CYP 3A4 inhibitor. Temporary interruption of therapy and/or a dose reduction may be necessary in patients who develop toxicities. Consider discontinuing treatment if a response has not occurred by 90 days. Treatment with ponatinib (median treatment duration, 12.8 months) was evaluated in adult patients with chronic phase (CP, n = 267), accelerated phase (AP, n = 83), or blast phase (BP, n = 62) CML whose disease was resistant or intolerant to prior tyrosine kinase inhibitor therapy with dasatinib or nilotinib or had a T315I-positive mutation in a multi-national, open-label, phase II trial (PACE trial). At a median follow-up of 15 months, the primary endpoint of major cytogenetic response (MCyR) rate at 12 months was 56% and the complete cytogenetic response rate was 46% in CP-CML patients. The MCyR rate was 70% in the CP-CML cohort with the T315I mutation (n = 64). In patients with CP-CML who achieved a MCyR, the median time to response was 2.8 months (range, 1.6 to 11.3 months). The estimated 12-month progression-free survival (PFS) and overall survival (OS) rates were 80% and 94%, respectively. At a minimum follow-up of 48 months, the duration of MCyR ranged from 2.7 to 50.3+ months. Treatment with ponatinib resulted in 6-month major hematologic response (MaHR) rates (primary endpoint) of 55% and 31% in patients with AP-CML (median follow-up, 16 months) and BP-CML (median follow-up, 6 months), respectively. In the cohort of patients with the T315I mutation, the MaHR rate was 50% in patients with AP-CML (n = 18) and 29% in patients with BP-CML (n = 24). In patients with AP-CML and BP-CML who achieved a MaHR, the median times to response were 3 weeks (range, 2 to 25 weeks) and 4.1 weeks (range, 1.7 to 16.1 weeks), respectively. The estimated 12-month PFS rate was 55% for patients with AP-CML and 19% in patients with BP-CML; the estimated 12-month OS rates were 84% and 29%, respectively. At a minimum follow-up of 48 months, the median duration of MaHR was 12.9 months (range, 1.2 to 52+ months) and 6 months (range, 1.8 to 47.4+ months) in patients with AP-CML and BP-CML, respectively.

    For the treatment of chronic phase, accelerated phase, or blast phase CML for whom no other tyrosine kinase inhibitor therapy is indicated.
    Oral dosage
    Adults

    45 mg orally once daily. The optimal dosage of ponatinib is not established with 68% of patients requiring dosage reductions to 30 mg or 15 mg once daily during clinical trials. Consider dosage reduction for CP-CML and AP-CML patients who have achieved a major cytogenetic response. Avoid the concomitant use of strong 3A4 inducers if possible; a dose reduction is necessary if ponatinib is co-administered with a strong CYP3A4 inhibitor. Temporary interruption of therapy and/or a dose reduction may be necessary in patients who develop toxicity. Consider discontinuing treatment if a response has not occurred by 90 days. Treatment with ponatinib (median treatment duration, 12.8 months) was evaluated in adult patients with chronic phase (CP, n = 267), accelerated phase (AP, n = 83), or blast phase (BP, n = 62) CML whose disease was resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy with dasatinib or nilotinib or had a T315I-positive mutation in a multinational, open-label, phase II trial (PACE trial). At a median follow-up of 15 months, the primary endpoint of major cytogenic response (MCyR) rate at 12 months was 56% and the complete cytogenic response rate was 46% in CP-CML patients. The MCyR rate was 51% in the CP-CML cohort with resistance/intolerance to prior TKI therapy (n = 203). In patients with CP-CML who achieved a MCyR, the median time to response was 2.8 months (range, 1.6 to 11.3 months). The estimated 12-month progression-free survival (PFS) and overall survival (OS) rates were 80% and 94%, respectively. At a minimum follow-up of 48 months, the duration of MCyR ranged from 2.7 to 50.3+ months. Treatment with ponatinib resulted in 6-month major hematologic response (MaHR) rates (primary endpoint) of 55% and 31% in patients with AP-CML (median follow-up, 16 months) and BP-CML (median follow-up, 6 months), respectively. In the cohort of patients with resistance/intolerance to prior TKI therapy, the MaHR rate was 57% in patients with AP-CML (n = 65) and 32% in patients with BP-CML (n = 38). In patients with AP-CML and BP-CML who achieved a MaHR, the median times to response were 3 weeks (range, 2 to 25 weeks) and 4.1 weeks (range, 1.7 to 16.1 weeks), respectively. The estimated 12-month PFS rate was 55% for patients with AP-CML and 19% in patients with BP-CML; the estimated 12-month OS rates were 84% and 29%, respectively. At a minimum follow-up of 48 months, the median duration of MaHR was 12.9 months (range, 1.2 to 52+ months) and 6 months (range, 1.8 to 47.4+ months) in patients with AP-CML and BP-CML, respectively.

    For the treatment of newly diagnosed, chronic phase CML†.
    Oral dosage
    Adults

    Two clinical trials were stopped early due to a concern over an increased risk of ponatinib-related toxicity, particularly vascular thrombotic events and arterial occlusive events in patients with newly diagnosed, chronic phase CML. Ponatinib is not recommended for use in these patients.

    For the treatment of acute lymphocytic leukemia (ALL).
    For the treatment of T315I-positive, Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ ALL).
    Oral dosage
    Adults

    45 mg orally once daily. The optimal dosage is not established with 68% of patients requiring dosage reductions to 30 mg or 15 mg once daily during clinical trials. Avoid the concomitant use of strong 3A4 inducers if possible; a dose reduction is necessary if ponatinib is co-administered with a strong CYP3A4 inhibitor. Temporary interruption of therapy and/or a dose reduction may be necessary in patients who develop toxicity. Consider discontinuing treatment if a response has not occurred by 90 days. Treatment with ponatinib (median treatment duration, 12.8 months) was evaluated in 32 adult patients with Ph+ ALL whose disease was resistant or intolerant to prior tyrosine kinase inhibitor therapy with dasatinib or nilotinib or had a T315I-positive mutation in a multinational, open-label, phase II trial (PACE trial). At a median follow-up of 15 months, the major hematologic response (MaHR) rate at 6 months (primary endpoint) was 41% in Ph+ ALL patients; additionally, the complete hematologic response rate was 38%.The MaHR rate was 36% in the Ph+ ALL cohort with the T315I mutation (n = 22). In Ph+ ALL patients who achieved a MaHR, the median time to response was 2.9 weeks (range, 1.6 to 24 weeks) and the median duration of response was 3 months (range, 2 to 14+ months). The estimated 12-month progression-free survival and overall survival rates were 7% and 40%, respectively.

    For the treatment of Philadelphia chromosome positive acute lymphocytic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor therapy is indicated.
    Oral dosage
    Adults

    45 mg orally once daily. The optimal dosage is not established with 68% of patients requiring dosage reductions to 30 mg or 15 mg once daily during clinical trials. Avoid the concomitant use of strong 3A4 inducers if possible; a dose reduction is necessary if ponatinib is co-administered with a strong CYP3A4 inhibitor. Temporary interruption of therapy and/or a dose reduction may be necessary in patients who develop toxicity. Consider discontinuing treatment if a response has not occurred by 90 days. Treatment with ponatinib (median treatment duration, 12.8 months) was evaluated in 32 adult patients with Ph+ ALL whose disease was resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy with dasatinib or nilotinib or had a T315I-positive mutation in a multinational, open-label, phase II trial (PACE trial). At a median follow-up of 15 months, the major hematologic response (MaHR) rate at 6 months (primary endpoint) was 41% in Ph+ ALL patients; additionally, the complete hematologic response rate was 38%. The MaHR rate was 50% in the Ph+ ALL cohort with resistance/intolerance to prior TKI therapy (n = 10). In Ph+ ALL patients who achieved a MaHR, the median time to response was 2.9 weeks (range, 1.6 to 24 weeks) and the median duration of response was 3 months (range, 2 to 14+ months). The estimated 12-month progression-free survival and overall survival rates were 7% and 40%, respectively.

    MAXIMUM DOSAGE

    Adults

    45 mg/day PO; 30 mg/day PO if taking a strong 3A4 inhibitor.

    Geriatric

    45 mg/day PO; 30 mg/day PO if taking a strong 3A4 inhibitor.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Baseline Hepatic Impairment (Child-Pugh A, B, or C): 30 mg by mouth once daily.
    Dose Modification for Treatment-Induced Hepatotoxicity:
    Transaminase levels greater than 3-times the upper limit of normal (ULN) (grade 2 or higher): Hold ponatinib therapy until the toxicity resolves to grade 1 or less (less than 3-times the ULN), then resume therapy at a reduced dose (i.e., from 45 mg/day to 30 mg/day or from 30 mg/day to 15 mg/day). Discontinue therapy if Grade 2 or higher liver toxicity occurs at the 15 mg/day dosage.
    Transaminase levels 3-times the ULN or greater concurrently with bilirubin level greater than 2-times the ULN and alkaline phosphatase levels less than 2-times the ULN: Discontinue therapy.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. Ponatinib has not been studied in patients with renal impairment and the potential for moderate or severe renal impairment to affect hepatic elimination has not been determined. However, renal excretion is not a major route of ponatinib elimination.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    Ponatinib may be taken with or without food.
    Swallow tablets whole; do not crush or dissolve tablets.
    Do not take 2 doses at the same time if a dose is missed.
    A ponatinib dose adjustment is necessary in patients who ingest grapefruit juice.

    STORAGE

    Iclusig:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Cardiac disease, diabetes mellitus, hyperlipidemia, myocardial infarction or stroke, peripheral vascular disease

    Arterial occlusions (e.g., myocardial infarction or stroke, coronary artery occlusion, stenosis of large arterial vessels of the brain, mesenteric artery occlusion, and severe peripheral vascular disease) have occurred with ponatinib therapy. Digital or distal extremity necrosis requiring amputation has also occurred. Carefully consider the potential benefits compared with the risk of serious arterial occlusions prior to starting ponatinib. Hold or discontinue therapy in patients with a suspected or confirmed arterial occlusive event; perform a benefit-risk evaluation to determine whether to restart ponatinib therapy. Fatal and life-threatening arterial occlusions have been reported within 2 weeks of starting ponatinib and at doses as low as 15 mg/day. Patients with advanced age, cardiac disease or ischemia, diabetes mellitus, hyperlipidemia, and high blood pressure may be at increased risk for developing arterial occlusions. Recurrent or multi-site vascular occlusion has also been reported with ponatinib therapy; in some cases, occlusion occurred in patients without cardiac risk factors and in patients aged 50 years and younger. In a phase II trial, the time to onset of first cardiac vascular, cerebrovascular, and peripheral vascular arterial occlusive events ranged from 1 to 1,355 days.

    Thromboembolic disease, thrombophlebitis

    Venous thromboembolic disease (e.g., deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis) has occurred with ponatinib therapy. A dose reduction or therapy discontinuation may be necessary in patients who develop a serious venous thromboembolism.

    Hepatic disease, hepatotoxicity

    Severe hepatotoxicity, including fatal liver failure, has been reported with ponatinib therapy. Cases of irreversible elevated hepatic enzymes (e.g., increased AST and ALT levels) have also occurred with ponatinib use. Use ponatinib with caution in patients with hepatic disease; reduce the initial dose in patients with hepatic impairment. Monitor liver function tests at baseline and then at least monthly or as clinically indicated during therapy. Therapy interruption, dosage adjustment, or discontinuation may be necessary in patients who develop hepatotoxicity. The median time to onset of hepatotoxicity was 3 months (range, <1 to 47 months).

    Heart failure

    Congestive heart failure (CHF) or left ventricular dysfunction has been reported with ponatinib therapy; some cases were fatal. Monitor patients for signs and symptoms of CHF and treat as clinically indicated. Therapy interruption or discontinuation may be necessary in patients who develop new or worsening CHF.

    Alcoholism, pancreatitis

    Pancreatitis, treatment-emergent increased lipase levels, and hyperamylasemia have been reported with ponatinib therapy. Monitor serum lipase levels every 2 weeks for the first 2 months of ponatinib therapy, then monitor serum lipase levels monthly or as clinically indicated; consider additional monitoring in patients with a history of alcoholism or pancreatitis. Therapy interruption, dosage adjustment, or discontinuation may be necessary in patients who develop symptomatic elevated lipase levels or pancreatitis. In patients who have abdominal pain and elevated lipase levels, hold ponatinib therapy and evaluate for pancreatitis. Do not resume therapy until symptoms completely resolve and the lipase level is less than 1.5 times the upper limit of normal. The median time to onset of pancreatitis was 14 days (range, 3 to 1,452 days). Most cases of pancreatitis (74%) resolved within 2 weeks following therapy interruption or dose reduction.

    Bleeding, GI bleeding, intracranial bleeding

    Serious bleeding has been reported with ponatinib therapy, including GI bleeding and intracranial bleeding; some cases were fatal. Serious bleeding events occurred more frequently in patients with accelerated phase or blast phase chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. The majority of serious bleeding events occurred in patients who had grade 4 thrombocytopenia. Interrupt therapy and evaluate in patients who develop serious or severe bleeding.

    Ascites, edema, pericardial effusion, pleural effusion

    Serious fluid retention has been reported with ponatinib therapy, including fatal brain edema, pericardial effusion, pleural effusion, and ascites. Monitor patients for signs and symptoms of fluid retention and treat as clinically indicated. Therapy interruption, dosage adjustment, or discontinuation may be necessary in patients who develop serious fluid retention.

    Atrial fibrillation, atrial flutter, AV block, bradycardia, cardiac arrhythmias, QT prolongation, tachycardia

    Serious cardiac arrhythmias (e.g., atrial fibrillation, atrial flutter, AV block, bradycardia, tachycardia, QT prolongation) have been reported with ponatinib therapy. Hold therapy and evaluate if patients experience signs and symptoms of slow heart rate (e.g., fainting, dizziness) and rapid heart rate (e.g., palpitations, dizziness, and chest pain).

    Anemia, bone marrow suppression, leukopenia, neutropenia, thrombocytopenia

    Severe bone marrow suppression (e.g., anemia, leukopenia, neutropenia, and thrombocytopenia) has been reported with ponatinib therapy. Obtain a complete blood count (CBC) panel every 2 weeks for the first 3 months of ponatinib therapy, then monitor CBCs monthly or as clinically indicated. Therapy interruption and/or dose reduction may be necessary in patients who experience severe myelosuppression. Severe myelosuppression occurred more often in patients with accelerated phase or blast phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.

    Hyperuricemia, tumor lysis syndrome (TLS)

    Tumor lysis syndrome (TLS) and hyperuricemia have been reported with ponatinib use, particularly in patients with chronic myelogenous leukemia. Monitor uric acid levels. Provide adequate hydration and treat high uric acid levels prior to starting ponatinib therapy.

    Fistula, GI perforation, surgery

    Compromised wound healing is possible with ponatinib use based on its mechanism of action. One case of serious GI perforation/fistula was reported 38 days after a cholecystectomy procedure. Hold ponatinib therapy for at least 1 week prior to major surgery. After surgery, resume ponatinib therapy based on clinical judgment of adequate wound healing.

    Geriatric

    Geriatric patients (age >= 65 years) may experience a higher incidence of some ponatinib adverse events including asthenia, decreased appetite, decreased platelet count, dyspnea, increased lipase levels, muscle spasm, peripheral edema, and vascular occlusion; therefore, use ponatinib with caution in this patient population.

    Visual disturbance

    Ponatinib has been associated with serious visual disturbance leading to blurred vision or blindness. Serious adverse events including macular edema, retinal vein occlusion, and retinal hemorrhage have occurred. Ocular irritation, ocular pain, and dry eye have also been reported commonly. Conduct comprehensive eye exams at baseline and periodically throughout treatment. Counsel patients to promptly report symptoms of ocular toxicity.

    Hypertension, renal artery stenosis

    Serious hypertension including hypertensive crisis has been reported with ponatinib use. Renal artery stenosis associated with worsening, labile, or treatment-resistant hypertension has also occurred. Patients with pre-existing hypertension may be at increased risk for developing arterial occlusions. Monitor for and manage hypertension; treatment interruption, dose reduction, or discontinuation may be necessary. Hold ponatinib and consider a diagnosis of renal artery stenosis if a patient develops worsening, labile, or treatment-resistant hypertension.

    Neurotoxicity, peripheral neuropathy

    Neurotoxicity including peripheral neuropathy has been reported with ponatinib use. Monitor patients for symptoms of neuropathy such as hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, and neuropathic pain or weakness; consider interrupting therapy if neuropathy is suspected.

    Pregnancy

    Ponatinib may cause fetal harm in pregnant women based on its mechanism of action and data from animal studies. Females of reproductive potential should be advised to avoid pregnancy while taking ponatinib. Women who become pregnant while receiving ponatinib should be apprised of the potential hazard to the fetus. Embryo-fetal toxicity (e.g., increased resorptions, reduced body weight, external alterations, multiple fetal soft tissue and skeletal alterations, and reduced ossification) occurred in rats when ponatinib was administered during organogenesis; doses given in these studies resulted in ponatinib exposures that were less than the human exposure of ponatinib.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during ponatinib treatment. Pregnancy testing should be performed prior to starting ponatinib in female patients of reproductive potential. These patients should avoid pregnancy and use effective contraception during and for 3 weeks after the last ponatinib dose. Women who become pregnant while receiving ponatinib should be apprised of the potential hazard to the fetus. Infertility may occur with ponatinib use in females based on animal data. It is not known whether fertility effects are reversible.

    Breast-feeding

    It is not known if ponatinib is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in breast-fed infants including arterial occlusion, venous thromboembolism, heart failure, and hepatotoxicity, women should discontinue breast-feeding during ponatinib therapy and for 6 days after the last dose.

    ADVERSE REACTIONS

    Severe

    leukopenia / Delayed / 12.0-63.0
    neutropenia / Delayed / 23.0-59.0
    anemia / Delayed / 8.0-52.0
    thrombocytopenia / Delayed / 35.0-49.0
    lymphopenia / Delayed / 10.0-32.0
    myocardial infarction / Delayed / 0-21.0
    keratitis / Delayed / 0-14.0
    corneal erosion / Delayed / 0-14.0
    infection / Delayed / 0-13.0
    hypertensive crisis / Early / 12.0-12.0
    abdominal pain / Early / 6.0-10.0
    hypophosphatemia / Delayed / 10.0-10.0
    pulmonary edema / Early / 0-9.0
    heart failure / Delayed / 9.0-9.0
    stroke / Early / 0-9.0
    elevated hepatic enzymes / Delayed / 2.0-8.0
    pleural effusion / Delayed / 8.0-8.0
    asthenia / Delayed / 3.0-8.0
    fatigue / Early / 3.0-8.0
    atrial fibrillation / Early / 7.0-7.0
    pancreatitis / Delayed / 7.0-7.0
    rash (unspecified) / Early / 3.0-7.0
    hyperglycemia / Delayed / 7.0-7.0
    bleeding / Early / 6.0-6.0
    thromboembolism / Delayed / 6.0-6.0
    dyspnea / Early / 0-5.0
    hyponatremia / Delayed / 5.0-5.0
    pericardial effusion / Delayed / 4.0-4.0
    fluid retention / Delayed / 4.0-4.0
    fever / Early / 0-4.0
    hyperamylasemia / Delayed / 3.0-3.0
    diarrhea / Early / 1.0-3.0
    stomatitis / Delayed / 0-3.0
    constipation / Delayed / 0-3.0
    oral ulceration / Delayed / 0-3.0
    dysgeusia / Early / 0-3.0
    hypotonia / Delayed / 0-3.0
    peripheral neuropathy / Delayed / 0-3.0
    headache / Early / 0-3.0
    restless legs syndrome (RLS) / Delayed / 0-3.0
    weakness / Early / 0-3.0
    xerosis / Delayed / 0-3.0
    arthralgia / Delayed / 0-3.0
    bone pain / Delayed / 0-3.0
    musculoskeletal pain / Early / 0-3.0
    thrombosis / Delayed / 2.2-2.2
    syncope / Early / 2.0-2.0
    hematemesis / Delayed / 0-2.0
    GI bleeding / Delayed / 2.0-2.0
    nausea / Early / 0-2.0
    vomiting / Early / 0-2.0
    pruritus / Rapid / 0-2.0
    back pain / Delayed / 0-2.0
    chills / Rapid / 0-2.0
    hypokalemia / Delayed / 2.0-2.0
    hyperkalemia / Delayed / 2.0-2.0
    retinal thrombosis / Delayed / 0-2.0
    retinal hemorrhage / Delayed / 0-2.0
    macular edema / Delayed / 0-2.0
    pulmonary embolism / Delayed / 1.6-1.6
    bradycardia / Rapid / 0.4-1.0
    hepatic failure / Delayed / 0-1.0
    hypoalbuminemia / Delayed / 0-1.0
    hyperbilirubinemia / Delayed / 0-1.0
    intracranial bleeding / Delayed / 1.0-1.0
    cerebral edema / Early / 0-1.0
    peripheral edema / Delayed / 0-1.0
    tumor lysis syndrome (TLS) / Delayed / 0-1.0
    gastrointestinal fistula / Delayed / 0-1.0
    GI perforation / Delayed / 0-1.0
    anorexia / Delayed / 0-1.0
    erythema / Early / 0-1.0
    myalgia / Early / 0-1.0
    weight loss / Delayed / 0-1.0
    hypocalcemia / Delayed / 0-1.0
    hypernatremia / Delayed / 0-1.0
    metabolic acidosis / Delayed / 0-1.0
    hypertriglyceridemia / Delayed / 0-1.0
    nephrotoxicity / Delayed / 0-1.0
    atrial tachycardia / Early / 0.2-0.2
    AV block / Early / 0.2-0.2
    cardiac arrest / Early / 0.2-0.2
    ventricular tachycardia / Early / 0.2-0.2
    atrial flutter / Early / 0.2-0.2
    respiratory arrest / Rapid / 0.2-0.2
    avascular necrosis / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known

    Moderate

    iritis / Delayed / 0-14.0
    hyperemia / Delayed / 0-14.0
    conjunctivitis / Delayed / 0-14.0
    cataracts / Delayed / 0-14.0
    hypoglycemia / Early / 13.0-13.0
    hypercalcemia / Delayed / 12.0-12.0
    hyperuricemia / Delayed / 7.0-7.0
    blurred vision / Early / 6.0-6.0
    melena / Delayed / 0-2.0
    subdural hematoma / Early / 1.0-1.0
    phlebitis / Rapid / 0.7-0.7
    sinus tachycardia / Rapid / 0.4-0.4
    supraventricular tachycardia (SVT) / Early / 0.2-0.2
    QT prolongation / Rapid / 0.2-0.2
    ascites / Delayed / Incidence not known
    chest pain (unspecified) / Early / Incidence not known

    Mild

    cough / Delayed / 6.0-22.0
    pharyngitis / Delayed / 3.0-18.0
    dizziness / Early / 3.0-16.0
    ocular irritation / Rapid / 0-14.0
    ocular pain / Early / 0-14.0
    xerophthalmia / Early / 0-14.0
    muscle cramps / Delayed / 5.0-13.0
    insomnia / Early / 11.0-13.0
    alopecia / Delayed / 6.0-11.0

    DRUG INTERACTIONS

    Aliskiren: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and aliskiren, a P-gp substrate, may increase the exposure of aliskiren.
    Aliskiren; Amlodipine: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and aliskiren, a P-gp substrate, may increase the exposure of aliskiren.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and aliskiren, a P-gp substrate, may increase the exposure of aliskiren.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and aliskiren, a P-gp substrate, may increase the exposure of aliskiren.
    Aliskiren; Valsartan: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and aliskiren, a P-gp substrate, may increase the exposure of aliskiren.
    Aluminum Hydroxide: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Aluminum Hydroxide; Magnesium Carbonate: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Aluminum Hydroxide; Magnesium Hydroxide: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Aluminum Hydroxide; Magnesium Trisilicate: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and clarithromycin, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as lansoprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib may increase the plasma concentration of a P-gp substrate such as, lansoprazole.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and clarithromycin, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as omeprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib may increase the plasma concentration of a P-gp substrate such as, omeprazole.
    Antacids: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Aspirin, ASA; Omeprazole: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as omeprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib may increase the plasma concentration of a P-gp substrate such as, omeprazole.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenobarbital, unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenobarbital, unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Boceprevir: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and boceprevir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, boceprevir.
    Calcium Carbonate: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Calcium Carbonate; Risedronate: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Calcium; Vitamin D: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Carbamazepine: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as carbamazepine, unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. In addition myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution.
    Chloroquine: (Moderate) Concurrent use of chloroquine and ponatinib is not recommended as there is an increased risk of retinal toxicity.
    Clarithromycin: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and clarithromycin, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Colchicine: (Major) Concomitant use of ponatinib, a P-gp inhibitor, and colchicine, a P-gp substrate, may increase the exposure of colchicine. Life-threatening and fatal drug interactions have been reported in patients treated with colchicine given with P-gp inhibitors. If treatment with a P-gp inhibitor is required in patients with normal renal and hepatic function, the colchicine dose may need to be reduced or interrupted. Use of colchicine with P-gp inhibitors is contraindicated in patients with renal or hepatic impairment.
    Conivaptan: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and conivaptan, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Dabigatran: (Major) Concomitant use of ponatinib, a P-gp inhibitor, and dabigatran, a P-gp substrate, may increase the exposure of dabigatran. Concomitant use of P-gp inhibitors in patients with renal impairment may result in increased exposure of dabigatran compared to that seen with either factor alone. The use of dabigatran and P-gp inhibitors in patients with severe renal impairment (creatinine clearance of 15-30 ml/min) should be avoided.
    Dapagliflozin; Saxagliptin: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and saxagliptin, a P-gp substrate, may increase the exposure of saxagliptin.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Concomitant use of ponatinib and dasabuvir; ombitasvir; paritaprevir; ritonavir may increase systemic exposures of all 5 drugs. Ponatinib is a CYP3A4 substrate, and ritonavir is a strong CYP3A4 inhibitor. If use of ponatinib and a ritonavir-containing medication is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor, while dasabuvir, paritaprevir, ombitasvir and ritonavir are all P-gp substrates. (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and ritonavir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, ritonavir.
    Delavirdine: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and delavirdine, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Dexlansoprazole: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as dexlansoprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Dichlorphenamide: (Moderate) Use dichlorphenamide and ponatinib together with caution as both drugs can cause metabolic acidosis. Concurrent use may increase the severity of metabolic acidosis. Measure sodium bicarbonate concentrations at baseline and periodically during dichlorphenamide treatment. If metabolic acidosis occurs or persists, consider reducing the dose or discontinuing dichlorphenamide therapy.
    Digoxin: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and digoxin, a P-gp substrate, may increase the exposure of digoxin. Monitor serum digoxin concentrations if these agents are used together.
    Enzalutamide: (Major) Avoid coadministration of ponatinib with enzalutamide if possible due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Esomeprazole: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as esomeprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Esomeprazole; Naproxen: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as esomeprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Everolimus: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and everolimus, a P-gp substrate, may increase the exposure of everolimus. Use caution when everolimus is used in combination with P-gp inhibitors. If these agents are used together, reduce the everolimus (Afinitor) dose.
    Fexofenadine: (Moderate) Concomitant use of ponatinib, a P-glycoprotein (P-gp) inhibitor, and fexofenadine, a P-gp substrate, may increase the exposure of fexofenadine.
    Fexofenadine; Pseudoephedrine: (Moderate) Concomitant use of ponatinib, a P-glycoprotein (P-gp) inhibitor, and fexofenadine, a P-gp substrate, may increase the exposure of fexofenadine.
    Fosphenytoin: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate,with a strong CYP3A4 inducer such as phenytoin or fosphenytoin, unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Grapefruit juice: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate and grapefruit juice, a CYP3A4 inhibitor, as ponatinib plasma exposure may increase.
    H2-blockers: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and H2-blockers may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with H2-blockers unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Imatinib: (Moderate) Concomitant use of ponatinib, a CYP3A4 substrate, and imatinib, STI-571, a CYP3A4 inhibitor, may increase the exposure of ponatinib. The manufacturer recommends a reduced starting ponatinib dose when use of a strong CYP3A4 inhibitor cannot be avoided. Additionally, ponatinib may increase the plasma concentration of P-gp and ABCG2 (BCRP) substrates, such as imatinib.
    Indinavir: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and indinavir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, indinavir.
    Irinotecan: (Moderate) Concomitant use of ponatinib, an ABCG2 (BCRP) inhibitor, and irinotecan, an ABCG2 (BCRP) substrate, may increase the exposure of irinotecan.
    Isoniazid, INH: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and isoniazid, INH, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as rifampin, unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, rifampin. (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and isoniazid, INH, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as rifampin, unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, rifampin. (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and isoniazid, INH, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Itraconazole: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and itraconazole, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Ketoconazole: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and ketoconazole, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. Coadministration of a single oral dose of ponatinib 15 mg with ketoconazole 400 mg daily increased AUC and Cmax values by 78% and 47%, respectively, compared with ponatinib alone in a drug interaction study in 22 healthy volunteers. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Lansoprazole: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as lansoprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib may increase the plasma concentration of a P-gp substrate such as, lansoprazole.
    Lansoprazole; Naproxen: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as lansoprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib may increase the plasma concentration of a P-gp substrate such as, lansoprazole.
    Lapatinib: (Moderate) Concomitant use of ponatinib, a CYP3A4 substrate, and lapatinib, a CYP3A4 inhibitor, may increase the exposure of ponatinib. The manufacturer recommends a reduced starting ponatinib dose when use of a strong CYP3A4 inhibitor cannot be avoided. Additionally, ponatinib may increase the plasma concentration of P-gp and ABCG2 (BCRP) substrates, such as lapatinib.
    Lopinavir; Ritonavir: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and lopinavir; ritonavir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and ritonavir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, ritonavir.
    Magnesium Hydroxide: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Maraviroc: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and maraviroc, a P-gp substrate, may increase the exposure of maraviroc.
    Metformin; Saxagliptin: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and saxagliptin, a P-gp substrate, may increase the exposure of saxagliptin.
    Metformin; Sitagliptin: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and sitagliptin, a P-gp substrate, may increase the exposure of sitagliptin.
    Methotrexate: (Moderate) Concomitant use of ponatinib, an ABCG2 (BCRP) inhibitor, and methotrexate, an ABCG2 (BCRP) substrate, may increase the exposure of methotrexate.
    Mitoxantrone: (Moderate) Concomitant use of ponatinib, an ABCG2 (BCRP) inhibitor, and mitoxantrone, an ABCG2 (BCRP) substrate, may increase the exposure of mitoxantrone.
    Nefazodone: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and nefazodone, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Nelfinavir: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and nelfinavir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, nelfinavir.
    Nilotinib: (Moderate) Concomitant use of ponatinib, a CYP3A4 substrate, and nilotinib, a CYP3A4 inhibitor, may increase the exposure of ponatinib. The manufacturer recommends a reduced starting ponatinib dose when use of a strong CYP3A4 inhibitor cannot be avoided. Additionally, ponatinib may increase the plasma concentration of P-gp substrates, such as nilotinib.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Concomitant use of ponatinib and dasabuvir; ombitasvir; paritaprevir; ritonavir may increase systemic exposures of all 5 drugs. Ponatinib is a CYP3A4 substrate, and ritonavir is a strong CYP3A4 inhibitor. If use of ponatinib and a ritonavir-containing medication is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor, while dasabuvir, paritaprevir, ombitasvir and ritonavir are all P-gp substrates. (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and ritonavir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, ritonavir.
    Omeprazole: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as omeprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib may increase the plasma concentration of a P-gp substrate such as, omeprazole.
    Omeprazole; Sodium Bicarbonate: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as omeprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib may increase the plasma concentration of a P-gp substrate such as, omeprazole.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pantoprazole: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as pantoprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib may increase the plasma concentration of a P-gp substrate such as, pantoprazole.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Phenobarbital: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenobarbital, unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Phenytoin: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as phenytoin, unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Posaconazole: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and posaconazole, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, posaconazole.
    Rabeprazole: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and proton-pump inhibitors, such as rabeprazole, may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with proton-pump inhibitors unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Ranolazine: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and ranolazine, a P-gp substrate, may increase the exposure of ranolazine. If these agents are used together, down-titrate ranolazine based on clinical response in patients concomitantly treated with P-gp inhibitors.
    Rifampin: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as rifampin, unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, rifampin.
    Ritonavir: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and ritonavir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, ritonavir.
    Rosuvastatin: (Major) Concomitant use of ponatinib, an ABCG2 (BCRP) inhibitor, and rosuvastatin, an ABCG2 (BCRP) substrate, may increase the exposure of rosuvastatin.
    Saquinavir: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and saquinavir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, saquinavir.
    Saxagliptin: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and saxagliptin, a P-gp substrate, may increase the exposure of saxagliptin.
    Simvastatin; Sitagliptin: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and sitagliptin, a P-gp substrate, may increase the exposure of sitagliptin.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and antineoplastic agents should be avoided. Concurrent administration of antineoplastic agents with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving antineoplastic agents may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of antineoplastic agents prior to initiating therapy with sipuleucel-T.
    Sirolimus: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and sirolimus, a P-gp substrate, may increase the exposure of sirolimus. Use caution when sirolimus is used in combination with P-gp inhibitors. If these agents are used together, the sirolimus dosage may need to be adjusted. Because sirolimus is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Sitagliptin: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and sitagliptin, a P-gp substrate, may increase the exposure of sitagliptin.
    Sodium Bicarbonate: (Major) Ponatinib displays pH-dependent aqueous solubility; therefore, concomitant use of ponatinib and antacids may result in decreased bioavailability and plasma exposure of ponatinib. Avoid concomitant use of ponatinib with antacids unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of ponatinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as St. John's Wort, unless the benefit outweighs the possible risk of ponatinib underexposure. If the use of both agents is necessary, monitor patients for signs of reduced efficacy.
    Streptogramins: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and dalfopristin; quinupristin, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Sulfasalazine: (Moderate) Concomitant use of ponatinib, an ABCG2 (BCRP) inhibitor, and sulfasalazine, an ABCG2 (BCRP) substrate, may increase the exposure of sulfasalazine.
    Telaprevir: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and telaprevir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Telithromycin: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and telithromycin, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.
    Tolvaptan: (Moderate) Concomitant use of ponatinib, a P-gp inhibitor, and tolvaptan, a P-gp substrate, may increase the exposure of tolvaptan. If these agents are used together, the tolvaptan dosage may need to be reduced based on clinical response.
    Topotecan: (Moderate) Concomitant use of ponatinib, a P-gp and ABCG2 (BCRP) inhibitor, and topotecan, a P-gp and ABCG2 (BCRP) substrate, may increase the exposure of topotecan. If these drugs are used together, carefully monitor patients for topotecan adverse reactions such as bone marrow suppression and severe diarrhea.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Voriconazole: (Major) Concomitant use of ponatinib, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day.

    PREGNANCY AND LACTATION

    Pregnancy

    Ponatinib may cause fetal harm in pregnant women based on its mechanism of action and data from animal studies. Females of reproductive potential should be advised to avoid pregnancy while taking ponatinib. Women who become pregnant while receiving ponatinib should be apprised of the potential hazard to the fetus. Embryo-fetal toxicity (e.g., increased resorptions, reduced body weight, external alterations, multiple fetal soft tissue and skeletal alterations, and reduced ossification) occurred in rats when ponatinib was administered during organogenesis; doses given in these studies resulted in ponatinib exposures that were less than the human exposure of ponatinib.

    It is not known if ponatinib is secreted in human milk or if it has effects on the breast-fed infant or on milk production. Due to the risk of serious adverse reactions in breast-fed infants including arterial occlusion, venous thromboembolism, heart failure, and hepatotoxicity, women should discontinue breast-feeding during ponatinib therapy and for 6 days after the last dose.

    MECHANISM OF ACTION

    Ponatinib is an oral multi-tyrosine kinase inhibitor (TKI). In vitro, ponatinib inhibits BCR-ABL (IC50 concentration, 0.4 nanomolar (nM)) and T315I-mutant BCR-ABL (IC50 concentration, 2 nM) in addition to other tyrosine kinase proteins such as VEGFR, PDGFR, FGFR, EPH, Src family kinases, KIT, RET, FLT-3, and TIE-2 (IC50 concentration range, 0.1—20 nM) that promote the growth and development of cancer cells. In tumor cells with native or mutant BCR-ABL, including T315I mutant ABL, ponatinib inhibited growth in vitro and resulted in reduced tumor size in mice models. The Philadelphia chromosome encodes for the BCR-ABL oncogene and is found in most chronic myelogenous leukemia cells. A common mutation occurs in the kinase domain caused by a substitution of a threonine residue with isoleucine at amino acid position 315 (T315I mutation). This mutation causes drug resistance to imatinib and some second generation TKI agents such as nilotinib and dasatinib. The T315I mutation prevents the formation of an important hydrogen bond between TKI agents and T315 of the BCR-ABL molecule. Ponatinib was designed to bind while allowing for the accommodation of the bulky isoleucine side chain. It also has activity against several other BCR-ABL mutations including the E255K, Y253H, and G250E mutations.

    PHARMACOKINETICS

    Ponatinib is administered orally. It is highly bound to plasma proteins (> 99%) in vitro. Following oral doses of 45 mg/day for 28 days, the geometric mean apparent volume of distribution was 1223 liters and the geometric mean terminal elimination half-life was 24 hours (range, 12—66 hours) in patients with cancer. Ponatinib undergoes phase I and II metabolism in the liver (64% or more of the dose); it is also metabolized by esterases and/or amidases. In vitro, it is a substrate of the CYP3A/54 isoenzyme (primarily) and of the CYP2C8 and CYP2D6 isoenzymes. It is a P-glycoprotein (P-gp) inhibitor and a weak substrate of P-gp and ABCG2 (BCRP). Following a single oral dose of 14C-ponatinib, about 87% of the total radioactivity was recovered in the feces and about 5% of the radioactivity was recovered in the urine.
     
    Affected cytochrome P450 isoenzymes and drug transporters:  CYP3A4, CYP3A5, CYP2C9, CYP2D6, P-gp, BRCP, BSEP
    In vitro, ponatinib is a substrate of the CYP3A4 isoenzyme (primary) and of the CYP3A5, CYP2C8, and CYP2D6 isoenzymes to a lesser extent. It is an inhibitor and a weak substrate of P-glycoprotein (P-gp) and ABCG2 (BCRP) and an inhibitor of the bile salt export pump (BSEP) transporter systems in vitro. The starting dose should be reduced if concurrent use with a strong CYP3A4 inhibitor cannot be avoided. Avoid concomitant use with strong CYP3A4 inducers unless the benefit outweighs the possible risk of ponatinib underexposure. Additionally, ponatinib may increase the plasma concentration of P-gp or ABCG2 (BCRP) substrates.

    Oral Route

    The absolute bioavailability of ponatinib is not known. The aqueous solubility of ponatinib is pH dependent with higher pH levels corresponding to lower solubility and reduced bioavailability. Following a single ponatinib oral dose, the time to peak plasma concentration (Tmax) was 6 hours. In patients with advanced hematologic malignancies who received oral ponatinib 45 mg/day, the steady-state geometric mean maximum plasma concentration (Cmax) and AUC values were 73 nanograms (ng)/ml and 1253 ng X hour/ml, respectively. The median exposure increased by about 90% (range, 20%—440%) between the first dose and steady-state in cancer patients who received ponatinib 45 mg/day for 28 days. A ponatinib investigational capsule formulation exhibited dose proportional increases in Cmax and AUC values over a dose range of 15 to 60 mg in patients with cancer. The Cmax and AUC values did not significantly increase when ponatinib was administered with a high-fat or low-fat meal compared with fasting conditions in 22 healthy subjects; therefore, ponatinib may be taken with or without food.