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  • CLASSES

    Small Molecule Antineoplastic Breakpoint Cluster Region-Abelson (BCR-ABL) Inhibitors

    BOXED WARNING

    Cardiac disease, diabetes mellitus, hypercholesterolemia, occlusive vascular disease

    Arterial occlusive vascular disease/arterial occlusive events (AOEs) including myocardial infarction, stroke, stenosis of large arterial vessels of the brain, and severe peripheral vascular disease have been reported with ponatinib therapy; some cases required urgent revascularization procedures or were fatal. Monitor patients for evidence of AOEs. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or severity. Consider the benefits and risks prior to restarting ponatinib therapy. AOEs have occurred in patients without cardiac risk factors and in patients aged 50 years and younger. However, patients with advanced age, cardiac disease or ischemia, diabetes mellitus, hypercholesterolemia, and high blood pressure may be at increased risk for developing arterial AOEs.

    Thromboembolism

    Venous thromboembolism/venous thromboembolic events (VTEs) including deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis have been reported with ponatinib therapy. Monitor patients for evidence of VTEs. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or severity.

    Hepatic disease, hepatotoxicity

    Hepatotoxicity has been reported with ponatinib therapy; hepatic failure and death have occurred. Monitor liver function tests at baseline and then at least monthly or as clinically indicated during therapy. An initial dosage reduction is required in patients with baseline hepatic disease (Childs-Pugh class A, B, or C). Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or the severity of hepatotoxicity.

    Heart failure

    Heart failure events including congestive heart failure, decreased ejection fraction, and left ventricular hypertrophy have been reported with ponatinib therapy; some cases were fatal. Monitor patients for signs and symptoms of heart failure and manage as clinically indicated. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop new or worsening heart failure.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral multi-tyrosine kinase inhibitor (TKI)
    Used for 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); AP or BP CML or Ph+ ALL where no other tyrosine kinase inhibitor is indicated; or CP CML with resistance or intolerance to at least 2 prior TKIs
    Black box warning for arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity

    COMMON BRAND NAMES

    Iclusig

    HOW SUPPLIED

    Iclusig/Ponatinib 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 orally once daily until loss of response or unacceptable toxicity; consider discontinuing ponatinib therapy if a response has not occurred by 3 months. The optimal dose of ponatinib has not been established. Consider a dosage reduction for patients with CML in accelerated phase who have achieved a major cytogenetic response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with ponatinib 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 (dasatinib or nilotinib) or had a T315I-positive mutation in a randomized, open-label, phase 2 trial (PACE trial). After a median follow-up of 40.5 months, major cytogenetic response (MCyR) occurred in 55% of the overall population of patients with CP-CML and in 70% of the cohort of patients with a T315I mutation. A complete cytogenetic response (CCyR) occurred in 46% and 66% of patients, respectively. The median time to MCyR was 3 months; with a minimum follow-up of 60 months, the median duration had not been reached. Treatment with ponatinib resulted in a major hematologic response (MaHR) in 57% of patients with AP-CML (complete hematologic response [CHR], 51%) and in 31% of patients with BP-CML (CHR, 21%). The median time to MaHR was 0.8 months in patients with AP-CML and 1 month in those with BP-CML; the median duration of response was 14 months and 6.4 months, respectively.

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

    45 mg orally once daily until loss of response or unacceptable toxicity; consider discontinuing ponatinib therapy if a response has not occurred by 3 months. The optimal dose of ponatinib has not been established. Consider a dosage reduction for patients with CML in accelerated phase who have achieved a major cytogenetic response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with ponatinib 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 (dasatinib or nilotinib) or had a T315I-positive mutation in a multinational, open-label, phase 2 trial (PACE trial). After a median follow-up of 40.5 months, major cytogenetic response (MCyR) occurred in 55% of the overall population of patients with CP-CML; and 51% in the cohort of patients with resistance or intolerance to prior TKI therapy. A complete cytogenetic response (CCyR) occurred in 46% and 40% of patients, respectively. The median time to MCyR was 3 months; with a minimum follow-up of 60 months, the median duration had not been reached. Treatment with ponatinib resulted in a major hematologic response (MaHR) in 57% of patients with AP-CML (complete hematologic response [CHR], 51%) and in 31% of patients with BP-CML (CHR, 21%). The median time to MaHR was 0.8 months in patients with AP-CML and 1 month in those with BP-CML; the median duration of response was 14 months and 6.4 months, 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 chronic phase CML in patients with resistance or intolerance to at least 2 prior tyrosine kinase inhibitors.
    Oral dosage
    Adults

    45 mg orally once daily; reduce the dose to 15 mg PO once daily upon achievement of 1% or less BCR-ABL1. If loss of response occurs, the dose may be re-escalated to a previously tolerated dose of 30 mg or 45 mg PO once daily; in this case, continue ponatinib until loss of response at the re-escalated dose or unacceptable toxicity. Consider discontinuing ponatinib therapy if a response has not occurred by 3 months. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In a dose-optimization trial (the OPTIC trial), patients with chronic phase (CP) CML that was resistant or intolerant to at least 2 prior kinase inhibitors or who have the T315I mutation were treated with ponatinib at starting doses of 15 mg, 30 mg, or 45 mg once daily. After a median follow-up of 28.5 months, the major efficacy outcome of 1% or less BCR-ABL occurred in 42% of patients in the cohort of patients receiving a starting dose of 45 mg per day (n = 93); this rate was unchanged in patients with a T315I mutation. A major cytogenetic response (MCyR) was achieved by 12 months in 49% of patients who received a starting dose of 45 mg once daily. A response was maintained at the reduced dose of 15 mg in 73% of patients; the median duration of response was not reached.

    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 until loss of response or unacceptable toxicity; consider discontinuing ponatinib therapy if a response has not occurred by 3 months. The optimal dose of ponatinib has not been established. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with ponatinib was evaluated in adult patients with chronic phase (CP, n = 267), accelerated phase (AP, n = 83), blast phase (BP, n = 62) CML, or Philadelphia chromosome positive (Ph+) ALL (n = 32) whose disease was resistant or intolerant to prior tyrosine kinase inhibitor therapy (dasatinib or nilotinib) or had a T315I-positive mutation in a multinational, open-label, phase 2 trial (PACE trial). Treatment with ponatinib resulted in a major hematologic response (MaHR) in 41% of patients with Ph+ ALL; the rate of complete hematologic response (CHR) was 34%. The median time to MaHR was 0.7 months in patients with Ph+ ALL; the median duration of response was 3.5 months.

    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 until loss of response or unacceptable toxicity; consider discontinuing ponatinib therapy if a response has not occurred by 3 months. The optimal dose of ponatinib has not been established. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treatment with ponatinib was evaluated in adult patients with chronic phase (CP, n = 267), accelerated phase (AP, n = 83), blast phase (BP, n = 62) CML, or Philadelphia chromosome positive (Ph+) ALL (n = 32) whose disease was resistant or intolerant to prior tyrosine kinase inhibitor therapy (dasatinib or nilotinib) or had a T315I-positive mutation in a multinational, open-label, phase 2 trial (PACE trial). Treatment with ponatinib resulted in a major hematologic response (MaHR) in 41% of patients with Ph+ ALL; the rate of complete hematologic response (CHR) was 34%. The median time to MaHR was 0.7 months in patients with Ph+ ALL; the median duration of response was 3.5 months.

    MAXIMUM DOSAGE

    Adults

    45 mg/day PO.

    Geriatric

    45 mg/day PO.

    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
    Mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C): Reduce the starting dose to 30 mg by mouth once daily.
     Treatment Related Hepatotoxicity
    AST or ALT greater than 3 times ULN: Hold ponatinib therapy. Upon resolution to grade 1 or less, resume treatment at the next lower dose.
    AST or ALT at least 3 times ULN concurrent with bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULN: Discontinue ponatinib 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 break, crush, cut, chew, 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, hypercholesterolemia, occlusive vascular disease

    Arterial occlusive vascular disease/arterial occlusive events (AOEs) including myocardial infarction, stroke, stenosis of large arterial vessels of the brain, and severe peripheral vascular disease have been reported with ponatinib therapy; some cases required urgent revascularization procedures or were fatal. Monitor patients for evidence of AOEs. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or severity. Consider the benefits and risks prior to restarting ponatinib therapy. AOEs have occurred in patients without cardiac risk factors and in patients aged 50 years and younger. However, patients with advanced age, cardiac disease or ischemia, diabetes mellitus, hypercholesterolemia, and high blood pressure may be at increased risk for developing arterial AOEs.

    Thromboembolism

    Venous thromboembolism/venous thromboembolic events (VTEs) including deep venous thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis have been reported with ponatinib therapy. Monitor patients for evidence of VTEs. Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or severity.

    Hepatic disease, hepatotoxicity

    Hepatotoxicity has been reported with ponatinib therapy; hepatic failure and death have occurred. Monitor liver function tests at baseline and then at least monthly or as clinically indicated during therapy. An initial dosage reduction is required in patients with baseline hepatic disease (Childs-Pugh class A, B, or C). Therapy interruption, a dosage reduction, or discontinuation may be necessary based on recurrence or the severity of hepatotoxicity.

    Heart failure

    Heart failure events including congestive heart failure, decreased ejection fraction, and left ventricular hypertrophy have been reported with ponatinib therapy; some cases were fatal. Monitor patients for signs and symptoms of heart failure and manage as clinically indicated. Therapy interruption, a dosage reduction, or discontinuation may be necessary in patients who develop new or worsening heart failure.

    Alcoholism, pancreatitis

    Pancreatitis has 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, a dosage adjustment, or discontinuation may be necessary based on the severity of serum lipase level elevations. Evaluate patients for pancreatitis when lipase level elevation is accompanied by abdominal symptoms.

    Neutropenia, thrombocytopenia

    Myelosuppression including neutropenia and thrombocytopenia has been reported with ponatinib therapy. Obtain complete blood counts (CBCs) every 2 weeks for the first 3 months of ponatinib therapy, then monitor CBCs monthly or as clinically indicated. Therapy interruption and a dosage 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.

    Bleeding

    Serious bleeding has been reported with ponatinib therapy, including GI bleeding and subdural hematoma; some cases were fatal. Monitor patients for signs and symptoms of bleeding and mange as clinically indicated. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of the bleeding event. 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.

    Fluid retention

    Fluid retention events including pleural effusion, pericardial effusion, and cerebral edema have been reported with ponatinib therapy; some cases were fatal. Monitor patients for signs and symptoms of fluid retention and manage as clinically indicated. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of fluid retention.

    Cardiac arrhythmias

    Cardiac arrhythmias including atrial fibrillation or flutter, AV block, and QT prolongation have been reported with ponatinib therapy. Monitor patients for signs and symptoms of bradycardia (e.g., fainting, dizziness) or tachycardia (e.g., palpitations, dizziness, and chest pain) and manage as clinically indicated. Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of the cardiac arrhythmia.

    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, impaired wound healing, surgery

    Impaired wound healing has been reported with ponatinib therapy. Hold ponatinib for at least 1 week prior to elective surgery. Do not start or resume ponatinib until at least 2 weeks after major surgery and until adequate wound healing has occurred. The safety of resuming ponatinib therapy after wound healing complications have resolved has not been established. Gastrointestinal (GI) perforation or fistula has also occurred with ponatinib therapy; permanently discontinue ponatinib in patients who develop GI perforation.

    Geriatric

    Geriatric patients aged 65 years or older may have a higher incidence of treatment-related adverse events with ponatinib therapy including asthenia, decreased appetite, decreased platelet count, dyspnea, increased lipase levels, muscle spasm, peripheral edema, and vascular occlusion compared with younger patients.

    Ocular disease

    Ocular disease/toxicity including age-related macular degeneration, retinal vein occlusion, and retinal bleeding has been reported with ponatinib therapy. Perform an ophthalmologic exam prior to and periodically during treatment.

    Hypertension, renal artery stenosis

    Hypertension including hypertensive crisis has been reported with ponatinib therapy. Monitor patient blood pressure prior to and as clinically indicated during treatment. Treat hypertension as appropriate; patients may require urgent clinical intervention. Therapy interruption, a dosage adjustment, or discontinuation may be necessary if hypertension is not medically controlled. In patients with significant worsening, labile, or treatment-resistant hypertension, interrupt therapy and evaluate for renal artery stenosis.

    Neurotoxicity

    Neurotoxicity including peripheral neuropathy has been reported with ponatinib therapy. 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.Therapy interruption, a dosage adjustment, or discontinuation may be necessary based on recurrence or the severity of the neuropathy.

    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
    thrombocytopenia / Delayed / 31.0-40.0
    neutropenia / Delayed / 22.0-34.0
    lymphopenia / Delayed / 7.0-32.0
    hepatotoxicity / Delayed / 25.0-32.0
    pancreatitis / Delayed / 23.0-26.0
    infection / Delayed / 0-25.0
    anemia / Delayed / 14.0-20.0
    abdominal pain / Early / 3.2-13.0
    hypertension / Early / 0-13.0
    heart failure / Delayed / 9.0-12.0
    rash / Early / 3.1-12.0
    hypophosphatemia / Delayed / 3.2-10.0
    pleural effusion / Delayed / 2.1-9.0
    arthralgia / Delayed / 0-9.0
    atrial fibrillation / Early / 0-8.0
    fatigue / Early / 1.1-8.0
    asthenia / Delayed / 1.1-8.0
    bleeding / Early / 2.1-7.3
    fever / Early / 0-7.0
    hyperglycemia / Delayed / 1.1-7.0
    dyspnea / Early / 0-6.0
    thromboembolism / Delayed / 0-6.0
    hyponatremia / Delayed / 0-4.9
    fluid retention / Delayed / 0-4.5
    pericardial effusion / Delayed / 0-4.2
    elevated hepatic enzymes / Delayed / 0-3.6
    hyperamylasemia / Delayed / 0-3.6
    xerosis / Delayed / 0-3.3
    headache / Early / 0-3.3
    diarrhea / Early / 0.7-3.2
    hypertriglyceridemia / Delayed / 3.2-3.2
    constipation / Delayed / 0-3.1
    oral ulceration / Delayed / 0-3.1
    musculoskeletal pain / Early / 0-3.0
    bone pain / Delayed / 0-3.0
    hyperkalemia / Delayed / 0-2.2
    thrombosis / Delayed / 0-2.2
    hypertensive crisis / Early / 0-2.1
    macular degeneration / Delayed / 0-2.1
    hyperlipidemia / Delayed / 0.7-2.1
    syncope / Early / 0-2.0
    myocardial infarction / Delayed / 1.1-2.0
    peripheral neuropathy / Delayed / 0-1.8
    nausea / Early / 0-1.6
    vomiting / Early / 0-1.6
    stroke / Early / 1.1-1.6
    chills / Rapid / 0-1.6
    pulmonary embolism / Delayed / 0-1.6
    anorexia / Delayed / 0-1.2
    tumor lysis syndrome (TLS) / Delayed / 0.4-1.1
    myalgia / Early / 0-1.1
    bradycardia / Rapid / 0.4-1.0
    hyperbilirubinemia / Delayed / 0-0.9
    GI bleeding / Delayed / 0-0.9
    hypocalcemia / Delayed / 0-0.9
    macular edema / Delayed / 0-0.7
    retinal hemorrhage / Delayed / 0-0.7
    angioedema / Rapid / 0-0.4
    weight loss / Delayed / 0-0.4
    retinal thrombosis / Delayed / 0-0.4
    dizziness / Early / 0-0.4
    cardiac arrest / Early / 0-0.2
    atrial flutter / Early / 0-0.2
    AV block / Early / 0-0.2
    atrial tachycardia / Early / 0-0.2
    respiratory arrest / Rapid / 0-0.2
    ventricular tachycardia / Early / 0-0.2
    hypoalbuminemia / Delayed / 0-0.2
    metabolic acidosis / Delayed / 0-0.2
    nephrotoxicity / Delayed / 0-0.2
    hepatic failure / Delayed / Incidence not known
    cerebral edema / Early / Incidence not known
    GI perforation / Delayed / Incidence not known
    gastrointestinal fistula / Delayed / Incidence not known
    enterocolitis / Delayed / Incidence not known
    avascular necrosis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known
    thrombotic microangiopathy / Delayed / Incidence not known
    aortic dissection / Delayed / Incidence not known

    Moderate

    hyperuricemia / Delayed / 2.1-7.0
    hypothyroidism / Delayed / 3.0-3.2
    subdural hematoma / Early / 0-1.0
    phlebitis / Rapid / 0-0.7
    sinus tachycardia / Rapid / 0-0.4
    QT prolongation / Rapid / 0-0.2
    supraventricular tachycardia (SVT) / Early / 0-0.2
    colitis / Delayed / Incidence not known
    gastritis / Delayed / Incidence not known
    neurotoxicity / Early / Incidence not known
    blurred vision / Early / Incidence not known
    dehydration / Delayed / Incidence not known
    impaired wound healing / Delayed / Incidence not known
    hyperthyroidism / Delayed / Incidence not known
    hypercholesterolemia / Delayed / Incidence not known

    Mild

    cough / Delayed / 0-24.0
    pharyngitis / Delayed / 3.1-18.0
    anxiety / Delayed / 4.8-18.0
    muscle cramps / Delayed / 4.8-14.0
    insomnia / Early / 11.0-13.0
    alopecia / Delayed / 6.0-11.0
    gastroesophageal reflux / Delayed / Incidence not known
    xerophthalmia / Early / Incidence not known
    ocular pain / Early / Incidence not known

    DRUG INTERACTIONS

    Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid coadministration of ponatinib and clarithromycin due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of clarithromycin and consider alternative therapy. After clarithromycin has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting clarithromycin. Ponatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Apalutamide: (Major) Avoid coadministration of ponatinib with apalutamide if possible due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Atazanavir: (Major) Avoid coadministration of ponatinib and atazanavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of atazanavir and consider alternative therapy. After atazanavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting atazanavir. Ponatinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Atazanavir; Cobicistat: (Major) Avoid coadministration of ponatinib and atazanavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of atazanavir and consider alternative therapy. After atazanavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting atazanavir. Ponatinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%. (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Avoid coadministration of ponatinib with phenobarbital due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Carbamazepine: (Major) Avoid coadministration of ponatinib with carbamazepine due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Ceritinib: (Major) Avoid coadministration of ponatinib and ceritinib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ceritinib and consider alternative therapy. After ceritinib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ceritinib. Ponatinib is a CYP3A4 substrate; ceritinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Chloramphenicol: (Major) Avoid coadministration of ponatinib and chloramphenicol due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of chloramphenicol and consider alternative therapy. After chloramphenicol has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting chloramphenicol. Ponatinib is a CYP3A4 substrate; chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Chloroquine: (Moderate) Concurrent use of chloroquine and ponatinib is not recommended as there is an increased risk of retinal toxicity.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Clarithromycin: (Major) Avoid coadministration of ponatinib and clarithromycin due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of clarithromycin and consider alternative therapy. After clarithromycin has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting clarithromycin. Ponatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Cobicistat: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Darunavir: (Major) Avoid coadministration of ponatinib and darunavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of darunavir and consider alternative therapy. After darunavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting darunavir. Ponatinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Darunavir; Cobicistat: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%. (Major) Avoid coadministration of ponatinib and darunavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of darunavir and consider alternative therapy. After darunavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting darunavir. Ponatinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%. (Major) Avoid coadministration of ponatinib and darunavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of darunavir and consider alternative therapy. After darunavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting darunavir. Ponatinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ponatinib and ritonavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ritonavir and consider alternative therapy. After ritonavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ritonavir. Ponatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Delavirdine: (Major) Avoid coadministration of ponatinib and delavirdine due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of delavirdine and consider alternative therapy. After delavirdine has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting delavirdine. Ponatinib is a CYP3A4 substrate; delavirdine is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    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%.
    Fosamprenavir: (Major) Avoid coadministration of ponatinib and fosamprenavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of fosamprenavir and consider alternative therapy. After fosamprenavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting fosamprenavir. Ponatinib is a CYP3A4 substrate; fosamprenavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Fosphenytoin: (Major) Avoid coadministration of ponatinib with fosphenytoin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Grapefruit juice: (Major) Instruct patients to avoid grapefruit or grapefruit juice with ponatinib due to the potential for increased ponatinib exposure and subsequent toxicity. Ponatinib is a CYP3A4 substrate; grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Idelalisib: (Major) Avoid coadministration of ponatinib and idelalisib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of idelalisib and consider alternative therapy. After idelalisib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting idelalisib. Ponatinib is a CYP3A4 substrate; idelalisib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Indinavir: (Major) Avoid coadministration of ponatinib and indinavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of indinavir and consider alternative therapy. After indinavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting indinavir. Ponatinib is a CYP3A4 substrate; indinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid coadministration of ponatinib with rifampin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ponatinib exposure by 62%.
    Isoniazid, INH; Rifampin: (Major) Avoid coadministration of ponatinib with rifampin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ponatinib exposure by 62%.
    Itraconazole: (Major) Avoid coadministration of ponatinib and itraconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of itraconazole and consider alternative therapy. After itraconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting itraconazole. Ponatinib is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Ketoconazole: (Major) Avoid coadministration of ponatinib and ketoconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ketoconazole and consider alternative therapy. After ketoconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ketoconazole. Ponatinib is a CYP3A4 substrate; ketoconazole is a strong CYP3A4 inhibitor. Coadministration with ketoconazole increased the ponatinib AUC by 78%.
    Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid coadministration of ponatinib and clarithromycin due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of clarithromycin and consider alternative therapy. After clarithromycin has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting clarithromycin. Ponatinib is a CYP3A4 substrate; clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Letermovir: (Moderate) Avoid coadministration of ponatinib and letermovir in patients who are also taking cyclosporine due to the potential for increased ponatinib exposure; ponatinib may be taken with letermovir in patients who are not taking cyclosporine. If concurrent use of ponatinib and letermovir in combination with cyclosporine cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of letermovir with cyclosporine and consider alternative therapy. After cyclosporine has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting letermovir with cyclosporine. Ponatinib is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Lonafarnib: (Major) Avoid coadministration of ponatinib and lonafarnib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of lonafarnib and consider alternative therapy. After lonafarnib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting lonafarnib. Ponatinib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of ponatinib and ritonavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ritonavir and consider alternative therapy. After ritonavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ritonavir. Ponatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ponatinib with lumacaftor due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Lumacaftor; Ivacaftor: (Major) Avoid coadministration of ponatinib with lumacaftor due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and lumacaftor is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Mifepristone: (Major) Avoid coadministration of ponatinib and mifepristone due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of mifepristone and consider alternative therapy. After mifepristone has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting mifepristone. Ponatinib is a CYP3A4 substrate; mifepristone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%. The clinical significance of this interaction with the short-term use of mifepristone for termination of pregnancy is unknown.
    Mitotane: (Major) Avoid coadministration of ponatinib with mitotane due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Nefazodone: (Major) Avoid coadministration of ponatinib and nefazodone due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of nefazodone and consider alternative therapy. After nefazodone has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting nefazodone. Ponatinib is a CYP3A4 substrate; nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Nelfinavir: (Major) Avoid coadministration of ponatinib and nelfinavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of nelfinavir and consider alternative therapy. After nelfinavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting nelfinavir. Ponatinib is a CYP3A4 substrate; nelfinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Avoid coadministration of ponatinib and ritonavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ritonavir and consider alternative therapy. After ritonavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ritonavir. Ponatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Phenobarbital: (Major) Avoid coadministration of ponatinib with phenobarbital due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid coadministration of ponatinib with phenobarbital due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Phenytoin: (Major) Avoid coadministration of ponatinib with phenytoin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Posaconazole: (Major) Avoid coadministration of ponatinib and posaconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of posaconazole and consider alternative therapy. After posaconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting posaconazole. Ponatinib is a CYP3A4 substrate; posaconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Primidone: (Major) Avoid coadministration of ponatinib with primidone due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Ribociclib: (Major) Avoid coadministration of ponatinib and ribociclib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ribociclib and consider alternative therapy. After ribociclib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ribociclib. Ponatinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ponatinib and ribociclib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ribociclib and consider alternative therapy. After ribociclib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ribociclib. Ponatinib is a CYP3A4 substrate; ribociclib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Rifampin: (Major) Avoid coadministration of ponatinib with rifampin due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased ponatinib exposure by 62%.
    Rifapentine: (Major) Avoid coadministration of ponatinib with rifapentine due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Ritonavir: (Major) Avoid coadministration of ponatinib and ritonavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of ritonavir and consider alternative therapy. After ritonavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting ritonavir. Ponatinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Saquinavir: (Major) Avoid coadministration of ponatinib and saquinavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of saquinavir and consider alternative therapy. After saquinavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting saquinavir. Ponatinib is a CYP3A4 substrate; saquinavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    St. John's Wort, Hypericum perforatum: (Major) Avoid coadministration of ponatinib with St. Johns Wort due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
    Telithromycin: (Major) Avoid coadministration of ponatinib and telithromycin due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of telithromycin and consider alternative therapy. After telithromycin has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting telithromycin. Ponatinib is a CYP3A4 substrate; telithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Tipranavir: (Major) Avoid coadministration of ponatinib and tipranavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of tipranavir and consider alternative therapy. After tipranavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting tipranavir. Ponatinib is a CYP3A4 substrate; tipranavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Tucatinib: (Major) Avoid coadministration of ponatinib and tucatinib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of tucatinib and consider alternative therapy. After tucatinib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting tucatinib. Ponatinib is a CYP3A4 substrate; tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
    Voriconazole: (Major) Avoid coadministration of ponatinib and voriconazole due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of voriconazole and consider alternative therapy. After voriconazole has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting voriconazole. Ponatinib is a CYP3A4 substrate; voriconazole is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.

    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) and T315I-mutant BCR-ABL (IC50 concentration, 2 nanomolar) 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 to 20 nanomolar) 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 greater than 99% bound to plasma proteins in vitro. The mean apparent steady-state volume of distribution was 1,223 liters (CV, 102%) and the mean terminal elimination half-life was approximately 24 hours (range, 12 to 66 hours) in patients with cancer. Following a single oral dose of radiolabeled ponatinib, about 87% of the total radioactivity was recovered in the feces and about 5% was recovered in the urine.
     
    Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP3A5, CYP2C8, CYP2D6, P-glycoprotein (P-gp), BCRP
    At least 64% of each ponatinib dose undergoes Phase I and Phase II metabolism. In vitro, ponatinib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8, CYP2D6, and CYP3A5; it is also metabolized by esterases and/or amidases. Ponatinib is also a weak P-gp and BCRP substrate in vitro and inhibits P-gp, BCRP, and bile salt export pump (BSEP).

    Oral Route

    The absolute bioavailability of ponatinib is not known. Following a single oral dose of ponatinib, 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 mean Cmax and AUC were 73 nanograms/mL and 1,253 nanograms x hour/mL, respectively; median exposure increased by about 90% (range, 20% to 440%) between the first dose and steady-state. Ponatinib exhibited dose-proportional increases in steady-state Cmax and AUC over a dose range of 2 to 60 mg in patients with cancer.
    The Cmax and AUC of ponatinib were not different when ponatinib was administered with a high-fat (900 to 1,000 calories; approximately 60% to 67% fat) or low-fat meal (547 calories; approximately 11% to 12% fat) compared with fasting conditions in 22 healthy subjects. Administration with multiple doses of a proton pump inhibitor decreased the AUC of ponatinib by 6% and decreased the Cmax by 25%.