Iclusig

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Iclusig

Classes

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

Administration

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 2
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use gloves to handle. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
Emetic Risk
Minimal/Low
Administer prn antiemetics as necessary.

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.

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
pancreatitis / Delayed / 23.0-26.0
infection / Delayed / 0-25.0
anemia / Delayed / 14.0-20.0
hepatotoxicity / Delayed / 6.0-13.0
abdominal pain / Early / 3.2-13.0
hypertension / Early / 12.0-13.0
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
heart failure / Delayed / 1.1-7.0
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
hypertensive crisis / Early / 0-3.2
hypertriglyceridemia / Delayed / 3.2-3.2
constipation / Delayed / 0-3.1
oral ulceration / Delayed / 0-3.1
bone pain / Delayed / 0-3.0
musculoskeletal pain / Early / 0-3.0
hyperkalemia / Delayed / 0-2.2
thrombosis / Delayed / 0-2.2
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
angina / Early / 0-1.1
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
atrial flutter / Early / 0-0.2
AV block / Early / 0-0.2
ventricular tachycardia / Early / 0-0.2
cardiac arrest / Early / 0-0.2
atrial tachycardia / Early / 0-0.2
respiratory arrest / Rapid / 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

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.

Common Brand Names

Iclusig

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

Dosage And 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 27 months, the major efficacy outcome of 1% or less BCR-ABL at 12 months occurred in 48% 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 in the intention-to-treat analysis (n = 91) who received a starting dose of 45 mg once daily. A response was maintained at the reduced dose for at least 90 days in 28 patients and at least 1 year in 18 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.

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.

Drug Interactions

Adagrasib: (Major) Avoid coadministration of ponatinib and adagrasib due to the potential for increased ponatinib exposure. If concurrent use is necessary, 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 adagrasib and consider alternative therapy. After adagrasib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting adagrasib. Ponatinib is a CYP3A substrate; adagrasib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the ponatinib AUC by 78%.
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%.
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%.
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%.
Levoketoconazole: (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%.
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%.
Nirmatrelvir; 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%.
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%.
Vonoprazan; 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%.
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%.

How Supplied

Iclusig Oral Tab: 10mg, 15mg, 30mg, 45mg

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.

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%.

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.