Ponatinib hydrochloride, an inhibitor of multiple tyrosine kinases, is an antineoplastic agent.1, 2, 3, 4, 8, 13, 15, 16, 17
Chronic Myelogenous Leukemia or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Ponatinib is used for the treatment of adults with T315I-positive chronic phase, accelerated phase, or blast phase chronic myelogenous leukemia (CML).1 Ponatinib is also used for the treatment of chronic phase CML with resistance or intolerance to at least 2 prior kinase inhibitors and for the treatment of accelerated phase or blast phase CML in patients for whom no other kinase inhibitors are indicated.1 The manufacturer states that ponatinib is not indicated or recommended for the treatment of patients with newly diagnosed chronic phase CML.1
Ponatinib is used as monotherapy for the treatment of Ph+ acute lymphoblastic leukemia (ALL) in adults in whom no other kinase inhibitors are indicated or for the treatment of T315I-positive Ph+ ALL.1 Ponatinib also is used for the treatment of newly diagnosed Ph+ ALL in combination with chemotherapy.1 This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission at the end of induction.1 Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trial(s).1
Ponatinib is designated an orphan drug by FDA for use in these conditions.3
Clinical Experience in Chronic Phase CML
Efficacy of ponatinib in patients with chronic phase CML was evaluated in an open-label, multicenter, single-arm study (PACE) in adults with chronic, accelerated, or blast phase CML or Ph+ ALL following failure (due to resistance or intolerance) of prior tyrosine kinase inhibitor (TKI) therapy.1, 2, 27 In this study, resistance to prior TKI therapy in patients with chronic phase CML was defined as failure to achieve a complete hematologic response by 3 months, a minor cytogenetic response by 6 months, or a major cytogenetic response by 12 months of therapy; patients who experienced a loss of response or who developed a kinase domain mutation in the absence of a complete cytogenetic response or progressed to accelerated or blast phase CML at any time during prior TKI therapy were also considered resistant.1 Intolerance to prior TKI therapy in patients with chronic phase CML was defined as discontinuance of such therapy because of toxicities despite optimal management in the absence of a complete cytogenetic response.1 The primary efficacy end point in patients with chronic phase CML was major cytogenetic response (including complete and partial cytogenetic responses).1, 2
Patients in the study received an initial ponatinib dosage of 45 mg once daily.1 At the time of study completion, 267 evaluable patients with chronic phase CML had received a median of 35 months of treatment.1, 2 Major and complete cytogenetic responses were reported in 55 and 46%, respectively, of patients.1, 2 Major cytogenetic responses were reported in 51% of patients who were resistant to or intolerant of prior TKI therapy and in 70% of patients with the T315I BCR-ABL kinase domain mutation.1 Complete cytogenetic responses were reported in 40% of patients who were resistant to or intolerant of prior TKI therapy and 66% of patients with the T315I BCR-ABL kinase domain mutation.1 The median time to major cytogenetic response was 3 months;1 the majority of patients who achieved a major cytogenetic response by 12 months maintained response at 5 years.27
The OPTIC dose optimization trial evaluated the efficacy of ponatinib in patients with chronic phase CML whose disease was considered resistant or resistant/intolerant to at least 2 prior kinase inhibitors or who had the T315I BCR-ABL kinase domain mutation.1, 28 In this study, resistance to prior TKI therapy was defined as failure to achieve a complete hematologic response by 3 months, a minor cytogenetic response by 6 months, or a major cytogenetic response by 12 months of therapy.1 Patients who developed a new BCR-ABL1 kinase domain mutation or new clonal evolution while receiving prior TKI therapy were also considered resistant.1 Patients received ponatinib 45, 30, or 15 mg daily as a starting dosa patients who received a starting dosage of 45 or 30 mg had a dosage reduction to 15 mg once they achieved BCR-ABL1 ≤1%.1 The primary efficacy end point was BCR-ABL1 ≤1% at 12 months.1
A total of 94 patients received a ponatinib starting dose of 45 mg and were followed for a median of 27 months.1 At 12 months, 44% of these patients had achieved BCR-ABL1 ≤1%.1 This result was consistent regardless of the presence or absence of the T315I mutation.1 Of the 45 patients who had their dosage reduced after achieving BCR-ABL1 ≤1%, 62% maintained response for at least 90 days.1 Median duration of response was not reached.1 Major cytogenetic response by 12 months was achieved in 48% of patients; major cytogenetic response rates among patients with and without T315I mutations were 52 and 46%, respectively.
Efficacy of ponatinib in patients with accelerated or blast phase CML is based principally on the results of an open-label, multicenter, single-arm study (PACE) in adults with chronic, accelerated, or blast phase CML or Ph+ ALL following failure (due to resistance or intolerance) of prior TKI therapy.1, 2, 27 In this study, resistance to prior TKI therapy in patients with accelerated or blast phase CML was defined as failure to achieve a major hematologic response (by 3 months in patients with accelerated phase CML or 1 month in patients with blast phase CML), loss of major hematologic response at any time during therapy, or development of a kinase domain mutation in the absence of a complete major hematologic response during prior therapy with a TKI.1 Intolerance of prior TKI therapy in patients with accelerated or blast phase CML was defined as discontinuance of such therapy because of toxicities despite optimal management in the absence of a major hematologic response.1 The primary measure of efficacy in patients with accelerated or blast phase CML was major hematologic response (defined as either a complete hematologic response or no evidence of leukemia).1, 2
Patients in the study received an initial ponatinib dosage of 45 mg once daily.1 At the time of study completion, the median duration of treatment was 21.1 and 3.2 months in patients with accelerated and blast phase CML, respectively.1 Major and complete hematologic responses were reported in 57 and 51%, respectively, of patients with accelerated phase CML and in 31 and 21%, respectively, of patients with blast phase CML.1, 2 The median time to major hematologic response was 0.8 months and 1 month in patients with accelerated and blast phase CML, respectively.1 The median duration of major hematologic remission was 14 and 6.5 months in patients with accelerated and blast phase CML, respectively.1, 2
Guidelines recommend TKI therapy (i.e., bosutinib, dasatinib, imatinib, nilotinib, or asciminib) for the first-line treatment of newly diagnosed chronic phase CML; selection of the TKI should be based on risk score, toxicity profile, patient's age, ability to tolerate therapy, and presence of comorbid conditions.30 All of these TKIs are appropriate first-line options for patients with chronic phase CML across all risk scores.30 In patients with an intermediate- or high-risk score, disease progression to accelerated or blast phase CML occurs more frequently; bosutinib, dasatinib, nilotinib, and asciminib are associated with a reduced risk of disease progression than imatinib and are preferred for patients with an intermediate- or high-risk score.30
Ponatinib is a second-line treatment option in the guidelines and the preferred treatment option for patients with a T315I mutation in any CML phase.30 Ponatinib is also preferred for patients with no identifiable BCR::ABL1 mutations.30
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Efficacy of ponatinib as monotherapy in patients with Ph+ ALL is based principally on the results of an open-label, multicenter, single-arm study (PACE) in adults with chronic, accelerated, or blast phase CML or Ph+ ALL following failure (due to resistance or intolerance) of prior TKI therapy.1, 2, 27 In this study, resistance to prior TKI therapy in patients with Ph+ ALL was defined as failure to achieve a major hematologic response by 1 month, loss of major hematologic response at any time during therapy, or development of a kinase domain mutation in the absence of a complete major hematologic response during prior therapy with a TKI.1 Intolerance to prior TKI therapy in patients with Ph+ ALL was defined as discontinuance of such therapy because of toxicities despite optimal management in the absence of a major hematologic response.1 The primary measure of efficacy in patients with Ph+ ALL was major hematologic response (defined as either a complete hematologic response or no evidence of leukemia).1, 2
Patients in the study received an initial ponatinib dosage of 45 mg once daily.1 At the time of study completion, patients with Ph+ ALL had received a median of 2.9 months of treatment.1 Major or complete hematologic responses were reported in 41 or 34%, respectively, of patients.1, 2 The median time to major hematologic response was 0.7 months, and the median duration of major hematologic response was 3.5 months.1
Efficacy of ponatinib in combination with chemotherapy in patients with newly diagnosed Ph+ ALL was evaluated in the randomized, open-label, active-controlled, multicenter, phase 3, PhALLCON trial.1, 29 Study eligibility criteria included a new diagnosis of Ph+ ALL, an ECOG performance status score ≤2, and the absence of clinically significant or uncontrolled cardiovascular disease.29 A total of 245 patients were randomly assigned in a 2:1 ratio to either ponatinib 30 mg orally once daily or imatinib 600 mg orally once daily with reduced-intensity chemotherapy through induction (cycles 1-3), consolidation (cycles 4-9), and maintenance (cycles 10-20) phases.1, 29 Upon completion of cycle 20, patients were administered single-agent ponatinib or imatinib.1, 29 The ponatinib dosage was reduced to 15 mg once daily after induction and achievement of MRD-negative complete remission; the dosage was re-escalated to 30 mg once daily if a patient lost MRD negativity at any time after dose reduction.1, 29 Patients continued therapy until loss of efficacy, unacceptable toxicity, or progression to hematopoietic stem cell transplant.29 At the end of cycle 3, those who did not achieve MRD-negative complete remission were discontinued from the study.29 However, patients who achieved complete remission or complete remission with incomplete hematologic recovery with MRD-negativity at the end of induction could continue treatment per the investigator's discretion.1, 29 The primary study end point was MRD-negative complete remission at the end of cycle 3; the key secondary end point was event-free survival (defined as time from randomization until death from any cause, failure to achieve complete remission by the end of induction, or relapse from complete remission).29
The median age of patients in the PhALLCON study was 54 years (range: 19-82 years); 37.1% were ≥60 years of age.29 More than 50% of patients in each treatment group were female and over 90% in each group had an ECOG performance status of 0 or 1.29 The median duration of follow-up at the data cut-off date was 20.1 months (range: 17.8-23.1 months).29 Results revealed a significantly improved MRD-negative complete remission rate at the end of cycle 3 with ponatinib as compared to imatinib (34.4% versus 16.7%).29 Among patients with evaluable samples, MRD negativity was also significantly improved with ponatinib at the end of induction (43% versus 22.1%).29 The median duration of MRD-negative complete remission was not reached in the ponatinib group and was 18 months in the imatinib group.29 Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group.29
Guidelines for the treatment of newly diagnosed Ph+ALL recommend the administration of low-intensity chemotherapy and a first- or second-generation TKI (e.g., bosutinib, dasatinib, imatinib, or nilotinib) followed by allogeneic hematopoietic stem cell transplantation (HSCT) as standard therapy.36 Per the guidelines, the administration of ponatinib with chemotherapy may improve patient outcomes in Ph+ ALL as compared to first- or second-generation TKIs.36 Additionally, dasatinib or ponatinib in combination with blinatumomab provides elevated rates of molecular response and promising overall survival and event-free survival.36 For further information on the management of Ph+ ALL, refer to: [Web].
Dispensing and Administration Precautions
Ponatinib hydrochloride is administered orally once daily without regard to food.1 The tablets should be swallowed whole and should not be crushed, broken, cut, or chewed.1 If a dose is missed, the next dose should be taken at the regularly scheduled time the next day.1
Dosage of ponatinib hydrochloride is expressed in terms of ponatinib.1
Chronic Phase Chronic Myelogenous Leukemia
For the treatment of chronic phase chronic myelogenous leukemia (CML) in adults, the recommended initial dosage of ponatinib is 45 mg once daily, with a reduction to 15 mg once daily upon achievement of BCR::ABL1 IS≤1%.1 In patients with loss of response on 15 mg once daily, the dosage can be re-escalated to a previously tolerated dosage of 30 or 45 mg once daily.1 Continue ponatinib until loss of response at the re-escalated dosage or unacceptable toxicity occurs.1 Consider discontinuation if hematologic response has not occurred by 3 months.1
Accelerated Phase and Blast Phase CML
Optimal dosage of ponatinib has not been established.1 For the treatment of accelerated phase and blast phase CML in adults, the recommended initial dosage of ponatinib is 45 mg once daily.1 Consider dosage reduction in patients with accelerated phase CML who have achieved a major cytogenetic response.1 Continue ponatinib until loss of response or unacceptable toxicity occurs.1 Consider discontinuation if response has not occurred by 3 months.1
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
For the treatment of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in adults, the recommended initial dosage of ponatinib is 30 mg once daily in combination with chemotherapy, with a reduction to 15 mg once daily upon achievement of minimal residual disease (MRD)-negative (≤0.01% BCR::ABL1/ABL1) complete remission at the end of induction.1 Continue ponatinib with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity occurs.1
When used as monotherapy for the treatment of Ph+ ALL in adults in whom no other kinase inhibitors are indicated or for the treatment of T315I-positive Ph+ ALL, the optimal dosage of ponatinib has not been established.1 The recommended initial dosage of ponatinib is 45 mg once daily.1 Continue ponatinib until loss of response or unacceptable toxicity occurs.1 Consider discontinuation if response has not occurred by 3 months.1
Dosage Modification for Toxicity
If adverse reactions occur, temporary interruption of therapy, dosage reduction, and/or discontinuance of ponatinib may be necessary.1 If dosage modification is required, reduce the dosage of ponatinib as described in Table 1.1 Permanently discontinue ponatinib in patients who are unable to tolerate the lowest dosage described in Table 1.1
Dosage Reduction | Chronic Phase CML | Accelerated Phase or Blast Phase CML, or Ph+ ALL Monotherapy | Newly Diagnosed Ph+ ALL |
|---|---|---|---|
First | 30 mg once daily | 30 mg once daily | 15 mg once daily |
Second | 15 mg once daily | 15 mg once daily | 10 mg once daily |
Third | 10 mg once daily | Permanently discontinue if patient is unable to tolerate 15 mg once daily | Permanently discontinue if patient is unable to tolerate 10 mg once daily |
Subsequent reduction | Permanently discontinue if patient is unable to tolerate 10 mg once daily | Permanently discontinue if patient is unable to tolerate 15 mg once daily | Permanently discontinue if patient is unable to tolerate 10 mg once daily |
If an adverse reaction occurs, reduce ponatinib dosage, or interrupt or permanently discontinue therapy as described in Table 2.1
Adverse Reaction and Severity | Modification |
|---|---|
Cardiovascular or Cerebrovascular Arterial Occlusive Event (Grade 1) | Withhold ponatinib until resolved, then resume at the same dosage |
Cardiovascular or Cerebrovascular Arterial Occlusive Event (Grade 2) | Withhold ponatinib until grade 0 or 1, then resume at the next lower dosa discontinue ponatinib if event recurs |
Cardiovascular or Cerebrovascular Arterial Occlusive Event (Grade 3 or 4) | Discontinue ponatinib |
Peripheral Vascular or Other Arterial Occlusive Event (Grade 1) | Withhold ponatinib until resolved, then resume at the same dosage |
Peripheral Vascular or Other Arterial Occlusive Event (Grade 2) | Withhold ponatinib until grade 0 or 1, then resume at the same dosa if event recurs, withhold ponatinib until grade 0 or 1, then resume at the next lower dosage |
Peripheral Vascular or Other Arterial Occlusive Event (Grade 3) | Withhold ponatinib until grade 0 or 1, then resume at the next lower dosa discontinue ponatinib if event recurs |
Peripheral Vascular or Other Arterial Occlusive Event (Grade 4) | Discontinue ponatinib |
Venous Thromboembolism (Grade 1) | Withhold ponatinib until resolved, then resume at the same dosage |
Venous Thromboembolism (Grade 2) | Withhold ponatinib until grade 0 or 1, then resume at the same dosa if event recurs, withhold ponatinib until grade 0 or 1, then resume at the next lower dosage |
Venous Thromboembolism (Grade 3) | Withhold ponatinib until grade 0 or 1, then resume at the next lower dosa discontinue ponatinib if event recurs |
Venous Thromboembolism (Grade 4) | Discontinue ponatinib |
Heart Failure (Grade 2 or 3) | Withhold ponatinib until grade 0 or 1, then resume at the next lower dosa discontinue ponatinib if event recurs |
Heart Failure (Grade 4) | Discontinue ponatinib |
Hepatotoxicity (AST or ALT >3 times ULN) | Withhold ponatinib until grade 0 or 1, then resume at the next lower dosage |
Hepatotoxicity (AST or ALT ≥3 times ULN concurrent with bilirubin >2 times ULN and alkaline phosphatase <2 times ULN) | Discontinue ponatinib |
Elevated Serum Lipase (Serum lipase >1 to 1.5 times ULN) | Consider withholding ponatinib until resolution, then resume at same dosage |
Pancreatitis or Elevated Serum Lipase (Serum lipase >1.5 to 2 times ULN, serum lipase 2 to 5 times ULN and asymptomatic, or asymptomatic radiologic pancreatitis) | Withhold ponatinib until grade 0 or 1 (<1.5 times ULN), then resume at next lower dosage |
Pancreatitis or Elevated Serum Lipase (Serum lipase >2 to 5 times ULN and symptomatic, symptomatic grade 3 pancreatitis, or serum lipase >5 times ULN and asymptomatic) | Withhold ponatinib until complete resolution of symptoms and after recovery of lipase elevation to grade 0 or 1; then resume at the next lower dosage |
Symptomatic pancreatitis and serum lipase >5 times ULN | Discontinue ponatinib |
Myelosuppression (ANC <1000/mm3 or platelets <50,000/mm3) | Withhold ponatinib until ANC ≥1500/mm3 and platelets ≥75,000/mm3, then resume at the same dosa if myelosuppression recurs, withhold ponatinib until resolution, then resume at the next lower dosage |
Other Non-Hematologic Adverse Events (Grade 1) | Withhold ponatinib until resolved, then resume at the same dosage |
Other Non-Hematologic Adverse Events (Grade 2) | Withhold ponatinib until grade 0 or 1, then resume at the same dosa if event recurs, withhold ponatinib until grade 0 or 1, then resume at the next lower dosage |
Other Non-Hematologic Adverse Events (Grade 3 or 4) | Withhold ponatinib until grade 0 or 1, then resume at the next lower dosa if event recurs, discontinue ponatinib |
Dosage Modification for Concomitant Use with Strong CYP3A Inhibitors
Avoid concomitant use of ponatinib with strong inhibitors of cytochrome P-450 (CYP) 3A when possible.1 If concomitant use cannot be avoided, reduce the dosage of ponatinib as described in Table 3.1 After discontinuing a strong CYP3A inhibitor for 3-5 elimination half-lives, resume the dosage of ponatinib that was tolerated prior to initiating the strong CYP3A inhibitor.1
Current Ponatinib Dosage | Recommended Ponatinib Dosage with a Strong CYP3A Inhibitor |
|---|---|
45 mg once daily | 30 mg once daily |
30 mg once daily | 15 mg once daily |
15 mg once daily | 10 mg once daily |
10 mg once daily | Avoid coadministration of ponatinib with a strong CYP3A inhibitor |
In patients with chronic phase CML, accelerated phase CML, blast phase CML, or Ph+ ALL receiving ponatinib monotherapy who have pre-existing hepatic impairment (Child-Pugh class A, B, or C), reduce the initial dosage of ponatinib from 45 mg once daily to 30 mg once daily.1
In patients with newly diagnosed Ph+ ALL, no dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A).1 Patients with moderate or severe hepatic impairment (Child-Pugh class B or C) should be monitored closely and the ponatinib dosage modified in the event of adverse reactions.1
The manufacturer does not make any specific dosage recommendations for patients with renal impairment.1
Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly, caution is advised in dose selection for geriatric patients.1
The prescribing information for ponatinib includes a boxed warning on the risk of arterial occlusive events.1 Arterial occlusive events, including fatalities, have occurred in patients receiving ponatinib in clinical trials.1
Of the 94 patients receiving an initial dosage of ponatinib 45 mg daily in the OPTIC trial, 18% experienced arterial occlusive events; of these, 11, 4.3, and 3.2% experienced cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events, respectively.1 Median time to first cardiovascular, cerebrovascular, or peripheral vascular event was 9.4 months (range: 12 days to 5.7 years), 11.7 months (range: 15 days to 1.6 years) and 6.3 months (range: 23 days to 3.6 years), respectively.1 Grade 3 or 4 arterial occlusive events occurred in 7% of patients and included myocardial infarction (MI), acute coronary syndrome, arterial thrombosis, ischemic stroke, ischemic cerebral infarction, subclavian artery stenosis, and unstable angina.1 Four fatal events were reported.1 Arterial occlusive events occurred more frequently with increasing age.1
Of the 449 patients who received ponatinib in the PACE trial, 26% experienced arterial occlusive events; of these, 15, 7, and 11% experienced cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events, respectively.1 Median time to first cardiovascular, cerebrovascular, or peripheral vascular event was 1 year (range: 1 day to 4.1 years), 1.4 years (range: 2 days to 4.5 years) and 2 years (range: 10 days to 4.9 years), respectively.1 Grade 3 or 4 arterial occlusive events occurred in 14% of patients and included peripheral arterial occlusive disease, MI, coronary artery disease, and cerebral infarction.1 Fatal events occurred in 9 patients (2%); fatal and life-threatening events occurred within 2 weeks of starting treatment with ponatinib 45 mg daily, and at dosages as low as 15 mg daily.1 Arterial occlusive events were more frequent with increasing age and more common among patients with a history of ischemia, hypertension, diabetes, or hypercholesterolemia; however, these events occurred in patients with and without cardiovascular risk factors, including patients younger than 50 years of age.1 Some patients developed heart failure concurrent or subsequent to a myocardial ischemic event, and some patients required revascularization procedures (coronary, cerebrovascular, and peripheral arterial).1 Ponatinib caused stenosis over multiple segments in major arterial vessels that supply the brain (e.g., carotid, vertebral, middle cerebral artery).1 Some patients developed digital or distal extremity necrosis and required amputations.1 Renal artery stenosis associated with worsening, labile, or treatment-resistant hypertension occurred in some patients.1
In PACE, patients with uncontrolled hypertriglyceridemia and those with clinically significant or active cardiovascular disease, including any history of clinically significant atrial/ventricular arrhythmias or history of MI, unstable angina, or heart failure within the 3 months prior to the first dose of ponatinib, were excluded.1 Clinicians should consider whether the benefits of ponatinib therapy outweigh the risks in this situation.1
Of the 163 patients who received ponatinib in the PhALLCON trial, 6% experienced arterial occlusive events; of these, 3.1, 1.8, and 1.2% experienced cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events, respectively.1 Median time to first arterial occlusive event was 11.3 months (range: 8 days to 2.8 years).1 Grade 3 or 4 arterial occlusive events occurred in 3.7% of patients and included MI, peripheral arterial occlusive disease, angina pectoris, and cerebrovascular accident.1 A fatal event occurred in a single patient and these events occurred more frequently with increasing age.1
Patients were excluded from the OPTIC trial if they had uncontrolled hypertension or diabetes, or clinically significant, uncontrolled, or active cardiovascular disease, including any history of MI, peripheral vascular infarction, revascularization procedure, congestive heart failure, venous thromboembolism, or clinically significant atrial/ventricular arrhythmia.1 Patients were excluded from the PACE trial if they had uncontrolled hypertriglyceridemia or clinically significant or active cardiovascular disease, including any history of clinically significant atrial/ventricular arrhythmias or history of MI, unstable angina, or congestive heart failure within the 3 months prior to the first dose of ponatinib.1 Patients were excluded from the PhALLCON trial if they had uncontrolled hypertension, hypertriglyceridemia, or diabetes.1 Patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of MI, peripheral vascular infarction, revascularization procedure, venous thromboembolism, clinically significant atrial/ventricular tachyarrhythmias, unstable angina, or congestive heart failure within the 6 months prior to the initial ponatinib dose were also excluded.1
Consider whether the benefits of initiating ponatinib therapy outweigh the risks.1 Monitor patients for manifestations of arterial occlusive events.1 If arterial occlusion is suspected, interrupt or discontinue therapy.1 Following evaluation, weigh the risks and benefits of restarting ponatinib.1
The prescribing information for ponatinib includes a boxed warning on the risk of venous thromboembolic events (VTEs).1 Serious or severe VTEs have occurred in patients receiving ponatinib.1 Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, 2 patients experienced a VTE (grade 1 retinal vein occlusion and grade 2 phlebitis).1 Of the 449 patients who received ponatinib in the PACE trial, 6% experienced a VTE, including grade 3 or 4 events in 5.8%.1 Events reported in PACE included deep vein thrombosis (DVT), pulmonary embolism (PE), superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with vision loss.1 VTEs occurred in 10, 9, 6, and 3.5% of patients with blast phase chronic myelogenous leukemia (CML), Philadelphia chromosome-positive (Ph+) acute lymphocytic leukemia (ALL), chronic phase CML, and accelerated phase CML, respectively.1 Of the 163 patients who received ponatinib in the PhALLCON trial, 12% experienced a VTE, including grade 3 or 4 events in 3.1%.1 Events reported in PhALLCON included DVT, superficial vein thrombosis, embolism, PE, thrombosis, jugular vein thrombosis, and retinal vein occlusion.1 Median time to onset of initial VTE was 2.5 months (range: 6 days to 1.8 years).1
Monitor patients for manifestations of VTEs.1 If a VTE occurs, interrupt treatment, then resume at the same or a decreased dose or discontinue ponatinib based on recurrence/severity.1
The prescribing information for ponatinib includes a boxed warning on the risk of heart failure.1 Serious or severe heart failure events, including fatalities, have occurred in patients receiving ponatinib.1 Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, heart failure events occurred in 20%; 2.1% experienced grade 3 or 4 heart failure.1 The most frequently reported heart failure events were left ventricular hypertrophy (5%), left ventricular dysfunction (5%), increased brain natriuretic peptide (BNP; 5%), cardiac failure (3.2%), left atrial dilatation (2.1%), and reduced ejection fraction (2.1%).1 In the PACE study, heart failure events occurred in 9% of 449 patients; grade 3 or 4 heart failure events occurred in 7%.1 The most frequently reported heart failure events were congestive cardiac failure, decreased ejection fraction, and cardiac failure.1 In the PhALLCON study, heart failure occurred in 6% of 163 patients; grade 3 or 4 heart failure was reported in 1.2%.1 The most frequently reported heart failure event was increased BNP (2.5%).1
Monitor patients for manifestations of heart failure and manage as clinically indicated.1 If new or worsening heart failure occurs, interrupt treatment, then resume at a decreased dose or discontinue ponatinib.1
The prescribing information for ponatinib includes a boxed warning on the risk of hepatotoxicity.1 Hepatotoxicity, including liver failure and death, has been reported with ponatinib.1 Fulminant hepatic failure leading to death occurred in 3 patients; in one of these patients, hepatic failure occurred within 1 week of starting ponatinib.1 Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, 34% experienced hepatotoxicity, with 7% experiencing grade 3 or 4 hepatotoxicity.1 Median time to onset of hepatotoxicity was 4.1 months (range: 1 day to 4.8 years).1 The most frequent hepatotoxic events were elevations in liver enzymes (ALT, AST, alkaline phosphatase, gamma-glutamyl transferase).1 In the PACE trial, hepatotoxicity occurred in 32% of 449 patients; grade 3 or 4 hepatotoxicity occurred in 13%.1 Median time to onset of hepatotoxicity was 3.1 months (range: 1 day to 4.9 years).1 The most frequent hepatotoxic events were elevations in liver enzymes and bilirubin.1 In the PhALLCON trial, hepatotoxicity was reported in 66% of 163 patients; grade 3 or 4 hepatotoxicity occurred in 30%.1 Median time to onset of hepatotoxicity was 15 days (range: 1 day to 10 months).1 The most frequent hepatotoxic events were elevations in liver enzymes and bilirubin, decreased albumin, and decreased blood fibrinogen.1
Monitor liver function tests prior to initiation of therapy and at least monthly thereafter or as clinically indicated.1 If liver function test results are elevated, interrupt therapy and reduce dosage upon resumption or discontinue ponatinib.1
Other Warnings and Precautions
Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received ponatinib.1 Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, 37% experienced hypertension events and 14% experienced serious or severe hypertension.1 Grade 1, 2, and 3 elevations in blood pressure occurred in 44% of patients with normal initial blood pressure, 37% of patients with initial blood pressure less than grade 2, and 22% of patients with initial blood pressure less than grade 3, respectively.1 Hypertensive crisis occurred in 3 patients.1 In the PACE trial, hypertension events occurred in 32% of 449 patients, and 13% experienced serious or severe hypertension.1 Any post-baseline elevation of systolic or diastolic blood pressure of grade 2 or higher in patients with normal blood pressure occurred in 44%. Grade 1, 2, and 3 elevations in blood pressure occurred in 26, 45, and 26% of patients, respectively. Hypertensive crisis occurred in 2 patients.1 In the PhALLCON trial, hypertension was reported in 34% of 163 patients; serious or severe hypertension was seen in 14%.1 Grade 1, 2, and 3 elevations in blood pressure occurred in 25, 50, and 39% of patients, respectively.1
Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.1 Monitor patients for hypertension and treat as clinically indicated.1 If hypertension cannot be medically controlled, interruption, dosage reduction, or discontinuance of therapy may be necessary.1 For significant worsening, labile, or treatment-resistant hypertension, interrupt ponatinib and consider evaluation for renal artery stenosis.1
Serious or severe pancreatitis has occurred in patients receiving ponatinib.1 Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, 29% experienced pancreatitis (16% grade 3 or 4).1 Median time to onset of pancreatitis was 1 month (range: 3 days to 4.1 years).1 Pancreatitis led to interruption and/or dosage reduction in 23% of patients and discontinuation in 1.1% of patients.1 In 2 patients with clinical pancreatitis that led to dosage modification or treatment discontinuation, pancreatitis resolved within 2 weeks.1 Amylase and lipase elevations occurred in 15 and 40% of patients, respectively.1 In the PACE trial, pancreatitis occurred in 26% of 449 patients (17% grade 3 or 4).1 Median time to onset of pancreatitis was 29 days (range: 1 day to 4 years).1 Pancreatitis led to interruption and/or dosage reduction in 17% of patients and discontinuation in 0.4% of patients.1 Nineteen of the 28 cases of clinical pancreatitis leading to dosage modification or treatment discontinuation resolved within 2 weeks.1 Amylase and lipase elevations occurred in 18 and 39% of patients, respectively.1 In the PhALLCON trial, pancreatitis was reported in 34% of 163 patients; grade 3 or 4 pancreatitis in 15%.1 Median time to onset of pancreatitis was 8 days (range: 1 day to 2 years).1 Dose modification due to pancreatitis occurred in 7 patients, with pancreatitis resolving within 3 weeks.1 Amylase and lipase elevations were reported in 25 and 60% of patients, respectively.1
Monitor serum lipase concentrations every 2 weeks during the first 2 months of therapy and monthly (or as clinically indicated) thereafter; consider more frequent monitoring in patients with a history of pancreatitis or alcohol abuse.1 If elevations in serum lipase concentrations occur and are accompanied by abdominal pain, evaluate the patient for pancreatitis.1 If pancreatitis occurs, interrupt therapy, then resume at the same or a reduced dosage or discontinue therapy based on severity.1
Increased Toxicity in Newly Diagnosed Chronic Phase CML
Ponatinib is not indicated or recommended for use in patients with newly diagnosed chronic phase CML.1 In a prospective, randomized, clinical trial in the first-line treatment of newly-diagnosed patients with chronic phase CML, ponatinib 45 mg daily increased the risk of serious adverse reactions 2-fold compared to imatinib 400 mg once daily.1 Median treatment exposure was less than 6 months, and the trial was halted for safety.1 Arterial and venous thrombosis and occlusions occurred at least twice as often in patients receiving ponatinib compared to patients receiving imatinib.1 Patients receiving ponatinib also had a higher incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders.1
Peripheral and cranial neuropathy have occurred in patients receiving ponatinib.1 Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, 13% experienced neuropathy; peripheral neuropathy occurred in 11%, and 2 patients developed cranial neuropathy.1 The most commonly reported peripheral neuropathies were hypoesthesia, muscular weakness, and paresthesia.1 Median time to onset of peripheral neuropathy was 1.1 years (range: 1 months to 4.1 years) and median time to onset of cranial neuropathy was 3 years (range: 10.3 months to 5.2 years).1 In the PACE trial, 22% of 449 patients experienced neuropathy (2.4% grade 3 or 4).1 Peripheral neuropathy occurred in 20% of patients (1.8% grade 3 or 4); the most common peripheral neuropathies were paresthesia and hypoesthesia.1 Cranial neuropathy occurred in 3% of patients (0.7% grade 3 or 4).1 Median time to onset of peripheral neuropathy was 5.3 months (range: 1 day to 4.6 years) and median time to onset of cranial neuropathy was 1.2 years (range: 18 days to 4 years).1 In the PhALLCON trial, peripheral neuropathy was reported in 68% of 163 patients; grade 3 or 4 peripheral neuropathy occurred in 3.1%.1 The most common peripheral neuropathies were peripheral neuropathy, paresthesia, and peripheral sensory neuropathy.1 Median time to onset of peripheral neuropathy was 1.1 month (range: 1 day to 17.2 months).1 Cranial neuropathy was seen in 0.6% of patients.1
Monitor patients for manifestations of neuropathy (e.g., burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness).1 If neuropathy occurs, interrupt therapy, then resume at the same or a reduced dosage or discontinue therapy based on recurrence/severity.1
Serious ocular toxicities leading to blindness or blurred vision have occurred in patients receiving ponatinib.1 Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, 15% experienced ocular toxicity, and 1.1% experienced serious or severe ocular toxicity.1 The most frequent ocular toxicities were dry eye, blurred vision, and eye pain.1 Retinal toxicities, including age-related macular degeneration, arteriosclerotic retinopathy, retinal vascular disorder, and retinal vein occlusion, occurred in 4.3% of patients.1 In the PACE trial, ocular toxicity was reported in 30% of 449 patients; 3.6% of patients experienced serious or severe ocular toxicity.1 The most frequent ocular toxicities were dry eye, blurred vision, and eye pain.1 Retinal toxicity occurred in 3.6% of patients, with the most common retinal toxicities being macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floaters (0.7% each).1 Of the 163 patients in the PhALLCON trial, 33% experienced ocular toxicities including 1.8% with serious or severe ocular toxicity.1 The most frequent ocular toxicities included blurred vision and dry eye.1 Retinal toxicities were observed in 4.3% of patients with 0.6% experiencing grade 3 retinal vein occlusion; the most frequent toxicity was retinal hemorrhage (1.8%).1
Perform comprehensive ophthalmologic examinations at baseline and periodically during treatment with ponatinib.1
Fatal and serious hemorrhage events have occurred in patients receiving ponatinib.1 Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, 13% experienced hemorrha 1 patient experienced a serious subdural hematoma.1 In the PACE trial, hemorrhage occurred in 28% of 449 patients.1 Serious hemorrhage and fatal hemorrhage occurred in 6 and 1.3%, respectively.1 Serious bleeding events were more common in patients with accelerated phase CML, blast phase CML, and Ph+ ALL.1 The most common types of serious bleeding events were GI hemorrhage and subdural hematoma.1 Most hemorrhages occurred in patients with grade 4 thrombocytopenia.1 In the PhALLCON trial, 31% of 163 patients experienced hemorrhage, with 2.5% experiencing serious hemorrhage.1 Intracranial hemorrhage occurred in 1.2% of patients.1
Monitor patients for hemorrhage and manage as clinically indicated.1 If hemorrhage occurs, interrupt therapy, then resume at the same or a reduced dosage or discontinue therapy based on recurrence/severity.1
Fatal and serious fluid retention events have occurred in patients receiving ponatinib.1 Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, fluid retention occurred in 6%.1 The most common fluid retention events were peripheral edema, hydrothorax, and pleural effusion.1 In the PACE trial, fluid retention events occurred in 33% of 449 patients; 4.5% experienced serious fluid retention events and 1 patient experienced fatal brain edema.1 Serious fluid retention events included pleural effusion, pericardial effusion, and angioedema.1 The most common fluid retention events were peripheral edema, pleural effusion, pericardial effusion, and peripheral swelling.1 In the PhALLCON trial, 24% of 163 patients experienced fluid retention, with 1.2% experiencing serious fluid retention including pericardial effusion (1.2%).1 The most frequently occurring fluid retention events were peripheral edema and pleural effusion.1
Monitor patients for fluid retention and manage as clinically indicated.1 If fluid retention occurs, interrupt therapy, then resume at the same or a reduced dosage or discontinue therapy based on recurrence/severity.1
Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, cardiac arrhythmias occurred in 27%; grade 3 or 4 cardiac arrhythmias occurred in 5% of patients and included atrial fibrillation, cardiorespiratory arrest, supraventricular extrasystoles, supraventricular tachycardia, and syncope.1 In the PACE trial, cardiac arrhythmia occurred in 20% of 449 patients; grade 3 or 4 cardiac arrhythmia occurred in 7%.1 Ventricular arrhythmia occurred in 3.4% of the 89 patients who reported arrhythmia, with 1 event being grade 3 or 4.1 Symptomatic bradyarrhythmias requiring pacemaker implantation occurred in 1% of patients.1 Atrial fibrillation was the most frequent cardiac arrhythmia, occurring in 8% of patients (3.3% grade 3 or 4).1 Other grade 3 or 4 arrhythmia events included syncope, tachycardia, bradycardia, QT prolongation, atrial flutter, sinus bradycardia, supraventricular tachycardia, ventricular tachycardia, atrial tachycardia, complete atrioventricular block, cardiorespiratory arrest, loss of consciousness, and sinus node dysfunction.1 Arrhythmia led to hospitalization in 31 patients.1 Of 163 patients in the PhALLCON trial, 22% experienced cardiac arrhythmias; 2.5% experienced grade 3 or 4 events.1
Monitor patients for signs and symptoms of slow heart rate (e.g., fainting, dizziness) or rapid heart rate (e.g., chest pain, palpitations, dizziness) and manage as clinically indicated.1 If cardiac arrhythmias occur, interrupt therapy, then resume at the same or a reduced dosage or discontinue therapy based on recurrence/severity.1
Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, neutropenia, thrombocytopenia, and anemia occurred in 56, 66, and 38% of patients, respectively; events were grade 3 or 4 in 22, 31, and 14%, respectively.1 The median time to onset of grade 3 or 4 myelosuppression was 1.3 months (range: 1 day to 1.2 years).1 In the PACE trial, neutropenia, thrombocytopenia, and anemia occurred in 56, 63, and 52% of patients, respectively; events were grade 3 or 4 in 34, 40, and 20%, respectively.1 Myelosuppression occurred more commonly in patients with accelerated phase CML, blast phase CML, and Ph+ ALL.1 Grade 3 or 4 myelosuppression was observed early in treatment, with a median time to onset of 29 days (range: 1 day to 4.1 years).1 In the PhALLCON trial, neutropenia, thrombocytopenia, and anemia occurred in 66, 65, and 53%, respectively, of 163 patients.1 Grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in 63, 62, and 38% of patients, respectively.1 The median time to onset of grade 3 or 4 myelosuppression was 27 days (range: 1 day to 9.2 months).1
Monitor CBC every 2 weeks during the first 3 months of therapy and monthly (or as clinically indicated) thereafter.1 If hematologic toxicity occurs, interrupt therapy, then resume at the same or a reduced dosage upon resolution.1
Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, 1.1% developed serious tumor lysis syndrome and 2.1% developed hyperuricemia.1 In the PACE trial, 0.4% of 449 patients developed serious tumor lysis syndrome; 1 case occurred in a patient with advanced accelerated phase CML and 1 case occurred in a patient with blast phase CML.1 Hyperuricemia occurred in 7% of patients.1 In the PhALLCON trial, serious tumor lysis syndrome was reported in 0.6% of 163 patients; hyperuricemia was noted in 10% of patients.1
Ensure adequate hydration and treat hyperuricemia prior to initiation of ponatinib.1
Reversible Posterior Leukoencephalopathy Syndrome
Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in patients receiving ponatinib.1 Patients may present with hypertension, seizure, headache, decreased alertness, altered mental function, vision loss, and other visual and neurological disturbances.1 Magnetic resonance imaging is necessary to confirm the diagnosis.1 If RPLS occurs, interrupt ponatinib until resolution; the safety of resuming ponatinib upon resolution of RPLS is unknown.1
Wound Healing Complications and GI Perforation
Impaired wound healing occurred in patients receiving ponatinib.1 Withhold ponatinib for at least 1 week before elective surgery and do not administer following major surgery for at least 2 weeks and until adequate wound healing occurs.1 The safety of ponatinib resumption after resolution of wound healing complications has not been established.1
GI perforation or fistula occurred in patients receiving ponatinib.1 Permanently discontinue ponatinib in patients with GI perforation.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and findings from animal studies, ponatinib may cause fetal harm.1 In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the recommended human dose.1 There are no available data in human pregnancy.1
Verify the pregnancy status of females of reproductive potential prior to initiating ponatinib.1 Advise females of reproductive potential to use effective contraception during ponatinib therapy and for 3 weeks after the last dose.1 If used during pregnancy or if the patient becomes pregnant while receiving ponatinib, apprise the patient of the potential fetal hazard.1
Based on its mechanism of action and findings from animal studies, ponatinib may cause fetal harm.1 In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the recommended human dose.1 There are no available data in human pregnancy.1
Verify the pregnancy status of females of reproductive potential prior to initiating ponatinib.1 If used during pregnancy or if the patient becomes pregnant while receiving ponatinib, apprise the patient of the potential fetal hazard.1
There are no data on the presence of ponatinib in human milk or the effects on the breastfed child or on milk production.1 Because of the potential for serious adverse reactions to ponatinib in breastfed children, advise patients to avoid breastfeeding during ponatinib treatment and for 1 week following the last dose.1
Females and Males of Reproductive Potential
Based on its mechanism of action and findings from animal studies, ponatinib may cause fetal harm.1 Verify the pregnancy status of females of reproductive potential prior to initiating ponatinib.1 Advise females of reproductive potential to use effective contraception during ponatinib therapy and for 3 weeks after the last dose.1
Based on animal data, ponatinib may impair fertility in females of reproductive potential; it is not known whether these effects on fertility are reversible.1
Safety and efficacy have not been established in pediatric patients younger than 18 years of age.1
Of the 94 patients in the OPTIC trial who received ponatinib 45 mg daily as their initial dosage, 17% were 65 years of age or older and 2.1% were 75 years of age or older.1 Patients 65 years of age or older had lower rates of BCR-ABL1 IS≤1% at 12 months compared to younger patients (27% versus 47%); this continued at 60 months with rates of 40% and 64%, respectively.1 Patients 65 years of age or older were also more likely to experience arterial occlusive events compared to younger patients (38% versus 14%).1
In the PACE trial, 35% of patients were 65 years of age or older and 8% were 75 years of age or older.1 In patients with chronic phase CML, the major cytogenetic response rate was 40% in those 65 years of age and older compared with 65% in those younger than 65 years of age.1 In patients with accelerated or blast phase CML or with Ph+ ALL, the major hematologic response rate was 45% in those 65 years of age and older compared with 44% in those younger than 65 years of age.1 Arterial occlusive events occurred in 35% of patients 65 years of age or older and 21% of patients younger than 65 years of age.1
In the PhALLCON trial, 21% of patients were 65 years of age or older and 7% were 75 years of age or older.1 No differences in efficacy were seen in patients 65 years of age or older and younger patients.1 Arterial occlusive events occurred more frequently in patients 65 years of age and older as compared to those less than 65 years of age (21% versus 2.3%).1
Adverse reactions associated with ponatinib therapy (e.g., vascular occlusion, thrombocytopenia, peripheral edema, elevated serum lipase concentration, dyspnea, asthenia, muscle spasm, decreased appetite) may occur more frequently in patients 65 years of age or older.1 Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly, caution is advised in dose selection for geriatric patients.1
Patients with hepatic impairment are more likely to experience adverse reactions than patients with normal hepatic function.1 Reduce the initial dosage of ponatinib in patients with pre-existing hepatic impairment (Child-Pugh class A, B, or C) and chronic phase CML, accelerated phase CML, blast phase CML, or Ph+ ALL receiving monotherapy.1 Dosage adjustment is not recommended for patients with newly diagnosed Ph+ ALL and mild hepatic impairment (Child-Pugh class A).1 Patients with newly diagnosed Ph+ ALL and moderate or severe hepatic impairment (Child-Pugh class B or C) should be closely monitored for an increased incidence of adverse reactions; dosage modification may be necessary.1 The safety of multiple doses, or doses higher than 30 mg, has not been studied in patients with hepatic impairment.1
No clinically significant difference in the pharmacokinetics of ponatinib were observed in patients with mild to moderate renal impairment (creatinine clearance 30-89 mL/min).1 Data are lacking on use of ponatinib in patients with severe renal impairment.1 Although renal excretion is not a major route of elimination for the drug, the effect of severe renal impairment on hepatic elimination has not been established.1
The most common adverse reactions reported in >20% of patients receiving ponatinib as monotherapy include rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction, cardiac arrhythmias, and arterial occlusive events.1 Grade 3 or 4 laboratory abnormalities reported in more than 20% of patients include decreased platelet count, decreased neutrophil count, and decreased white blood cell count.1
The most common adverse reactions reported in patients receiving ponatinib in combination with chemotherapy include hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, peripheral neuropathy, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.1 Grade 3 or 4 laboratory abnormalities reported in more than 20% of patients include decreased white blood cell count, decreased neutrophil count, decreased platelet count, decreased lymphocytes, decreased hemoglobin, increased lipase, and increased ALT.1
Ponatinib is metabolized principally by cytochrome P-450 (CYP) isoenzyme 3A4 and, to a lesser extent, by CYP isoenzymes 2C8, 2D6, and 3A5.1 In vitro studies indicate that ponatinib does not inhibit the metabolism of substrates for CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A and does not induce the metabolism of substrates for CYP1A2, 2B6, or 3A.1
In vitro studies indicate that ponatinib inhibits the efflux transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and bile salt export pump (BSEP); the drug is a weak substrate for P-gp and BCRP.1 In vitro, the drug is not a substrate for organic anion transport polypeptide (OATP) 1B1, OATP1B3, or organic cation transporter (OCT) 1.1 Ponatinib does not inhibit OATP1B1, OATP1B3, OCT1, OCT2, organic anion transporter (OAT) 1, or OAT3.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Inhibitors of Cytochrome P-450 (CYP) 3A Isoenzyme
Concomitant use of ponatinib with strong inhibitors of CYP3A may result in increased plasma concentrations, leading to an increased risk of adverse reactions.1 When the strong CYP3A inhibitor ketoconazole was administered concomitantly with ponatinib, the peak plasma concentration and AUC of ponatinib was increased by 47 and 78%, respectively.1 Avoid concomitant administration of ponatinib and strong CYP3A inhibitors.1 If ponatinib is used concomitantly with a strong CYP3A inhibitor, the dosage of ponatinib should be reduced.1
Concomitant use of ponatinib with strong inducers of CYP3A may result in decreased ponatinib plasma concentrations.1 When rifampin, a strong CYP3A inducer, was administered concomitantly with ponatinib, the peak plasma concentration and AUC of ponatinib was decreased by 42 and 62%, respectively.1 The manufacturer recommends selecting concomitant medications with no or minimal CYP3A induction potential.1 Avoid concomitant use with strong CYP3A inducers unless the potential benefit outweighs the possible risk of decreased ponatinib exposure.1 If concomitant use cannot be avoided, monitor patients for signs of reduced ponatinib efficacy.1
Drugs Affecting Gastric Acidity
When lansoprazole, a proton pump inhibitor, was administered concomitantly with ponatinib, the peak plasma concentration and AUC of ponatinib was decreased by 25 and 6%, respectively.1
Ponatinib, a tyrosine kinase inhibitor (TKI), is an antineoplastic agent.1, 2, 4, 13, 15, 16, 17 Ponatinib inhibits multiple tyrosine kinases, including wild-type and mutant BCR-ABL , members of the Src family of tyrosine kinases, stem cell factor receptor [c-Kit], members of the Eph receptor kinase family, tyrosine kinase with immunoglobulin and epidermal growth factor homology [TIE-2], fms-like tyrosine kinase 3 [Flt-3], ret proto-oncogene [RET], members of the vascular endothelial growth factor [VEGF] family, members of the platelet-derived growth factor [PDGF] family, and members of the fibroblast growth factor [FGF] family.1, 3, 13, 15, 16, 17 The Philadelphia chromosome, characteristic of chronic myelogenous leukemia (CML), is created by a reciprocal translocation between chromosomes 9 and 22.8, 9 Translocation between these chromosomes results in production of an abnormal protein ( BCR-ABL tyrosine kinase) that exhibits enhanced tyrosine kinase activity (i.e., increased phosphorylation of tyrosine residues);10, 23 phosphorylation of tyrosine residues on growth factor receptors is thought to be important in stimulating cell proliferation and inhibiting cell death (apoptosis).8, 9, 24
Clinical resistance to imatinib in CML has been attributed to several mechanisms, but point mutations in the BCR-ABL kinase domain appear to be the most common, occurring in 30-90% of patients who develop resistance;13, 18 of these BCR-ABL kinase domain mutant forms, T315I accounts for 15-20% of clinically observed mutations.14 The T315I BCR-ABL kinase domain mutation confers resistance to the BCR-ABL TKIs imatinib, nilotinib, dasatinib, and bosutinib.1, 13, 17, 19 In vitro, ponatinib potently inhibits wild-type BCR-ABL and several BCR-ABL kinase domain mutant forms, including T315I.1, 13, 14, 17 Ponatinib has been shown to induce tumor regression in mouse models of tumors expressing wild-type and T315I mutant BCR-ABL .1 In vitro, the drug has also been shown to inhibit additional mutant tyrosine kinase receptors and oncogenic fusion proteins.15, 16, 20, 21, 22
AUC and peak plasma concentration of ponatinib are approximately dose proportional over the ponatinib dose range of 2-60 mg.1, 4 Peak plasma concentrations of ponatinib are achieved about 6 hours following oral administration of ponatinib.1 Food has no effect on AUC or peak plasma concentration of ponatinib.1 Ponatinib is mostly metabolized by phase I hepatic cytochrome P-450 (CYP) isoenzymes (i.e., CYP3A4 and, to a lesser extent, CYP2C8, 2D6, 3A5) and phase II hepatic conjugation; the drug is also metabolized by esterases and/or amidases.1 In vitro studies indicate that ponatinib is a weak substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).1 In vitro, ponatinib is greater than 99% bound to plasma proteins.1 Following administration of a single radiolabeled dose of ponatinib, approximately 87% of the dose was recovered in feces and 5% was recovered in urine.1 Following repeated administration of ponatinib 45 mg once daily, the elimination half-life of ponatinib was approximately 24 hours.1, 4 No clinically significant differences in ponatinib pharmacokinetics were observed based on age (19-85 years), body weight (41-152 kg), or mild to moderate renal impairment (creatinine clearance 30-89 mL/min).1
In a small phase 1 study, substantial changes in the mean QT interval corrected for rate (QTc) (i.e., greater than 20 msec) were not observed when ponatinib 30, 45, or 60 mg was administered once daily.1, 7
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web]. .
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets, film-coated | 10 mg (of ponatinib) | Iclusig® | Takeda |
15 mg (of ponatinib) | Iclusig® | Takeda | ||
30 mg (of ponatinib) | Iclusig® | Takeda | ||
45 mg (of ponatinib) | Iclusig® | Takeda |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions March 10, 2026. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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