Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.

Uses for PONATinib (Systemic)

Chronic Myelogenous Leukemia (CML) or Philadelphia Chromosome-Positive Acute Lymphocytic (Lymphoblastic) Leukemia (ALL) Following Treatment Failure

Treatment of T315I BCR-ABL mutation-positive chronic phase, accelerated phase, or blast phase CML and of T315I BCR-ABL mutation-positive Philadelphia chromosome-positive (Ph⁺) ALL in adults.

Treatment of accelerated phase CML, blast phase CML, or Ph⁺ ALL in adults in whom no other tyrosine kinase inhibitor (TKI) therapy may be used; designated an orphan drug by FDA for these uses.

Treatment of chronic phase CML with resistance or intolerance to ≥2 prior kinase inhibitors in adults.

Not recommended for treatment of newly diagnosed chronic phase CML.

According to some experts, ponatinib is the agent of choice in patients with CML and the T315I mutation, and in instances where other TKIs are not indicated. Important factors to consider when deciding to initiate ponatinib treatment in CML include disease state, mutational status, line of treatment, reason for change of therapy (resistance or intolerance), and specific comorbidities. Patients with T315I BCR-ABL mutation-positive Ph+ ALL may respond to ponatinib therapy.

PONATinib (Systemic) Dosage and Administration

General

Pretreatment Screening

• Verify pregnancy status of females of reproductive potential prior to initiating ponatinib.

• Perform liver function tests at baseline.

• Measure blood pressure at baseline.

• Conduct a comprehensive eye exam at baseline.

• Ensure adequate hydration and treat high uric acid levels prior to initiating ponatinib.

Patient Monitoring

• Monitor liver function tests at least monthly or as clinically indicated.

• Monitor serum lipase every 2 weeks for the first 2 months, then monthly thereafter or as clinically indicated; consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse.

• Monitor CBC every 2 weeks for the first 3 months, then monthly or as clinically indicated.

• Monitor blood pressure as clinically indicated.

• Monitor for evidence of arterial occlusive events and venous thromboembolism.

• Monitor for signs or symptoms of heart failure.

• Monitor for signs and symptoms suggestive of slow heart rate (e.g., fainting, dizziness) or rapid heart rate (e.g., chest pain, palpitations, dizziness).

• Monitor for symptoms of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain or weakness).

• Conduct comprehensive eye exams periodically during treatment.

• Monitor for the presence of fluid retention and hemorrhage.

Dispensing and Administration Precautions

• To avoid medication errors, the Institute for Safe Medication Practices (ISMP) recommends that prescribers communicate both the brand and generic names for ponatinib on the prescription order form.

• Based on ISMP, ponatinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Administration

Oral Administration

Administer orally once daily without regard to meals.

Swallow tablets whole; do not crush, break, cut, or chew tablets.

If a dose is missed, give next dose at the regularly scheduled time the next day.

Dosage

Available as ponatinib hydrochloride; dosage expressed in terms of ponatinib.

Adults

Chronic Phase CML

Oral

Initially, 45 mg once daily; reduce to 15 mg once daily upon achievement of BCR-ABL1 ^IS ≤1%.

• Re-escalate dosage to a previously tolerated dosage of 30 or 45 mg once daily if response is lost on 15 mg once daily.

• Continue until loss of response at re-escalated dosage or unacceptable toxicity.

• Consider discontinuation if hematologic response not achieved by 3 months.

Accelerated Phase or Blast Phase CML or Ph+ ALL

Oral

Initially, 45 mg once daily; optimal dosage not established.

• Consider dosage reduction in patients with accelerated phase CML who have achieved major cytogenetic response.

• Continue until loss of response or unacceptable toxicity.

• Consider discontinuation if hematologic response not achieved by 3 months.

Dosage Modification for Toxicity

If adverse reactions occur, temporary interruption of therapy, dosage reduction, and/or discontinuance of ponatinib may be necessary. If dosage modification required, reduce dosage as described in Table 1. Permanently discontinue in patients who are unable to tolerate the lowest dosage described in Table 1.

If an adverse reaction occurs, reduce ponatinib dosage, or interrupt or permanently discontinue therapy as described in Table 2.

Dosage Modification for Concomitant Use with Potent CYP3A Inhibitors

Avoid concomitant use of ponatinib with potent CYP3A inhibitors when possible. If concomitant use cannot be avoided, reduce ponatinib dosage as described in Table 3. After discontinuing a potent CYP3A inhibitor for 3–5 elimination half-lives, resume the dosage of ponatinib that was tolerated prior to initiating the potent CYP3A inhibitor.

Special Populations

Hepatic Impairment

Hepatic impairment (Child-Pugh class A, B, or C): reduce initial dosage from 45 mg once daily to 30 mg once daily.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Use

Select dosage with caution because of greater frequency of age-related decreases in hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.

Contraindications

• None.

Warnings/Precautions

Warnings

Arterial Occlusive Events

Arterial occlusive events, including fatalities, have occurred in patients receiving ponatinib in clinical trials.

Consider whether benefits of ponatinib therapy outweigh risks. Monitor patients for manifestations of arterial occlusive events. If arterial occlusion is suspected, interrupt or discontinue therapy. Following evaluation, weigh the risks and benefits of restarting ponatinib.

Venous Thromboembolic Events

Serious or severe venous thromboembolic events have occurred in patients receiving ponatinib.

Monitor patients for manifestations of venous thromboembolic events. If a venous thromboembolic event occurs, interrupt treatment, then resume at the same or a decreased dose or discontinue ponatinib based on recurrence/severity.

Heart Failure

Serious or severe heart failure events, including fatalities, have occurred.

Monitor for manifestations of heart failure; manage as clinically indicated.

If new or worsening heart failure occurs, interrupt therapy and reduce dosage upon resumption or discontinue ponatinib.

Hepatotoxicity

Risk of hepatotoxicity, including liver failure and death. Fulminant hepatic failure resulting in death following 1 week of therapy has occurred rarely. Liver enzyme elevations occur commonly.

Fatalities occurred in patients with blast phase CML or Ph+ ALL.

Perform liver function tests prior to initiation of therapy and at least monthly thereafter or as clinically indicated.

If hepatotoxicity occurs, interrupt therapy and reduce dosage, or discontinue ponatinib.

Other Warnings and Precautions

Hypertension

Serious or severe hypertension, including hypertensive crisis, observed. Blood pressure elevations occur commonly. Urgent clinical intervention for symptoms associated with hypertension (e.g., confusion, headache, chest pain, shortness of breath) may be required.

Monitor BP and treat as clinically indicated. If hypertension is not medically controlled, interrupt therapy, reduce the dosage, or discontinue ponatinib. For significant worsening, labile, or treatment-resistant hypertension, interrupt ponatinib and consider evaluation for renal artery stenosis.

Pancreatitis

Pancreatitis and pancreatic laboratory abnormalities (e.g., elevated serum amylase and lipase) observed. Most cases resolve within 2 weeks of interruption of therapy or dosage reduction.

Monitor serum lipase concentrations every 2 weeks during the first 2 months of therapy and then monthly thereafter or as clinically indicated; consider more frequent monitoring in patients with a history of pancreatitis or alcohol abuse. If serum lipase concentrations are elevated and accompanied by abdominal pain, evaluate the patient for pancreatitis.

If pancreatitis occurs, interrupt therapy, then resume at the same or a reduced dosage, or discontinue ponatinib.

Increased Toxicity in Newly Diagnosed Chronic Phase CML

Ponatinib not indicated or recommended for use in patients with newly diagnosed chronic phase CML. Arterial and venous thrombosis and occlusions occurred at least twice as often in patients receiving ponatinib compared to patients receiving imatinib. Patients receiving ponatinib also had a higher incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders.

Neuropathy

Peripheral and cranial neuropathy observed; onset has occurred during the initial month of therapy. Most common peripheral neuropathies were paresthesia, hypoesthesia, and muscular weakness.

Monitor patient for manifestations of neuropathy.

If neuropathy occurs, interrupt therapy, then resume at the same or a reduced dosage, or discontinue ponatinib.

Ocular Toxicity

Serious ocular toxicities leading to blindness or blurred vision observed. Retinal toxicities (i.e., macular edema, age-related macular degeneration, retinal vein occlusion, retinal hemorrhage, vitreous floaters), blurred vision, eye pain, and dry eye have occurred.

Perform comprehensive ophthalmologic examination at baseline and periodically during therapy.

Hemorrhage

Hemorrhage, sometimes serious or fatal, observed; increased incidence of serious hemorrhage in patients with accelerated or blast phase CML or Ph⁺ ALL than in patients with chronic phase CML. Most serious hemorrhagic events were GI hemorrhage or subdural hematoma. Hemorrhagic events occurred principally in patients with grade 4 thrombocytopenia.

Monitor for hemorrhage and manage as clinically indicated. If hemorrhage occurs, interrupt therapy, then resume at the same or a reduced dosage, or discontinue ponatinib.

Fluid Retention

Risk of serious fluid retention (i.e., pleural effusion, pericardial effusion, angioedema); brain edema resulting in death reported rarely.

Monitor for signs and symptoms of fluid retention. If fluid retention develops, manage patients as clinically indicated and interrupt therapy, then resume at the same or a reduced dosage, or discontinue ponatinib.

Cardiac Arrhythmias

Grade 3 or 4 cardiac arrhythmia events, sometimes requiring hospitalization, reported, including atrial fibrillation, atrial flutter, ventricular arrhythmia, symptomatic bradyarrhythmia requiring pacemaker implantation, cardiorespiratory arrest, supraventricular extrasystoles, supraventricular and ventricular tachycardia, atrial tachycardia, sinus bradycardia, bradycardia, QT prolongation, complete atrioventricular block, sinus node dysfunction, loss of consciousness, and syncope.

Monitor 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. If cardiac arrhythmias occur, interrupt therapy, then resume at the same or a reduced dosage, or discontinue ponatinib.

Myelosuppression

Risk of grade 3 or 4 myelosuppression (i.e., neutropenia, anemia, thrombocytopenia); incidence increased in patients with blast or accelerated phase CML or Ph⁺ ALL.

Monitor CBCs every 2 weeks during the first 3 months of therapy and then monthly (or as clinically indicated) thereafter. If hematologic toxicity occurs, interrupt therapy, then resume at the same or a reduced dosage.

Tumor Lysis Syndrome

Tumor lysis syndrome and hyperuricemia reported.

Ensure adequate hydration and treat hyperuricemia prior to initiation of ponatinib.

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) reported. Symptoms include hypertension, seizure, headache, decreased alertness, altered mental function, vision loss, and other visual and neurological disturbances. Magnetic resonance imaging is necessary to confirm diagnosis.

If RPLS occurs, interrupt ponatinib until resolution; safety of resuming ponatinib upon resolution is unknown.

Wound Healing Complications and GI Perforation

Impaired wound healing reported. Withhold ponatinib for ≥1 week before elective surgery and do not administer following major surgery for ≥2 weeks and until adequate wound healing occurs. Safety of ponatinib resumption after resolution of wound healing complications not established.

Gastrointestinal perforation or fistula reported. Permanently discontinue ponatinib in patients with GI perforation.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and findings from animal studies. Verify pregnancy status of females of reproductive potential prior to initiating therapy. Advise females of reproductive potential to use effective contraception during therapy and for 3 weeks after the last dose. If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm based on mechanism of action and findings from animal studies. No data available in human pregnancy. Verify pregnancy status of females of reproductive potential prior to initiating therapy. If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.

Lactation

No data on the presence of ponatinib in human milk or effects on the breastfed child or on milk production. Advise patients to avoid breastfeeding during ponatinib treatment and for 6 days following the last dose.

Females and Males of Reproductive Potential

Based on its mechanism of action and findings from animal studies, ponatinib may cause fetal harm. Verify the pregnancy status of females of reproductive potential prior to initiating therapy. Advise females of reproductive potential to use effective contraception during therapy and for 3 weeks after the last dose.

May impair fertility in females of reproductive potential; not known whether these effects on fertility are reversible.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

In the OPTIC trial in patients with chronic phase CML, patients ≥65 years of age had lower rates of BCR-ABL1 ^IS ≤1% at 12 months compared to younger patients (27% versus 47%). Patients ≥65 years of age were also more likely to experience arterial occlusive events compared to younger patients (38% versus 9%).

In the PACE trial, the major cytogenetic response rate in patients with chronic phase CML was 40% in patients ≥65 years of age compared with 65% in patients <65 years of age. In patients with accelerated or blast phase CML or Ph+ ALL, the major hematologic response rate was 45% in patients ≥65 years of age compared with 44% in patients <65 years of age. Arterial occlusive events occurred in 35% of patients ≥65 years of age and 21% of patients <65 years of age.

Certain toxicities may occur more frequently in geriatric patients ≥65 years of age. Select dosage cautiously in geriatric patients.

Hepatic Impairment

Hepatic impairment (Child-Pugh class A, B, or C) did not increase pharmacokinetic exposure to ponatinib, but patients with hepatic impairment are more likely to experience adverse reactions. Reduce initial dosage of ponatinib in patients with pre-existing hepatic impairment.

Renal Impairment

No clinically significant difference in pharmacokinetics observed in patients with mild to moderate renal impairment (Cl_cr 30–89 mL/min). Data lacking in patients with severe renal impairment.

Common Adverse Effects

Most common adverse reactions (>20%) 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, arterial occlusive events.

Grade 3 or 4 laboratory abnormalities (>20%) include decreased platelet count, decreased neutrophil count, decreased white blood cell count.

General

Pretreatment Screening

• Verify pregnancy status of females of reproductive potential prior to initiating ponatinib.

• Perform liver function tests at baseline.

• Measure blood pressure at baseline.

• Conduct a comprehensive eye exam at baseline.

• Ensure adequate hydration and treat high uric acid levels prior to initiating ponatinib.

Patient Monitoring

• Monitor liver function tests at least monthly or as clinically indicated.

• Monitor serum lipase every 2 weeks for the first 2 months, then monthly thereafter or as clinically indicated; consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse.

• Monitor CBC every 2 weeks for the first 3 months, then monthly or as clinically indicated.

• Monitor blood pressure as clinically indicated.

• Monitor for evidence of arterial occlusive events and venous thromboembolism.

• Monitor for signs or symptoms of heart failure.

• Monitor for signs and symptoms suggestive of slow heart rate (e.g., fainting, dizziness) or rapid heart rate (e.g., chest pain, palpitations, dizziness).

• Monitor for symptoms of neuropathy (e.g., hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain or weakness).

• Conduct comprehensive eye exams periodically during treatment.

• Monitor for the presence of fluid retention and hemorrhage.

Dispensing and Administration Precautions

• To avoid medication errors, the Institute for Safe Medication Practices (ISMP) recommends that prescribers communicate both the brand and generic names for ponatinib on the prescription order form.

• Based on ISMP, ponatinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Administration

Oral Administration

Administer orally once daily without regard to meals.

Swallow tablets whole; do not crush, break, cut, or chew tablets.

If a dose is missed, give next dose at the regularly scheduled time the next day.

Dosage

Available as ponatinib hydrochloride; dosage expressed in terms of ponatinib.

Adults

Chronic Phase CML

Oral

Initially, 45 mg once daily; reduce to 15 mg once daily upon achievement of BCR-ABL1 ^IS ≤1%.

• Re-escalate dosage to a previously tolerated dosage of 30 or 45 mg once daily if response is lost on 15 mg once daily.

• Continue until loss of response at re-escalated dosage or unacceptable toxicity.

• Consider discontinuation if hematologic response not achieved by 3 months.

Accelerated Phase or Blast Phase CML or Ph+ ALL

Oral

Initially, 45 mg once daily; optimal dosage not established.

• Consider dosage reduction in patients with accelerated phase CML who have achieved major cytogenetic response.

• Continue until loss of response or unacceptable toxicity.

• Consider discontinuation if hematologic response not achieved by 3 months.

Dosage Modification for Toxicity

If adverse reactions occur, temporary interruption of therapy, dosage reduction, and/or discontinuance of ponatinib may be necessary. If dosage modification required, reduce dosage as described in Table 1. Permanently discontinue in patients who are unable to tolerate the lowest dosage described in Table 1.

If an adverse reaction occurs, reduce ponatinib dosage, or interrupt or permanently discontinue therapy as described in Table 2.

Dosage Modification for Concomitant Use with Potent CYP3A Inhibitors

Avoid concomitant use of ponatinib with potent CYP3A inhibitors when possible. If concomitant use cannot be avoided, reduce ponatinib dosage as described in Table 3. After discontinuing a potent CYP3A inhibitor for 3–5 elimination half-lives, resume the dosage of ponatinib that was tolerated prior to initiating the potent CYP3A inhibitor.

Special Populations

Hepatic Impairment

Hepatic impairment (Child-Pugh class A, B, or C): reduce initial dosage from 45 mg once daily to 30 mg once daily.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Use

Select dosage with caution because of greater frequency of age-related decreases in hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.

Principally metabolized by CYP3A4 and, to a lesser extent, by CYP isoenzymes 2C8, 2D6, and 3A5.

Does not inhibit metabolism of substrates for CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A; does not induce metabolism of substrates for CYP1A2, 2B6, or 3A.

Inhibits P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and bile salt export pump (BSEP); is a weak substrate for P-gp and BCRP.

Not a substrate for organic anion transport polypeptide (OATP) 1B1 or OATP1B3, or organic cation transporter (OCT) 1; does not inhibit OATP1B1, OATP1B3, OCT1, OCT2, organic anion transporter (OAT) 1, or OAT3.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations of ponatinib). Avoid concomitant use when possible; if used concomitantly, reduce dosage of ponatinib.

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased plasma concentrations of ponatinib). Manufacturer recommends selecting medications with no or minimal CYP3A induction potential. Avoid concomitant use with potent CYP3A inducers unless potential benefit outweighs possible risk of reduced ponatinib exposure. Monitor for signs of reduced ponatinib efficacy if concomitant use cannot be avoided.

Specific Drugs and Food