Ponatinib: Drug information

For additional information see "Ponatinib: Patient drug information"

For abbreviations, symbols, and age group definitions show table

ALERT: US Boxed Warning

Arterial occlusive events:

Arterial occlusive events (AOEs), including fatalities, have occurred in ponatinib-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients 50 years of age and younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ponatinib based on severity. Consider benefit-risk to guide a decision to restart ponatinib.

Heart failure:

Heart failure, including fatalities, occurred in ponatinib-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue ponatinib for new or worsening heart failure.

Hepatotoxicity:

Hepatotoxicity, liver failure, and death have occurred in ponatinib-treated patients. Monitor liver function tests. Interrupt or discontinue ponatinib based on severity.

Venous thromboembolic events:

Venous thromboembolic events (VTEs) have occurred in ponatinib-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue ponatinib based on severity.

Brand Names: US

Iclusig

Brand Names: Canada

Iclusig

Pharmacologic Category

Antineoplastic Agent, BCR-ABL Tyrosine Kinase Inhibitor;
Antineoplastic Agent, Tyrosine Kinase Inhibitor

Dosing: Adult

Dosage guidance:

Safety: Ensure adequate hydration and manage elevated uric acid levels prior to initiating therapy to minimize risk of tumor lysis syndrome. Withhold ponatinib treatment for at least 1 week prior to elective surgery; do not administer ponatinib for at least 2 weeks following major surgery and until adequate wound healing.

Acute lymphoblastic leukemia, Philadelphia chromosome positive, newly diagnosed

Acute lymphoblastic leukemia, Philadelphia chromosome positive (Ph+), newly diagnosed (combination therapy): Note: Treatment cycle length is 28 days.

Induction (cycles 1 to 3): Oral: 30 mg once daily (in combination with vincristine and dexamethasone) for 3 cycles.

Consolidation (cycles 4 to 9): Oral: 30 mg once daily (or decreased to 15 mg once daily if in minimal residual disease [MRD]-negative complete remission [CR] [≤0.01% BCR::ABL1/ABL1] at the end of induction), in combination with alternating cycles of methotrexate (cycles 4, 6, and 8) and cytarabine (cycles 5, 7, and 9) for 6 cycles. If MRD negativity is lost at any time following dose reduction to 15 mg once daily, ponatinib dose may be reescalated to 30 mg once daily.

Maintenance (cycles 10 to 20 and beyond): Oral: 30 mg once daily (or decreased to 15 mg once daily if in MRD-negative CR [≤0.01% BCR::ABL1/ABL1] at the end of induction), in combination with vincristine and prednisone for 11 cycles, followed by ponatinib (as a single agent) until relapse from CR, progression of disease, unacceptable toxicity, or start of alternative therapy, including hematopoietic cell transplantation (HCT). If MRD negativity is lost at any time following dose reduction to 15 mg once daily, ponatinib dose may be reescalated to 30 mg once daily.

Acute lymphoblastic leukemia, Philadelphia chromosome positive

Acute lymphoblastic leukemia, Philadelphia chromosome positive (Ph+) (single-agent therapy in patients for whom no other kinase inhibitors are indicated): Oral: Initial: 45 mg once daily (as a single agent); continue until loss of response or unacceptable toxicity. Consider discontinuing if response has not occurred by 3 months.

Acute lymphoblastic leukemia, Philadelphia chromosome positive, T315I positive

Acute lymphoblastic leukemia, Philadelphia chromosome positive (Ph+), T315I positive (single-agent therapy): Oral: Initial: 45 mg once daily (as a single agent); continue until loss of response or unacceptable toxicity. Consider discontinuing if response has not occurred by 3 months.

Chronic myeloid leukemia, chronic phase

Chronic myeloid leukemia, chronic phase (with resistance or intolerance to at least 2 prior kinase inhibitors): Oral: Initial: 45 mg once daily (as a single agent); reduce the dose to 15 mg once daily upon achievement of ≤1% BCR-ABL1^IS; patients with a loss of response can reescalate dose to a previously tolerated dose of 30 or 45 mg once daily. Continue treatment until a loss of response at the reescalated dose or until unacceptable toxicity; consider discontinuing if hematologic response has not occurred by 3 months. Note: Ponatinib is not recommended for treatment of newly diagnosed chronic phase chronic myeloid leukemia.

Chronic myeloid leukemia, accelerated or blast phase

Chronic myeloid leukemia, accelerated or blast phase (in patients for whom no other kinase inhibitors are indicated): Oral: Initial: 45 mg once daily (as a single agent); consider reducing the dose for patients with accelerated phase who have achieved a major cytogenetic response. Continue until loss of response or unacceptable toxicity; consider discontinuing if response has not occurred by 3 months.

Chronic myeloid leukemia, T315I positive, chronic phase

Chronic myeloid leukemia, T315I positive, chronic phase: Oral: Initial: 45 mg once daily (as a single agent); reduce the dose to 15 mg once daily upon achievement of ≤1% BCR-ABL1^IS; patients with a loss of response can reescalate dose to a previously tolerated dose of 30 or 45 mg once daily. Continue treatment until a loss of response at the reescalated dose or until unacceptable toxicity; consider discontinuing if hematologic response has not occurred by 3 months.

Chronic myeloid leukemia, T315I positive, accelerated or blast phase

Chronic myeloid leukemia, T315I positive, accelerated or blast phase: Oral: Initial: 45 mg once daily (as a single agent); consider reducing the dose for patients with accelerated phase who have achieved a major cytogenetic response. Continue until loss of response or unacceptable toxicity; consider discontinuing if response has not occurred by 3 months.

Missed dose: If a dose is missed, administer the next dose at the regularly scheduled time the next day.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Note: Kidney function estimated using the Cockcroft-Gault equation.

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, mild to moderate impairment had no clinically significant effect on ponatinib pharmacokinetics.

CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

Hepatic impairment prior to treatment initiation:

Acute lymphoblastic leukemia (ALL), Philadelphia chromosome-positive (Ph+), newly diagnosed (combination therapy):

Mild impairment (Child-Turcotte-Pugh class A): No dose adjustment necessary.

Moderate to severe impairment (Child-Turcotte-Pugh class B, C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied; however, there may be a potential increased incidence of adverse reactions [eg, GI events, including pancreatitis]); monitor patients closely and modify dosage in the event of adverse reactions.

Chronic myeloid leukemia (accelerated, chronic, or blast phase) and Ph+ ALL (single agent therapy):

Mild to severe impairment (Child-Turcotte-Pugh class A, B, or C): Reduce initial dose to 30 mg once daily. There may be a potential increased incidence of adverse reactions (eg, GI events, including pancreatitis); monitor patients closely and modify dosage in the event of adverse reactions.

Acute hepatotoxicity during treatment:

AST or ALT >3 times ULN: Interrupt ponatinib until grade 0 or 1, then resume at the next lower dose.

ALT or AST ≥3 times ULN with concurrent bilirubin >2 times ULN and alkaline phosphatase <2 times ULN: Discontinue ponatinib.

Dosing: Adjustment for Toxicity: Adult

Note: Other concomitant anticancer therapies may also require treatment interruption, dosage reduction, and/or discontinuation.

**Ponatinib Dosage Reduction Levels for Adverse Reactions**
Dose reduction	Dose for chronic phase chronic myeloid leukemia (CML)	Dose for accelerated or blast phase CML and for Ph+ acute lymphoblastic leukemia (ALL)	Dose for newly diagnosed Ph+ ALL
Usual (initial) dose	45 mg once daily	45 mg once daily	30 mg once daily
First dose reduction	30 mg once daily	30 mg once daily	15 mg once daily
Second dose reduction	15 mg once daily	15 mg once daily	10 mg once daily
Third dose reduction	10 mg once daily	Permanently discontinue ponatinib if unable to tolerate 15 mg once daily.	Permanently discontinue ponatinib if unable to tolerate 10 mg once daily.
Subsequent dose reductions	Permanently discontinue ponatinib if unable to tolerate 10 mg once daily.

**Ponatinib Dosage Modifications for Adverse Reactions**
Adverse reaction	Severity	Ponatinib dose modification
Hematologic toxicity	ANC <1,000/mm³ or platelets <50,000/mm³	Interrupt ponatinib until ANC ≥1,500/mm³ and platelets ≥75,000/mm³, then resume at the same dose. For recurrence, interrupt ponatinib until resolution, then resume at the next lower dose.
Cardiovascular: Arrhythmia	Symptoms of slow or rapid heart rate	Manage as clinically indicated. Interrupt ponatinib; upon recovery, resume at the same dose, at a reduced dose, or discontinue (based on the severity and/or recurrence).
Cardiovascular: Heart failure	Any	Manage as clinically indicated.
	Grades 2 or 3	Interrupt ponatinib until grade 0 or 1, then resume at the next lower dose. Discontinue ponatinib for recurrence.
	Grade 4	Discontinue ponatinib.
Cardiovascular: Hypertension	If indicated, initiate appropriate antihypertensive therapy to reduce the risk for cardiovascular complications (ASCO [Armenian 2017], ESC [Lyon 2022]).
	Associated with confusion, headache, chest pain, or dyspnea	May require urgent clinical intervention.
	Medically uncontrolled	Interrupt, reduce dose, or discontinue ponatinib.
	Significant worsening, labile, or treatment-resistant	Interrupt ponatinib and evaluate for renal artery stenosis.
Arterial occlusive event (cardiovascular or cerebrovascular)	Grade 1	Interrupt ponatinib until resolved, then resume at the same dose.
	Grade 2	Interrupt ponatinib until grade 0 or 1, then resume at the next lower dose. Discontinue ponatinib for recurrence.
	Grades 3 or 4	Discontinue ponatinib.
Arterial occlusive event (peripheral vascular and other) or venous thromboembolic event	Grade 1	Interrupt ponatinib until resolved, then resume at the same dose.
	Grade 2	Interrupt ponatinib until grade 0 or 1, then resume at the same dose. For recurrence, interrupt ponatinib until grade 0 or 1, then resume at the next lower dose.
	Grade 3	Interrupt ponatinib until grade 0 or 1, then resume at the next lower dose. Discontinue ponatinib for recurrence.
	Grade 4	Discontinue ponatinib.
Fluid retention		Manage as clinically indicated. Interrupt ponatinib; upon recovery, resume at the same dose, at a reduced dose, or discontinue (based on the severity and/or recurrence).
GI perforation		Permanently discontinue ponatinib.
Hemorrhage		Manage as clinically indicated. Interrupt ponatinib; upon recovery, resume at the same dose, at a reduced dose, or discontinue (based on the severity and/or recurrence).
Neuropathy	Hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain, or weakness	Interrupt ponatinib; upon recovery, resume at the same dose, at a reduced dose, or discontinue (based on the severity and/or recurrence).
Pancreatitis and elevated lipase	Serum lipase >1 to 1.5 times ULN	Consider interrupting ponatinib until resolution, then resume at the same dose.
	Serum lipase >1.5 to 2 times ULN, 2 to 5 times ULN and asymptomatic, or asymptomatic radiographic pancreatitis	Interrupt ponatinib until grade 0 or 1 (<1.5 times ULN), then resume at the next lower dose.
	Serum lipase >2 to 5 times ULN and symptomatic, symptomatic grade 3 pancreatitis, or serum lipase >5 times ULN and asymptomatic	Interrupt ponatinib until complete resolution of symptoms and after recovery of lipase elevation to grade 0 or 1, then resume at the next lower dose.
	Symptomatic pancreatitis and serum lipase >5 times ULN	Discontinue ponatinib.
Reversible posterior leukoencephalopathy syndrome		Interrupt ponatinib until resolution. The safety of resuming ponatinib is unknown.
Other nonhematologic adverse reactions	Grade 1	Interrupt ponatinib until resolved, then resume at the same dose.
	Grade 2	Interrupt ponatinib until grade 0 or 1, then resume at the same dose. For recurrence, interrupt ponatinib until grade 0 or 1, then resume at the next lower dose.
	Grades 3 or 4	Interrupt ponatinib until grade 0 or 1, then resume at the next lower dose. Discontinue ponatinib for recurrence.

Dosing: Older Adult

Refer to adult dosing. Use caution when selecting initial dosing in older adults.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults.

>10%:

Cardiovascular: Cardiac arrhythmia (16% to 25%; ventricular arrhythmia: 3%), edema (≤41%), heart failure (6% to 16%), hypertension (31% to 53%; severe hypertension: 2% to 13%), occlusive arterial disease (13% to 31%; including carotid, vertebral, and middle cerebral artery and renal artery stenosis), peripheral edema (17%)

Dermatologic: Alopecia (6% to 11%), cellulitis (4% to 13%), skin rash (50% to 75%), xeroderma (12% to 42%)

Endocrine & metabolic: Decreased serum albumin (28%), decreased serum bicarbonate (20% to 27%), decreased serum calcium (30%), decreased serum phosphate (27% to 34%), decreased serum sodium (27%), fluid retention (≤41%), hyperlipidemia (3% to 28%), increased serum glucose (48% to 54%), increased serum potassium (20%), increased serum triglycerides (44%), weight loss (5% to 13%)

Gastrointestinal: Abdominal pain (25% to 54%; severe: 6%), constipation (11% to 53%), decreased appetite (8% to 31%), diarrhea (13% to 29%; grades 3/4: ≤3%), increased serum amylase (18%), increased serum lipase (≤40%), nausea (22% to 34%; grades 3/4: ≤2%), pancreatitis (≤32%), stomatitis (9% to 24%; grades 3/4: 1% to 3%), vomiting (19% to 27%; grades 3/4: 2%)

Genitourinary: Urinary tract infection (2% to 14%)

Hematologic & oncologic: Anemia (52%; grades 3/4: 20%), decreased white blood cell count (56%; grades 3/4: 12% to 63%), febrile neutropenia (1% to 25%), hemorrhage (12% to 38%; grades 3/4: 2% to 13%; major hemorrhage: 6%), lymphocytopenia (42%; grades 3/4: 7% to 32%), neutropenia (56%; grades 3/4: 34%), thrombocytopenia (63%; grades 3/4: 40%)

Hepatic: Hepatotoxicity (16% to 39%), increased serum alanine aminotransferase (41% to 49%), increased serum alkaline phosphatase (23% to 40%), increased serum aspartate aminotransferase (35% to 40%), increased serum bilirubin (13%)

Infection: Sepsis (3% to 28%)

Nervous system: Anxiety (5% to 18%), asthenia (≤47%), chills (8% to 13%), dizziness (3% to 17%), fatigue (≤47%), headache (17% to 43%), insomnia (11% to 13%), neuropathy (9% to 26%), peripheral neuropathy (5% to 20%; grades 3/4: 2%)

Neuromuscular & skeletal: Arthralgia (30% to 61%), muscle spasm (5% to 14%), musculoskeletal pain (6% to 11%), myalgia (6% to 24%), ostealgia (9% to 14%)

Ophthalmic: Ocular toxicity (30%; including blindness, blurred vision, dry eye syndrome, eye pain)

Renal: Increased serum creatinine (21%)

Respiratory: Cough (6% to 24%), dyspnea (16% to 23%), nasopharyngitis (3% to 18%), pneumonia (8% to 22%), upper respiratory tract infection (3% to 14%)

Miscellaneous: Fever (16% to 40%)

1% to 10%:

Cardiovascular: Acute myocardial infarction (grades 3/4: 2%), atrial fibrillation (8%), bradycardia (≤1%; including leading to pacemaker implantation), coronary artery disease (grades 3/4: 2%), deep vein thrombosis (2%), pericardial effusion (4%), peripheral arterial disease (occlusive: grades 3/4: 3%), pulmonary embolism (2%), reduced ejection fraction (3%), swelling of the extremities (4%), syncope (2%), venous thromboembolism (4% to 10%)

Endocrine & metabolic: Hyperuricemia (7%), hypothyroidism (3%), impaired glucose tolerance (9%)

Hematologic & oncologic: Second primary malignant neoplasm (6%)

Nervous system: Cerebral infarction (grades 3/4: 2%), cerebrovascular occlusion (7%), cranial nerve disorder (3%), hypoesthesia (4%), paresthesia (5%)

Ophthalmic: Retinal toxicity (4%; including macular edema, retinal hemorrhage, retinal vein occlusion, vitreous floaters)

Respiratory: Pleural effusion (9%)

<1%:

Cardiovascular: Atrial flutter, atrial tachycardia, complete atrioventricular block, hypertensive crisis, prolonged QT interval on ECG, retinal thrombosis, sinus bradycardia, sinus node dysfunction, superficial thrombophlebitis, supraventricular tachycardia, tachycardia, ventricular tachycardia

Gastrointestinal: Gastrointestinal hemorrhage

Hematologic & oncologic: Tumor lysis syndrome

Hepatic: Hepatic failure

Hypersensitivity: Angioedema

Nervous system: Loss of consciousness, subdural hematoma

Frequency not defined: Hepatic: Increased gamma-glutamyl transferase

Postmarketing:

Cardiovascular: Aneurysm (arterial), aortic aneurysm, aortic dissection, coronary artery dissection, myocardial rupture (aortic rupture and arterial rupture), peripheral vascular disease

Dermatologic: Erythema multiforme, erythema nodosum, Stevens-Johnson syndrome

Endocrine & metabolic: Dehydration, hyperthyroidism

Gastrointestinal: Gastrointestinal fistula, gastrointestinal perforation

Hematologic & oncologic: Thrombotic microangiopathy

Nervous system: Cerebrovascular accident, reversible posterior leukoencephalopathy syndrome

Neuromuscular & skeletal: Panniculitis

Miscellaneous: Wound healing impairment

Contraindications

There are no contraindications listed in the manufacturer’s US labeling.

Canadian labeling: Hypersensitivity to ponatinib or any component of the formulation; unmanaged cardiovascular risk factors, including uncontrolled hypertension; patients not adequately hydrated and with uncorrected hyperuricemia

Warnings/Precautions

Concerns related to adverse effects:

• Arrhythmias: Cardiac arrhythmias have been reported with ponatinib. Grade 3 or 4 arrhythmias included atrial fibrillation, atrial flutter, atrioventricular block, bradyarrhythmia (symptomatic; leading to pacemaker implant), bradycardia, cardio-respiratory arrest, loss of consciousness, QT interval prolongation, sinus bradycardia, sinus node dysfunction, supraventricular extrasystoles, syncope, tachycardia (including supraventricular and atrial), and ventricular arrhythmia. Some cases required hospitalization.

• Arterial occlusion: Arterial occlusive events (AOEs), including cardiovascular, cerebrovascular, and peripheral AOEs, and fatalities, have occurred in ponatinib-treated patients. AOEs included myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Grade 3 or 4 AOEs have been observed; the most frequent grade 3 or higher AOEs were myocardial infarction, acute coronary syndrome, cardiac arrest, coronary artery disease, arterial thrombosis, cerebrovascular accident, ischemic stroke, ischemic cerebral infarction, peripheral arterial occlusive disease, and angina. Some patients experienced recurrent or multisite vascular occlusion. In treated patients for all indications, the median time to onset of the first AOE was ~4 months to ~2 years (range: 1 day to 4.9 years). Some patients developed heart failure concurrent or subsequent to a myocardial ischemic event. Ponatinib caused stenosis over multiple segments in major arterial vessels that supply the brain (eg, carotid, vertebral, middle cerebral artery). Patients developed digital or distal extremity necrosis and required amputations. Patients with and without cardiovascular risk factors, including patients 50 years of age and younger, experienced these events. AOEs were more frequent with increasing age and in patients with a history of ischemia, hypertension, diabetes, or hypercholesterolemia. Renal artery stenosis (associated with worsening or refractory hypertension) has been reported. In clinical trials, patients with uncontrolled hypertension, hypertriglyceridemia, diabetes, cardiovascular disease (clinically significant, uncontrolled, or active), any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, venous thromboembolism, clinically significant atrial/ventricular tachyarrhythmias, heart failure, and unstable angina within 3 to 6 months prior to treatment were excluded.

• Bone marrow suppression: Neutropenia, thrombocytopenia, and anemia commonly occur with ponatinib, including grade 3 or 4 hematologic toxicity. In treated patients for all indications, the median onset of grade 3 or 4 hematologic toxicity was ~1 to 1.4 months (range: 1 day to 4 years). The incidence of myelosuppression was greater in patients with accelerated or blast phase chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) than in chronic phase CML.

• Fluid retention: Serious and fatal fluid retention events have occurred with ponatinib. Peripheral edema, pleural effusion, pericardial effusions, angioedema, and a case of brain edema have been reported.

• GI perforation: GI perforation or fistula have occurred with ponatinib.

• Heart failure: Serious or severe heart failure, including fatalities, occurred in ponatinib-treated patients. Grade 3 and 4 heart failure events have been reported, including left ventricular hypertrophy, increased brain natriuretic peptide, congestive cardiac failure, decreased ejection fraction, and cardiac failure.

• Hemorrhage: Serious and fatal hemorrhagic events occurred with ponatinib, including events such as intracranial hemorrhage, subdural hematoma, and GI hemorrhages. Serious bleeding episodes occurred more frequently in patients with accelerated or blast phase CML, and Ph+ ALL; most hemorrhages occurred in patients with grade 4 thrombocytopenia.

• Hepatotoxicity: Hepatotoxicity, liver failure, and death have occurred in ponatinib-treated patients. Fulminant hepatic failure leading to death has been reported, with hepatic failure occurring within 1 week of ponatinib initiation in one patient. Grade 3 or 4 hepatotoxicity has been observed. In treated patients for all indications, the median time to onset of hepatotoxicity was 15 days to 3.1 months (range: 1 day to 4.9 years). The most frequent hepatotoxic events were elevations of ALT, AST, bilirubin, alkaline phosphatase, and gamma-glutamyl transferase, and decreased albumin and fibrinogen. Some events had not resolved by date of last follow-up.

• Hypertension: Serious or severe hypertension, including hypertensive crisis, has occurred with ponatinib. Hypertension has been reported in patients with a without a prior hypertension history.

• Neuropathy: Peripheral neuropathy has occurred, including grade 3 and 4 events. The most frequently reported peripheral neuropathies were hypoesthesia, muscular weakness, paresthesia, and peripheral sensory neuropathy. Cases of cranial neuropathy developed (rarely), including grade 3 or 4 events. In treated patients for all indications, the median time to onset of peripheral neuropathy was 1.1 to 7.7 months (range: 1 day to 4.6 years) and for cranial neuropathy was 1.2 to 2.1 years (range: 1 day to 4.2 years).

• Ocular toxicity: Serious or severe ocular events leading to blindness and blurred vision have occurred with ponatinib. Blurred vision, eye pain, and dry eye were the most frequent ocular toxicities. Retinal toxicities, including macular edema, age-related macular degeneration, retinal vein occlusion, retinal hemorrhage, and vitreous floaters have also been reported.

• Pancreatitis: Serious or severe pancreatitis has occurred with ponatinib, including grade 3 or 4 events. Amylase and lipase elevations have occurred. In treated patients for all indications, the median time to onset of pancreatitis was 8 to 29 days (range: 1 day to 4 years). A majority of clinical pancreatitis cases that led to dose modification or discontinuation resolved within 2 to 3 weeks.

• Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS), also known as posterior reversible encephalopathy syndrome, has been reported with ponatinib. Patients may present with hypertension, seizure, headache, decreased alertness, altered mental status, vision loss, and other visual and/or neurological disturbances. MRI is necessary to diagnose RPLS.

• Tumor lysis syndrome: Hyperuricemia and serious tumor lysis syndrome (rare) were reported with ponatinib.

• Venous thromboembolism: Serious or severe venous thromboembolic events (VTEs) have occurred in ponatinib-treated patients. VTEs included deep vein thrombosis, superficial vein thrombosis, embolism, pulmonary embolism/thrombosis, jugular vein thrombosis, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis (with vision loss).

• Wound healing impairment: Wound healing impairment has occurred with ponatinib. Withhold ponatinib treatment for at least 1 week prior to elective surgery; do not administer ponatinib for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming ponatinib treatment after resolution of wound healing complications has not been established.

Disease-related concerns:

• Chronic phase CML (newly diagnosed): In a randomized study of first-line treatment of newly diagnosed chronic phase CML, a 2-fold increased risk of serious adverse reaction was demonstrated for ponatinib as compared to imatinib; the study was stopped due to safety concerns. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ponatinib arm of the study (compared to the imatinib arm); a higher incidence of hematologic toxicity, pancreatitis, hepatotoxicity, heart failure, hypertension, and dermatologic/subcutaneous tissue disorders was also observed in patients receiving ponatinib. Ponatinib is not indicated and not recommended for treatment of newly diagnosed chronic phase CML.

Special populations:

• Older adult: Patients ≥65 years of age are more likely to experience vascular occlusion, decreased appetite, dyspnea, increased lipase, asthenia, muscle spasms, peripheral edema, and thrombocytopenia.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as hydrochloride:

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

Generic Equivalent Available: US

Pricing: US

Tablets (Iclusig Oral)

10 mg (per each): $833.24

15 mg (per each): $833.24

30 mg (per each): $833.24

45 mg (per each): $833.24

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as hydrochloride:

Iclusig: 15 mg, 45 mg

Prescribing and Access Restrictions

Patient access and support is available through the ARIAD PASS program. Information regarding program enrollment may be found at http://www.ariadpass.com or by calling 1-855-447-PASS (7277). In Canada, ponatinib is available through the Iclusig Controlled Distribution Program; information about the program may be found at www.iclusigcdp.ca or by calling 1-888-867-7426.

Administration: Adult

Oral: Administer with or without food. Swallow tablets whole; do not crush, break, cut or chew.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 1]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/203469s037lbl.pdf#page=43, must be dispensed with this medication.

Use: Labeled Indications

Acute lymphoblastic leukemia, Philadelphia chromosome-positive:

Treatment (in combination with chemotherapy) of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

Treatment (as a single agent) of Ph+ ALL in adults for whom no other kinase inhibitors are indicated.

Treatment (as a single agent) of T315I-positive Ph+ ALL.

Chronic myeloid leukemia:

Treatment (as a single agent) of chronic myeloid leukemia (CML) in chronic phase in adults with resistance or intolerance to at least 2 prior kinase inhibitors.

Treatment (as a single agent) of CML in accelerated or blast phase in adults for whom no other kinase inhibitors are indicated.

Treatment (as a single agent) of T315I-positive CML in chronic, accelerated, or blast phase.

Limitations of use: Ponatinib is not indicated and not recommended for treatment of newly diagnosed chronic phase CML.

Medication Safety Issues

Sound-alike/look-alike issues:

PONATinib may be confused with asciminib, axitinib, bosutinib, cabozantinib, crizotinib, dasatinib, enasidenib, imatinib, neratinib, nilotinib, pacritinib, PAZOPanib, pegaptanib, pemigatinib, pexidartinib, pralsetinib, ruxolitinib.

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (chemotherapeutic agent, parenteral and oral) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).

Metabolism/Transport Effects

Substrate of BCRP/ABCG2, CYP2C8 (minor), CYP2D6 (minor), CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits BSEP/ABCB11

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Androgens: Hypertension-Associated Agents may enhance the hypertensive effect of Androgens. Risk C: Monitor therapy

Antithymocyte Globulin (Equine): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Antithymocyte Globulin (Equine). Specifically, these effects may be unmasked if the dose of immunosuppressive therapy is reduced. Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Antithymocyte Globulin (Equine). Specifically, infections may occur with greater severity and/or atypical presentations. Risk C: Monitor therapy

Antithyroid Agents: Myelosuppressive Agents may enhance the neutropenic effect of Antithyroid Agents. Risk C: Monitor therapy

Baricitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

BCG Products: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Brincidofovir: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

Brivudine: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Chikungunya Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Chikungunya Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Chikungunya Vaccine (Live). Risk X: Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy

Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination

Cladribine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing these oncologic agents several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Management: Administer a 2nd dose using an mRNA COVID-19 vaccine (at least 4 weeks after the primary vaccine dose) and a bivalent booster dose (at least 2 months after the additional mRNA dose or any other boosters). Risk D: Consider therapy modification

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Give a 3-dose primary series for all patients aged 6 months and older taking immunosuppressive medications or therapies. Booster doses are recommended for certain age groups. See CDC guidance for details. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

COVID-19 Vaccine (Virus-like Particles): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Virus-like Particles). Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of PONATinib. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of PONATinib. Management: Avoid coadministration of ponatinib with strong CYP3A4 inducers unless the potential benefit of concomitant treatment outweighs the risk of reduced ponatinib exposure. Monitor patients for reduced ponatinib efficacy if combined. Risk D: Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of PONATinib. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of PONATinib. Management: Avoid concomitant use if possible. If combined, reduce ponatinib dose as follows: If taking 45 mg, reduce to 30 mg; if taking 30 mg, reduce to 15 mg; if taking 15 mg, reduce to 10 mg. If taking 10 mg, avoid concomitant use with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor patients for signs/symptoms of serious infections. Risk D: Consider therapy modification

Deucravacitinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Etrasimod: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

Filgotinib: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider therapy modification

Inebilizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate at least 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification

Linezolid: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Mumps- Rubella- or Varicella-Containing Live Vaccines: May enhance the adverse/toxic effect of Immunosuppressants (Miscellaneous Oncologic Agents). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Mumps- Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Nadofaragene Firadenovec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Nadofaragene Firadenovec. Specifically, the risk of disseminated adenovirus infection may be increased. Risk X: Avoid combination

Natalizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy

Pidotimod: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk X: Avoid combination

Pneumococcal Vaccines: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Pneumococcal Vaccines. Risk C: Monitor therapy

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy

Rabies Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If combined, check for rabies antibody titers, and if vaccination is for post exposure prophylaxis, administer a 5th dose of the vaccine. Risk D: Consider therapy modification

Ritlecitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ritlecitinib. Risk X: Avoid combination

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Ruxolitinib (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Sipuleucel-T: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Solriamfetol: May enhance the hypertensive effect of Hypertension-Associated Agents. Risk C: Monitor therapy

Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Miscellaneous Oncologic Agents). Risk C: Monitor therapy

Tacrolimus (Topical): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Tertomotide: Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tofacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Tofacitinib. Risk X: Avoid combination

Typhoid Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Ublituximab: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Ublituximab. Risk C: Monitor therapy

Upadacitinib: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Live): Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Vaccines (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Live). Risk X: Avoid combination

Vaccines (Non-Live/Inactivated/Non-Replicating): Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Vaccines (Non-Live/Inactivated/Non-Replicating). Management: Give non-live/inactivated/non-replicating vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before or during therapy should be revaccinated at least 3 after therapy is complete. Risk D: Consider therapy modification

Yellow Fever Vaccine: Immunosuppressants (Miscellaneous Oncologic Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Miscellaneous Oncologic Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Food Interactions

Ponatinib serum concentrations may be increased when taken with grapefruit or grapefruit juice. Management: Avoid grapefruit and grapefruit juice.

Reproductive Considerations

Verify pregnancy status prior to use in patients who could become pregnant. Patients who could become pregnant should use effective contraception during treatment and for 3 weeks after the last ponatinib dose.

Changes in menstrual patterns have been reported with tyrosine kinase inhibitor (TKI) therapy (Yu 2019).

Based on the mechanism of action, TKIs have the potential to adversely affect fertility by acting on receptors in the ovaries or testis; primarily when administered prior to puberty in males. Although there are cases showing difficulty conceiving, successful pregnancies have also been reported. Fertility data related to long-term TKI use are limited. Recommendations are available for fertility preservation prior to TKI treatment (ASCO [Oktay 2018]; Madabhavi 2019; Rambhatla 2021).

Patients planning to become pregnant but currently receiving a TKI should minimize the risk of first trimester exposure (Rambhatla 2021). Discontinuing TKI therapy for chronic myeloid leukemia can be considered if the patient is eligible for a tumor-free remission, allowing a washout period before attempting to conceive (Baccarani 2019; ELN [Hochhaus 2020]; Madabhavi 2019). Because the time to conception can be highly variable, treatment may also be discontinued at the first positive pregnancy test, prior to organogenesis in select patients (Abruzzese 2020).

Pregnancy Considerations

Based on findings from animal reproduction studies and its mechanism of action, in utero exposure to ponatinib may cause fetal harm.

Treatment of chronic myeloid leukemia in pregnant patients should be individualized based on gestational age, hematologic parameters, and clinical condition at presentation. If pregnancy is detected in the first trimester in patients already on a tyrosine kinase inhibitor (TKI), treatment should be discontinued as soon as pregnancy is confirmed. Treatments other than a TKI are recommended in pregnant patients not eligible for a tumor-free remission. If a TKI is needed, use of agents other than ponatinib may be considered after the first trimester. Close maternal and fetal monitoring is recommended (Abruzzese 2020; BSH [Smith 2020]; ELN [Hochhaus 2020]; Madabhavi 2019).

The European Society for Medical Oncology has published guidelines for diagnosis, treatment, and follow up of cancer during pregnancy. The guidelines recommend referral to a facility with expertise in cancer during pregnancy and encourage a multidisciplinary team (obstetrician, neonatologist, oncology team) approach (ESMO [Peccatori 2013]).

Breastfeeding Considerations

It is not known if ponatinib is present in breast milk.

Due to the potential for serious adverse reactions in the breastfed infant, the manufacturer recommends that breastfeeding be discontinued during therapy and for 1 week after the last ponatinib dose. Patients diagnosed with chronic myeloid leukemia requiring a tyrosine kinase inhibitor may consider short-term breastfeeding for the first 2 to 5 days postpartum to provide the benefits of colostrum to the newborn prior to starting or restarting therapy (Abruzzese 2020; Madabhavi 2019).

Dietary Considerations

Avoid grapefruit juice.

Monitoring Parameters

CBC with differential and platelets every 2 weeks for the first 3 months, then monthly or as clinically indicated; liver function tests at baseline and at least monthly thereafter or more frequently if clinically warranted; serum lipase every 2 weeks for the first 2 months and monthly thereafter or as clinically indicated (consider additional monitoring in patients with a history of pancreatitis or alcohol abuse); serum electrolytes; uric acid (assess prior to treatment). Evaluate pregnancy status prior to treatment initiation (in patients who could become pregnant). Monitor blood pressure at baseline and as clinically indicated. Monitor for signs/symptoms of arterial occlusive events or venous thromboembolic events, hemorrhage, arrhythmias, heart failure, fluid retention, pancreatitis (evaluate for pancreatitis in patients with lipase elevation and abdominal symptoms), GI perforation/fistula, hepatotoxicity (jaundice, anorexia, bleeding, bruising), peripheral and cranial neuropathy (hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness), reversible posterior leukoencephalopathy syndrome (MRI is necessary to confirm diagnosis), and tumor lysis syndrome. Monitor patients with hepatic impairment more closely for potentially increased adverse events. Monitor for signs/symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations, or dizziness). Perform a comprehensive ocular exam at baseline and periodically during treatment. Monitor adherence.

Additional cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking; repeat assessment every 3 months for the first year and then every 6 to 12 months thereafter (ASCO [Armenian 2017]; ESC [Lyon 2022]). Check ECG at baseline, every 3 months for the first year and every 6 to 12 months thereafter. Consider baseline echocardiography in all patients; repeat every 3 months for high- and very high-risk patients (ESC [Lyon 2022]).

The American Society of Clinical Oncology hepatitis B virus screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends hepatitis B virus (HBV) screening with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total Ig or IgG, and antibody to hepatitis B surface antigen (anti-HBs) prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow up.

Mechanism of Action

Ponatinib is a pan-BCR-ABL tyrosine kinase inhibitor with in vitro activity against cells expressing native or mutant BCR-ABL (including T315I); it also inhibits VEGFR, FGFR, PDGFR, EPH, and SRC kinases, as well as KIT, RET, TIE2, and FLT3.

Pharmacokinetics (Adult Data Unless Noted)

Absorption: Plasma concentrations not affected by food.

Distribution: V_d: 1,223 L.

Protein binding: >99% to plasma proteins.

Metabolism: Hepatic; primarily via CYP3A4; CYP2C8, CYP2D6, and CYP3A5 are also involved in metabolism. Phase II metabolism occurs via esterases and/or amidases.

Half-life elimination: ~24 hours (range: 12 to 66 hours).

Time to peak: ≤6 hours.

Excretion: Feces (~87%); urine (~5%).

Brand Names: International

International Brand Names by Country

For country code abbreviations (show table)

(AE) United Arab Emirates: Iclusig;
(AR) Argentina: Nibclus | Ponatib | Ponazic | Tokiner;
(AT) Austria: Iclusig;
(AU) Australia: Iclusig;
(BD) Bangladesh: Ponatinix | Ponaxen;
(BE) Belgium: Iclusig;
(BG) Bulgaria: Iclusig;
(BR) Brazil: Iclusig;
(CH) Switzerland: Iclusig;
(CL) Chile: Iclusig;
(CO) Colombia: Iclusig;
(DE) Germany: Iclusig;
(EC) Ecuador: Iclusig | Nibclus;
(EE) Estonia: Iclusig;
(EG) Egypt: Iclusig;
(ES) Spain: Iclusig;
(FI) Finland: Iclusig;
(FR) France: Iclusig;
(GB) United Kingdom: Iclusig;
(GR) Greece: Iclusig;
(HU) Hungary: Iclusig;
(IE) Ireland: Iclusig;
(IT) Italy: Iclusig;
(JP) Japan: Iclusig;
(KR) Korea, Republic of: Iclusig;
(LB) Lebanon: Iclusig;
(LT) Lithuania: Iclusig;
(LV) Latvia: Iclusig;
(MX) Mexico: Iclusig;
(MY) Malaysia: Iclusig;
(NL) Netherlands: Iclusig;
(NO) Norway: Iclusig;
(PH) Philippines: Iclusig;
(PL) Poland: Iclusig;
(PR) Puerto Rico: Iclusig;
(PT) Portugal: Iclusig;
(QA) Qatar: Iclusig;
(RO) Romania: Iclusig;
(RU) Russian Federation: Iclusig;
(SA) Saudi Arabia: Iclusig;
(SE) Sweden: Iclusig;
(SG) Singapore: Iclusig;
(SI) Slovenia: Iclusig;
(SK) Slovakia: Iclusig;
(TH) Thailand: Iclusig;
(TW) Taiwan: Iclusig

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Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2017;35(8):893-911. doi:10.1200/JCO.2016.70.5400 [PubMed 27918725]
Baccarani M, Abruzzese E, Accurso V, et al. Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP. Blood Adv. 2019;3(24):4280-4290. doi:10.1182/bloodadvances.2019000865 [PubMed 31869412]
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Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966-984. doi:10.1038/s41375-020-0776-2 [PubMed 32127639]
Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO provisional clinical opinion update. J Clin Oncol. 2020;38(31):3698-3715. doi:10.1200/JCO.20.01757 [PubMed 32716741]
Iclusig (ponatinib) [prescribing information]. Lexington, MA: Takeda Pharmaceuticals America Inc; March 2024.
Iclusig (ponatinib) tablets [product monograph]. St-Laurent, Quebec, Canada: Paladin Labs Inc; September 2023.
Lishner M, Avivi I, Apperley JF, et al. Hematologic malignancies in pregnancy: management guidelines from an international consensus meeting. J Clin Oncol. 2016;34(5):501-508. doi:10.1200/JCO.2015.62.4445 [PubMed 26628463]
Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43(41):4229-4361. doi:10.1093/eurheartj/ehac244 [PubMed 36017568]
Madabhavi I, Sarkar M, Modi M, Kadakol N. Pregnancy outcomes in chronic myeloid leukemia: a single center experience. J Glob Oncol. 2019;5:1-11. doi:10.1200/JGO.18.00211 [PubMed 31584851]
Oktay K, Harvey BE, Partridge AH, et al. Fertility preservation in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2018;36(19):1994-2001. doi:10.1200/JCO.2018.78.1914 [PubMed 29620997]
Peccatori FA, Azim HA Jr, Orecchia R, et al; ESMO Guidelines Working Group. Cancer, pregnancy and fertility: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi160-170. doi:10.1093/annonc/mdt199 [PubMed 23813932]
Rambhatla A, Strug MR, De Paredes JG, Cordoba Munoz MI, Thakur M. Fertility considerations in targeted biologic therapy with tyrosine kinase inhibitors: a review. J Assist Reprod Genet. 2021;38(8):1897-1908. doi:10.1007/s10815-021-02181-6 [PubMed 33826052]
Shah NP, “Ponatinib: Targeting the T315I Mutation in Chronic Myelogenous Leukemia,” Clin Adv Hematol Oncol, 2011, 9(12):925-6. [PubMed 22252660]
Smith G, Apperley J, Milojkovic D, et al; British Society for Haematology. A British Society for Haematology guideline on the diagnosis and management of chronic myeloid leukaemia. Br J Haematol. 2020;191(2):171-193. doi:10.1111/bjh.16971 [PubMed 32734668]
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Ponatinib: Drug information