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Ponatinib

Medically reviewed by Drugs.com. Last updated on Sep 28, 2020.

Pronunciation

(poe NA ti nib)

Index Terms

  • AP24534
  • Ponatinib HCl
  • Ponatinib Hydrochloride

Dosage Forms

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

Tablet, Oral:

Iclusig: 15 mg, 45 mg

Brand Names: U.S.

  • Iclusig

Pharmacologic Category

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

Pharmacology

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.

Absorption

Plasma concentrations not affected by food

Distribution

Vd: 1223 L

Metabolism

Primarily hepatic through CYP3A4; CYP2C8, CYP2D6, and CYP3A5 are also involved in metabolism. Phase II metabolism occurs via esterases and/or amidases.

Excretion

Feces (~87%); urine (~5%)

Time to Peak

≤6 hours

Half-Life Elimination

~24 hours (range: 12 to 66 hours)

Protein Binding

>99% to plasma proteins

Use: Labeled Indications

Acute lymphoblastic leukemia: Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in patients for whom no other tyrosine kinase inhibitor therapy is indicated or who are T315I-positive.

Chronic myeloid leukemia: Treatment of chronic myeloid leukemia (CML) in chronic, accelerated, or blast phase in patients for whom no other tyrosine kinase inhibitor therapy is indicated or who are T315I-positive.

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

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

Dosing: Adult

Note: The optimal ponatinib dose has not been identified. Consider discontinuing therapy if no response has occurred by 3 months (90 days) of therapy.

Acute lymphoblastic leukemia (ALL), Philadelphia chromosome-positive (Ph+), T315I-positive or in patients for whom no other tyrosine kinase inhibitor therapy is indicated: Oral: Initial: 45 mg once daily

Chronic myeloid leukemia (CML; chronic, accelerated, or blast phase), T315I-positive or in patients for whom no other tyrosine kinase inhibitor therapy is indicated: Oral: Initial: 45 mg once daily; consider reducing the dose for patients in chronic or accelerated phase who have achieved a major cytogenetic response

Note: Ponatinib is not recommended for treatment of newly diagnosed chronic phase CML.

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Hematologic: ANC <1000/mm3 or platelets <50,000/mm3:

First occurrence: Interrupt therapy; upon recovery of ANC to ≥1500/mm3 and platelets to ≥75,000/mm3, resume therapy at 45 mg daily.

Second occurrence: Interrupt therapy; upon recovery of ANC to ≥1500/mm3 and platelets to ≥75,000/mm3, resume therapy at a reduced dose of 30 mg daily.

Third occurrence: Interrupt therapy; upon recovery of ANC to ≥1500/mm3 and platelets to ≥75,000/mm3, resume therapy at a reduced dose of 15 mg daily.

Nonhematologic toxicity:

Arterial or venous occlusive reactions: Interrupt therapy; do not resume ponatinib in the event of serious occlusive events unless the potential benefit of therapy outweighs the risk of recurrent occlusions and other treatment options are not available.

GI perforation: Permanently discontinue therapy.

Pancreatitis and lipase elevations:

Asymptomatic grade 1 or 2 serum lipase elevation: Consider interrupting therapy or dose reduction.

Asymptomatic grade 3 or 4 serum lipase elevation (>2 times ULN) or asymptomatic radiologic pancreatitis (grade 2): If toxicity occurs at a dose of 45 mg daily, interrupt therapy; upon recovery to ≤ grade 1 (<1.5 times ULN), resume therapy at a reduced dose of 30 mg daily. If toxicity occurs at a dose of 30 mg daily, interrupt therapy; upon recovery to ≤ grade 1, resume therapy at a reduced dose of 15 mg daily. If toxicity occurs at a dose of 15 mg daily, discontinue therapy.

Symptomatic grade 3 pancreatitis: If toxicity occurs at a dose of 45 mg daily, interrupt therapy; upon recovery of serum lipase elevation to ≤ grade 1 and complete symptom resolution, resume therapy at a reduced dose of 30 mg daily. If toxicity occurs at a dose of 30 mg daily, interrupt therapy; upon recovery of serum lipase elevation to ≤ grade 1 and complete symptom resolution, resume therapy at a reduced dose of 15 mg daily. If toxicity occurs at a dose of 15 mg daily, discontinue therapy.

Grade 4 pancreatitis: Discontinue therapy.

Reversible posterior leukoencephalopathy syndrome (RPLS): Interrupt therapy for RPLS diagnosis; resume only if RPLS resolves and if the benefit outweighs the risk.

Other nonhematologic toxicities: For serious reactions (other than arterial or venous occlusion), modify the dose or interrupt treatment; do not restart therapy until symptom resolution or unless the benefit of therapy outweighs the risk of recurrent toxicity.

Administration

Administer with or without food. Swallow tablets whole (do not crush or dissolve).

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).

Drug Interactions

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

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

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

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

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

CYP3A4 Inducers (Strong): May decrease the serum concentration of PONATinib. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of PONATinib. Management: Reduce the adult starting dose of ponatinib to 30 mg daily during treatment with any strong CYP3A4 inhibitor. 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. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Grapefruit Juice: May increase the serum concentration of PONATinib. Management: Reduce ponatinib starting dose to 30 mg daily if patients consume grapefruit consistently or in large amounts. Grapefruit effects on ponatinib metabolism are variable and poorly predictable, consider advising patients to avoid grapefruit during treatment. Consider therapy modification

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

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

St John's Wort: May decrease the serum concentration of PONATinib. Avoid combination

Adverse Reactions

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

>10%:

Cardiovascular: Acute myocardial infarction, arterial ischemia (11% to 42%), cardiac arrhythmia (19%; ventricular arrhythmia: 3%), cardiac failure (6% to 15%), cerebrovascular accident, coronary occlusion, hypertension (53% to 74%; severe hypertension: 3% to 12%), mesenteric artery occlusion, occlusive arterial disease, peripheral arterial disease, peripheral edema, peripheral vascular disease

Dermatologic: Alopecia (6% to 11%), cellulitis (3% to 11%), pruritus (5% to 13%), skin rash (28% to 63%), xeroderma (25% to 42%)

Endocrine & metabolic: Decreased serum albumin (27%), decreased serum bicarbonate (19%), decreased serum calcium (30%), decreased serum glucose (13%), decreased serum phosphate (33%), decreased serum potassium (18%), decreased serum sodium (27%), fluid retention (31%), increased serum calcium (12%), increased serum glucose (54%), increased serum potassium (19%), weight loss (5% to 13%)

Gastrointestinal: Abdominal pain (34% to 48%; severe abdominal pain: 5%), constipation (27% to 53%), decreased appetite (8% to 31%), diarrhea (13% to 29%), increased serum amylase (18%), increased serum lipase (38% to 42%), nausea (22% to 34%), stomatitis (9% to 23%; grades 3/4: 1% to 3%), vomiting (18% to 27%)

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

Hematologic & oncologic: Anemia (grades 3/4: 8% to 52%), bone marrow depression (59%; grade 3/4: 50%), febrile neutropenia (1% to 25%), hemorrhage (28%; major hemorrhage [6%]), leukopenia (grades 3/4: 12% to 63%), lymphocytopenia (grades 3/4: 10% to 32%), neutropenia (grades 3/4: 23% to 59%), thrombocytopenia (grades 3/4: 35% to 49%)

Hepatic: Hepatotoxicity (29%), increased serum alanine aminotransferase, increased serum alkaline phosphatase (40%), increased serum aspartate aminotransferase, increased serum bilirubin (13%)

Infection: Sepsis (2% to 13%)

Nervous system: Chills (8% to 13%), dizziness (3% to 16%), fatigue, headache (25% to 43%), insomnia (11% to 13%), pain (6% to 16%), peripheral neuropathy (4% to 24%; grades 3/4: 1% to 3%)

Neuromuscular & skeletal: Arthralgia (13% to 33%), asthenia, back pain (13% to 21%), limb pain (13% to 23%), muscle spasm (5% to 14%), musculoskeletal pain (6% to 11%), myalgia (6% to 24%), ostealgia (9% to 14%)

Ophthalmic: Conjunctival edema, conjunctival hemorrhage, conjunctival hyperemia, conjunctival irritation, conjunctivitis, corneal abrasion, corneal erosion, dry eye syndrome, eye pain

Renal: Increased serum creatinine (21%)

Respiratory: Cough (6% to 22%), dyspnea (6% to 20%), nasopharyngitis (3% to 18%), pleural effusion, pneumonia (6% to 16%), upper respiratory tract infection (3% to 14%)

Miscellaneous: Fever (25% to 40%)

1% to 10%:

Cardiovascular: Atrial fibrillation (4% to 7%), bradycardia, cerebrovascular occlusion (7% to 9%), deep vein thrombosis (2%), left ventricular dysfunction, pericardial effusion, pulmonary embolism (2%), reduced ejection fraction (3%), subdural hematoma (1%), syncope (2%), venous thromboembolism (4% to 10%)

Dermatologic: Erythema of skin (6% to 10%)

Endocrine & metabolic: Hyperuricemia (7%), hypothyroidism (3%), increased serum sodium (10%), increased serum triglycerides (3%)

Gastrointestinal: Dysgeusia (2%), gastrointestinal hemorrhage (1% to 9%), pancreatitis (6% to 7%)

Hepatic: Ascites

Nervous system: Cranial nerve disorder (2%), hyperesthesia (1%), hypoesthesia (3%), intracranial hemorrhage (1%), myasthenia (2%), paresthesia (5%)

Neuromuscular & skeletal: Swelling of the extremities (3%)

Ophthalmic: Blurred vision (6%), macular edema, retinal hemorrhage, retinal vein occlusion

<1%:

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

Hematologic & oncologic: Tumor lysis syndrome

Hepatic: Hepatic failure

Nervous system: Loss of consciousness

Frequency not defined:

Cardiovascular: Hypertensive crisis

Ophthalmic: Blepharitis, cataract, corneal ulcer, eyelid edema, glaucoma, iridocyclitis, iritis, ocular hyperemia, periorbital edema

Postmarketing:

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

Dermatologic: Erythema multiforme, severe dermatological reaction, Stevens-Johnson syndrome

Endocrine & metabolic: Dehydration, hyperthyroidism

Gastrointestinal: Gastrointestinal fistula, gastrointestinal perforation

Hematologic & oncologic: Thrombotic microangiopathy

Nervous system: Reversible posterior leukoencephalopathy syndrome

Miscellaneous: Wound healing impairment

ALERT: U.S. Boxed Warning

Arterial occlusion:

Arterial occlusions have occurred in at least 35% of ponatinib-treated patients. Some patients experienced more than 1 type of event. Events observed included fatal myocardial infarction (MI), 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 and younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop ponatinib immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart ponatinib therapy.

Heart failure:

Heart failure, including fatalities, occurred in 9% of ponatinib-treated patients. Monitor cardiac function. Interrupt or stop ponatinib for new or worsening heart failure.

Hepatotoxicity:

Hepatotoxicity, liver failure, and death have occurred in ponatinib-treated patients. Monitor hepatic function. Interrupt ponatinib if hepatotoxicity is suspected.

Venous thromboembolism:

Venous occlusive events have occurred in 6% of ponatinib-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of ponatinib in patients who develop serious venous thromboembolism.

Warnings/Precautions

Concerns related to adverse effects:

• Arrhythmias: Cardiac arrhythmias (bradyarrhythmias and tachyarrhythmias) have been reported. The most commonly reported arrhythmia was atrial fibrillation; ~50% of events were grade 3 or 4. Other grade 3 or 4 rhythm disorders have occurred (case reports). Some events required hospitalization; symptomatic bradyarrhythmia which required pacemaker implantation occurred in a few cases. Monitor for sign/symptoms of bradycardia (fainting, dizziness, chest pain) and tachycardia (palpitations, dizziness). May require therapy interruption and further evaluation.

• Arterial occlusion: [US Boxed Warning]: Arterial occlusions have occurred in at least 35% of ponatinib-treated patients. Some patients experienced more than 1 type of event. Events included fatal myocardial infarction (MI), stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures; incidents were observed in patients with and without cardiovascular risk factors (including patients ≤50 years of age). Monitor closely for arterial occlusion; interrupt or discontinue therapy immediately for arterial occlusion. Consider risk:benefit ratio when deciding to restart therapy. Fatal and life-threatening arterial occlusion may occur within 2 weeks of therapy initiation and is not dose dependent (events have occurred at doses as low as 15 mg daily), and may cause recurrent or multisite occlusion. The most common risk factors for developing arterial occlusive events were hypertension, hyperlipidemia, and history of cardiac disease. Increasing age and a prior history of ischemia, hypertension, diabetes, or hyperlipidemia are also risk factors for development of ponatinib-associated vascular occlusion. Patients have required a revascularization procedure (cerebrovascular, coronary, and peripheral arterial) due to serious arterial thrombosis/occlusion. MI and coronary artery occlusion may result in heart failure due to myocardial ischemia. Cerebrovascular occlusion (including fatal stroke) has occurred; may cause stenosis over multiple segments in major arterial vessels that supply the brain. Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life-threatening peripheral arterial disease, have occurred. Some patients have required amputation due to digital or distal extremity necrosis. Renal artery stenosis (associated with worsening or refractory hypertension) has been reported.

• Bone marrow suppression: Severe myelosuppression (grade 3 or 4) is commonly observed with ponatinib, and the incidence was greater in patients with accelerated or blast phase CML and Ph+ ALL. The median onset to severe myelosuppression was 1 month (range: up to 40 months). Monitor blood counts closely; may require therapy interruption and/or dosage reduction.

• Fluid retention/edema: Serious fluid retention events, including fatality due to brain edema (case report), were observed in ponatinib-treated patients. Peripheral edema, pleural effusions, pericardial effusions, and peripheral swelling were commonly seen. Monitor patients for fluid retention; may require therapy interruption, dosage reduction, or discontinuation.

• GI perforation: Serious GI perforation (fistula) occurred very rarely; monitor for signs/symptoms of perforation and/or fistula. Permanently discontinue if GI perforation occurs.

• Heart failure:[US Boxed Warning]: Serious heart failure (HF) or left ventricular dysfunction, including fatalities, were reported in clinical trials. Monitor for signs/symptoms of HF; interrupt or discontinue ponatinib therapy for new or worsening HF.The most commonly reported heart failure events were congestive heart failure and decreased ejection fraction. Treat as clinically warranted if HF develops. Consider ponatinib discontinuation in the event of serious HF.

• Hemorrhage: Hemorrhagic events occurred in ponatinib-treated patients, including serious events such as cerebral (subdural hematoma) and GI hemorrhages; fatalities were reported. Serious bleeding episodes occurred more frequently in patients with accelerated or blast phase CML, and Ph+ ALL; most patients had grade 4 thrombocytopenia. Monitor platelet levels closely and for signs/symptoms of bleeding, and interrupt therapy if necessary.

• Hepatotoxicity: [US Boxed Warning]: Liver failure and death resulting from ponatinib-induced hepatotoxicity were observed; monitor liver function prior to and at least monthly (or as clinically indicated) during treatment. The median time to onset was 3 months (range: less than 1 month to 47 months). Hepatotoxicity may require treatment interruption (followed by dose reduction) or discontinuation. One case of fulminant hepatic failure leading to death occurred within 1 week of therapy initiation; acute liver failure has also occurred. Treatment may commonly result in ALT and/or AST, bilirubin, and alkaline phosphatase elevations. ALT/AST elevations may be irreversible.

• Hypertension: Treatment-emergent blood pressure elevations (systolic or diastolic) developed in over two-thirds of ponatinib-treated patients; symptomatic hypertension or hypertensive crisis were reported in several patients, requiring urgent intervention. Blood pressure may worsen in patients with preexisting hypertension. Monitor blood pressure closely, and manage elevated pressures as clinically indicated. May require therapy interruption, dosage reduction, or discontinuation if hypertension is resistant to medical management. Renal artery stenosis (associated with worsening, labile, or treatment-resistant hypertension) has occurred in some patients receiving ponatinib. Evaluate for renal artery stenosis for hypertension that significantly worsens, is labile, or treatment-resistant.

• Neuropathy: Peripheral and cranial neuropathy have been reported. Peripheral neuropathy, paresthesia, hypoesthesia, hyperesthesia, dysgeusia, and muscular weakness occurred most frequently; cranial neuropathy occurred rarely. In one-quarter of patients who experienced symptoms, neuropathy developed during the first month of therapy. Monitor for signs/symptoms of neuropathy; consider interrupting treatment if neuropathy develops.

• Ocular toxicity: Serious ocular events such as blindness and blurred vision have occurred with ponatinib use. Macular edema, retinal vein occlusion, and retinal hemorrhage have been reported in a small percentage of patients; conjunctival irritation, corneal erosion or abrasion, dry eye, conjunctivitis, conjunctival hemorrhage, hyperaemia and edema, or eye pain occurred more frequently. Other toxicities include cataracts, periorbital edema, blepharitis, glaucoma, eyelid edema, ocular hyperaemia, iritis, iridocyclitis, and ulcerative keratitis. Perform comprehensive ophthalmic exams prior to therapy initiation and periodically during treatment.

• Pancreatitis: Treatment-related lipase elevations and clinical pancreatitis occurred in clinical studies, including grade 3 and 4 events. The median time to onset was 14 days (range: 3 days to ~48 months); the majority of cases resolved within 2 weeks of therapy interruption or dose reduction. Monitor serum lipase every 2 weeks for the first 2 months and monthly thereafter or as clinically indicated; more frequent monitoring may be considered in patients with a history of pancreatitis or alcohol abuse. Monitor for clinical signs of pancreatitis, such as abdominal symptoms; interrupt therapy if necessary. Do not reinitiate treatment until complete resolution of symptoms and lipase level is <1.5 times ULN.

• Reversible posterior leukoencephalopathy syndrome: Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in postmarketing surveillance. Signs/symptoms include seizure, headache, decreased awareness, altered mental status, vision loss, and other visual and/or neurological disturbances. Hypertension is common; RPLS is diagnosed through MRI of the brain. Discontinue ponatinib for RPLS diagnosis; resume only if RPLS resolves and the benefit of treatment outweighs the risk.

• Tumor lysis syndrome: Hyperuricemia and serious tumor lysis syndrome (rare) were reported. Patients should receive adequate hydration and be monitored for elevated uric acid levels and/or the development of tumor lysis syndrome. Manage elevated uric acid levels prior to initiating therapy.

• Venous thromboembolism: [US Boxed Warning]: Venous occlusive events have occurred in 6% of ponatinib-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of ponatinib in patients who develop serious venous thromboembolism. Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis have been reported.

• Wound healing impairment: As ponatinib inhibits vascular endothelial growth factor activity, therapy may impair wound healing. Hold therapy for at least 1 week prior to elective surgery; resume therapy ≥2 weeks following major surgery and until adequate wound healing.

Disease-related concerns:

• Cardiovascular disease: Patients with or without cardiovascular risk factors, and those with a prior history of ischemia, hypertension, diabetes, or hyperlipidemia may be at increased risk for vascular occlusion when treated with ponatinib. Monitor for signs/symptoms of occlusion; interrupt therapy and consider discontinuation if thrombosis/occlusion occurs.

• 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 occlusion events 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.

• Hepatic impairment: A single-dose (30 mg) pharmacokinetic study found that ponatinib exposure was not increased in patients with hepatic impairment (Child-Pugh class A, B, or C) as compared to patients with normal hepatic function. While generally well tolerated, patients with hepatic impairment did have an increased overall incidence of adverse reactions (eg, GI disorders, pancreatitis). Monitor closely when administering to patients with impaired hepatic function. The starting dose should be reduced in patients with hepatic impairment.

Special populations:

• Elderly: Patients ≥65 years of age may be more likely to experience vascular occlusion, weakness, decreased appetite, dyspnea, increased lipase, muscle spasms, peripheral edema, and thrombocytopenia; monitor closely. Cautious dose selection is recommended based on greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Monitoring Parameters

CBC with differential and platelets every 2 weeks for the first 3 months, then monthly or as clinically needed; 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 (more frequently in patients with a history of pancreatitis or alcohol abuse); serum electrolytes and uric acid; monitor cardiac function and blood pressure. Monitor for signs/symptoms of arterial/venous occlusion or thromboembolism, hemorrhage, fluid retention, pancreatitis (clinical signs), gastrointestinal perforation/fistula, hepatotoxicity (jaundice, anorexia, bleeding, bruising), reversible posterior leukoencephalopathy syndrome; comprehensive ocular exam at baseline and periodically; signs/symptoms of neuropathy

Reproductive Considerations

Verify pregnancy status prior to initiating ponatinib treatment. Women of childbearing potential should use effective contraception during treatment and for 3 weeks after the last dose.

Pregnancy Considerations

Based on animal data and its mechanism of action, ponatinib is expected to cause fetal harm if used during pregnancy.

Patient Education

What is this drug used for?

• It is used to treat leukemia.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loss of strength and energy

• Nausea

• Vomiting

• Constipation

• Dry skin

• Diarrhea

• Abdominal pain

• Common cold symptoms

• Nose irritation

• Throat irritation

• Bone pain

• Joint pain

• Muscle pain

• Muscle spasm

• Back pain

• Lack of appetite

• Weight loss

• Hair loss

• Trouble sleeping

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Heart problems like cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin

• Infection

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding

• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting

• Electrolyte problems like mood changes, confusion, muscle pain or weakness, abnormal heartbeat, seizures, lack of appetite, or severe nausea or vomiting

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit

• Pale skin of extremities

• Blue/gray skin discoloration of extremities

• Vision changes

• Eye pain

• Severe eye irritation

• Sensitivity to light

• Abnormal heartbeat

• Slow heartbeat

• Fast heartbeat

• Swelling

• Severe dizziness

• Passing out

• Severe headache

• Abdominal swelling

• Dry eyes

• Mouth irritation

• Mouth sores

• Floater in the eye

• Change in taste

• Nerve problems like sensitivity to heat or cold; decreased sense of touch; burning, numbness, or tingling; pain, or weakness in the arms, hands, legs, or feet

• Posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache

• Tumor lysis syndrome like fast heartbeat or abnormal heartbeat; any passing out; unable to pass urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.