(poe NA ti nib)
- Ponatinib HCl
- Ponatinib Hydrochloride
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Iclusig: 15 mg, 45 mg
Brand Names: U.S.
- Antineoplastic Agent, BCR-ABL Tyrosine Kinase Inhibitor
- Antineoplastic Agent, Tyrosine Kinase Inhibitor
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.
Plasma concentrations not affected by food
Vd: 1223 L
Primarily hepatic through CYP3A4; CYP2C8, CYP2D6, and CYP3A5 are also involved in metabolism. Phase II metabolism occurs via esterases and/or amidases.
Feces (~87%); urine (~5%)
Time to Peak
~24 hours (range: 12 to 66 hours)
>99% to plasma proteins
Use: Labeled Indications
Acute lymphoblastic leukemia: Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in patients who are T315I-positive or for whom no other tyrosine kinase inhibitor therapy is indicated.
Chronic myeloid leukemia: Treatment of chronic myeloid leukemia (CML) in chronic, accelerated, or blast phase in patients who are T315I-positive or for whom no other tyrosine kinase inhibitor therapy is indicated.
Limitations of use: Ponatinib is not indicated and not recommended for treatment of newly diagnosed chronic phase CML.
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
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 strong CYP3A inhibitors: Reduce ponatinib dose to 30 mg once daily when administered with concomitant strong CYP3A inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole).
Refer to adult dosing.
Dosing: Renal Impairment
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); although renal excretion is not a major excretion route for ponatinib.
Dosing: Hepatic Impairment
Hepatic impairment prior to treatment initiation: Mild-to-severe impairment (Child-Pugh class A, B, or C): Initial: 30 mg once daily; monitor closely for toxicity.
Hepatotoxicity during treatment:
AST or ALT >3 times ULN (≥ Grade 2): If toxicity occurs at a dose of 45 mg daily, interrupt therapy; upon recovery to ≤ grade 1 (<3 times ULN), resume therapy at 30 mg daily. If toxicity occurs at a dose of 30 mg daily, interrupt therapy; upon recovery to ≤ grade 1, resume therapy at 15 mg daily. If toxicity occurs at a dose of 15 mg daily, discontinue therapy.
ALT or AST ≥3 times ULN with bilirubin >2 times ULN and alkaline phosphatase <2 times ULN: Discontinue therapy.
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.
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.
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.
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.
Administer with or without food. Swallow tablets whole (do not crush or dissolve). Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria). NIOSH recommends single gloving for administration of intact tablets (NIOSH 2014).
Avoid grapefruit juice.
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).
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). 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: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor. Consider therapy modification
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
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 when patients consume grapefruit consistently or in large amounts. Since grapefruit effects on CYP3A mediated metabolism are variable and poorly predictable, consider advising patients to avoid. Consider therapy modification
St John's Wort: May decrease the serum concentration of PONATinib. Avoid combination
Cardiovascular: Hypertension (53% to 71%), peripheral edema (13% to 22%; grades 3/4: ≤1%), arterial ischemia (3% to 20%; grades 3/4: ≤11%; including cardiac, cerebrovascular, and peripheral-vascular ischemia), cardiac failure (6% to 15%; including congestive heart failure, reduced ejection fraction, pulmonary edema, cardiogenic shock, cardiorespiratory arrest, right ventricular failure), myocardial infarction (12%)
Central nervous system: Fatigue or weakness (31% to 39%), headache (25% to 39%), pain (6% to 16%), chills (7% to 13%), insomnia (7% to 12%), dizziness (3% to 11%)
Dermatologic: Skin rash (34% to 54%), xeroderma (24% to 39%), cellulitis (≤11%)
Endocrine & metabolic: Increased serum glucose (58%), decreased serum phosphate (57%), decreased serum calcium (52%), decreased serum sodium (29%), decreased serum glucose (24%), decreased serum potassium (16%), increased serum potassium (15%), decreased serum bicarbonate (11%)
Gastrointestinal: Abdominal pain (34% to 49%), constipation (24% to 47%), increased serum lipase (41%; grades 3/4: 15%), nausea (22% to 32%), decreased appetite (8% to 31%), diarrhea (13% to 26%), vomiting (13% to 24%), stomatitis (9% to 23%), weight loss (5% to 13%), gastrointestinal hemorrhage (2% to 11%; grades 3/4: ≤6%)
Genitourinary: Urinary tract infection (≤12%)
Hematologic & oncologic: Neutropenia (grades 3/4: 24% to 63%), leukopenia (grades 3/4: 14% to 63%), thrombocytopenia (grades 3/4: 36% to 57%), anemia (grades 3/4: 9% to 55%), bone marrow depression (severe grade 3 or 4: 48%), lymphocytopenia (grades 3/4: 10% to 37%), febrile neutropenia (1% to 25%), hemorrhage (24%; including cerebral hemorrhage and gastrointestinal hemorrhage)
Hepatic: Increased serum ALT (53%; grades 3/4: 8%), increased serum AST (41%; grades 3/4: 4%), increased serum alkaline phosphatase (37%), decreased serum albumin (28%), increased serum bilirubin (19%)
Infection: Sepsis (1% to 22%)
Miscellaneous: Fever (23% to 32%)
Neuromuscular & skeletal: Arthralgia (13% to 31%), myalgia (6% to 22%), limb pain (9% to 17%), back pain (11% to 16%), peripheral neuropathy (6% to 16%; including burning sensation), muscle spasm (5% to 13%), ostealgia (9% to 12%)
Respiratory: Dyspnea (6% to 21%), pleural effusion (3% to 19%; grades 3/4: ≤3%), cough (6% to 18%), pneumonia (3% to 13%), nasopharyngitis (3% to 12%), upper respiratory tract infection (≤11%)
1% to 10%:
Cardiovascular: Peripheral ischemia (8%), supraventricular tachycardia (5%), venous thromboembolism (5%), atrial fibrillation (4%), pericardial effusion (1% to 3%), cerebral hemorrhage (2%), bradycardia (1%; symptomatic)
Endocrine & metabolic: Increased serum sodium (10%), hyperuricemia (7%), increased serum calcium (5%), increased serum triglycerides (3%)
Gastrointestinal: Pancreatitis (6%; grade 3: 5%), increased serum amylase (3%)
Ophthalmic: Blurred vision (6%), retinal toxicity (3%, including macular edema, retinal vein occlusion, retinal hemorrhage)
Renal: Increased serum creatinine (7%)
Frequency not defined:
Cardiovascular: Cerebrovascular accident
Gastrointestinal: Mouth pain, oral mucosa ulcer, oropharyngeal pain, throat ulcer, tongue ulcer
Ophthalmic: Cataract, conjunctival irritation, corneal ulcer, dry eye syndrome, eye pain, glaucoma, iridocyclitis, iritis, keratitis
<1% (Limited to important or life-threatening): Acute hepatic failure, ascites, atrial flutter, atrial tachycardia, cerebral edema, complete atrioventricular block, gastrointestinal fistula, gastrointestinal perforation, mesenteric artery occlusion, pulmonary embolism, retinal vein thrombosis, sick sinus syndrome, tumor lysis syndrome (serious)
Concerns related to adverse effects:
• Arrhythmias: Cardiac arrhythmias (bradyarrhythmias and tachyarrhythmias) have been reported. Symptomatic bradyarrhythmia which required pacemaker implantation occurred in a few patients; other rhythms identified were complete heart block, sick sinus syndrome, and atrial fibrillation with bradycardia and pauses. Tachyarrhythmias reported include atrial fibrillation (most common), atrial flutter, supraventricular tachycardia, and atrial tachycardia; some events required hospitalization. Monitor for sign/symptoms of bradycardia (fainting, dizziness, chest pain) and tachycardia (palpitations, dizziness). May require therapy interruption.
• Bone marrow suppression: Severe myelosuppression (grade 3 or 4) was commonly observed in clinical trials, and the incidence was greater in patients with accelerated or blast phase CML and Ph+ ALL. Monitor blood counts closely; may require therapy interruption and/or dosage reduction.
• Fluid retention/edema: Serious fluid retention events, including one fatality due to brain edema (very rare), were observed in ponatinib-treated patients. Peripheral edema, pleural effusions, and pericardial effusions were commonly seen; effusions and ascites were less common. Monitor patients for fluid retention; may require therapy interruption, dosage reduction, or discontinuation.
• Gastrointestinal perforation: Serious gastrointestinal perforation (fistula) occurred very rarely; monitor for signs/symptoms of perforation and/or fistula.
• 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. Treat as clinically warranted if HF develops. Consider ponatinib discontinuation in the event of serious HF.
• Hemorrhage: Hemorrhagic events occurred commonly in ponatinib-treated patients, including serious events such as cerebral and gastrointestinal 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. 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 result in ALT and/or AST elevations, and may be irreversible.
• Hypertension: Treatment-emergent hypertension developed in over half 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, and hyperesthesia occurred most frequently; cranial neuropathy occurred rarely. In one-third 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 or corneal irritation, dry eye, or eye pain occurred more frequently. Other toxicities include cataracts, glaucoma, 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; 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.
• 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. Correct elevated uric acid levels prior to initiating therapy.
• Vascular occlusion: [US Boxed Warning]: Arterial and venous thrombosis and occlusions have occurred in ponatinib-treated patients. 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 thromboembolism/vascular occlusion; interrupt or discontinue therapy immediately for vascular occlusion. Consider risk:benefit ratio when deciding to restart therapy. Fatal and life-threatening vascular 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. Increasing age and a prior history of ischemia, hypertension, diabetes, or hyperlipidemia are risk factors for development of ponatinib-associated vascular occlusion. Many patients 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. 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. Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, superficial thrombophlebitis, and retinal vein thrombosis, have been reported. May require dosage adjustment or discontinuation. Monitor for signs/symptoms of arterial or venous thromboembolism.
• Wound healing impairment: As ponatinib inhibits VEGF activity, therapy may impair wound healing. Hold therapy for at least 1 week prior to major surgery; resume therapy post procedure based on clinical judgment of appropriate wound healing.
• 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, gastrointestinal disorders, pancreatitis). Monitor closely when administering to patients with impaired hepatic function. The starting dose should be reduced in patients with hepatic impairment.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• 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.
• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2014 criteria).
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, blood pressure, signs/symptoms of arterial/venous occlusion or thromboembolism, hemorrhage, fluid retention, pancreatitis (clinical signs), gastrointestinal perforation/fistula, hepatotoxicity (jaundice, anorexia, bleeding, bruising); comprehensive ocular exam at baseline and periodically; signs/symptoms of neuropathy
Pregnancy Risk Factor
Adverse events were observed in animal reproduction studies when administered in doses lower than or equivalent to the normal human dose. Based on its mechanism of action, adverse effects on pregnancy would be expected. Women of childbearing potential should be advised to avoid pregnancy during therapy.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, vomiting, constipation, dry skin, diarrhea, rhinitis, pharyngitis, bone pain, joint pain, muscle pain, muscle spasm, back pain, lack of appetite, weight loss, or insomnia. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes); signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities); angina; coughing up blood; shortness of breath; chest pain that spreads to jaw, neck, arms, back, or stomach; signs of heart problems (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); signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice); signs of infection; signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; 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); signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting); signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit); pale skin; skin discoloration of extremities; vision changes; eye pain; eye irritation; blindness; facial droop; angina; abnormal heartbeat; bradycardia; tachycardia; severe dizziness; passing out; severe headache; confusion; abdominal edema; severe abdominal pain; dry eyes; mouth irritation; mouth sores; floater in the eye; severe loss of strength and energy; burning or numbness feeling; or signs of tumor lysis syndrome (tachycardia or abnormal heartbeat; any passing out; urinary retention; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
More about ponatinib
- Other brands: Iclusig