Ponatinib (Monograph)

Brand name: Iclusig
Drug class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
Chemical name: 3-(2-Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-benzamide hydrochloride
Molecular formula: C₂₉H₂₇F₃N₆O•HCl
CAS number: 1114544-31-8

Medically reviewed by Drugs.com on Jun 8, 2023. Written by ASHP.

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.

Uses for Ponatinib

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

Treatment of T315I Bcr-Abl mutation-positive chronic phase, accelerated phase, or blast phase CML.

Treatment of chronic phase, accelerated phase, or blast phase CML in patients in whom no other tyrosine kinase inhibitor therapy may be used; designated an orphan drug by FDA for this use.

Treatment of T315I Bcr-Abl mutation-positive Philadelphia chromosome-positive (Ph⁺) ALL.

Treatment of Ph⁺ ALL in patients in whom no other tyrosine kinase inhibitor therapy may be used; designated an orphan drug by FDA for this use.

Efficacy determined based on response rate in a noncomparative, open-label study in patients with chronic, accelerated, or blast phase CML or Ph⁺ ALL following failure (secondary to resistance or intolerance) of prior tyrosine kinase inhibitor therapy. Consider whether benefit of initiating ponatinib therapy outweighs the risks. (See Cautions.)

Ponatinib Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to meals.

Swallow tablets whole; do not crush or dissolve tablets.

Dosage

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

Adults

CML or Ph+ ALL

Oral

Initially, 45 mg once daily; optimal dosage not established. In clinical trials, dosage reductions to 30 or 15 mg once daily required in 59% of patients.

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

If therapeutic response not evident after 3 months (90 days) of therapy, consider discontinuance of ponatinib.

Dosage Modification

≥Grade 3 adverse events increased with dosage over the dosage range of 15–45 mg once daily.

Hematologic Toxicity

If neutropenia (ANC <1000/mm³) or thrombocytopenia (platelets <50,000/mm³) occurs at a dosage of 45 mg once daily, withhold ponatinib. When ANC ≥1500/mm³ and platelets ≥75,000/mm³, resume therapy at original dosage (45 mg once daily).

If neutropenia or thrombocytopenia recurs at a dosage of 45 mg once daily, temporarily interrupt therapy again until ANC ≥1500/mm³ and platelets ≥75,000/mm³, then resume therapy at a reduced dosage of 30 mg once daily.

If neutropenia or thrombocytopenia recurs at a dosage of 30 mg once daily, temporarily interrupt therapy again until ANC ≥1500/mm³ and platelets ≥75,000/mm³, then resume therapy at a reduced dosage of 15 mg once daily.

Hepatotoxicity

If hepatotoxicity (serum ALT or AST >3 times ULN [grade 2 or greater]) occurs at a dosage of 45 mg once daily, withhold ponatinib. When serum ALT and AST return to <3 times ULN (grade 1 or less), resume therapy at a reduced dosage of 30 mg once daily.

If hepatotoxicity occurs at a dosage of 30 mg once daily, withhold ponatinib. When serum ALT and AST return to <3 times ULN (grade 1 or less), resume therapy at a reduced dosage of 15 mg once daily.

If hepatotoxicity occurs at a dosage of 15 mg once daily, discontinue ponatinib.

If serum ALT or AST ≥3 times ULN concurrent with total bilirubin >2 times ULN and alkaline phosphatase <2 times ULN, discontinue ponatinib.

Pancreatitis or Elevated Serum Lipase

If asymptomatic grade 1 or 2 elevations of serum lipase concentrations occur, consider interrupting therapy or reducing ponatinib dosage.

If asymptomatic grade 3 or 4 elevations of serum lipase concentrations (>2 times ULN) or asymptomatic grade 2 pancreatitis (confirmed by radiologic evidence) occurs at a dosage of 45 mg once daily, withhold ponatinib. When serum lipase concentrations decrease to grade 1 or less (<1.5 times ULN), resume therapy at a reduced dosage of 30 mg once daily. If such asymptomatic elevations of serum lipase concentrations or asymptomatic pancreatitis recurs at a dosage of 30 mg daily, interrupt therapy again until serum lipase concentrations decrease to grade 1 or less (<1.5 times ULN), then resume therapy at a reduced dosage of 15 mg once daily.

If symptomatic grade 3 pancreatitis occurs at a dosage of 45 mg once daily, withhold ponatinib. When symptoms resolve completely and serum lipase concentrations decrease to grade 1 or less, resume therapy at a reduced dosage of 30 mg once daily. If symptomatic grade 3 pancreatitis recurs at a dosage of 30 mg daily, interrupt therapy again until symptoms resolve completely and serum lipase concentrations decrease to grade 1 or less, then resume therapy at a reduced dosage of 15 mg once daily.

If asymptomatic grade 3 or 4 elevations of serum lipase concentrations (>2 times ULN), asymptomatic grade 2 pancreatitis (confirmed by radiologic evidence), or symptomatic grade 3 pancreatitis occurs at a dosage of 15 mg daily, discontinue ponatinib.

If grade 4 pancreatitis occurs, discontinue ponatinib.

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

If used concomitantly with a potent CYP3A inhibitor, reduce ponatinib dosage to 30 mg once daily. (See Drugs and Foods Affecting Hepatic Microsomal Enzymes under Interactions.)

Other Nonhematologic Effects

If a serious adverse nonhematologic reaction occurs, withhold ponatinib. Resume therapy at a reduced dosage when the toxicity resolves or if the potential benefit of resuming therapy outweighs the risk of recurrent toxicity. If an arterial or venous occlusive event occurs, do not resume ponatinib therapy unless the potential benefit outweighs the risk of recurrent arterial or venous occlusive events and no other treatment options exist.

Special Populations

Hepatic Impairment

Moderate to severe hepatic impairment (Child-Pugh class B or C): Avoid use, unless the anticipated net benefit of therapy outweighs the risk of toxicity. (See Hepatic Impairment under Cautions.)

Renal Impairment

No special dosage recommendations at this time. (See Renal Impairment under Cautions.)

Geriatric Patients

Certain ponatinib toxicities may be more frequent in geriatric patients. (See Geriatric Use under Cautions.) Select dosage with caution because of greater frequency of age-related decreases in hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.

Cautions for Ponatinib

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Warnings

Vascular Occlusion

Arterial and venous occlusions and thromboembolic events, including fatal MI, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and requirement for urgent revascularization procedures, occurred in ≥27% of patients receiving ponatinib in phase 1 and 2 studies. Recurrent or multi-site vascular occlusion also may occur. Vascular occlusive events in patients with or without cardiovascular risk factors, including in patients ≤50 years of age, observed. Fatal or life-threatening vascular occlusion may occur as early as the initial 2 weeks of therapy and at dosages as low as 15 mg daily. In a phase 1 study, median time to onset of vascular occlusive events was 5 months.

Arterial occlusion and thrombosis, sometimes of more than one type, occurred in ≥20% of patients receiving ponatinib in premarketing trial. Vascular occlusion requiring revascularization procedure has occurred. Fatal or life-threatening MI or coronary artery occlusion occurred in 12% of patients; some patients have developed heart failure. Cerebrovascular events, including fatal stroke, occurred in 6% of patients; stenosis over multiple segments of large arterial vessels of the brain may occur. Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life-threatening peripheral arterial disease, occurred in 8% of patients; digital or distal extremity necrosis requiring amputation observed. Consider whether the benefit of initiating ponatinib therapy outweighs the risks. Monitor patient for manifestations of arterial occlusion and thromboembolic events. If arterial occlusion is suspected, interrupt therapy or discontinue ponatinib. Following evaluation, consider whether the benefit of restarting ponatinib therapy outweighs the risks.

Venous thromboembolic events (e.g., DVT, PE, superficial thrombophlebitis, retinal vein thrombosis) observed. Monitor patient for manifestations of venous thromboembolic events. If a serious venous thromboembolic event occurs, consider dosage modification or discontinue ponatinib. (See Other Nonhematologic Effects under Dosage and Administration.)

Heart Failure

Serious heart failure, sometimes fatal, and left ventricular dysfunction have occurred.

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

If new or worsening heart failure occurs, interrupt therapy or discontinue ponatinib. If serious heart failure occurs, consider discontinuing ponatinib.

Hepatic Effects

Risk of hepatotoxicity, including acute or fulminant hepatic failure, sometimes severe or fatal; liver biopsies predominantly showed hepatocellular necrosis. Fulminant hepatic failure resulting in death following 1 week of therapy has occurred rarely. ALT or AST elevations occur commonly.

Severe hepatotoxicity observed in all disease cohorts; however, fatalities occurred only in Ph⁺ ALL patients or CML patients in blast crisis.

Cross-sensitivity of hepatotoxicity between tyrosine kinase inhibitors unlikely.

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

If hepatotoxicity occurs, interrupt therapy, reduce dosage, or discontinue ponatinib. (See Hepatotoxicity under Dosage and Administration.)

Other Warnings and Precautions

Hypertension

Treatment-emergent hypertension occurs commonly. Serious symptomatic hypertension, including hypertensive crisis, observed. Urgent clinical intervention for symptoms associated with hypertension (e.g., confusion, headache, chest pain, shortness of breath) may be required.

Monitor BP and treat as clinically indicated. If hypertension not medically controlled, interrupt therapy, reduce dosage, or discontinue ponatinib. (See Other Nonhematologic Effects under Dosage and Administration)

Pancreatitis

Pancreatitis and pancreatic laboratory abnormalities (e.g., elevated serum amylase and lipase) observed. In the premarketing trial, most cases were grade 3. Most cases resolve within 2 weeks of interruption of therapy or dosage reduction.

Monitor serum lipase concentrations every 2 weeks during the first 2 months of therapy and then monthly thereafter or as clinically indicated; consider more frequent monitoring in patients with a history of pancreatitis or alcohol abuse.

If pancreatitis occurs, interrupt therapy and/or reduce dosage. (See Pancreatitis or Elevated Serum Lipase under Dosage and Administration.)

Neuropathy

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

Monitor patient for manifestations of neuropathy.

If neuropathy occurs, interrupt therapy.

Ocular Effects

Serious ocular toxicities leading to blindness or blurred vision observed. Retinal toxicities (i.e., macular edema, retinal vein occlusion, retinal hemorrhage), conjunctival or corneal irritation, dry eye, eye pain, visual blurring, cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis have occurred.

Perform comprehensive ophthalmologic examination at baseline and periodically during therapy.

Hemorrhage

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

If serious or severe hemorrhage occurs, interrupt therapy.

Fluid Retention or Edema

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

Monitor for signs and symptoms of fluid retention. If fluid retention develops, manage patients as clinically indicated and interrupt therapy, reduce dosage, or discontinue ponatinib. (See Other Nonhematologic Effects under Dosage and Administration.)

Cardiac Arrhythmias

Symptomatic bradyarrhythmias (i.e., complete heart block, sick sinus syndrome, atrial fibrillation with bradycardia and pauses) requiring pacemaker implantation have occurred.

Supraventricular tachyarrhythmias, including atrial fibrillation, atrial flutter, supraventricular tachycardia, and atrial tachycardia, observed in premarketing trial; approximately half of these patients required hospitalization. Atrial fibrillation most common supraventricular arrhythmia.

If cardiac arrhythmias occur, interrupt therapy.

Myelosuppression

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

Monitor CBCs every 2 weeks during the first 3 months of therapy and then monthly (or as clinically indicated) thereafter. If hematologic toxicity occurs, interrupt therapy and/or reduce dosage. (See Hematologic Toxicity under Dosage and Administration.)

Tumor Lysis Syndrome

Tumor lysis syndrome occurred in patients with advanced CML (i.e., accelerated or blast phase CML or Ph⁺ ALL). Hyperuricemia occurred principally in patients with chronic phase CML.

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

Wound Healing Complications and GI Perforation

Effect of ponatinib on wound healing not established. Serious GI perforation occurred in at least one patient 38 days after cholecystectomy.

Inhibitors of vascular endothelial growth factor receptor (VEGFR), including ponatinib, may impair wound healing; discontinue ponatinib ≥7 days prior to scheduled major surgery. Base decision to resume therapy on clinical assessment of adequacy of wound healing.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryo and fetal toxicity demonstrated in animals. Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.

Lactose-intolerant Patients

45-mg oral tablet contains 121 mg of lactose monohydrate.

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether ponatinib is distributed into milk; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in patients <18 years of age.

Geriatric Use

In premarketing trial in patients with chronic phase CML, major cytogenetic response rate was 38% in patients ≥65 years of age compared with 64% in patients <65 years of age.

In premarketing trial in patients with accelerated or blast phase CML or Ph⁺ ALL, major hematologic response rate was 47% in patients ≥65 years of age compared with 40% in patients <65 years of age.

In premarketing trial, vascular occlusion events occurred in 46% of patients ≥65 years of age. Certain toxicities may occur more frequently in geriatric patients ≥65 years of age. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Data lacking in patients with hepatic impairment.

Renal Impairment

Data lacking in patients with renal impairment.

Common Adverse Effects

Hypertension, arterial ischemia, cardiac failure, abdominal pain, constipation, nausea, diarrhea, vomiting, oral mucositis, GI hemorrhage, febrile neutropenia, sepsis, pneumonia, urinary tract infection, upper respiratory tract infection, nasopharyngitis, cellulitis, headache, peripheral neuropathy, dizziness, pleural effusion, cough, dypsnea, rash and related conditions, dry skin, arthralgia, myalgia, pain in extremity, back pain, muscle spasms, bone pain, fatigue/asthenia, pyrexia, thrombocytopenia, anemia, neutropenia, leukopenia, lymphopenia, peripheral edema, pain, chills, decreased appetite, decreased weight, insomnia.

Interactions for Ponatinib

Principally metabolized by CYP3A4 and, to a lesser extent, by CYP isoenzymes 2C8, 2D6, and 3A5. Ponatinib is a substrate of CYP3A4/5 and, to a lesser extent, CYP2C8 and 2D6.

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

Inhibits P-glycoprotein (P-gp, ABCB1), ABCG2 (breast cancer resistance protein [BCRP]), and BSEP (bile salt export pump); appears to be a weak substrate for P-gp and ABCG2.

Not a substrate for organic anion transport protein (OATP) 1B1 or OATP1B3; does not inhibit the organic cation transporters (OCT) 1, OCT2, OAT1, or OAT3.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations and AUC of ponatinib). Reduce dosage of ponatinib.

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased systemic exposure of ponatinib). Avoid concomitant use unless potential benefit outweighs possible risk of reduced ponatinib exposure. Monitor for signs of reduced ponatinib efficacy if concomitant use cannot be avoided.

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased oral bioavailability of ponatinib) with drugs that increase gastric pH. Avoid concomitant use unless potential benefit outweighs possible risk of reduced ponatinib exposure. Monitor for signs of reduced ponatinib efficacy if concomitant use cannot be avoided.

Substrates of P-glycoprotein or ABCG2 Transport Systems

Substrates of P-gp: Ponatinib inhibits P-gp and ABCG2.

Specific Drugs and Food

Ponatinib Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained within 6 hours.

AUC and peak plasma concentration are approximately dose proportional over the ponatinib dose range of 2–60 mg.

Food

High-fat or low-fat meal did not affect peak plasma concentrations and AUC.

Distribution

Extent

Not known whether ponatinib is distributed into milk.

Plasma Protein Binding

>99%.

Elimination

Metabolism

Principally metabolized by phase I hepatic CYP isoenzymes (i.e., CYP3A4 and, to a lesser extent, CYP2C8, 2D6, and 3A5) and phase II hepatic conjugation; also metabolized by esterases and/or amidases.

Elimination Route

Eliminated in feces (87%) and urine (5%).

Half-life

Mean terminal half-life: approximately 24 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Inhibits multiple tyrosine kinases, including wild-type and mutant Bcr-Abl, members of the Src family, c-Kit, members of the Eph family, TIE-2, Flt-3, RET, members of the vascular endothelial growth factor (VEGF) family, members of the platelet-derived growth factor (PDGF) family, and members of the fibroblast growth factor (FGF) family.

• Inhibits Bcr-Abl tyrosine kinase, an abnormal protein created by the Philadelphia chromosome abnormality in CML and Ph⁺ ALL that exhibits enhanced tyrosine kinase activity (i.e., increased phosphorylation of tyrosine residues).

• Potently inhibits Bcr-Abl kinase domain mutant forms, including T315I; also inhibits additional mutant tyrosine kinase receptors and oncogenic fusion proteins in vitro.

Advice to Patients

• Importance of advising patients to swallow ponatinib tablets whole and not to crush or dissolve the tablets. Inform clinician before ingesting grapefruit juice while taking ponatinib.

• Importance of advising patient that if a dose of ponatinib is missed, the next dose should be taken at the regularly scheduled time; the dose should not be doubled.

• Risk of arterial and venous thromboembolic events. Importance of getting emergency help and contacting clinician if any symptoms suggestive of a thromboembolic event occur (e.g., chest pain or pressure, shortness of breath, unilateral numbness or weakness, speech difficulty, headache, vision changes, severe abdominal pain, leg pain or swelling, or arm, back, neck, or jaw pain).

• Risk of heart failure or cardiac arrhythmias. Importance of immediately reporting irregular or slow or fast heart beat, dizziness, fainting or feeling faint, chest pain, or shortness of breath.

• Risk of hepatotoxicity and importance of liver function test monitoring. Importance of immediately reporting any manifestations of hepatotoxicity (e.g., jaundice, unusual fatigue or drowsiness, unusually dark or “tea-colored” urine).

• Risk of fetal harm. Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.

• Risk of hypertension. Importance of regular monitoring of BP during treatment. Importance of immediately reporting headache, dizziness, chest pain, or shortness of breath.

• Risk of pancreatitis and importance of serum lipase monitoring. Importance of immediately reporting abdominal pain, nausea, and vomiting.

• Risk of neuropathy. Importance of informing clinician if symptoms of neuropathy occur (e.g., hypoesthesia, hyperesthesia, paresthesia, discomfort, burning or tingling sensation, neuropathic pain or weakness, muscle weakness, vision changes, difficulty moving the eye, sagging or drooping of the face or eyelids).

• Risk of adverse ocular effects and importance of ophthalmologic examinations prior to and during ponatinib therapy. Importance of informing clinician if perceived flashes of light, light sensitivity, floaters, dry or itchy eyes, blurred vision, and/or eye pain occur.

• Risk of bleeding. Importance of promptly informing clinician of any episodes or signs of bleeding (e.g., unusual bleeding, bruising, confusion, headache, change in speech, drowsiness).

• Risk of cytopenias. Importance of informing clinician of fever or other signs and symptoms of infection.

• Risk of tumor lysis syndrome.

• Risk of fluid retention. Importance of contacting clinician promptly if swelling, weight gain, shortness of breath, or coughing occur.

• Risk of wound healing complications. Importance of informing clinician about and discontinuing ponatinib use before any scheduled major surgery.

• Risk of GI perforation. Importance of immediately reporting any manifestations of GI perforation (e.g., abdominal pain or swelling, high fever).

• Importance of informing clinicians if patient is lactose intolerant.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses (e.g., hypertension or other cardiovascular disease, thromboembolic events, hepatic disease).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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