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Iclusig

Generic Name: Ponatinib
Class: Antineoplastic Agents
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

Warning(s)

Special Alerts:

[UPDATED 10/31/2013] The US Food and Drug Administration (FDA) has asked the manufacturer of the leukemia chemotherapy drug Iclusig (ponatinib) to suspend marketing and sales of Iclusig because of the risk of life-threatening blood clots and severe narrowing of blood vessels. FDA will continue to evaluate the drug to further understand its risks and potential patient populations in which the benefits of the drug may outweigh the risks. Patients currently receiving Iclusig should discuss with their health care professionals the risks and benefits of continuing treatment with the drug.

The drug manufacturer, Ariad Pharmaceuticals, has agreed to FDA’s request to suspend marketing and sales of Iclusig while FDA continues to evaluate the safety of the drug. For more information please visit: .

[Posted 10/11/2013] ISSUE: FDA is investigating an increasing frequency of reports of serious and life-threatening blood clots and severe narrowing of blood vessels (arteries and veins) of patients taking the leukemia chemotherapy drug Iclusig (ponatinib). Data from clinical trials and postmarket adverse event reports show that serious adverse events have occurred in patients treated with Iclusig, including heart attacks resulting in death, worsening coronary artery disease, stroke, narrowing of large arteries of the brain, severe narrowing of blood vessels in the extremities, and the need for urgent surgical procedures to restore blood flow. FDA is actively working to further evaluate these adverse events and will notify the public when more information is available.

BACKGROUND: Iclusig is a prescription medicine used to treat adults diagnosed with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), who are no longer benefiting from previous treatment or who did not tolerate other treatment. At the time of Iclusig's approval in December 2012, the drug label contained information about the risks of blood clots in the Boxed Warning and Warnings and Precautions sections. In clinical trials conducted before approval, serious arterial blood clots occurred in 8 percent of Iclusig-treated patients, and blood clots in the veins occurred in 3 percent of Iclusig-treated patients. In the most recent clinical trial data submitted by the manufacturer to FDA, at least 20 percent of all participants treated with Iclusig have developed blood clots or narrowing of blood vessels.

RECOMMENDATION: Health care professionals should consider for each patient, whether the benefits of Iclusig treatment are likely to exceed the risks of treatment. Patients taking Iclusig should seek immediate medical attention if they experience symptoms suggesting a heart attack such as chest pain or pressure, pain in their arms, back, neck or jaw, or shortness of breath; or symptoms of a stroke such as numbness or weakness on one side of the body, trouble talking, severe headache, or dizziness. FDA is providing this information to patients and health care professionals while it continues its investigation.

For more information visit the FDA website at:

Warning(s)

  • Arterial Thromboembolism
  • Serious or fatal arterial thromboembolic events (i.e., cardiovascular, cerebrovascular, and peripheral vascular thrombosis) observed.1 (See Thromboembolism under Cautions.)

  • If an arterial thromboembolic event occurs, interrupt or discontinue ponatinib.1

  • Hepatic Toxicity
  • Severe or fatal hepatotoxicity, including acute hepatic failure and fulminant hepatic failure, observed.1 (See Hepatic Effects under Cautions.)

  • Monitor liver function tests prior to initiation of therapy and at least monthly thereafter or as clinically indicated.1

  • If hepatotoxicity occurs, interrupt therapy, reduce dosage, or discontinue ponatinib.1 (See Hepatic Effects under Cautions.)

Introduction

Antineoplastic agent; an inhibitor of multiple receptor tyrosine kinases.2 3 4 13 15 16 17

Uses for Iclusig

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Treatment of chronic phase, accelerated phase, or blast phase CML in adults following failure (secondary to resistance or intolerance) of prior tyrosine kinase inhibitor therapy; designated an orphan drug by FDA for this use.1 2 3 4 8

Slideshow: Aging Issues: 12 of the Most Common Health Concerns Affecting Seniors

Treatment of Philadelphia chromosome-positive (Ph+) ALL in adults following failure (secondary to resistance or intolerance) of tyrosine kinase inhibitor therapy; designated an orphan drug by FDA for this use.1 2 3 4 8

Iclusig Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to meals.1

Swallow tablets whole; do not crush or dissolve tablets.1

Dosage

Available as ponatinib hydrochloride; dosage expressed in terms of ponatinib.1

Adults

CML or Ph+ ALL Following Treatment Failure
Oral

45 mg once daily.1 Continue therapy for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1

Dosage Modification
Hematologic Toxicity

If neutropenia (ANC <1000/mm3) or thrombocytopenia (platelets <50,000/mm3) occurs at a dosage of 45 mg once daily, withhold ponatinib.1 When ANC ≥1500/mm3 and platelets ≥75,000/mm3, resume therapy at original dosage (45 mg once daily).1

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.1

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.1

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.1 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.1

If hepatotoxicity occurs at a dosage of 30 mg once daily, withhold ponatinib.1 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.1

If hepatotoxicity occurs at a dosage of 15 mg once daily, discontinue ponatinib.1

If serum ALT or AST ≥3 times ULN concurrent with total bilirubin >2 times ULN and alkaline phosphatase <2 times ULN, discontinue ponatinib.1

Pancreatitis or Elevated Serum Lipase

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

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.1 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.1 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.1

If symptomatic grade 3 pancreatitis occurs at a dosage of 45 mg once daily, withhold ponatinib.1 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.1 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.1

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.1

If grade 4 pancreatitis occurs, discontinue ponatinib.1

Concomitant Use with Drugs Affecting Hepatic Microsomal Enzymes

If used concomitantly with a potent CYP3A inhibitor, reduce ponatinib dosage to 30 mg once daily.1 (See Drugs and Foods Affecting Hepatic Microsomal Enzymes under Interactions.)

Other Nonhematologic Effects

If a serious adverse nonhematologic reaction occurs, withhold ponatinib.1 Resume therapy at a reduced dosage when the toxicity resolves or if the potential benefit of resuming therapy outweighs the risk of recurrent toxicity.1 If a serious ischemic reaction occurs, do not resume ponatinib therapy unless the potential benefit outweighs the risk of recurrent ischemia 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.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No special dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

Certain ponatinib toxicities may be more frequent in geriatric patients.1 (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.1

Cautions for Iclusig

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Warnings

Thromboembolism

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Arterial thromboembolic events (e.g., cardiovascular, cerebrovascular, peripheral vascular thrombosis), sometimes serious or fatal, reported.1 Serious arterial thrombosis requiring revascularization procedure reported.1 Most common arterial thromboembolic event was MI or worsening CAD; approximately half of these patients developed CHF.1 In the premarketing clinical trial, digital or distal extremity necrosis reported; amputation required in 2 patients with concomitant diabetes mellitus and peripheral arterial disease.1 Most patients who experienced a serious arterial thromboembolic event had ≥1 cardiovascular risk factors (e.g., MI, CAD, angina, stroke, TIA, hypertension, diabetes mellitus, hyperlipidemia, cigarette smoking).1 If an arterial thromboembolic event occurs, interrupt therapy or discontinue ponatinib.1

Venous thromboembolic events (e.g., DVT, PE, portal vein thrombosis, retinal vein thrombosis) reported.1 If a serious venous thromboembolic event occurs, consider dosage modification or discontinue ponatinib.1 (See Other Nonhematologic Effects under Dosage and Administration.)

Hepatic Effects

Risk of hepatotoxicity, including acute or fulminant hepatic failure, sometimes severe or fatal;1 liver biopsies predominantly showed hepatocellular necrosis.6 Fulminant hepatic failure resulting in death following 1 week of therapy reported rarely.1 ALT or AST elevations occur commonly.1 6

Severe hepatotoxicity reported in all disease cohorts; however, fatal cases reported only in Ph+ ALL patients or CML patients in blast crisis.1

Cross-sensitivity of hepatotoxicity between tyrosine kinase inhibitors unlikely.6

Perform liver function tests prior to initiation of therapy and at least monthly thereafter or as clinically indicated.1

If hepatotoxicity occurs, interrupt therapy, reduce dosage, or discontinue ponatinib.1 (See Hepatotoxicity under Dosage and Administration.)

Other Warnings and Precautions

Congestive Heart Failure

Severe CHF and left ventricular dysfunction, sometimes fatal, reported.1

Monitor patient for manifestations of CHF and provide appropriate treatment as clinically indicated; interrupt therapy if necessary.1 If serious CHF occurs, consider discontinuing ponatinib.1

Hypertension

Treatment-emergent hypertension occurs commonly.1 Serious symptomatic hypertension, including hypertensive crisis, reported; urgent clinical intervention for symptoms associated with hypertension (e.g., confusion, headache, chest pain, shortness of breath) has been required.1

Monitor BP and treat as clinically indicated.1

Pancreatitis

Pancreatitis and pancreatic laboratory abnormalities (e.g., elevated serum amylase and lipase) reported.1 In the premarketing trial, most cases were grade 3.1 Most cases resolve within 2 weeks of interruption of therapy or dosage reduction.1

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.1

If pancreatitis occurs, interrupt therapy and/or reduce dosage.1 (See Pancreatitis or Elevated Serum Lipase under Dosage and Administration.)

Hemorrhage

Hemorrhage, sometimes serious or fatal, reported; increased incidence of serious hemorrhage in patients with accelerated or blast phase CML or Ph+ ALL than in patients with chronic phase CML.1 Most serious hemorrhagic events were cerebral or GI hemorrhage.1

If serious or severe hemorrhage or thrombocytopenia occurs, interrupt therapy and/or reduce dosage.1 (See Hematologic Toxicity under Dosage and Administration.)

Fluid Retention or Edema

Risk of serious fluid retention (i.e., pleural effusion, pericardial effusion, ascites); fatal cerebral edema reported rarely.1

Monitor for signs and symptoms of fluid retention.1 If fluid retention develops, manage patients as clinically indicated and interrupt therapy, reduce dosage, or discontinue ponatinib.1 (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 reported.1

Supraventricular tachyarrhythmias, including atrial fibrillation, atrial flutter, supraventricular tachycardia, and atrial tachycardia, reported in premarketing trial; approximately half of these patients required hospitalization.1 Atrial fibrillation most common supraventricular arrhythmia.1

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.1

Monitor CBCs every 2 weeks during the first 3 months of therapy and then monthly (or as clinically indicated) thereafter.1 If hematologic toxicity occurs, interrupt therapy and/or reduce dosage.1 (See Hematologic Toxicity under Dosage and Administration.)

Tumor Lysis Syndrome

Tumor lysis syndrome reported in patients with advanced CML (i.e., accelerated or blast phase CML or Ph+ ALL).1 Hyperuricemia reported principally in patients with chronic phase CML.1

Ensure adequate hydration and treat hyperuricemia prior to initiation of ponatinib.1

Wound Healing Complications and GI Perforation

Effect of ponatinib on wound healing not established.1 Serious GI perforation reported in at least one patient 38 days after cholecystectomy.1

Inhibitors of vascular endothelial growth factor receptor (VEGFR), including ponatinib, may impair wound healing; discontinue ponatinib ≥7 days prior to scheduled major surgery.1 Base decision to resume therapy on clinical assessment of adequacy of wound healing.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryo and fetal toxicity demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.1

Lactose-intolerant Patients

45-mg oral tablet contains 121 mg of lactose monohydrate.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether ponatinib is distributed into milk; discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in patients <18 years of age.1

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.1

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.1

Certain toxicities may occur more frequently in geriatric patients ≥65 years of age.1 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Data lacking in patients with hepatic impairment.1

Renal Impairment

Data lacking in patients with renal impairment.1

Common Adverse Effects

Hypertension,1 arterial ischemia,1 cardiac failure,1 abdominal pain,1 constipation,1 nausea,1 diarrhea,1 vomiting,1 oral mucositis,1 GI hemorrhage,1 febrile neutropenia,1 sepsis,1 pneumonia,1 urinary tract infection,1 upper respiratory tract infection,1 nasopharyngitis,1 cellulitis,1 headache,1 peripheral neuropathy,1 dizziness,1 pleural effusion,1 cough,1 dypsnea,1 rash and related conditions,1 dry skin,1 arthralgia,1 myalgia,1 pain in extremity,1 back pain,1 muscle spasms,1 bone pain,1 fatigue/asthenia,1 pyrexia,1 thrombocytopenia,1 anemia,1 neutropenia,1 leukopenia,1 lymphopenia,1 peripheral edema,1 pain,1 chills,1 decreased appetite,1 decreased weight,1 insomnia.1

Interactions for Iclusig

Principally metabolized by CYP3A4 and, to a lesser extent, by CYP isoenzymes 2C8, 2D6, and 3A5.1 Ponatinib is a substrate of CYP3A4/5 and, to a lesser extent, CYP2C8 and 2D6.1

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.1

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 ABCG2.1

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

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Possible pharmacokinetic interaction (increased plasma concentrations and AUC of ponatinib).1 Reduce dosage of ponatinib.1

Potent CYP3A inducers: Possible pharmacokinetic interaction (decreased systemic exposure of ponatinib).1 Avoid concomitant use unless potential benefit outweighs possible risk of reduced ponatinib exposure.1 Monitor for signs of reduced ponatinib efficacy if concomitant use cannot be avoided.1

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased oral bioavailability of ponatinib) with drugs that increase gastric pH.1 Avoid concomitant use unless potential benefit outweighs possible risk of reduced ponatinib exposure.1 Monitor for signs of reduced ponatinib efficacy if concomitant use cannot be avoided.1

Substrates of P-glycoprotein or ABCG2 Transport Systems

Substrates of P-gp: Ponatinib inhibits P-gp and ABCG2.1

Specific Drugs and Food

Drug or Food

Interaction

Comments

Aliskiren

Effect of coadministration of ponatinib with substrates of P-gp not established1

Ambrisentan

Effect of coadministration of ponatinib with substrates of P-gp not established1

Antacids

Possible decreased ponatinib bioavailability secondary to decreased solubility at higher pH1

Avoid concomitant use, unless potential benefit outweighs risk of reduced ponatinib exposure1

If concomitant use cannot be avoided, monitor for reduced efficacy1

Anticonvulsants (carbamazepine, phenytoin)

Possible decreased systemic exposure of ponatinib1

Avoid concomitant use, unless potential benefit outweighs risk of reduced ponatinib exposure1

If concomitant use cannot be avoided, monitor for reduced efficacy1

Antifungals, azoles (i.e., itraconazole, ketoconazole, posaconazole, voriconazole)

Possible increased peak concentration and AUC of ponatinib1

Ketoconazole: Increased ponatinib AUC by 78% and peak concentration by 47%1

Posaconazole: Effect of coadministration of ponatinib with substrates of P-gp not established1

Reduce ponatinib dosage to 30 mg once daily1

Antimycobacterials, rifamycins (e.g., rifampin)

Possible decreased systemic exposure of ponatinib1

Avoid concomitant use, unless potential benefit outweighs risk of reduced ponatinib exposure1

If concomitant use cannot be avoided, monitor for reduced efficacy1

Colchicine

Effect of coadministration of ponatinib with substrates of P-gp not established1

Conivaptan

Possible increased peak concentration and AUC of ponatinib1

Reduce ponatinib dosage to 30 mg once daily1

Dabigatran

Effect of coadministration of ponatinib with substrates of P-gp not established1

Digoxin

Effect of coadministration of ponatinib with substrates of P-gp not established1

Everolimus

Effect of coadministration of ponatinib with substrates of P-gp not established1

Fexofenadine

Effect of coadministration of ponatinib with substrates of P-gp not established1

Grapefruit juice

Possible increased peak concentration and AUC of ponatinib1

Reduce ponatinib dosage to 30 mg once daily1

HCV protease inhibitors (e.g., boceprevir, telaprevir)

Possible increased peak concentration and AUC of ponatinib1

Reduce ponatinib dosage to 30 mg once daily1

Histamine H2-receptor antagonists

Possible decreased ponatinib bioavailability secondary to decreased solubility at higher pH1

Avoid concomitant use, unless potential benefit outweighs risk of reduced ponatinib exposure1

If concomitant use cannot be avoided, monitor for reduced efficacy1

HIV protease inhibitors (e.g., indinavir, lopinavir, nelfinavir, ritonavir, saquinavir)

Possible increased peak concentration and AUC of ponatinib1

Reduce ponatinib dosage to 30 mg once daily1

Imatinib

Effect of coadministration of ponatinib with substrates of P-gp and ABCG2 not established1

Irinotecan

Effect of coadministration of ponatinib with substrates of ABCG2 not established1

Lapatinib

Effect of coadministration of ponatinib with substrates of P-gp and ABCG2 not established1

Macrolides (e.g., clarithromycin, telithromycin)

Possible increased peak concentration and AUC of ponatinib1

Reduce ponatinib dosage to 30 mg once daily1

Maraviroc

Effect of coadministration of ponatinib with substrates of P-gp not established1

Methotrexate

Effect of coadministration of ponatinib with substrates of ABCG2 not established1

Mitoxantrone

Effect of coadministration of ponatinib with substrates of ABCG2 not established1

Nefazodone

Possible increased peak concentration and AUC of ponatinib1

Reduce ponatinib dosage to 30 mg once daily1

Nilotinib

Effect of coadministration of ponatinib with substrates of P-gp not established1

Proton-pump inhibitors

Possible decreased ponatinib bioavailability secondary to decreased solubility at higher pH1

Avoid concomitant use, unless potential benefit outweighs risk of reduced ponatinib exposure1

If concomitant use cannot be avoided, monitor for reduced efficacy1

Ranolazine

Effect of coadministration of ponatinib with substrates of P-gp not established1

Rosuvastatin

Effect of coadministration of ponatinib with substrates of ABCG2 not established1

Saxagliptin

Effect of coadministration of ponatinib with substrates of P-gp not established1

Sirolimus

Effect of coadministration of ponatinib with substrates of P-gp not established1

Sitagliptin

Effect of coadministration of ponatinib with substrates of P-gp not established1

St. John's wort (Hypericum perforatum)

Possible decreased systemic exposure of ponatinib1

Avoid concomitant use, unless potential benefit outweighs risk of reduced ponatinib exposure1

If concomitant use cannot be avoided, monitor for reduced efficacy1

Sulfasalazine

Effect of coadministration of ponatinib with substrates of ABCG2 not established1

Tolvaptan

Effect of coadministration of ponatinib with substrates of P-gp not established1

Topotecan

Effect of coadministration of ponatinib with substrates of P-gp and ABCG2 not established1

Iclusig Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained within 6 hours.1

AUC and peak plasma concentration are approximately dose proportional over the ponatinib dose range of 2–60 mg.1 4

Food

High-fat or low-fat meal did not affect peak plasma concentrations and AUC.1

Distribution

Extent

Not known whether ponatinib is distributed into milk.1

Plasma Protein Binding

>99%.1

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.1

Elimination Route

Eliminated in feces (87%) and urine (5%).1

Half-life

Mean terminal half-life: approximately 24 hours.1 24

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

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.1 13 15 16 17

  • 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).1 10 23 24

  • Potently inhibits Bcr-Abl kinase domain mutant forms, including T315I;1 13 14 17 also inhibits additional mutant tyrosine kinase receptors and oncogenic fusion proteins in vitro.15 16 20 21 22

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • Importance of advising patients to swallow ponatinib tablets whole and not to crush or dissolve the tablets.1 5 Inform clinician before ingesting grapefruit juice while taking ponatinib.1 5

  • 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.1 5

  • Risk of arterial and venous thromboembolic events.1 5 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, leg pain or swelling, or arm, back, neck, or jaw pain).1 5

  • Risk of hepatotoxicity and importance of liver function test monitoring.1 5 Importance of immediately reporting any manifestations of hepatotoxicity (e.g., jaundice, unusual fatigue or drowsiness, unusually dark or “tea-colored” urine, nausea, vomiting).1 5

  • Risk of fetal harm.1 5 Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 5 Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.1 5

  • Risk of hypertension.1 5 Importance of regular monitoring of BP during treatment.1 5 Importance of immediately reporting headache, dizziness, chest pain, or shortness of breath.1 5

  • Risk of adverse cardiovascular effects.1 Importance of immediately reporting irregular or slow or fast heart beat, palpitations, dizziness, fainting or feeling faint, chest pain, or shortness of breath.1 5

  • Risk of pancreatitis and importance of serum lipase monitoring.1 5 Importance of immediately reporting abdominal pain, nausea, and vomiting.1 5

  • Risk of bleeding.1 5 Importance of promptly informing clinician of any episodes or signs of bleeding (e.g., unusual bleeding, bruising, confusion, headache, change in speech, drowsiness).1 5

  • Risk of cytopenias.1 5 Importance of informing clinician of fever or other signs and symptoms of infection.1 5

  • Risk of tumor lysis syndrome.1 5

  • Risk of fluid retention.1 5 Importance of contacting clinician promptly if swelling, weight gain, shortness of breath, or coughing occur.1 5

  • Risk of wound healing complications.1 5 Importance of informing clinician about and discontinuing ponatinib use before any scheduled major surgery.1 5

  • Risk of GI perforation.1 Importance of immediately reporting any manifestations of GI perforation (e.g., abdominal pain or swelling, high fever).1 5

  • Importance of informing clinicians if patient is lactose intolerant.1 5

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1 5

  • Importance of informing patients of other important precautionary information.1 5 (See Cautions.)

Preparations

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Ponatinib Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

15 mg (of ponatinib)

Iclusig

Ariad

45 mg (of ponatinib)

Iclusig

Ariad

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 31, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Ariad Pharmaceuticals, Inc. Iclusig (ponatinib hydrochloride) tablets prescribing information. Cambridge, MA; 2012 Dec.

2. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 203469Orig1s000: Summary Review. From FDA website.

3. US Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2013 May 29.

4. Cortes JE, Kantarjian H, Shah NP et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012; 367:2075-88. [PubMed 23190221]

5. Ariad Pharmaceuticals, Inc. Iclusig (ponatinib hydrochloride) tablets medication guide. Cambridge, MA; 2012 Dec.

6. Shah RR, Morganroth J, Shah DR. Hepatotoxicity of Tyrosine Kinase Inhibitors: Clinical and Regulatory Perspectives. Drug Saf. 2013; :.

7. Sonnichsen D, Dorer DJ, Cortes J et al. Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies. Cancer Chemother Pharmacol. 2013; 71:1599-607. [PubMed 23609479]

8. Wong SF, Mirshahidi H. Use of tyrosine kinase inhibitors for chronic myeloid leukemia: management of patients and practical applications for pharmacy practitioners. Ann Pharmacother. 2011; 45:787-97. [PubMed 21672900]

9. Dufies M, Cassuto O, Jacquel A et al. Ponatinib circumvents all types of imatinib resistance in chronic myelogenous leukemia cell lines. Cell Cycle. 2013; 12:. [PubMed 23673326]

10. Weisberg E, Griffin J. Mechanisms of resistance imatinib (STI-571) in preclinical models and in leukemia patients. Drug Resistance Updates. 2001; 4:22-8. [PubMed 11512149]

11. Bristol-Myers Squibb, Plainsboro, NJ: Personal communication on dasatinib.

12. Kantarjian H, Pasquini R, Hamerschlak N et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007; 109:5143-50. [PubMed 17317857]

13. Cassuto O, Dufies M, Jacquel A et al. All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to ponatinib. Oncotarget. 2012; 3:1557-65. [PubMed 23238683]

14. Zhou T, Commodore L, Huang WS et al. Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem Biol Drug Des. 2011; 77:1-11. [PubMed 21118377]

15. Zirm E, Spies-Weisshart B, Heidel F et al. Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation. Br J Haematol. 2012; 157:483-92. [PubMed 22409268]

16. Gozgit JM, Wong MJ, Wardwell S et al. Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. Mol Cancer Ther. 2011; 10:1028-35. [PubMed 21482694]

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