poe-NA-ti-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

• T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
• Accelerated phase or blast phase CML or Ph+ ALL when no other kinase inhibitor is indicated.
• Chronic phase CML in patients who have resistance or intolerance to 2 prior kinase inhibitors.

• Inhibits kinases, which are involved in various stages of cell proliferation.

• Decreased progression of leukemia with improved survival.

Absorption: Well absorbed following oral administration, absorption is pH dependant (↑ gastric pH may ↓ absorption).

Distribution: Unknown.

Protein Binding: >99%.

Metabolism/Excretion: Highly metabolized, primarily by CYP3A4; metabolites eliminated in feces (87%) and urine (5%).

Half-life: 24 hr (range 12–66 hr).

(response as noted by disease markers)

*For resistant/intolerant chronic phase CML

†For accelerated/blast phase CML or Ph+ALL

Contraindicated in:

• Concurrent use of strong CYP3A4 inhibitors
• Moderate to severe hepatic impairment
• Newly diagnosed chronic phase CML
• OB: Pregnancy
• Lactation: Lactation.

Use Cautiously in:

• History of ischemia, thromboembolic disease, diabetes, dyslipidemia, hypertension, peripheral arterial disease, HF, or arrhythmias
• History of liver disease or pancreatitis
• Impending elective surgery
• Rep: Women of reproductive potential
• Pedi: Safety and effectiveness not established in children.
• Geri: ↑risk of adverse reactions in older adults; consider age, organ function, concurrent disease states and medications

CNS: dizziness, fatigue, headache, weakness, insomnia, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), STROKE.

CV: arrhythmias, arterial thrombosis, hypertension, mI, peripheral arterial disease, peripheral edema, VENOUS THROMBOEMBOLISM, HF, pericardial effusion.

Derm: dry skin, rash, ERYTHEMA MULTIFORME, impaired wound healing, STEVENS-JOHNSON SYNDROME.

EENT: blindness, blurred vision, cataracts, dry eye, eye pain, glaucoma, iritis, macular edema, retinal hemorrhage, retinal vein occlusion, ulcerative keratitis.

Endo: hyperglycemia, hypothyroidism.

F and E: hyperkalemia, hypocalcemia, hypokalemia, hyponatremia, hypophosphatemia.

GI: abdominal pain, constipation, diarrhea, hepatotoxicity, nausea, mucositis, ↓ appetite, FISTULA FORMATION, GI PERFORATION, PANCREATITIS.

GU: ↓fertility (females).

Hemat: anemia, bleeding, leukopenia, neutropenia, thrombocytopenia, LYMPHOPENIA.

MS: arthralgia, back pain, bone pain, extremity pain, muscle spasm, myalgia, muscle weakness.

Neuro: peripheral neuropathy.

Resp: pleural effusion.

Misc: fever, TUMOR LYSIS SYNDROME.

Drug-Drug:

• Levels and risk of toxicity may be ↑ by CYP3A4 inhibitors including clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole; concurrent use should be avoided, but if necessary daily dose of ponatinib should not exceed 30 mg.
• Levels and effectiveness may be ↓ by CYP3A4 inducers including carbamazepine, phenytoin and rifampin; avoid concurrent use if possible.
• Levels and effectiveness may be ↑ by drugs that ↑ gastric pH including proton pump inhibitors, H₂ blockers and antacids; concurrent use should be avoided if possible.

Natural-Natural Products:

• Levels and effectiveness may be ↓ by St. John's wort; concurrent use should be avoided.

Drug-Food:

• Levels and risk of toxicity may be ↑ by grapefruit juice; concurrent use should be avoided.

Chronic Phase Chronic Myeloid Leukemia

• PO (Adults): 45 mg once daily; ↓ to 15 mg once daily upon achievement of 1% BCR-ABL1I. If loss of response occurs, may then ↑ to 30 mg once daily or 45 mg once daily. Continue until loss of response at re-escalated dose or unacceptable toxicity. Consider discontinuing therapy if hematologic response has not occurred within 3 mo. Concurrent use of strong CYP3A4 inhibitor — If current dose 45 mg once daily, ↓ to 30 mg once daily. If current dose 30 mg once daily, ↓ to 15 mg once daily. If current dose 15 mg once daily, ↓ to 10 mg once daily. If current dose 10 mg once daily, avoid concurrent use.

Acute Phase Chronic Myeloid Leukemia, Blast Phase Chronic Myeloid Leukemia, or Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

• PO (Adults): 45 mg once daily. In patients with acute phase CML, consider ↓ dose upon achievement of major cytogenetic response. Continue until loss of response or unacceptable toxicity. Consider discontinuing therapy if hematologic response has not occurred within 3 mo. Concurrent use of strong CYP3A4 inhibitor — If current dose 45 mg once daily, ↓ to 30 mg once daily. If current dose 30 mg once daily, ↓ to 15 mg once daily. If current dose 15 mg once daily, ↓ to 10 mg once daily. If current dose 10 mg once daily, avoid concurrent use.

• Tablets (contain lactose): 10 mg; 15 mg; 30 mg; 45 mg;

• Monitor for signs and symptoms of HF (shortness of breath, chest pain, palpitations, dizziness, fainting). Treat symptomatically, consider discontinuation if serious.
• Monitor BP and heart rate periodically during therapy. May cause hypertension. Treat hypertension to normalize BP. May require interruption of therapy, dose reduction, or discontinuation.
• Assess for bleeding during therapy. Interrupt therapy if severe hemorrhage occurs.
• Monitor for fluid retention. May require interruption, reduction of dose, or discontinuation of therapy.
• Monitor for signs and symptoms of vascular thrombosis (chest pain, shortness of breath, weakness on one side of the body, speech problems, leg pain, leg swelling). May require interruption or discontinuation of therapy.
• Monitor for signs and symptoms of neuropathy (hypoesthesia, hyperesthesia, paresthesia, discomfort, burning sensation, neuropathic pain or weakness). May require interruption of therapy.
• Conduct comprehensive eye exams at baseline and periodically during treatment. May cause ocular toxicity (blurred vision, cataracts, glaucoma, iritis, iridocyclitis, ulcerative keratitis).
• Assess skin during therapy. If bullous, blistering, and exfoliative skin conditions, including Stevens-Johnson syndrome/toxic epidermal necrolysis, occur, interrupt or discontinue treatment. Rash may require treatment with corticosteroids or anti-infectives with anti-inflammatory properties; acne treatments may aggravate dry skin and erythema.
• Assess for symptoms of PRES (headache, altered mental status, seizures, visual disturbances, hypertension) periodically during therapy. Confirm diagnosis by radiologic procedure. If PRES is suspected or diagnosed, maintain BP control and immediately reduce immunosuppression. Symptoms are usually reversed on reduction or discontinuation of immunosuppression.

• Verify negative pregnancy status before starting therapy.
• Obtain CBC and platelet counts every 2 wk for first 3 mo, then monthly or as clinically indicated. If neutropenia (absolute neutrophil count [ANC] <1 × 10⁹/L) or thrombocytopenia (platelet <50 × 10⁹/L) occur unrelated to leukemia, hold ponatinib and resume initial 45 mg dose after recovery to ANC <1.5 × 10⁹/L and platelet <75 × 10⁹/L. For second occurrence, hold ponatinib and resume at 30 mg dose after recovery to ANC <1.5 × 10⁹/L and platelet <75 × 10⁹/L. For third occurrence, hold ponatinib and resume at 15 mg dose after recovery to ANC <1.5 × 10⁹/L and platelet <75 × 10⁹/L.
  • Monitor AST, ALT, alkaline phosphatase, and bilirubin at baseline, at least monthly, or as clinically indicated. May require interruption, dose reduction, or discontinuation. If ↑ liver transaminase >3× the ULN(Grade 2 or higher) with 45 mg dose, interrupt and monitor hepatic function. Resume at 30 mg dose after recovery Grade 1 (<3× upper limit of normal); With 30 mg dose, interrupt and resume at 15 mg dose after recovery Grade 1. With 15 mg dose, discontinue ponatinib. If ↑ AST or ALT 3 × the upper limit of normal concurrent with ↑ bilirubin >2 × upper limit of normal and alkaline phosphatase <2× upper limit of normal, discontinue ponatinib.
  • Monitor serum lipase every 2 wk during first 2 mo and then monthly and as clinically indicated. Monitor patients with a history of pancreatitis or alcohol abuse more closely. If asymptomatic Grade 1 or 2 ↑ of serum lipase,consider interrupting or reducing ponatinib dose.If asymptomatic Grade 3 or 4 ↑ of serum lipase (>2× ULN) or asymptomatic radiologic pancreatitis (Grade 2 pancreatitis) occurs with 45 mg dose, hold ponatinib and resume at 30 mg after recovery to Grade 1 (<1.5× ULN). With 30 mg dose,hold ponatinib and resume at 15 mg after recovery to Grade 1. With 15 mg dose,discontinue ponatinib. If symptomatic Grade 3 ↑ of lipase pancreatitis occurs at 45 mg dose, hold ponatinib and resume at 30 mg after complete resolution of symptoms and after recovery to Grade 1. Occurs at 30 mg dose, hold ponatinib and resume at 15 mg after complete resolution of symptoms and after recovery to Grade 1. Occurs at 15 mg dose, discontinue ponatinib.
  • Monitor uric acid levels prior to therapy and treat high levels prior to therapy to minimize risk of tumor lysis syndrome.
  • May cause ↑ serum glucose, potassium, sodium, serum creatinine, calcium, and triglycerides. May ↓ serum phosphorous, calcium, sodium, glucose, potassium, and bicarbonate.

• Do not confuse ponatinib with pazopanib.
• Hold ponatinib at least 1 wk prior to and 2 wk following surgery; may compromise wound healing.
• PO: Administer once daily without regard to food. DNC: Swallow tablet whole; do not crush, break, or chew.

• Instruct patient to take ponatinib as directed and not to change dose or stop taking unless advised by health care professional. If a dose is missed, omit and take next dose the next day in the morning. Do not double doses to make up for missed dose. Advise patient to read Medication Guide before starting and periodically during therapy in case of changes.
• Caution patient to notify health care professional immediately if symptoms suggestive of a blood clot (chest pain, shortness or breath, weakness on one side of the body, speech problems, leg pain, leg swelling), liver failure (yellowing of eyes or skin, tea-colored urine, drowsiness), HF, pancreatitis (nausea, vomiting, abdominal pain or discomfort), neuropathy, unusual bleeding, easy bruising, fluid retention (leg swelling, abdominal swelling, weight gain, shortness of breath) or fever occurs.
• Advise patient to notify health care professional if signs of slow heart rate (fainting, dizziness, chest pain) or signs of rapid heart rate (palpitations, dizziness) occur.
• Instruct patient to maintain adequate hydration to minimize risk of tumor lysis syndrome.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
• Advise patient to notify health care provider of therapy prior to surgery or if had recent surgery.
• Rep: Ponatinib may cause fetal harm. Advise females of reproductive potential to use effective contraception during and for 3 wks after final dose of therapy and to notify health care professional if pregnancy is planned or suspected. Advise patient to avoid breastfeeding during and for 6 days after last dose of therapy. May impair fertility in female patients.

• Decreased progression of leukemia.

Iclusig

NDC Code^*

• 63020- Millennium Pharmaceuticals, Inc.
  • 63020-533- Iclusig
    • 63020-533-30- 30 TABLET, FILM COATED in 1 BOTTLE (63020-533-30)

• 63020- Millennium Pharmaceuticals, Inc.
  • 63020-534- Iclusig
    • 63020-534-30- 30 TABLET, FILM COATED in 1 BOTTLE (63020-534-30)

• 63020- Millennium Pharmaceuticals, Inc.
  • 63020-535- Iclusig
    • 63020-535-30- 30 TABLET, FILM COATED in 1 BOTTLE (63020-535-30)

• 63020- Millennium Pharmaceuticals, Inc.
  • 63020-535- Iclusig
    • 63020-535-60- 60 TABLET, FILM COATED in 1 BOTTLE (63020-535-60)

• 76189- ARIAD Pharmaceuticals, Inc.
  • 76189-533- Iclusig
    • 76189-533-30- 30 TABLET, FILM COATED in 1 BOTTLE (76189-533-30)

• 76189- ARIAD Pharmaceuticals, Inc.
  • 76189-534- Iclusig
    • 76189-534-30- 30 TABLET, FILM COATED in 1 BOTTLE (76189-534-30)

• 76189- ARIAD Pharmaceuticals, Inc.
  • 76189-534- Iclusig
    • 76189-534-90- 90 TABLET, FILM COATED in 1 BOTTLE (76189-534-90)

• 76189- ARIAD Pharmaceuticals, Inc.
  • 76189-535- Iclusig
    • 76189-535-30- 30 TABLET, FILM COATED in 1 BOTTLE (76189-535-30)

• 76189- ARIAD Pharmaceuticals, Inc.
  • 76189-535- Iclusig
    • 76189-535-60- 60 TABLET, FILM COATED in 1 BOTTLE (76189-535-60)

• 76189- ARIAD Pharmaceuticals, Inc.
  • 76189-535- Iclusig
    • 76189-535-80- 180 TABLET, FILM COATED in 1 BOTTLE (76189-535-80)