ponatinib

poe-NA-ti-nib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

High Alert

Newly diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) (in combination with chemotherapy).
T315I-positive Ph+ ALL.
Ph+ ALL when no other kinase inhibitor is indicated.
T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase, or blast phase).
Accelerated phase or blast phase CML 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.

Therapeutic effects:

Decreased progression of leukemia with improved survival.

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

Distribution: Unknown.

Protein Binding: >99%.

Metabolism/Excretion: Primarily metabolized in the liver via the CYP3A4 isoenzyme; metabolites eliminated in feces (87%) and urine (5%).

Half-Life: 24 hr (range 12–66 hr).

(response as noted by disease markers)

ROUTE	ONSET	PEAK	DURATION
PO*	unknown	84 days	unknown
PO‡	unknown	21 days	3.2–9.5 mo

*For resistant/intolerant chronic phase CML

‡For accelerated/blast phase CML or Ph+ALL

Contraindicated in:

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.

CV: arrhythmias, arterial thrombosis, hypertension, mI, peripheral arterial disease, peripheral edema, DEEP VEIN THROMBOSIS (DVT), pericardial effusion, HF

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, pancreatitis, ↓appetite, FISTULA FORMATION, GI PERFORATION

GU: ↓fertility (females)

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

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

Neuro: dizziness, fatigue, headache, peripheral neuropathy, weakness, insomnia, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), STROKE

Resp: pleural effusion, PULMONARY EMBOLISM (PE)

Misc: fever, TUMOR LYSIS SYNDROME

Drug-drug:

CYP3A4 inhibitors, including clarithromycin, conivaptan, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, and voriconazole, may ↑ levels and risk of toxicity; avoid concurrent use.
CYP3A4 inducers, including carbamazepine, phenytoin, and rifampin, may ↓ levels and effectiveness; avoid concurrent use.
Drugs that gastric pH, including proton pump inhibitors, H2 blockers, and antacids, may ↓ levels and effectiveness; avoid concurrent use.

Natural-Natural Products:

St. John's wort may ↓ levels and effectiveness; avoid concurrent use.

Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

PO (Adults ): 30 mg once daily. ↓ to 15 mg once daily on achievement of minimum residual disease-negative (≤0.01% BCR::ABL1/ABL1) complete remission at the end of induction. Continue in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity. Concurrent use of strong CYP3A4 inhibitor: 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.

Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia for Whom No Other Kinase Inhibitors Are Indicated or T315I-Positive Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

PO (Adults ): 45 mg once daily. 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.

Hepatic Impairment

PO (Adults ): Mild, moderate, or severe hepatic impairment: If current dose 45 mg once daily, ↓ to 30 mg once daily.

Chronic Phase Chronic Myeloid Leukemia

PO (Adults ): 45 mg once daily; ↓ to 15 mg once daily on 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.

Hepatic Impairment

PO (Adults ): Mild, moderate, or severe hepatic impairment: If current dose 45 mg once daily, ↓ to 30 mg once daily.

Acute Phase Chronic Myeloid Leukemia or Blast Phase Chronic Myeloid Leukemia

PO (Adults ): 45 mg once daily. In patients with acute phase CML, consider ↓ dose on 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.

Hepatic Impairment

PO (Adults ): Mild, moderate, or severe hepatic impairment: If current dose 45 mg once daily, ↓ to 30 mg once daily.

(Generic available)

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.If Grade 2 or 3 occurs, hold dose until Grade <1; resume at next ↓dose. If Grade 4 or recurring reaction, discontinue therapy.
Monitor BP and HR periodically during therapy. May cause hypertension. Treat hypertension to normalize BP. May require interruption of therapy, dose ↓, or discontinuation.
Assess for bleeding during therapy. Interrupt therapy if severe hemorrhage occurs.
Monitor for arterial occlusive events (MI, stroke, peripheral arterial disease). If Grade 1 events occur, hold therapy until resolved; then resume at same dose. If Grade 2 events occur, hold therapy until Grade <1; then resume at next lower dose. Discontinue if recurring reactions. If Grade ≥3 events occur, discontinue therapy.
Monitor for fluid retention. May require interruption, ↓ of dose, or discontinuation of therapy.
Monitor for signs and symptoms of DVT/PE (chest pain, shortness of breath, weakness on one side of the body, speech problems, leg pain, leg swelling). If Grade 1 event occurs, hold therapy until resolved; then resume at same dose.If Grade 2 event occurs,hold therapy until Grade <1; then resume at same dose. If recurring event occurs, hold therapy until Grade <1; then resume at next lower dose. If Grade 4 event occurs, discontinue 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 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.

Lab Test Considerations:

Verify negative pregnancy status before starting therapy.
Obtain CBC every 2 wk for first 3 mo, then monthly or as clinically indicated. If neutropenia (ANC <1 × 10⁹/L) or thrombocytopenia (platelets <50 × 10⁹/L) occur unrelated to leukemia, hold ponatinib and resume at same dose after recovery to ANC >1.5 × 10⁹/L and platelets >75 × 10⁹/L. If recurrence occurs, hold ponatinib and resume at next lower dose after recovery to ANC >1.5 × 10⁹/L and platelets >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 ↑ transaminases >3 times upper limit of normal (ULN), hold ponatinib until Grade <1; then resume at next lower dose. If ↑ AST or ALT ≥3 times ULN concurrent with ↑ bilirubin >2 times ULN and alkaline phosphatase <2 times the ULN, 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 serum lipase >1 to 1.5 times ULN, consider holding therapy until resolution; then resume at same dose.If serum lipase >1.5–2 times ULN, asymptomatic ↑ of serum lipase (2–5 times ULN), or asymptomatic radiologic pancreatitis,, hold ponatinib until Grade <1; then resume therapy at next lower dose. If symptomatic ↑ of serum lipase (2–5 times ULN), symptomatic Grade 3 pancreatitis, or asymptomatic ↑ of serum lipase (>5 times ULN),hold ponatinib until complete resolution of symptoms and after recovery of serum lipase levels; then resume therapy at next lower dose.
- Monitor uric acid levels prior to therapy and treat high levels prior to therapy to minimize risk of tumor lysis syndrome.
- May ↑ serum glucose, potassium, sodium, creatinine, calcium, and triglycerides. May ↓ serum phosphorous, calcium, sodium, glucose, potassium, and bicarbonate.

Do not confuse ponatinib with pazopanib.
Hold ponatinib ≥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.
Dose Reductions for Adverse Reactions for Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia:First,15 mg once daily.Second,10 mg once daily. Third and subsequent reduction,permanently discontinue if unable to tolerate 10 mg once daily.
Dose Reductions for Adverse Reactions for Acute Phase Chronic Myeloid Leukemia or Blast Phase Chronic Myeloid Leukemia:First,30 mg once daily.Second,15 mg once daily. Third and subsequent reduction,permanently discontinue if unable to tolerate 15 mg once daily.
Dose Reductions for Adverse Reactions for Chronic Phase Chronic Myeloid Leukemia:First,30 mg once daily. Second,15 mg once daily. Third,10 mg once daily. Subsequent reduction,permanently discontinue if unable to tolerate 10 mg once daily.

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Instruct patient to take 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 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.
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 HR (fainting, dizziness, chest pain) or signs of rapid HR (palpitations, dizziness) occur.
Instruct patient to maintain adequate hydration to minimize risk of tumor lysis syndrome.
Advise patient to notify health care professional of therapy prior to surgery or if had recent surgery.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for 3 wk 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

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