General

**REMS Drug**

Genetic Implications:

Pronunciation:
poe-na-ti-nib

Trade Name(s)

• Iclusig

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

•  T315I-positive chronic myeloid leukemia (CML) (chronic phase/accelerated phase/blast phase).
•  T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
• Chronic phase/accelerated phase/blast phase CML when no other tyrosine kinase inhibitor is indicated.
•  Ph+ ALL when no other tyrosine kinase inhibitor is indicated.

Action

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

Therapeutic Effect(s):

Decreased progression of leukemia with improved survival.

Pharmacokinetics

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

Distribution: Unknown.

Protein Binding: >99%.

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

Half-life: 24 hr (range 12–66 hr).

TIME/ACTION PROFILE (response as noted by disease markers for resistant/intolerant Chronic Phase CML)

TIME/ACTION PROFILE (response as noted by disease markers for Accelerated/Blast Phase CML or Ph+ALL)

Contraindication/Precautions

Contraindicated in:

• Concurrent strong CYP3A4 inhibitors
• Moderate to severe hepatic impairment;
• Newly diagnosed chronic phase CML;
• OB:  May cause fetal harm;
•  Lactation: Avoid breastfeeding.

Use Cautiously in:

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

Adverse Reactions/Side Effects

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

CV: ARRHYTHMIAS, ARTERIAL THROMBOSIS, HF, MYOCARDIAL INFARCTION, PERIPHERAL ARTERIAL DISEASE, VENOUS THROMBOEMBOLISM, hypertension, fluid retention/edema

GI: FISTULA FORMATION, HEPATOTOXICITY, PANCREATITIS, abdominal pain, constipation, diarrhea, nausea, mucositis, ↓ appetite

EENT: BLINDNESS, blurred vision, cataracts, glaucoma, iritis, macular edema, retinal hemorrhage, retinal vein occlusion, ulcerative keratitis

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

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

Endo: hyperglycemia

GU: ↓ fertility (females)

Hemat: BLEEDING, ANEMIA, LEUKOPENIA, LYMPHOPENIA, NEUTROPENIA, THROMBOCYTOPENIA

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

Neuro: peripheral neuropathy

Misc: TUMOR LYSIS SYNDROME, fever

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

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:

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.

Route/Dosage

PO (Adults): 45 mg once daily; modify for various degrees of toxicity;  Concurrent strong CYP3A4 inhibitors– 30 mg once daily.

Hepatic Impairment 
PO (Adults): Child-Pugh A, B, or C– 30 mg once daily.

Availability

Tablets (contain lactose): 15 mg, 45 mg

Assessment

• 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 throughout therapy. If bullous, blistering, and exfoliative skin conditions, including Stevens-Johnson syndrome/toxic epidermal necrolysis, occur, interrupt or discontinue treatment. Skin 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.

Lab Test Considerations:

• Verify negative pregnancy status before starting therapy.

• Obtain CBC and platelet counts every 2 wk for first 3 mo, than monthly or as clinically indicated.  If neutropenia (ANC <1 × 10⁹ /L) and thrombocytopenia (platelet <50 × 10⁹ /L) occur unrelated to leukemia , interrupt therapy and resume initial 45 mg dose after recovery to ANC <1.5 × 10⁹ /L and platelet <75 × 10⁹ /L.  For second occurrence , interrupt therapy and resume at 30 mg dose after recovery to ANC <1.5 × 10⁹ /L and platelet <75 × 10⁹ /L.  For third occurrence , interrupt therapy 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 upper limit of normal (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 occurs , consider interruption or dose reduction.  If symptomatic Grade 3 or 4 ↑ of lipase (>2 × upper limit of normal) or asymptomatic radiologic pancreatitis (Grade 2 pancreatitis) occurs at 45 mg dose , interrupt therapy and resume at 30 mg after recovery to ≤Grade 1 (<1.5 × upper limit of normal).  Occurs at 30 mg dose , interrupt therapy and resume at 15 mg after recovery to ≤Grade 1 (<1.5 × upper limit of normal).  Occurs at 15 mg dose , discontinue ponatinib.  If symptomatic Grade 3 pancreatitis occurs at 45 mg dose , interrupt therapy and resume at 30 mg after complete resolution of symptoms and recovery to ≤Grade 1.  Occurs at 30 mg dose , interrupt therapy and resume at 15 mg after complete resolution of symptoms and 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.

Potential Diagnoses

• Risk for infection (Indications) 

Implementation

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

Patient/Family Teaching

• Instruct patient to take ponatinib as directed and not to change dose or stop taking unless advised by health care professional. Do not double doses to make up for missed dose.
• 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), heart failure, 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 provider of therapy prior to surgery or if had recent surgery.
• Rep:  Advise female patient that ponatinib is teratogenic. Advise patient 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.

Evaluation/Desired Outcomes

Decreased progression of leukemia.