ponatinib

ponatinib

(poe-na-ti-nib) ,

Inclusig

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: kinase inhibitors
Pregnancy Category: D

Indications

Treatment of chronic phase/accelerated phase/blast phase chronic myeloid leukemia (CML) that is tolerant/resistant to previous treatment with tyrosine kinase inhibitors.Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) that is resistant/tolerant to previous treatment with tyrosine kinase inhibitors.

Action

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

Therapeutic effects

Decreased progression of leukemia resistant to previous kinase inhibitor therapy 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)

ROUTEONSETPEAKDURATION
POunknown84 daysunknown

Time/action profile (response as noted by disease markers for Accelerated/Blast Phase CML or Ph+ALL)

ROUTEONSETPEAKDURATION
POunknown21 days3.2–9.5 mo

Contraindications/Precautions

Contraindicated in: Concurrent strong CYP3A4 inhibitors; Obstetric / Lactation: Pregnancy or breastfeeding should be avoided; Moderate to severe hepatic impairment.
Use Cautiously in: History of cardiovascular disease, thromboembolic disease or hypertension; History of liver disease or pancreatitis; Impending elective surgery; Geriatric: ↑ risk of adverse reactions; consider age, organ function, concurrent disease states and medications; Pediatric: Safety and effectiveness not established.

Adverse Reactions/Side Effects

Central nervous system

  • dizziness (most frequent)
  • fatigue (most frequent)
  • headache (most frequent)
  • weakness (most frequent)
  • insomnia

Cardiovascular

  • arrhythmias (life-threatening)
  • arterial thrombosis
  • hypertension (life-threatening)
  • CHF (life-threatening)
  • thromboembolism (life-threatening)
  • fluid retention/edema

Gastrointestinal

  • fistula formation (life-threatening)
  • hepatotoxicity (life-threatening)
  • pancreatitis (life-threatening)
  • abdominal pain (most frequent)
  • constipation (most frequent)
  • diarrhea (most frequent)
  • nausea (most frequent)
  • mucositis (most frequent)
  • ↓ appetite

Dermatologic

  • dry skin (most frequent)
  • rash (most frequent)
  • compromised wound healing

Fluid and Electrolyte

  • hyperkalemia
  • hypocalcemia
  • hypokalemia
  • hyponatremia
  • hypophosphatemia

Endocrinologic

  • hyperglycemia

Hematologic

  • bleeding
  • anemia (life-threatening)
  • leukopenia (life-threatening)
  • lymphopenia (life-threatening)
  • neutropenia (life-threatening)
  • thrombocytopenia (life-threatening)

Musculoskeletal

  • arthralgia (most frequent)
  • back pain (most frequent)
  • bone pain (most frequent)
  • extremity pain (most frequent)
  • muscle spasm (most frequent)
  • myalgia (most frequent)

Neurologic

  • peripheral neuropathy (most frequent)

Miscellaneous

  • tumor lysis syndrome (life-threatening)
  • fever (most frequent)

Interactions

Drug-Drug interaction

Blood levels and risk of toxicity may be ↑ by CYP3A4 inhibitors including bocepravir, clarithromycin, conivaptan, indinvair, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole ; concurrent use should be avoided, but if necessary daily dose of ponatinib should not exceed 30 mg. Blood levels and effectiveness may be ↓ by CYP3A4 inducers including carbamazepine, phenytoin and rifampin ; avoid concurrent use if possible. Blood levels and effectiveness may be ↑ drugs that ↑ gastric pH including proton pump inhibitors, H2 blockers and antacids ; concurrent use should be avoided if possible.Levels and effectiveness may be ↓ by St. John's wort; concurrent use should be avoided.Levels and risk of toxicity may be ↑ by grapefruit juice; concurrent use should be avoided.

Route/Dosage

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

Availability

Tablets (contain lactose): 15 mg, 45 mg

Nursing implications

Nursing assessment

  • Monitor for signs and symptoms of CHF (shortness of breath, chest pain, palpitations, dizziness, fainting). Treat symptomatically, consider discontinuation if serious.
  • Monitor blood pressure and heart rate periodically during therapy. May cause hypertension.
  • 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.
  • Lab Test Considerations: 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, creatinine, calcium, and triglycerides. May ↓ serum phosphorous, calcium, sodium, glucose, potassium, and bicarbonate.

Potential Nursing Diagnoses

Risk for infection (Indications)

Implementation

  • Interrupt ponatinib at least 1 wk prior to major surgery; may compromise wound healing.
  • Oral: 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), congestive heart failure, pancreatitis (nausea, vomiting, abdominal pain or discomfort), 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.
  • Advise female patient that ponatinib is teratogenic. Advise patient to use effective contraception during therapy and to notify health care professional if pregnancy is planned or suspected or if breastfeeding.

Evaluation/Desired Outcomes

  • Decreased progression of leukemia.
References in periodicals archive ?
For the quarter ended June 30, 2019, net product revenues of Iclusig (ponatinib) were $24 million as compared to $20 million for the same period in 2018.
Tenders are invited for electronic auction among small businesses and socially oriented non-profit organizations for the right to conclude a contract for the supply of drugs (ponatinib) for individual provision of certain categories of citizens eligible for state social assistance (in accordance with the decisions of medical commissions) in moscow ( dsp z1918985).
Muna's MSc research thesis, titled 'The Role of p90 Ribosomal S6 Kinase and Autophagy in Sunitinib and Ponatinib-Induced Cardiotoxicity', investigated the cardiotoxic effects associated with ponatinib and sunitinib, small molecules tyrosine kinase inhibitors, used for various types of cancer.
According to the circular, the ministry clarified that the World Health Organisation had previously issued a warning against the spread of counterfeit medicines, and that the fake medicine contained paracetamol instead of the active ingredient Ponatinib Hydrochloride.
Treatment of CML changed significantly over the past years, especially after the introduction of tyrosine kinase inhibitors with first generation Imatinib, second generation Nilotinib, Bosutinib and third generation drugs such as ponatinib. Treatment with TKI have markedly improved survival in CML patients.
There are ongoing studies concerning the efficacy of the new FGF1 inhibitor ponatinib. [9,14]
Mechanisms of mitochondrial toxicity of the kinase inhibitors ponatinib, regorafenib and sorafenib in human hepatic HepG2 cells.
Multitargeted kinase inhibitors, such as dabrafenib, vemurafenib, sorafenib, pazopanib, and ponatinib, are currently used for the treatment of cancer, which have later emerged as having antinecroptotic activity [59-61].
Nilotinib, dasatinib, and bosutinib are some prominent examples of second generation TKIs and ponatinib are an example of a third generation of TKI.
Ponatinib induces apoptosis in imatinib-resistant human mast cells by dephosphorylating mutant D816V KIT and silencing betacatenin signaling.
The acquisition grants the Japanese pharma firm access to Ariad's Iclusig (ponatinib), which is used in the treatment of selected patients suffering from chronic myeloid leukaemia or acute lymphoblastic leukaemia.