Ponatinib

What is Ponatinib?

• Ponatinib (Iclusig) is a kinase inhibitor used for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL).

Ponatinib

Ponatinib in its binding site

Ponatinib molecule ball

Ponatinib molecule spacefill

What are the uses of this medicine?

Iclusig is a prescription medicine used to treat adults who have:

• chronic phase chronic myeloid leukemia (CML) who did not tolerate or no longer benefit from treatment with at least 2 prior kinase inhibitor medicines
• accelerated phase or blast phase CML, or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who cannot receive any other kinase inhibitor medicines
• a specific type of abnormal gene (T315I-positive) chronic phase, accelerated phase, or blast phase CML, or T315I-positive Ph+ ALL

Limitations of Use:

• Iclusig is not for use to treat people with newly diagnosed chronic phase CML.

How does this medicine work?

• Ponatinib (poe na’ ti nib) is a broad spectrum inhibitor of the unique BCR-ABL tyrosine kinase receptor, which is the product of a fusion gene resulting from the translocation between chromosomes 9 and 22 that underlies the Philadelphia chromosome of chronic myelogenous leukemia (CML).
• The abnormal tyrosine kinase receptor is constitutively expressed and causes abnormal cell growth and proliferation.
• Inhibition of the enzyme can lead to dramatic reversal of progression of leukemia and is highly effective, although limited by the development of tumor resistance caused by mutations in the kinase.
• Ponatinib is actually a multi-kinase inhibitor and also has activity against scr, c-Kit and ephrin receptors, among others.

Who Should Not Use this medicine ?

Limitations of Use:

• Iclusig is not for use to treat people with newly diagnosed chronic phase CML.

What drug interactions can this medicine cause?

• Avoid coadministration or reduce Iclusig dose if coadministration with strong CYP3A Inhibitors cannot be avoided.
• Avoid coadministration with strong CYP3A Inducers.

Is this medicine FDA approved?

• Ponatinib received approval for use in the United States in 2012.
• Ponatinib was subsequently withdrawn after identification of severe side effects of vascular thromboses, but then reapproved with a narrowing of indications and boxed warnings.

How should this medicine be used?

Recommended dosage:

Recommended Dosage in CP-CML:

• Starting dose is 45 mg orally once daily with a reduction to 15 mg once daily upon achievement of ≤1% BCR-ABL1IS.

Recommended Dosage in AP-CML, BP-CML, and Ph+ ALL:

• Starting dose is 45 mg orally once daily.

Hepatic Impairment:

• Reduce the starting dose to 30 mg orally once daily.

Administration:

• Take Iclusig exactly as your healthcare provider tells you to take it.
• Do not change your dose or stop taking Iclusig unless your healthcare provider tells you.
• Swallow Iclusig tablets whole. Do not crush, break, cut, chew or dissolve Iclusig tablets.
• Take Iclusig with or without food.
• Do not eat grapefruit or drink grapefruit juice during treatment with Iclusig.
• If you miss a dose of Iclusig, take your next dose at your regularly scheduled time the next day. Do not take 2 doses at the same time to make up for a missed dose.
• If you take too much Iclusig, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the dosage forms and brand names of this medicine?

This medicine is available in fallowing doasage form:

• As Tablets: 10 mg, 15 mg, 30 mg and 45 mg.

This medicine is available in fallowing brand namesː

• Iclusig

What side effects can this medication cause?

The most common side effects of this medicine include:

• skin rash
• joint pain
• stomach-area (abdomen) pain
• headache
• constipation
• dry skin
• high blood pressure
• tiredness
• swelling of your hands, ankles, feet, face, or all of your body (fluid retention and edema)
• fever
• nausea
• inflammation of the pancreas
• increase in lipase levels (a blood test done to check your pancreas)
• bleeding
• low hemoglobin in the blood (anemia)
• liver problems
• blood clots or blockage in blood vessels (arteries)
• low blood platelet counts
• low blood levels of white blood cells (including neutrophils)

Iclusig can cause serious side effects, including:

• Blood clots or blockage in your blood vessels (arteries and veins)
• Heart problems
• Liver problems
• High blood pressure (hypertension)
• Inflammation of the pancreas (pancreatitis)
• Neuropathy
• Eye problems
• Serious bleeding
• Fluid retention
• Irregular heartbeat
• Low blood cell counts
• Tumor Lysis Syndrome (TLS)
• Reversible Posterior Leukoencephalopathy Syndrome
• Wound healing problems
• A tear in your stomach or intestinal wall (perforation)

What special precautions should I follow?

• Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received Iclusig. Monitor blood pressure and manage hypertension as clinically indicated. Interrupt, dose reduce or stop Iclusig if hypertension is not medically controlled.
• Serious or severe pancreatitis has occurred in patients who received Iclusig. Monitor serum lipase. Interrupt then resume at the same or reduced dose or discontinue Iclusig based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms.
• Neuropathy may oocur with Iclusig. Monitor for symptoms of peripheral and cranial neuropathy. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity
• Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Conduct comprehensive eye exams at baseline and periodically during treatment.
• Fatal and serious hemorrhage events have occurred in patients who received Iclusig. Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity.
• Fatal and serious fluid retention events have occurred in patients who received Iclusig. Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity.
• Cardiac Arrhythmias may occur. Monitor for signs or symptoms of arrhythmias and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue Iclusig based on recurrence/severity.
• Myelosuppression may occur. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 × 109/L or platelets less than 50 × 109/L, interrupt Iclusig until ANC at least 1.5 × 109/L and platelets at least 75 × 109/L, then resume at same or reduced dose.
• Tumor Lysis Syndrome may occur. Ensure adequate hydration and correct elevated uric acid levels prior to initiating Iclusig.
• Reversible posterior leukoencephalopathy syndrome (RPLS; also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received Iclusig. Interrupt Iclusig until resolution. The safety of resumption of Iclusig in patients upon resolution of RPLS is unknown.
• Impaired wound healing occurred in patients receiving Iclusig. Withhold Iclusig for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Iclusig after resolution of wound healing complications has not been established.
• Based on its mechanism of action and findings from animal studies, Iclusig can cause fetal harm when administered to a pregnant woman. Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception.

What to do in case of emergency/overdose?

Symptoms of overdosage may include:

• uncorrected QT interval
• pneumonia
• sepsis
• fatigue
• non-cardiac chest pain
• atrial fibrillation
• pericardial effusion

Treatment of overdosage:

• In the event of an overdosage, stop Iclusig, observe the patient and provide supportive treatment as appropriate.

Can this medicine be used in pregnancy?

• Based on findings in animals and its mechanism of action, Iclusig can cause fetal harm when administered to a pregnant woman.
• There are no available data on Iclusig use in pregnant women.

Can this medicine be used in children?

• Safety and effectiveness have not been established in pediatric patients.

What are the active and inactive ingredients in this medicine?

• Active ingredient: ponatinib
• Inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type B), colloidal silicon dioxide and magnesium stearate. The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol and titanium dioxide.

Who manufactures and distributes this medicine?

• Distributed by: Takeda Pharmaceuticals America, Inc. Lexington

What should I know about storage and disposal of this medication?

• Store Iclusig at room temperature between 68°F to 77°F (20°C to 25°C).

• Dailymed label info on Ponatinib
• FDA Ponatinib