Iclusig (ponatinib)

WARNING

ARTERIAL OCCLUSION, VENOUS THROMBOEMBOLISM, HEART FAILURE, and HEPATOTOXICITY

Arterial Occlusion

• Arterial occlusions have occurred in at least 35% of Iclusig-treated patients. Some patients experienced more than 1 type of event. Events observed included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop Iclusig immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart Iclusig therapy.

Venous Thromboembolism

• Venous occlusive events have occurred in 6% of Iclusig-treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure

• Heart failure, including fatalities, occurred in 9% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.

Hepatotoxicity

• Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

Iclusig may cause serious side effects, including:

Your healthcare provider may do blood tests to check for TLS.

• High blood pressure. Your blood pressure should be checked regularly and any high blood pressure should be treated while you are taking Iclusig. Tell your healthcare provider if you get confusion, headaches, dizziness, chest pain or shortness of breath.
• Inflammation of the pancreas (pancreatitis). Tell your healthcare provider if you get any of the following symptoms: sudden stomach-area pain or discomfort, nausea, and vomiting. Your healthcare provider should do blood tests to check for pancreatitis during treatment with Iclusig.
• Neuropathy. Iclusig may cause damage to the nerves in your arms, brain, hands, legs, or feet (neuropathy). Tell your healthcare provider if you get any of these symptoms during treatment with Iclusig:
  • muscle weakness, tingling, burning, pain, and loss of feeling in your hands and feet
  • double vision and other problems with eyesight, trouble moving the eye, drooping of part of the face, sagging or drooping eyelids, and change in taste
• Effects on the eye. Serious eye problems that can lead to blindness or blurred vision may happen with Iclusig. Tell your healthcare provider if you get any of the following symptoms: bleeding in the eye, perceived flashes of light, light sensitivity, floaters, dry inflamed, swollen, or itchy eyes, and eye pain. Your healthcare provider will monitor your vision before and during your treatment with Iclusig.
• Severe bleeding. Iclusig can cause bleeding which can be serious and may lead to death. Tell your healthcare provider if you get any signs of bleeding during treatment with Iclusig including:
  • vomiting blood or if your vomit looks like coffee-grounds
  • unusual vaginal bleeding
  • nose bleeds that happen often
  • pink or brown urine
  • drowsiness or difficulty being
  • red or black (looks like tar) stools awakened
  • coughing up blood or blood clots
  • confusion
  • unusual bleeding or bruising of your skin
  • headache
  • change in speech
  • menstrual bleeding that is heavier than normal
• Fluid retention. Your body may hold too much fluid (fluid retention). Tell your healthcare provider right away if you get any of these symptoms during treatment with Iclusig:
  • swelling of your hands, ankles, feet, face, or all over your body
  • weight gain
  • shortness of breath and cough
• Irregular heartbeat. Iclusig may cause an irregular heartbeat. Tell your healthcare provider right away if you experience loss of consciousness, fainting, dizziness, chest pain or palpitations.
• Low blood cell counts. Iclusig may cause low blood cell counts, which can be severe. Your healthcare provider will check your blood counts regularly during treatment with Iclusig. Tell your healthcare provider right away if you have a fever or any signs of an infection while taking Iclusig.
• Tumor Lysis Syndrome (TLS). TLS is caused by a fast breakdown of cancer cells. TLS can cause you to have:
  • kidney failure and the need for dialysis treatment
  • an abnormal heartbeat
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS – also known as PosteriorReversible Encephalopathy Syndrome – PRES). Iclusig may trigger a condition called RPLS. Call your healthcare provider right away if you get headaches, seizures, confusion, changes in vision or problems thinking.
• Wound healing problems. Wound healing problems have happened in some people who take Iclusig. Tell your healthcare provider if you plan to have any surgery before or during treatment with Iclusig.
  • You should stop taking Iclusig at least 1 week before planned surgery.
  • Your healthcare provider should tell you when you may start taking Iclusig again after surgery.
• A tear in your stomach or intestinal wall (perforation). Tell your healthcare provider right away if you get:
  • severe pain in your stomach-area (abdomen)
  • swelling of the abdomen
  • high fever

The most common side effects of Iclusig include:

• stomach-area (abdomen) pain
• skin rash
• constipation
• headache
• dry skin
• blood clots or blockage in blood vessels (arteries)
• tiredness
• high blood pressure
• fever
• joint pain
• nausea
• diarrhea
• increase in lipase levels (a blood test done to check your pancreas)
• vomiting
• muscle pain
• pain in arms, hands, legs, and feet

Your healthcare provider may change your dose, temporarily stop, or permanently stop treatment with Iclusig if you have certain side effects.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all of the possible side effects of Iclusig. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA1088.

Recommended Dosage

CP-CML

The recommended starting dosage is 45 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of ≤1% BCR-ABL1^IS. Patients with loss of response can re-escalate the dose of Iclusig to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Continue Iclusig until loss of response at the re-escalated dose or unacceptable toxicity.

Consider discontinuing Iclusig if hematologic response has not occurred by 3 months.

AP-CML, BP-CML, And Ph+ ALL

The optimal dose of Iclusig has not been identified.

The recommended starting dosage of Iclusig is 45 mg orally once daily. Consider reducing the dose of Iclusig for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response. Continue Iclusig until loss of response or unacceptable toxicity.

Consider discontinuing Iclusig if response has not occurred by 3 months.

Administration

Advise patients of the following:

• Iclusig may be taken with or without food.
• Swallow tablets whole. Do not crush, break, cut or chew tablets.
• If a dose is missed, take the next dose at the regularly scheduled time the next day.

Dosage Modifications For Adverse Reactions

Recommended dosage modifications of Iclusig for adverse reactions are provided in Table 1 and recommended dose reductions of Iclusig for adverse reactions are presented in Table 2.

Table 1: Recommended Dosage Modifications for Iclusig for Adverse Reactions

Table 2: Recommended Dose Reductions for Iclusig for Adverse Reactions

Dosage Modification For Coadministration Of Strong CYP3A Inhibitors

Avoid coadministration of Iclusig with strong CYP3A inhibitors. If coadministration of a strong CYP3A inhibitor cannot be avoided, reduce the dosage of Iclusig as recommended in Table 3.

After the strong CYP3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the Iclusig dosage that was tolerated prior to initiating the strong CYP3A inhibitor.

Table 3: Recommended Iclusig Dosage for Coadministration of Strong CYP3A Inhibitors

Dosage For Patients With Hepatic Impairment

Reduce the starting dose of Iclusig from 45 mg orally once daily to 30 mg orally once daily in patients with pre-existing hepatic impairment (Child-Pugh A, B, or C).

Effects Of Other Drugs On Iclusig

Strong CYP3A Inhibitors

• Coadministration of Iclusig with a strong CYP3A inhibitor increases ponatinib plasma concentrations, which may increase the risk of Iclusig adverse reactions. Avoid coadministration of Iclusig with strong CYP3A inhibitors.
• If coadministration of Iclusig with strong CYP3A inhibitors cannot be avoided, reduce the Iclusig dosage.

Strong CYP3A Inducers

• Coadministration of Iclusig with a strong CYP3A inducer decreases ponatinib plasma concentrations.
• Avoid coadministration of Iclusig with strong CYP3A inducers unless the benefit outweighs the risk of decreased ponatinib exposure.
• Monitor patients for reduced efficacy.
• Selection of concomitant medication with no or minimal CYP3A induction potential is recommended.

• 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.
• There is no data on the presence of ponatinib in human milk or the effects on the breastfed child or on milk production.
• Because of the potential for serious adverse reactions in the breastfed child from ponatinib, advise women not to breastfeed during treatment with Iclusig and for 6 days following the last dose.