Iclusig (ponatinib) for Leukemia: Side Effects & Dosage

Generic drug: ponatinib

Brand name: Iclusig

What is Iclusig (ponatinib), and how does it work?

What is Iclusig and how is it used?

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

• chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL) who cannot receive any other tyrosine kinase inhibitor (TKI) medicines
• a specific type of abnormal gene (T315I-positive) chronic phase, accelerated phase, or blast phase CML, or T315I-positive Ph+ ALL

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

It is not known if Iclusig is safe and effective in children less than 18 years of age.

What are the side effects of Iclusig?

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.

What is the dosage for Iclusig?

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

Adverse ReactionSeverityIclusig Dosage Modifications
AOE: cardiovascular or cerebrovascular Grade 1Interrupt Iclusig until resolved, then resume at same dose.Grade 2Interrupt Iclusig until Grade 0 or 1, then resume at next lower dose. Discontinue Iclusig if recurrence.Grade 3 or 4Discontinue Iclusig.
AOE: peripheral vascular and other or VTE Grade 1Interrupt Iclusig until resolved, then resume at same dose.Grade 2Interrupt Iclusig until Grade 0 or 1, then resume at same dose. If recurrence, interrupt Iclusig until Grade 0 or 1, then resume at next lower dose.Grade 3Interrupt Iclusig until Grade 0 or 1, then resume at next lower dose. Discontinue Iclusig if recurrence.Grade 4Discontinue Iclusig.Heart Failure Grade 2 or 3Interrupt Iclusig until Grade 0 or 1, then resume at next lower dose. Discontinue Iclusig if recurrence.Grade 4Discontinue Iclusig.
Hepatotoxicity AST or ALT greater than 3 times ULNInterrupt Iclusig until Grade 0 or 1, then resume at next lower dose.AST or ALT at least 3 times ULN concurrent with bilirubin greater than 2 times ULN and alkaline phosphatase less than 2 times ULNDiscontinue Iclusig.
Pancreatitis and Elevated LipaseSerum lipase greater than 1 to 1.5 times ULNConsider interrupting Iclusig until resolution then resume at same dose.Serum lipase greater than 1.5 to 2 times ULN, 2 to 5 times ULN and asymptomatic, or asymptomatic radiologic pancreatitisInterrupt Iclusig until Grade 0 or 1 (less than 1.5 times ULN) then resume at next lower dose.Serum lipase greater than 2 to 5 times ULN and symptomatic, symptomatic Grade 3 pancreatitis, or serum lipase greater than 5 times ULN and asymptomaticInterrupt Iclusig until complete resolution of symptoms and after recovery of lipase elevation Grade 0 or 1, then resume at next lower dose.Symptomatic pancreatitis and serum lipase greater than 5 times ULNDiscontinue Iclusig.
MyelosuppressionANC less than 1 x 10⁹/L or Platelets less than 50 x 10⁹/LInterrupt Iclusig until ANC at least 1.5 x 10⁹/L and platelet at least 75 x 10⁹/L, then resume at same dose.
If recurrence, interrupt Iclusig until resolution, then resume at next lower dose.
Other Non-hematologic Adverse Reactions Grade 1Interrupt Iclusig until resolved, then resume at same dose.Grade 2Interrupt Iclusig until Grade 0 or 1, then resume at same dose.
If recurrence, interrupt Iclusig until Grade 0 or 1, then resume at next lower dose.Grade 3 or 4Interrupt Iclusig until Grade 0 or 1, then resume at next lower dose.
Discontinue Iclusig if recurrence.Based on CTCAE v5.0: Grade 1 mild, Grade 2 moderate, Grade 3 severe, Grade 4 life-threatening ULN = Upper Limit of Normal for the lab; AOE = Arterial Occlusive Event; VTE = Venous Thromboembolic Event; ANC = absolute neutrophil count

Table 2: Recommended Dose Reductions for Iclusig for Adverse Reactions

Dose ReductionDosage for Patients with CP-CMLDosage for Patients with AP-CML, BP-CML, and Ph+ ALLFirst30 mg orally once daily30 mg orally once dailySecond15 mg orally once daily15 mg orally once dailyThird10 mg orally once dailyPermanently discontinue Iclusig in patients unable to tolerate 15 mg orally once daily.Subsequent ReductionPermanently discontinue Iclusig in patients unable to tolerate 10 mg orally once daily.

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

Current Iclusig DosageRecommended Iclusig Dosage with a Strong CYP3A Inhibitor45 mg orally once daily30 mg orally once daily30 mg orally once daily15 mg orally once daily15 mg orally once daily10 mg orally once daily10 mg orally once dailyAvoid coadministration of Iclusig with a strong CYP3A inhibitor

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).

What drugs interact with Iclusig?

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.

Is Iclusig safe to use while pregnant or breastfeeding?

• 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.