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Black Box Warning
WARNING: VASCULAR OCCLUSION, HEART FAILURE, AND HEPATOTOXICITY
See full prescribing information for complete Boxed Warning.
Vascular Occlusion:
Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including 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 thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit-risk consideration should guide a decision to restart Iclusig therapy.
Heart Failure:
Heart failure, including fatalities, occurred in 8% 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 (ponatinib) is a kinase inhibitor indicated for the:
Treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL).
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.
Dosing
Recommended Dosing
The optimal dose of Iclusig has not been identified. In clinical trials, the starting dose of Iclusig was 45 mg administered orally once daily. However, 59% of the patients required dose reductions to 30 mg or 15 mg once daily during the course of therapy.
Start dosing with 45 mg once daily. Consider reducing the dose of Iclusig for chronic phase (CP) CML and accelerated phase (AP) CML patients who have achieved a major cytogenetic response.
Consider discontinuing Iclusig if response has not occurred by 3 months (90 days).
Iclusig may be taken with or without food. Tablets should be swallowed whole.
Dose Modifications for Myelosuppression
Suggested dose modifications for neutropenia (ANC* less than 1.0 × 109/L) and thrombocytopenia (platelet less than 50 × 109/L) that are unrelated to leukemia are summarized in Table 1.
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Dose Modifications for Non-Hematologic Adverse Reactions
If a serious non-hematologic adverse reaction occurs, modify the dose or interrupt treatment. Do not restart Iclusig in patients with arterial or venous occlusive reactions unless the potential benefit outweighs the risk of recurrent arterial or venous occlusions and the patient has no other treatment options. For serious reactions other than arterial or venous occlusion, do not restart Iclusig until the serious event has resolved or the potential benefit of resuming therapy is judged to outweigh the risk.
Hepatic Toxicity
Recommended modifications for hepatic toxicity are summarized in Table 2.
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Pancreatitis and Elevation of Lipase
Recommended modifications for pancreatic adverse reactions are summarized in Table 3.
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Dose Modification for Use With Strong CYP3A Inhibitors
The recommended dose should be reduced to 30 mg once daily when administering Iclusig with strong CYP3A inhibitors.
Dose Modification for Use in Patients with Hepatic Impairment
The recommended starting dose is 30 mg once daily in patients with hepatic impairment (Child-Pugh A, B, or C)
DOSAGE FORMS AND STRENGTHS
15 mg and 45 mg round, white, film-coated tablets.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ponatinib hydrochloride in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ponatinib hydrochloride in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ponatinib hydrochloride in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ponatinib hydrochloride in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ponatinib hydrochloride in pediatric patients.
Contraindications
None
Warnings
WARNING: VASCULAR OCCLUSION, HEART FAILURE, AND HEPATOTOXICITY
See full prescribing information for complete Boxed Warning.
Vascular Occlusion:
Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including 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 thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit-risk consideration should guide a decision to restart Iclusig therapy.
Heart Failure:
Heart failure, including fatalities, occurred in 8% 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.
Vascular Occlusion
Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can cause fatal and life-threatening vascular occlusion within 2 weeks of starting treatment. Iclusig can also cause recurrent or multi-site vascular occlusion.
In the dose-escalation (phase 1) clinical trial, 48% (31/65) of patients with CML or Ph+ ALL developed vascular occlusive events. The median time to onset of the first vascular occlusion event was 5 months. Iclusig can cause fatal and life-threatening vascular occlusion in patients treated at dose levels as low as 15 mg per day.
Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Vascular occlusion adverse events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia (see TABLE 4).
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Arterial Occlusion and Thrombosis
Arterial occlusion and thrombosis occurred in at least 20% (91/449) of Iclusig-treated patients with some patients experiencing events of more than one type. Patients have required revascularization procedures (cerebrovascular, coronary, and peripheral arterial) due to vascular occlusion from Iclusig.
Cardiac vascular occlusion, including fatal and life-threatening myocardial infarction and coronary artery occlusion has occurred in 12% (55/449) of Iclusig-treated patients. Patients have developed heart failure concurrent or subsequent to the myocardial ischemic event.
Cerebrovascular occlusion, including fatal stroke, has occurred in 6% (27/449) of Iclusig-treated patients. Iclusig can cause stenosis over multiple segments in major arterial vessels that supply the brain (e.g., carotid, vertebral, middle cerebral artery).
Peripheral arterial occlusive events, including fatal mesenteric artery occlusion and life-threatening peripheral arterial disease, have occurred in 8% (36/449) of Iclusig-treated patients. Patients have developed digital or distal extremity necrosis and have required amputations.
Clinicians should consider whether the benefits of Iclusig treatment are expected to exceed the risks of therapy. In patients suspected of developing arterial thrombotic events, interrupt or stop Iclusig. A benefit-risk consideration should guide a decision to restart Iclusig therapy. .
Venous Thromboembolism
Venous thromboembolic events occurred in 5% (23/449) of Iclusig-treated patients, including deep venous thrombosis (8 patients), pulmonary embolism (6 patients), superficial thrombophlebitis (3 patients), and retinal vein thrombosis (2 patients). Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Ponatinib hydrochloride in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ponatinib hydrochloride in the drug label.
