ICLUSIG- ponatinib hydrochloride tablet, film coated
ARIAD Pharmaceuticals, Inc.
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 (5.1).
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 (5.2).
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 (5.3).
Hepatotoxicity:
Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected (2.3, 5.4).
1 INDICATIONS AND USAGE
Iclusig (ponatinib) is a kinase inhibitor indicated for the:
Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
Treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
Limitations of use:
Iclusig is not indicated and is not recommended for the treatment of patients with newly diagnosed chronic phase CML [see Warnings and Precautions (5.7)].
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
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, in the phase 2 trial, 68% 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 patients with chronic phase (CP) CML and accelerated phase (AP) CML 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.
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I. In mice, treatment with ponatinib reduced the size of tumors expressing native or T315I mutant BCR-ABL when compared to controls.