Ponatinib

ICLUSIG ® is indicated for the treatment of adult patients with: Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Newly diagnosed Ph+ ALL in combination with chemotherapy. This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). As monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL. Chronic Myeloid Leukemia (CML) Chronic phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors. Accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated. T315I-positive CML (chronic phase, accelerated phase, or blast phase).

Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC 50 concentrations of 0.4 nM and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC 50 concentrations between 0.1 nM 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.

Recommended Dosage in Newly Diagnosed Ph+ ALL: Starting dose is 30 mg orally once daily in combination with chemotherapy, with a reduction to 15 mg once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction. Recommended Dosage in Monotherapy for Ph+ ALL for Whom No Other Kinase Inhibitors are Indicated or T315I-positive Ph+ ALL: Starting dose is 45 mg orally once daily. 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::ABL1 IS. Recommended Dosage in AP-CML and BP-CML: Starting dose is 45 mg orally once daily. Hepatic Impairment: See the Full Prescribing Information for dosage modifications for hepatic impairment. ICLUSIG may be taken with or without food.

None. None.

Boxed warning: Arterial occlusive events (AOEs), including fatalities, have occurred in ICLUSIG-treated patients. AOEs 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. Hypertension: Monitor blood pressure and manage hypertension as clinically indicated. Interrupt, dose reduce or stop ICLUSIG if hypertension is not medically controlled. Pancreatitis: 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: Monitor for symptoms of peripheral and cranial neuropathy.

The following clinically significant adverse reactions are described elsewhere in the labeling: Arterial Occlusive Events Venous Thromboembolic Events Heart Failure Hepatotoxicity Hypertension Pancreatitis Neuropathy Ocular Toxicity Hemorrhage Fluid Retention Cardiac Arrhythmias Myelosuppression Tumor Lysis Syndrome Reversible Posterior Leukoencephalopathy Syndrome Impaired Wound Healing and Gastrointestinal Perforation Most common adverse reactions (occurring in >20% of patients) are: ICLUSIG as a single agent: rash and related conditions, arthralgia, abdominal pain, fatigue, headache, constipation, hypertension, dry skin, hepatotoxicity, fluid retention and edema, pyrexia, pancreatitis/lipase elevation, nausea, hemorrhage, anemia, AOEs, and cardiac arrhythmias.

Strong CYP3A Inhibitors: Avoid coadministration or reduce ICLUSIG dose if coadministration cannot be avoided. Strong CYP3A Inducers: Avoid coadministration.

Store ICLUSIG tablets at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).