ponatinib 30 MG Oral Tablet [Iclusig]

INDICATIONS AND USAGE 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 [see Clinical Studies (14) ] . 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). ICLUSIG is a kinase inhibitor 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). ( 1 ) As monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL. ( 1 ) Chronic Myeloid Leukemia (CML) Chronic phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors. ( 1 ) Accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated. ( 1 ) T315I-positive CML (chronic phase, accelerated phase, or blast phase). ( 1 ) Limitations of Use : ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. ( 5.7 ) Limitations of Use : ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML [see Warnings and Precautions (5.7) ] .

DOSAGE AND ADMINISTRATION 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. ( 2.1 ) 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. ( 2.1 ) 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 . ( 2.1 ) Recommended Dosage in AP-CML and BP-CML : Starting dose is 45 mg orally once daily. ( 2.1 ) Hepatic Impairment : See the Full Prescribing Information for dosage modifications for hepatic impairment. ( 2.4 ) ICLUSIG may be taken with or without food. ( 2.1 ) 2.1 Recommended Dosage Newly Diagnosed Ph+ ALL The recommended starting dosage of ICLUSIG in combination with chemotherapy is 30 mg orally once daily with a reduction to 15 mg orally once daily upon achievement of MRD-negative (≤0.01% BCR::ABL1/ABL1) CR at the end of induction. Continue ICLUSIG in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity [see Clinical Studies (14) ] . For a description of dosing of agents administered in combination with ICLUSIG, [see Clinical Studies (14) ] . Monotherapy for Ph+ ALL for Whom No Other Kinase Inhibitors Are Indicated or T315I-positive Ph+ ALL The optimal dose of ICLUSIG has not been identified. The recommended starting dosage of ICLUSIG is 45 mg orally once daily. Continue ICLUSIG until loss of response or unacceptable toxicity. Consider discontinuing ICLUSIG if response has not occurred by 3 months. CP-CML The recommended starting dosage of ICLUSIG 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 and BP-CML 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. 2.2 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 Reaction Severity ICLUSIG Dosage Modifications 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 AOE: cardiovascular or cerebrovascular [see Warnings and Precautions (5.1) ] Grade 1 Interrupt ICLUSIG until resolved, then resume at same dose. Grade 2 Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence. Grade 3 or 4 Discontinue ICLUSIG. AOE: peripheral vascular and other or VTE [see Warnings and Precautions (5.1 , 5.2) ] Grade 1 Interrupt ICLUSIG until resolved, then resume at same dose. Grade 2 Interrupt 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 Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence. Grade 4 Discontinue ICLUSIG. Heart Failure [see Warnings and Precautions (5.3) ] Grade 2 or 3 Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence. Grade 4 Discontinue ICLUSIG. Hepatotoxicity [see Warnings and Precautions (5.4) ] AST or ALT greater than 3 times ULN Interrupt 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 ULN Discontinue ICLUSIG. Pancreatitis and Elevated Lipase [see Warnings and Precautions (5.6) ] Serum lipase greater than 1 to 1.5 times ULN Consider 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 pancreatitis Interrupt 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 asymptomatic Interrupt 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 ULN Discontinue ICLUSIG. Myelosuppression [see Warnings and Precautions (5.13) ] ANC less than 1 × 10 9 /L or Platelets less than 50 × 10 9 /L Interrupt ICLUSIG until ANC at least 1.5 × 10 9 /L and platelet at least 75 × 10 9 /L, then resume at same dose. If recurrence, interrupt ICLUSIG until resolution, then resume at next lower dose. Other Non-hematologic Adverse Reactions [see Warnings and Precautions (5.5 , 5.8 , 5.10 , 5.11 , 5.12) ] Grade 1 Interrupt ICLUSIG until resolved, then resume at same dose. Grade 2 Interrupt 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 4 Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose. Discontinue ICLUSIG if recurrence. Table 2: Recommended Dose Reductions for ICLUSIG for Adverse Reactions Dose Reduction Dosage for Patients with CP-CML Dosage for Patients with AP-CML, BP-CML, and Ph+ ALL Monotherapy Dosage for Patients with Newly Diagnosed Ph+ ALL First 30 mg orally once daily 30 mg orally once daily 15 mg orally once daily Second 15 mg orally once daily 15 mg orally once daily 10 mg orally once daily Third 10 mg orally once daily Permanently discontinue ICLUSIG in patients unable to tolerate 15 mg orally once daily. Permanently discontinue ICLUSIG in patients unable to tolerate 10 mg orally once daily. Subsequent Reduction Permanently discontinue ICLUSIG in patients unable to tolerate 10 mg orally once daily. 2.3 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 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Table 3: Recommended ICLUSIG Dosage for Coadministration of Strong CYP3A Inhibitors Current ICLUSIG Dosage Recommended ICLUSIG Dosage with a Strong CYP3A Inhibitor 45 mg orally once daily 30 mg orally once daily 30 mg orally once daily 15 mg orally once daily 15 mg orally once daily 10 mg orally once daily 10 mg orally once daily Avoid coadministration of ICLUSIG with a strong CYP3A inhibitor 2.4 Dosage for Patients with Hepatic Impairment For patients with CP-CML, AP-CML, BP-CML, and Ph+ ALL

WARNINGS AND PRECAUTIONS Hypertension : Monitor blood pressure and manage hypertension as clinically indicated. Interrupt, dose reduce or stop ICLUSIG if hypertension is not medically controlled. ( 2.2 , 5.5 ) 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. ( 2.2 , 5.6 ) Neuropathy : Monitor for symptoms of peripheral and cranial neuropathy. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. ( 2.2 , 5.8 ) Ocular Toxicity : Conduct comprehensive eye exams at baseline and periodically during treatment. ( 5.9 ) Hemorrhage : Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. ( 2.2 , 5.10 ) Fluid Retention : Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. ( 2.2 , 5.11 ) Cardiac Arrhythmias : Monitor for signs or symptoms of arrhythmias and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. ( 5.12 ) Myelosuppression : Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 × 10 9 /L or platelets less than 50 × 10 9 /L, interrupt ICLUSIG until ANC at least 1.5 × 10 9 /L and platelets at least 75 × 10 9 /L, then resume at same or reduced dose. ( 2.2 , 5.13 ) Tumor Lysis Syndrome : Ensure adequate hydration and correct elevated uric acid levels prior to initiating ICLUSIG. ( 5.14 ) Reversible Posterior Leukoencephalopathy Syndrome (RPLS) : Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG in patients upon resolution of RPLS is unknown. ( 5.15 ) Impaired Wound Healing and Gastrointestinal Perforation : Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. ( 5.16 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.17 , 8.1 , 8.3 ) 5.1 Arterial Occlusive Events Arterial occlusive events (AOEs), including fatalities, occurred in patients who received ICLUSIG [see Adverse Reactions (6.1) ] . In PhALLCON, 6% of 163 patients experienced AOEs, of which 3.1%, 1.8%, and 1.2% experienced cardiovascular, cerebrovascular, and peripheral vascular AOEs, respectively. The median time to onset of the first AOE was 11.3 months (range: 8 days to 2.8 years). Grade 3 or 4 AOEs occurred in 3.7% of patients; the most frequent Grade 3 or 4 AOEs were myocardial infarction (1.2%), peripheral arterial occlusive disease (1.2%), angina pectoris and cerebrovascular accident (0.6% each). Fatal AOE of sudden death occurred in 1 patient (0.6%). AOEs were more frequent with increasing age [see Use in Specific Populations (8.5) ] . In PhALLCON, patients with uncontrolled hypertension, hypertriglyceridemia, or diabetes were excluded. Patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, venous thromboembolism, clinically significant atrial/ventricular tachyarrhythmias, unstable angina, or congestive heart failure within the 6 months prior to the first dose of ICLUSIG, were also excluded. In OPTIC, of the 94 patients who received a starting dose of 45 mg (45 mg → 15 mg), 18% experienced AOEs, of which 11%, 4.3%, and 3.2% experienced cardiovascular, cerebrovascular or peripheral vascular AOEs, respectively. The median time to onset of the first cardiovascular, cerebrovascular, or peripheral vascular event was 9.4 months (range: 12 days to 5.7 years), 11.7 months (range: 15 days to 1.6 years), and 6.3 months (range: 23 days to 3.6 years), respectively. Grade 3 or 4 AOEs occurred in 7% of patients; the most frequent Grade 3 or 4 AOEs were myocardial infarction, acute coronary syndrome, arterial thrombosis, ischemic stroke, ischemic cerebral infarction, subclavian artery stenosis and unstable angina (1.1% each). Fatal AOEs occurred in 4 patients (4.3%); including sudden death (2.1%), myocardial ischemia (1.1%) and myocardial infarction (1.1%). AOEs were more frequent with increasing age [see Use in Specific Populations (8.5) ] . In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, congestive heart failure, venous thromboembolism, or clinically significant atrial/ventricular arrhythmias, were excluded. In PACE, 26% of 449 patients experienced AOEs, of which 15%, 7%, and 11% experienced cardiovascular, cerebrovascular, and peripheral vascular AOEs, respectively. Some patients experienced recurrent or multisite vascular occlusion. The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular AOEs was 1 year (range: 1 day to 4.1 years), 1.4 years (range: 2 days to 4.5 years), and 2 years (range: 10 days to 4.9 years), respectively. Grade 3 or 4 AOEs occurred in 14% of patients; the most frequent Grade 3 or 4 AOEs were peripheral arterial occlusive disease (3.1%), myocardial infarction (2%), coronary artery disease (1.6%), and cerebral infarction (1.6%). Fatal AOEs occurred in 9 patients (2%); the most frequent fatal AOE was cardiac arrest (0.9%). In PACE, fatal and life-threatening AOEs occurred within 2 weeks of starting treatment at 45 mg, and 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 AOEs. AOEs were more frequent with increasing age [see Use in Specific Populations (8.5) ] and in patients with history of ischemia, hypertension, diabetes, or hypercholesterolemia. The most common risk factors in patients with AOEs were history of hypertension (67%; 77/115), hypercholesterolemia (59%; 68/115), and non-ischemic cardiac disease (43%; 49/115). In PACE, patients developed heart failure concurrent or subsequent to a myocardial ischemic event [see Warnings and Precautions (5.3) ] . Patients required revascularization procedures (coronary, cerebrovascular, and peripheral arterial). ICLUSIG caused stenosis over multiple segments in major arterial vessels that supply the brain (e.g., carotid, vertebral, middle cerebral artery). Patients developed digital or distal extremity necrosis and required amputations. Renal artery stenosis associated with worsening, labile or treatment-resistant hypertension occurred in some ICLUSIG-treated patients [see Warnings and Precautions (5.5) ] . In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease, including any history of clinically significant atrial/ventricular arrhythmias or history of myocardial infarction, unstable angina, or congestive heart failure within the 3 months prior to the first dose of ICLUSIG, were excluded [see Adverse Reactions (6.1) ] . Consider whether the benefits of ICLUSIG are expected to exceed the risks. Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity [see Dosage and Administration (2.2) ] . Consider benefit-risk to guide a decision to restart ICLUSIG. 5.2 Venous Thromboembolic Events Serious or severe VTEs have occurred in patients who r

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action 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.