ICLUSIG

Ponatinib is a kinase inhibitor.

The chemical name for ponatinib hydrochloride is 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide hydrochloride.

The molecular formula is

C 29 H 28 ClF 3 N 6 O which corresponds to a formula weight of 569.02 g/mol.

Its structure is shown below

Ponatinib HCl is an off-white to yellow powder with pKa of 2.77 and 7.8.

The solubility of ponatinib in pH 1.7, 2.7, and 7.5 buffers is 7790 mcg/mL, 3.44 mcg/mL, and 0.16 mcg/mL, respectively, indicating a decrease in solubility with increasing pH.

Each tablet for oral administration contains 10 mg, 15 mg, 30 mg or 45 mg of ponatinib equivalent to 10.68 mg, 16.03 mg, 32.05 mg, and 48.08 mg of ponatinib hydrochloride with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type B), colloidal silicon dioxide, magnesium stearate and a tablet coating.

The tablet coating consists of talc, polyethylene glycol, polyvinyl alcohol, and titanium dioxide.

The use of the

Pontenepe drug includes: chronic pulmonary abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal abdominal absa (Philadelphia chromosomesa) (Posive), where the buntain pulse abalaesis can be used to treat acute ly lymolecinal abdominal abdominate (T315I) and the rehyd of abala.

The use of the puntainep puppets is a combination of warnings known as the long-term pain-infestation (Black Box Warnings), which are the most severe of warnings that can be attached to a puppet, and include: the use of the pupatenepine pupamine can increase the risk of infection with arterial or intestinal infections, which may result in fatal cases of ingestion of the heart muscle, strokes, or the narrowing of blood artery in the brain, and other cases that may require the re-infusion of blood vessels (the re-inducing period), which requires monitoring of the development of the symptoms of these cases, and the temporary or permanent use of the pupaineplyteplysis based on the patient's condition.

The use of the pupaineplyplyplyplyplyatomatics, which may result in the use of the pupatomatical, the use of the papatomatics, the use of the papa, the patomaticatomatics, the pupapolyapoly.

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. 12.2 Pharmacodynamics In PACE, the dose intensity-safety relationship indicated that there are significant increases in Grade ≥3 adverse reactions (hypertension, thrombocytopenia, pancreatitis, neutropenia, rash, ALT increase, AST increase, lipase increase, myelosuppression) over the dose range of 15 mg to 45 mg. In addition to dose, increased age and history of ischemia, hypertension, diabetes, or hypercholesterolemia were also contributory factors to a higher incidence of AOEs.

In OPTIC, an exposure-response relationship between ponatinib exposure and molecular response rate at 12 months was observed.

A relationship between higher ponatinib exposures and higher incidence of adverse reactions, including thrombocytopenia (Grade ≥3) and AOEs, was observed.

In vitro, there was no significant inhibition of platelet aggregation with ponatinib at concentrations seen clinically and up to 0.7 mcg/mL (1.23 μM).

Cardiac Electrophysiology The QT interval prolongation potential of ICLUSIG was assessed in 39 patients with cancer who received ICLUSIG 30 mg, 45 mg, or 60 mg (0.67 to 1.33 times the approved maximum recommended starting dose) orally once daily.

No large mean increase (i.e., >20 msec) in QTc interval was detected. 12.3 Pharmacokinetics Ponatinib administered to patients with cancer exhibited approximately dose proportional increases in both steady-state C max and AUC over the dose range of 2 mg to 60 mg (0.04 to 1.33 times the approved maximum recommended starting dose).

The mean (CV%) C max and AUC of ICLUSIG 45 mg orally once daily at presumed steady-state in patients with advanced hematologic malignancies were 73 ng/mL (74%) and 1253 ng∙hr/mL (73%), respectively.

The mean (CV%) C max and AUC of ICLUSIG 30 mg orally once daily at presumed steady-state in patients with advanced hematologic malignancies were 65 ng/mL (28%) and 1080 ng∙hr/mL (29%), respectively.

Exposure increased by approximately 90% (median) [range: 20% to 440%] between the first dose and presumed steady-state.

The absolute bioavailability of ponatinib is unknown.

Peak concentrations of ponatinib are observed within 6 hours after ICLUSIG oral administration.

Following ingestion of either a high-fat (approximately to 1000 calories with approximately 150, 250, and to 600 calories derived from protein, carbohydrate, and fat, respectively) or low-fat meal (approximately 547 calories with approximately and 63 calories derived from protein, carbohydrate, and fat, respectively) by 22 healthy volunteers, plasma ponatinib exposures (AUC and C max ) were not different when compared to fasting conditions.

Ponatinib is greater than 99% bound to plasma proteins in vitro.

There was no plasma protein binding displacement of ponatinib (145 nM) in vitro by other highly protein bound medications (ibuprofen, nifedipine, propranolol, salicylic acid, and warfarin).

The mean (CV%) apparent steady-state volume of distribution is 1,223 liters (102%) following oral administration of ICLUSIG 45 mg orally once daily for 28 days in patients with cancer.

The mean (range) terminal elimination half-life of ponatinib was approximately 24 (12 to 66) hours following ICLUSIG 45 mg orally once daily for 28 days in patients with cancer.

At least 64% of a dose undergoes Phase I and Phase II metabolism.

CYP3A4 and to a lesser extent CYP2C8, CYP2D6 and CYP3A5 are involved in the Phase I metabolism of ponatinib in vitro.

Ponatinib is also metabolized by esterases and/or amidases.

Following a single oral dose of radiolabeled ponatinib, approximately 87% of the radioactive dose was recovered in the feces and approximately 5% in the urine.

No clinically significant differences in the pharmacokinetics of ponatinib were observed based on age (19 to 85 years), body weight (41 to 152 kg), and mild to moderate renal impairment (creatinine clearance to 89 mL/min, estimated by the Cockcroft-Gault equation).

ICLUSIG has not been studied in patients with severe renal impairment.

Although renal excretion is not a major route of ponatinib elimination, the potential for severe renal impairment to affect hepatic elimination has not been determined.

A single 30 mg oral dose of ICLUSIG was administered to subjects with normal hepatic function and to subjects with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment.

Compared to subjects with normal hepatic function, there was no trend of increased ponatinib exposure in subjects with hepatic impairment.

There was an increased incidence of adverse reactions (e.g., gastrointestinal disorders, including a case of severe pancreatitis) in subjects with hepatic impairment compared to subjects with normal hepatic function.

Drug Interaction Studies Clinical Studies Strong

CYP3A Inhibitors: Coadministration of ponatinib with multiple doses of ketoconazole (strong CYP3A inhibitor) increased the ponatinib AUC 0-INF by 78% and C max by 47%.

CYP3A Inducers: Coadministration of ponatinib with multiple doses of rifampin (strong CYP3A inducer) decreased the ponatinib AUC 0-INF by 62% and C max by 42%.

Coadministration of ponatinib with multiple doses of lansoprazole (proton pump inhibitor) decreased the ponatinib AUC 0-INF by 6% and C max by 25%.

Ponatinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A, or CYP2D6 and does not induce CYP1A2, CYP2B6, or CYP3A.

Ponatinib is a weak substrate for both P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Ponatinib is not a substrate for organic anion transporting polypeptides (OATP1B1, OATP1B3) and organic cation transporter 1 (OCT1).

Ponatinib inhibits

P-gp, BCRP, and bile salt export pump (BSEP).

Ponatinib does not inhibit

OATP1B1, OATP1B3, OCT1, OCT2, or the organic anion transporters OAT1 and OAT3.

Pontinib is a drug used to treat certain cases of leukemia.

The buntatinep process mechanism belongs to a group of medicines known as kinastase inhibitors, as it discourages certain types of enzymes that have certain genetic distortions, reducing the tumors associated with these enzymes.

Do you have questions on this subject? Ask Sina, artificial intelligence to answer all your medical questions.

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.

The most common

Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.

ICLUSIG in combination with chemotherapy: hepatotoxicity, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.

Grade 3 or 4 laboratory abnormalities (>20%) are decreased white blood cell count, decreased neutrophil cell count, decreased platelet count, decreased lymphocyte cell count, decreased hemoglobin, increased lipase, and increased alanine aminotransferase.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most common adverse reactions identified in the Highlights of the Prescribing Information are based on two safety populations.

The first is from a pooled safety population of 543 patients with CML or resistant or intolerant Ph+ ALL (OPTIC and PACE studies) who received ICLUSIG as a single agent at a starting dose of 45 mg orally once daily.

In this pooled safety population, the most common (>20%) adverse reactions were 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.

Grade 3 or 4 laboratory abnormalities (>20%) were platelet count decreased, neutrophil cell count decreased, and white blood cell decreased.

The second safety population is from 163 patients with newly diagnosed Ph+ ALL (PhALLCON study) who received ICLUSIG in combination with chemotherapy at a starting dose of 30 mg orally once daily.

The most common adverse reactions (>20%) included hepatotoxicity, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia, and cardiac arrhythmias.

Grade 3 or 4 laboratory abnormalities (>20%) included decreased white blood cell count, decreased neutrophil cell count, decreased platelet count, decreased lymphocyte cell count, decreased hemoglobin, increased lipase, and increased ALT.

Ph+ ALL The safety of ICLUSIG was evaluated in PhALLCON, a randomized, active-controlled, multicenter trial conducted in patients with newly diagnosed Ph+ ALL.

Patients received

ICLUSIG (n=163) or imatinib 600 mg (n=81) in combination with reduced-intensity chemotherapy followed by continued treatment with ICLUSIG or imatinib as a single agent (imatinib in combination with chemotherapy is not an approved regimen in adult patients).

In the

ICLUSIG arm, patients received a starting dosage of ICLUSIG 30 mg orally once daily in combination with chemotherapy, with a reduction to 15 mg orally once daily upon achievement of MRD-negative CR at the end of induction.

The median duration of exposure was 9.0 months (range: <1 month to 4.2 years) in the ICLUSIG arm and 5.2 months (range: <1 month to 4.4 years) in the imatinib arm.

Patients with uncontrolled hypertension, hypertriglyceridemia, or diabetes and 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, history of myocardial infarction, unstable angina, or congestive heart failure within the 6 months prior to the first dose of ICLUSIG, were excluded.

Serious adverse reactions occurred in 63% of patients receiving ICLUSIG in combination with chemotherapy.

Serious adverse reactions in >2% of patients included febrile neutropenia (18%), pyrexia (6%), thrombocytopenia (4.3%), sepsis (3.7%), septic shock (3.7%), anemia (2.5%), hemorrhage (2.5%), neutropenia (2.5%), pancreatitis (2.5%), peripheral neuropathy (2.5%), pneumonia (2.5%) and acute kidney injury (2.5%).

Fatal adverse reactions occurred in 6% of patients who received ICLUSIG in combination with chemotherapy, including sepsis (3.7%), sudden death, pneumonitis and respiratory failure (0.6%, each).

Permanent discontinuation of

ICLUSIG due to adverse reactions occurred in 13% of patients.

Adverse reactions resulting in permanent discontinuation of ICLUSIG in >2% of patients included arterial occlusive events and sepsis.

Dosage modifications (dose interruption or reduction) of ICLUSIG due to adverse reactions occurred in 71% of patients.

Adverse reactions leading to dose interruption or reduction of ICLUSIG in >5% of patients included increased ALT, neutropenia, increased lipase, thrombocytopenia, increased AST, febrile neutropenia, and abdominal pain.

Table 4 summarizes the adverse reactions in patients receiving ICLUSIG or imatinib in combination with chemotherapy in PhALLCON.

Table 4: Adverse Reactions (>10%) in Patients with Newly Diagnosed Ph+ ALL in PhALLCON Adverse Reaction ICLUSIG 30 mg → 15 mg with Chemotherapy (n = 163) Imatinib 600 mg with Chemotherapy (n = 81) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Graded using CTCAE v5.0 Hepatobiliary.

Disorders Hepatotoxicity 66 30 57 14 Musculoskeletal and Connective Tissue.

Disorders Arthralgia Includes arthralgia, arthritis, back pain, flank pain, intervertebral disc degeneration, joint swelling, osteoarthritis, neck pain, pain, pain in extremity, pain of skin, sciatica, spinal pain, tendonitis, and tenosynovitis. 47 4.3 35 1.2 Myalgia 13 1.2 10 1.2 Nervous System.

Disorders Headache 45 1.8 43 1.2 Neuropathy peripheral 33 1.2 24 1.2 Paresthesia 22 0 10 0 Peripheral sensory neuropathy 12 0 12 0 Skin and Subcutaneous Tissue.

Disorders Rash and related conditions 47 1.2 33 1.2 Gastrointestinal.

Disorders Abdominal pain Includes abdominal discomfort, abdominal distension, abdominal pain, abdominal pain lower, abdominal pain upper, chronic gastritis, colitis, enteritis, enterocolitis, gastric ulcer, gastritis, gastroenteritis, gastrointestinal pain, gastroesophageal reflux disease, and helicobacter gastritis. 43 4.9 28 0 Constipation 41 0.6 21 1.2 Nausea 37 3.1 52 7 Oral mucositis 35 4.9 30 10 Pancreatitis/lipase elevation 34 15 37 20 Vomiting 24 1.2 40 2.5 Diarrhea 20 0 35 2.5 General.

Disorders Pyrexia 44 4.3 26 2.5 Fatigue or asthenia 40 2.5 38 3.7 Fluid retention and edema 24 0.6 48 3.7 Vascular.

Disorders Hypertension 34 14 15 7 Hemorrhage 31 1.8 30 7 Venous thromboembolic events 12 3.1 10 2.5 Blood and Lymphatic System.

Disorders Febrile neutropenia 28 25 22 20 Metabolism and Nutrition.

Disorders Impaired glucose tolerance 20 4.9 20 9 Hyperlipidemia 16 1.2 15 1.2 Decreased appetite 10 0 19 3.7 Cardiac.

Disorders Cardiac arrhythmias 22 2.5 17 6.

Infections Sepsis Includes abdominal sepsis, bacteremia, bacterial sepsis, device-related sepsis, escherichia bacteremia, fungemia, klebsiella bacteremia, klebsiella sepsis, neutropenic sepsis, pseudomonal sepsis, sepsis, septic shock, staphylococcal bacteremia, staphylococcal sepsis, streptococcal bacteremia, and urosepsis. 17 12 15 11 Pneumonia 11 7 11 6 Respiratory, Thoracic, and Mediastinal.

Disorders Cough 17 0 6 0 Dyspnea 13 1.2 4.9 2.5 Clinically relevant adverse reactions in ≤10% of patients receiving ICLUSIG with chemotherapy: urinary tract infection (10%), arterial occlusive events (6%), cardiac failure (6%), and acute kidney injury (4.3%).

Table 5 summarizes the laboratory abnormalities in PhALLCON for patients who received ICLUSIG or imatinib in combination with chemotherapy.

Table 5: Select Laboratory Abnormalities (≥20%) that Worsened from Baseline in Patients with Newly Diagnosed Ph+ ALL in PhALLCON Laboratory Abnormality ICLUSIG 30 mg → 15 mg with Chemotherapy (n = 163) Imatinib 600 mg with Chemotherapy (n = 81) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) ALT = alanine aminotransferase, AST = aspartate aminotransferase Graded using CTCAE v5.0 Hematologic Laboratory Tests White blood cell decreased 79 71 78 70 Lymphocyte cell count decreased 77 61 94 89 Neutrophil cell count decreased 66 63 57 53 Platelet count decreased 65 62 64 53 Hemoglobin decreased 53 38 59 49 Liver Function Tests ALT increased 69 21 62 7 AST increased 53 7 48 6 Alkaline phosphatase increased 44 1.2 24 0 Total bilirubin increased 25 0.6 24 0 Direct bilirubin increased 24 4.3 24 1.2 Pancreatic Enzymes Lipase increased 60 24 78 38 Amylase increased 25 6 35 7 Chemistry Calcium decreased 67 3.1 69 4.9 Phosphate decreased 58 16 85 36 Potassium decreased 44 10 74 25 Albumin decreased 42 1.8 56 0 Glucose increased 34 2.5 38 2.5 Creatinine increased 34 3.7 48 4.9 Sodium decreased 32 3.1 35 3.7 Potassium increased 31 3.7 12 0 Magnesium decreased 15 0.6 31 2.5 Previously Treated CP-CML The safety of ICLUSIG was evaluated in OPTIC.

Patients received one of three starting doses of ICLUSIG: 45 mg orally once daily (n=94), 30 mg orally once daily (n=94), or 15 mg orally once daily (n=94).

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.

Only the safety information for the recommended starting dosage (45 mg) is described below.

Patients who received a starting dose of ICLUSIG 45 mg orally once daily had a mandatory dose reduction to 15 mg once daily upon achievement of ≤1% BCR::ABL1 IS.

Of these patients, 76% were exposed for 1 year or longer, 59% were exposed for two years or longer and 43% were exposed to five years or longer.

The median time to the response-based dose reduction to 15 mg was 6.4 months (range: 3.1 months to 1.8 years).

Serious adverse reactions occurred in 40%.

Overdoses with

ICLUSIG were reported in clinical trials.

One patient was estimated to have been administered 540 mg via nasogastric tube.

Two hours after the overdosage, the patient had an uncorrected QT interval of 520 ms.

Subsequent ECGs showed normal sinus rhythm with uncorrected QT intervals of 480 ms and 400 ms.

The patient died 9 days after the overdosage from pneumonia and sepsis.

Another patient self-administered 165 mg on Cycle 1 Day 2.

The patient experienced fatigue and non-cardiac chest pain on Day 3.

Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and a moderate pericardial effusion.

In the event of an overdosage, stop ICLUSIG, observe the patient and provide supportive treatment as appropriate.

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.

Starting dose is 45 mg orally once daily with a reduction to 15 mg once daily upon achievement of ≤1% BCR::ABL1 IS.

Starting dose is 45 mg orally once daily.

See the Full Prescribing Information for dosage modifications for hepatic impairment.

ICLUSIG may be taken with or without food. 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.

ICLUSIG in combination with chemotherapy for up to 20 cycles until loss of response or unacceptable toxicity.

For a description of dosing of agents administered in combination with ICLUSIG, .

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.

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.

ICLUSIG until loss of response at the re-escalated dose or unacceptable toxicity.

ICLUSIG if hematologic response has not occurred by 3 months.

AP-CML and BP-CML The optimal dose of ICLUSIG has not been identified.

Consider reducing the dose of

ICLUSIG for patients with accelerated phase (AP) CML who have achieved a major cytogenetic response.

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 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 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.

ICLUSIG if recurrence.

Grade 3 or 4 Discontinue ICLUSIG.

AOE: peripheral vascular and other or VTE 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.

Grade 4 Discontinue ICLUSIG.

Grade 2 or 3 Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.

Hepatotoxicity 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.

Serum lipase greater than 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 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.

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.

Grade 1 Interrupt ICLUSIG until resolved, then resume at same dose.

Grade 3 or 4 Interrupt ICLUSIG until Grade 0 or 1, then resume at next lower dose.

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 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 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 receiving monotherapy, 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).

For patients with newly diagnosed

Ph+ ALL, no dosage adjustment is recommended when administering ICLUSIG to patients with mild hepatic impairment (Child-Pugh A).

Closely monitor patients with moderate or severe hepatic impairment (Child-Pugh B or C) and modify the ICLUSIG dosage in the event of adverse reactions.

tablets are available in the following configurations.

Presentation 10 mg 63020-536-30 oval, white to off-white, biconvex film-coated tablets with debossed "NZ" on one side and plain on the other side 30 tablets in a wide-mouth white high density polyethylene (HDPE) bottle with a desiccant canister and induction sealed child resistant closure. 15 mg 63020-535-30 round, white, biconvex film-coated tablets with debossed "A5" on one side and plain on the other side 30 tablets in a wide-mouth white high density polyethylene (HDPE) bottle with a desiccant canister and induction sealed child resistant closure. 63020-535-60 60 tablets in a wide-mouth white high density polyethylene (HDPE) bottle with a desiccant canister and induction sealed child resistant closure. 30 mg 63020-533-30 round, white, biconvex film-coated tablets with debossed "C7" on one side and plain on the other side 30 tablets in a wide-mouth white high density polyethylene (HDPE) bottle with a desiccant canister and induction sealed child resistant closure. 45 mg 63020-534-30 round, white, biconvex film-coated tablets with debossed "AP4" on one side and plain on the other side 30 tablets in a wide-mouth white high density polyethylene (HDPE) bottle with a desiccant canister and induction sealed child resistant closure.

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) .

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) .

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.

In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the maximum recommended human dose of 45 mg/day.

Advise pregnant women of the potential risk to a fetus.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Ponatinib was studied for effects on embryo-fetal development in pregnant rats given oral doses of 0.3 mg/kg/day, 1 mg/kg/day, and 3 mg/kg/day during organogenesis (25 rats per group).

At the maternally toxic dose of 3 mg/kg/day (equivalent to the AUC in patients receiving the maximum recommended dose of 45 mg/day), ponatinib caused embryo-fetal toxicity as shown by increased resorptions, reduced body weight, external alterations, multiple soft tissue and skeletal alterations, and reduced ossification.

Embryo-fetal toxicities also were observed at 1 mg/kg/day (approximately 24% the AUC in patients receiving the maximum recommended dose of 45 mg/day) and involved multiple fetal soft tissue and skeletal alterations, including reduced ossification.

Safety and effectiveness of

ICLUSIG have not been established in pediatric patients.

A juvenile toxicity study in 15 day old rats was conducted with daily oral gavage administration of ponatinib at 0.75 mg/kg/day, 1.5 mg/kg/day, or 3 mg/kg/day for 21 days.

There were no adverse effects of ponatinib on juvenile rat developmental parameters (vaginal opening, preputial separation or bone measurements) observed in this study.

Once daily oral administration of 3 mg/kg/day ponatinib to juvenile rats beginning on Day 15 postpartum (pp) resulted in mortality related to inflammatory effects after to 7 days following initiation of treatment.

The dose of 3 mg/kg/day is approximately 0.32 times the maximum recommended human dose of 45 mg/day on a mg/m 2 basis for a child.

Of the 163 patients with Ph+ALL who received ICLUSIG in PhALLCON, 21% were 65 years and older and 7% were 75 years and older.

Overall, no differences in efficacy of ICLUSIG were observed between patients 65 years of age or older compared to younger patients.

AOEs occurred in 21% (7/34) of patients 65 years and older and 2.3% (3/129) of patients less than 65 years of age.

Of the 94 patients with CP-CML who received ICLUSIG at a starting dose of 45 mg in OPTIC, 17% were 65 years and older and 2.1% were 75 years and older.

Patients aged 65 years and older had a lower ≤1% BCR::ABL1 IS rate at 12 months (27%) than patients less than 65 years of age (47%).

By 60 months, patients aged 65 years and older had a ≤1% BCR::ABL1 IS rate of 40% and patients less than 65 years of age had a rate of 64%.

AOEs occurred in 38% (6/16) of patients 65 years and older and 14% (11/78) of patients less than 65 years of age.

Of the 449 patients who received ICLUSIG in PACE, 35% were 65 years and older and 8% were 75 years and older.

In patients with

CP-CML, patients aged 65 years and older had a lower major cytogenetic response rate (40%) as compared with patients less than 65 years of age (65%).

AP-CML, BP-CML, and Ph+ ALL, patients aged 65 years and older had a similar hematologic response rate (45%) as compared with patients less than 65 years of age (44%).

AOEs occurred in 35% (54/155) of patients 65 years and older and in 21% (61/294) of patients less than 65 years of age.

Patients aged 65 years or older are more likely to experience adverse reactions including vascular occlusion, decreased platelet count, peripheral edema, increased lipase, dyspnea, asthenia, muscle spasms, and decreased appetite.

In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.