Iclusig ponatinib hydrochloride 30 mg Tablet, Film Coated, 30-count

1 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) ] .

2 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 )

2.1Recommended 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.

2.2Dosage 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 s…

3 DOSAGE FORMS AND STRENGTHS Tablets, film-coated: 10 mg of ponatinib: Oval, white to off-white, biconvex, debossed "NZ" on one side and plain on the other side 15 mg of ponatinib: Round, white, biconvex, debossed "A5" on one side and plain on the other side 30 mg of ponatinib: Round, white, biconvex, debossed "C7" on one side and plain on the other side 45 mg of ponatinib: Round, white, biconvex, debossed "AP4" on one side and plain on the other side Tablets : 10 mg, 15 mg, 30 mg, and 45 mg. ( 3 )

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Arterial Occlusive Events and Venous Thromboembolic Events Inform patients that serious arterial thromboses (including arterial stenosis sometimes requiring revascularization) and VTEs have occurred. Advise patients to immediately contact their healthcare provider with any symptoms suggestive of a blood clot such as chest pain, shortness of breath, weakness on one side of the body, speech problems, leg pain, or leg swelling [see Warnings and Precautions (5.1 , 5.2) ] .

Heart Failure and Cardiac Arrhythmias Inform patients of the possibility of heart failure, and abnormally slow or fast heart rates. Advise patients to contact their healthcare provider if they experience symptoms such as shortness of breath, chest pain, palpitations, dizziness, or fainting [see Warnings and Precautions (5.3 , 5.12) ] . Hepatotoxicity Inform patients of the possibility of developing liver function abnormalities and serious hepatotoxicity.

Advise patients to immediately contact their healthcare provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see Warnings and Precautions (5.4) ] . Hypertension Inform patients of the possibility of new or worsening of existing hypertension. Advise patients to contact their healthcare provider for elevated blood pressure or if symptoms of hypertension occur including confusion, headache, dizziness, chest pain, or shortness of breath [see Warnings and Precautions (5.5) ] .

Pancreatitis Inform patients of the possibility of developing pancreatitis that may be accompanied by nausea, vomiting, abdominal pain, or abdominal discomfort, and to promptly report these symptoms [see Warnings and Precautions (5.6) ] . Neuropathy Inform patients of the possibility of developing peripheral or cranial neuropathy while being treated with ICLUSIG. Advise patients to report symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness [see Warnings and Precautions (5.8) ] .

Ocular Toxicity Inform patients of the possibility of ocular toxicity while being treated with ICLUSIG. Advise patients to report symptoms of ocular toxicity, such as blurred vision, dry eye, or eye pain [see Warnings and Precautions (5.9) ] . Hemorrhage Inform patients of the possibility of serious bleeding and to immediately contact their healthcare provider with any signs or symptoms suggestive of hemorrhage such as unusual bleeding or easy bruising [see Warnings and Precautions (5.10) ] .

Fluid Retention Inform patients of the possibility of developing fluid retention and to contact their healthcare provider for symptoms such as leg swelling, abdominal swelling, weight gain, or shortness of breath [see Warnings and Precautions (5.11) ] . Myelosuppression Inform patients of the possibility of developing low blood cell counts; inform patients to report immediately should fever develop, particularly in association with any suggestion of infection [see Warnings and Precautions (5.13) ] . Tumor Lysis Syndrome Inform patients of the possibility of developing TLS and to immediately contact their healthcare provider for any signs or symptoms associated with TLS [see Warnings and Precautions (5.14) ] .

Advise patients to be adequately hydrated when taking ICLUSIG to reduce the risk of TLS. Reversible Posterior Leukoencephalopathy Syndrome (RPLS – also known as Posterior Reversible Encephalopathy Syndrome) Inform patients of the possibility of developing Reversible Posterior Leukoencephalopathy Syndrome while being treated with ICLUSIG. Advise patients to report symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances [see Warnings and Precautions (5.15) ] .

Impaired Wound Healing and Gastrointestinal Perforation Inform patients that impaired wound heal…

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 10/2025 MEDICATION GUIDE ICLUSIG ® (eye-CLUE-sig) (ponatinib) tablets What is the most important information I should know about ICLUSIG?

ICLUSIG can cause serious side effects, including: Blood clots or blockage in your blood vessels (arteries and veins). Blood clots or blockage in your blood vessels may lead to heart attack, stroke, or death. A blood clot or blockage in your blood vessels can prevent proper blood flow to your heart, brain, bowels (intestines), legs, eyes, and other parts of your body.

You may need emergency surgery or treatment in a hospital. Get medical help right away if you get any of the following symptoms: chest pain or pressure pain in your arms, legs, back, neck or jaw shortness of breath numbness or weakness on one side of your body leg swelling trouble talking headache dizziness severe stomach area pain decreased vision or loss of vision Blood clots or blockage in your blood vessels can happen in people with or without risk factors for heart and blood vessel disease, including people 50 years of age or younger.

The most common risk factors for these problems are a history of high blood pressure (hypertension), high cholesterol, and heart disease. Blood clots or blockages in your blood vessels happen more often in people as they get older, and in people with a history of decreased blood flow, high blood pressure, diabetes, or high cholesterol. Heart problems.

ICLUSIG can cause heart problems, including heart failure which can be serious and may lead to death. Heart failure means your heart does not pump blood well enough. ICLUSIG can also cause irregular, slow, or fast heartbeats and heart attack.

Your healthcare provider will check you for heart problems during your treatment with ICLUSIG. Get medical help right away if you get any of the following symptoms: shortness of breath, chest pain, fast or irregular heartbeats, dizziness, or feel faint. Liver problems.

ICLUSIG can cause liver problems, including liver failure, which can be severe and may lead to death. Your healthcare provider will do blood tests before and during your treatment with ICLUSIG to check for liver problems. Get medical help right away if you get any of these symptoms of liver problems during treatment: yellowing of your skin or the white part of your eyes dark "tea-colored" urine sleepiness loss of appetite bleeding or bruising See " What are the possible side effects of ICLUSIG? " for information about side effects.

What is ICLUSIG? ICLUSIG is a prescription medicine used to treat adults who have: Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) in combination with chemotherapy in newly diagnosed Ph+ ALL alone in adults with Ph+ ALL who cannot receive any other kinase inhibitor medicines or who have a specific type of abnormal gene (T315I-positive) Ph+ ALL Chronic Myeloid Leukemia (CML) chronic phase CML who did not tolerate or no longer benefit from treatment with at least 2 prior kinase inhibitor medicines accelerated phase or blast phase CML who cannot receive any other kinase inhibitor medicines a specific type of abnormal gene (T315I-positive) chronic phase, accelerated phase, or blast phase CML ICLUSIG is not for use to treat people with newly diagnosed chronic phase CML.

It is not known if ICLUSIG is safe and effective in children. Before you take ICLUSIG, tell your healthcare provider about all of your medical conditions, including if you: have a history of blood clots in your blood vessels (arteries or veins) have heart problems, including heart failure, irregular heartbeats, and QT prolongation have diabetes have a history of high cholesterol have liver problems have had inflammation of your pancreas (pancreatitis) have high blood pressure have bleeding problems plan to have surgery or have had a recent surgery.

You should stop taking ICLUSIG at least 1 week before planned surgery. See " What are the poss…