Iclusig

WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITY

BOXED WARNING SECTION

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

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).

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

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

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

None.

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

The following clinically significant adverse reactions are described elsewhere in the labeling: Arterial Occlusive Events [see Warnings and Precautions (5.1) ] Venous Thromboembolic Events [see Warnings and Precautions (5.2) ] Heart Failure [see Warnings and Precautions (5.3) ] Hepatotoxicity [see Warnings and Precautions (5.4) ] Hypertension [see Warnings and Precautions (5.5) ] Pancreatitis [see Warnings and Precautions (5.6) ] Neuropathy [see Warnings and Precautions (5.8) ] Ocular Toxicity [see Warnings and Precautions (5.9) ] Hemorrhage [see Warnings and Precautions (5.10) ] Fluid Retention [see Warnings and Precautions (5.11) ] Cardiac Arrhythmias [see Warnings and Precautions (5.12) ] Myelosuppression [see Warnings and Precautions (5.13) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.14) ] Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.15) ] Impaired Wound Healing and Gastrointestinal Perforation [see Warnings and Precautions (5.16) ]

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

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.

11 DESCRIPTION

DESCRIPTION SECTION

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.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

ICLUSIG tablets are available in the following configurations. Strength NDC Number Description 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.

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

SPL UNCLASSIFIED SECTION

SPL UNCLASSIFIED SECTION

Distributed by: Takeda Pharmaceuticals America, Inc. Cambridge, MA 02142 ICLUSIG and are registered trademarks of ARIAD Pharmaceuticals, Inc. TAKEDA and are registered trademarks of Takeda Pharmaceutical Company Limited. ©2025 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved. ICL348 R12

SPL MEDGUIDE SECTION

SPL MEDGUIDE SECTION

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 possible side effects of ICLUSIG? " are lactose (milk sugar) intolerant. ICLUSIG tablets contain lactose. eat grapefruit or drink grapefruit juice. See " How should I take ICLUSIG? " are pregnant or plan to become pregnant. ICLUSIG can harm your unborn baby. Your healthcare provider will do a pregnancy test before you start taking ICLUSIG. For females who can become pregnant: Use an effective form of birth control during treatment and for 3 weeks after your last dose of ICLUSIG. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with ICLUSIG. ICLUSIG may affect your ability to have children. Tell your healthcare provider if this is a concern for you. are breastfeeding or plan to breastfeed. It is not known if ICLUSIG passes into your breast milk. Do not breastfeed during treatment and for 1 week after your last dose of ICLUSIG. Tell your healthcare provider about all the medicines you take, including prescription medicines and over-the-counter medicines, vitamins, and herbal supplements. ICLUSIG and other medicines may affect each other causing side effects. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I take ICLUSIG? Take ICLUSIG exactly as your healthcare provider tells you to take it. Do not change your dose or stop taking ICLUSIG unless your healthcare provider tells you. Swallow ICLUSIG tablets whole. Do not crush, break, cut, chew or dissolve ICLUSIG tablets. Take ICLUSIG with or without food. Do not eat grapefruit or drink grapefruit juice during treatment with ICLUSIG. If you miss a dose of ICLUSIG, take your next dose at your regularly scheduled time the next day. Do not take 2 doses at the same time to make up for a missed dose. If you take too much ICLUSIG, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of ICLUSIG? ICLUSIG may cause serious side effects, including: See " What is the most important information I should know about ICLUSIG? " High blood pressure (hypertension). High blood pressure is common during treatment with ICLUSIG and can also be serious or severe. ICLUSIG can cause new or worsening high blood pressure. Your blood pressure should be checked regularly, and any high blood pressure should be treated during treatment with ICLUSIG. Tell your healthcare provider right away if you get confusion, headaches, dizziness, chest pain or shortness of breath. Inflammation of the pancreas (pancreatitis). Pancreatitis is common during treatment with ICLUSIG and can also be serious or severe. Tell your healthcare provider right away if you get any of the following symptoms: sudden stomach-area pain or discomfort, nausea, and vomiting. Your healthcare provider should do blood tests to check for pancreatitis during treatment with ICLUSIG. Neuropathy. ICLUSIG may cause damage to the nerves in your arms, brain, hands, legs, or feet (neuropathy). Tell your healthcare provider right away if you get any of these symptoms during treatment with ICLUSIG: muscle weakness, tingling, burning, pain, discomfort or loss of feeling in your hands and feet double vision and other problems with eyesight, trouble moving the eye, drooping of part of the face, sagging or drooping eyelids, or change in taste Eye problems. Serious eye problems that can lead to blindness or blurred vision may happen with ICLUSIG. Tell your healthcare provider right away if you get any of the following symptoms: bleeding in the eye, perceived flashes of light, light sensitivity, floaters, blurred vision, dry, inflamed, swollen, or itchy eyes, or eye pain. Your healthcare provider will monitor your vision before and during your treatment with ICLUSIG. Bleeding. Bleeding is common during treatment with ICLUSIG and can also be serious and may lead to death. Tell your healthcare provider right away if you get any signs of bleeding during ...

PRINCIPAL DISPLAY PANEL - 15 mg Tablet Bottle Label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 63020-535-30 ICLUSIG ® (ponatinib) tablets 15 mg Each tablet contains 15 mg ponatinib equivalent to 16.03 mg ponatinib HCl Dispense Attached Medication Guide 30 tablets Rx only Takeda

PRINCIPAL DISPLAY PANEL - 45 mg Tablet Bottle Label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 63020-534-30 ICLUSIG ® (ponatinib) tablets 45 mg Each tablet contains 45 mg ponatinib equivalent to 48.08 mg ponatinib HCl Dispense Attached Medication Guide 30 tablets Rx only Takeda

PRINCIPAL DISPLAY PANEL - 30 mg Tablet Bottle Label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 63020-533-30 ICLUSIG ® (ponatinib) tablets 30 mg Each tablet contains 30 mg ponatinib equivalent to 32.05 mg ponatinib HCl Dispense Attached Medication Guide 30 tablets Rx only Takeda

PRINCIPAL DISPLAY PANEL - 10 mg Tablet Bottle Label

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC 63020-536-30 ICLUSIG ® (ponatinib) tablets 10 mg Each tablet contains 10 mg ponatinib equivalent to 10.68 mg ponatinib HCl Dispense Attached Medication Guide 30 tablets Rx only Takeda