Product Information for the Patient

Iclusig 15 mg Film-Coated Tablets

Iclusig 30 mg Film-Coated Tablets

Iclusig 45 mg Film-Coated Tablets

ponatinib

Read this entire product information carefully before starting to take this medicine, as it contains important information for you.

• Keep this product information, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed only for you, and you should not give it to others even if they have the same symptoms as you, as it may harm them.
• If you experience any side effects, consult your doctor or pharmacist, even if they are not listed in this product information. See section 4.

Iclusig isused to treatadults with the following types ofleukemiawho no longer benefit from treatment with other medications or have a known genetic difference called T315I mutation:

• Chronic myeloid leukemia (CML): a blood cancer related to the presence of too many abnormal leukocytes in the blood and bone marrow (where blood cells are formed).

• Acute lymphoblastic leukemia with Philadelphia chromosome positive (ALL Ph+): a type of leukemia related to the presence of too many immature leukocytes in the blood and bone marrow. In this type of leukemia, part of the DNA (genetic material) has been rearranged, forming an abnormal chromosome, the Philadelphia chromosome.

Iclusig belongs to a group of medications called tyrosine kinase inhibitors. In patients with CML and ALL Ph+, DNA modifications trigger a signal that tells the body to produce abnormal leukocytes. Iclusig blocks this signal and, as a result, stops the production of these cells.

Do not take Iclusig

• if you areallergicto ponatinib or any of the other ingredients of this medication (listed in section 6).

Warnings and precautions

Consult your doctor or pharmacist before starting Iclusig if:

• you have liver or pancreatic disease or kidney dysfunction. Your doctor may want to take extra precautions
• you have a history of alcoholism
• you have had a heart attack or stroke in the past
• you have had blood clots in the blood vessels
• you have had renal artery stenosis (narrowing of the blood vessels in one or both kidneys)
• you have heart problems, such as heart failure, irregular heartbeat, or prolonged QT interval
• you have high blood pressure
• you have or have had an aneurysm (enlargement and weakening of the wall of a blood vessel) or a tear in the wall of a blood vessel
• you have a history of bleeding disorders
• you have ever had or may have hepatitis B infection at this time. This is because Iclusig may reactivate hepatitis B, which can be fatal in some cases. Your doctor should carefully check for signs of this infection before starting treatment.

Your doctor will perform:

• heart function and artery and vein assessments
• a complete blood test

This will be repeated every two weeks for the first three months after starting treatment. After that, it will be done once a month or as indicated by your doctor.

• Tests to measure a serum protein called lipase

Lipase serum protein will be determined every two weeks for the first two months and then periodically. If lipase increases, it may be necessary to interrupt treatment or reduce the dose.

• Liver function tests

Liver function tests will be performed periodically as indicated by your doctor.

A reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in patients treated with ponatinib. Symptoms may include sudden onset of severe headaches, confusion, seizures, and vision changes. You should seek immediate medical attention if you experience any of these symptoms during treatment with ponatinib, as it may be severe.

Children and adolescents

Do not administer this medication to children under 18 years of age, as there is no data available in the pediatric population.

Other medications and Iclusig

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication.

The following medications may affect Iclusig or be affected by this medication:

• ketoconazole, itraconazole, voriconazole:antifungal medications
• indinavir, nelfinavir, ritonavir, saquinavir:medications for HIV infection
• clarithromycin, telithromycin, troleandomycin:medications for bacterial infections
• nefazodone:a medication for depression
• St. John's Wort:a plant-based medication for depression
• carbamazepine:a medication for epilepsy, mania, depression, and certain painful conditions
• phenobarbital, phenytoin:medications for epilepsy
• rifabutin, rifampicin:medications for tuberculosis or other infections
• digoxin:a medication for heart failure
• dabigatran:a medication to prevent blood clots
• colchicine:a medication for gout attacks
• pravastatin,rosuvastatin:medications to lower high cholesterol levels
• methotrexate:a medication for severe joint inflammation (rheumatoid arthritis), cancer, and psoriasis, a skin disease
• sulfasalazine:a medication for severe joint and intestinal inflammation

Taking Iclusig with food and drinks

Avoid grapefruit products, such as grapefruit juice.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor or pharmacist before using this medication.

• Contraception in men and women

Women of childbearing age treated with Iclusig should not become pregnant. Men treated with Iclusig should not father children during treatment. Effective contraception should be used during treatment.

Use Iclusig during pregnancyonly if your doctor tells you it is absolutely necessary, as there is a risk to the fetus.

• Breastfeeding

You should stop breastfeeding during treatment with Iclusig. It is unknown whether Iclusig passes into breast milk.

Driving and operating machinery

You should exercise special caution when driving and operating machinery because patients taking Iclusig may experience visual disturbances, dizziness, drowsiness, and fatigue.

Iclusig contains lactose

If your doctor has told you that you have a certain sugar intolerance, consult with them before taking this medication.

Follow exactly the administration instructions for this medication as indicated by your doctor or pharmacist. If in doubt, consult your doctor or pharmacist again.

Iclusig treatment should be prescribed by a doctor experienced in treating leukemia.

Iclusig is available as:

• a 45 mg film-coated tablet for the recommended dose
• a 15 mg film-coated tablet and a 30 mg film-coated tablet to allow for dose adjustments

The recommended initial dose is one 45 mg film-coated tablet once a day.

Your doctor may reduce your dose or tell you to temporarily stop taking Iclusig if:

• a satisfactory response to treatment is achieved
• the number of certain white blood cells called neutrophils decreases
• the number of platelets decreases
• a severe side effect not related to blood occurs:

• pancreatitis
• an increase in serum lipase and amylase concentrations

• heart or blood vessel problems
• liver disease

Iclusig use may be resumed at the same dose or a lower dose once the event is resolved or controlled.

Your doctor may evaluate your response to treatment at regular intervals.

Administration Form

Swallow the tablets whole with a glass of water. Tablets may be taken with or without food. Do not crush or dissolve the tablets.

Do not swallow the container with the desiccant in the bottle.

Treatment Duration

Take Iclusig daily for the prescribed period. This is a long-term treatment.

If you take more Iclusig than you should

Consult your doctor immediately.

If you forget to take Iclusig

Do not take a double dose to make up for the missed dose. Take the next dose at the usual time.

If you interrupt treatment with Iclusig

Do not stop taking Iclusig without your doctor's authorization.

If you have any other questions about the use of this medication, ask your doctor or pharmacist.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Patients 65 years of age or older may be more likely to experience side effects.

Seek immediate medical attention if you experience any of the following severe side effects.

Immediately contact a doctor if abnormal results are obtained in blood tests.

Severe side effects(frequent: may affect up to 1 in 10 people):

• • Pulmonary infection (may cause difficulty breathing)
• Pancreatitis. Inform your doctor immediately if your pancreas becomes inflamed. Symptoms include intense pain in the stomach and back.
• Fever, often with other signs of infection due to a decrease in white blood cell count
• Myocardial infarction (symptoms include: increased heart rate, chest pain, difficulty breathing)
• Changes in blood concentrations:

• Decreased red blood cell count (symptoms include: weakness, dizziness, and fatigue)
• Decreased platelet count (symptoms include: increased tendency to bleed or bruise)
• Decreased count of a type of white blood cell called neutrophils (symptoms include: increased tendency to develop infections)
• Increased concentration of a type of serum protein called lipase

• Abnormal heart rhythm, pulse anomalies
• Heart failure (symptoms include: weakness, fatigue, and swelling of the legs)
• Pressure causing discomfort, feeling of fullness, constriction, or pain in the center of the chest (angina pectoris) and non-cardiac chest pain
• Hypertension
• Carotid artery stenosis
• Coronary artery problems
• Blood infection
• Swelling, or red areas on the skin that feel warm and sensitive (cellulitis)
• Dehydration
• Difficulty breathing
• Fluid in the thorax (may cause respiratory difficulties)
• Diarrhea
• Formation of a blood clot in a deep vein, sudden venous obstruction, or blood clot in a pulmonary artery (symptoms include: redness, shortness of breath, and difficulty breathing)
• Cerebrovascular accident (symptoms include: difficulty speaking or moving, drowsiness, migraines, and abnormal sensations)
• Circulatory problems (symptoms include: pain in the legs or arms and coldness of the hands and feet)
• Blood clot in the main arteries that supply blood to the head or neck (carotid artery)
• Constipation
• Decreased sodium in the blood
• Increased tendency to bleed or bruise

Otherspossible side effects that may occur with the following frequencies are:

Frequent side effects(may affect more than 1 in 10 people):

• Upper respiratory tract infection (may cause difficulty breathing)
• Decreased appetite
• Insomnia
• Headache, dizziness
• Cough
• Diarrhea, vomiting, nausea
• Increased concentrations of several liver enzymes in the blood called:

• Alanine aminotransferase
• Aspartate aminotransferase

• Skin rash, dry skin, pruritus
• Pain in bones, joints, muscles, back, arms, or legs, muscle spasms
• Fatigue, fluid accumulation in the arms and/or legs, fever, pain

Common side effects(may affect up to 1 in 10 people):

• Folliculitis, swelling, red areas on the skin or under the skin that feel warm and sensitive
• Reduced thyroid gland activity
• Fluid retention
• Low concentrations of calcium, phosphate, or potassium in the blood
• Increased concentrations of sugar or uric acid in the blood, elevated triglyceride levels in the blood
• Weight loss
• Transient ischemic attack
• Nerve disorder in the arms or legs (often causes numbness and pain in the hands and feet)
• Lethargy, migraines
• Increased or decreased sense of touch or sensitivity, abnormal sensations such as pins and needles, itching
• Blurred vision, dry eyes, eye infection, visual disturbances
• Swelling of the eyelids or around the eyes due to excess fluid
• Palpitations
• Pain in one or both legs when walking or exercising, which disappears after resting for a few minutes
• Shortness of breath, flushing
• Nasal bleeding, difficulty speaking, hypertension
• Increased concentrations of liver and pancreatic enzymes in the blood:

• Amilase
• Alkaline phosphatase
• Gamma-glutamyltransferase

• Stomach burning caused by reflux of stomach juices, inflammation of the mouth, discomfort, indigestion, or abdominal swelling, dry mouth
• Gastrointestinal bleeding (symptoms include: stomach pain, vomiting blood)
• Increased bilirubin concentration in the blood, the yellow degradation product of blood pigment (symptoms include: dark-colored urine)
• Pain in bones or neck
• Skin rash, peeling of the skin, abnormal skin thickening, redness, bruising, pain in the skin, changes in skin color, hair loss
• Swelling of the face due to fluid accumulation
• Nocturnal sweating, increased sweating
• Erectile dysfunction (inability to develop or maintain an erection)
• Chills, pseudogripal disease

Rare side effects(may affect up to 1 in 1,000 people):

• Red, painful nodules, skin rash, skin redness (inflammation of subcutaneous tissue)

Unknown frequency(cannot be estimated from available data):

• • Recurrence (reactivation) of hepatitis B infection if you have had hepatitis B in the past (a liver infection)
• Concerning skin eruptions that present blisters or peeling and spread throughout the body, plus feeling tired. Inform your doctor immediately if you experience these symptoms.
• Increased and weakened wall of a blood vessel or tearing of the wall of a blood vessel (aneurysms and arterial dissections).

Reporting side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through thenational notification system included in theAppendix V.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the outer packaging and on the bottle label after CAD. The expiration date is the last day of the month indicated.

Store in the original packaging to protect it from light.

The bottle contains a plastic container with a molecular sieve desiccant. Store the container within the bottle. Do not ingest the container with the desiccant.

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications that you no longer need. This will help protect the environment.

Composition of Iclusig

• The active ingredient is ponatinib.

Each film-coated tablet of 15 mg contains 15 mg of ponatinib (as ponatinib hydrochloride).

Each film-coated tablet of 30 mg contains 30 mg of ponatinib (as ponatinib hydrochloride).

Each film-coated tablet of 45 mg contains 45 mg of ponatinib (as ponatinib hydrochloride).

• The other components are lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal anhydrous silica, magnesium stearate, talc, macrogol 4000, polyvinyl alcohol and titanium dioxide (E171). See section 2 “Iclusig contains lactose”.

Appearance of Iclusig and packaging contents

Iclusig film-coated tablets are white, round and rounded on the upper and lower faces.

Iclusig 15 mg film-coated tablets have approximately 6 mm in diameter and “A5” on one face.

Iclusig 30 mg film-coated tablets have approximately 8 mm in diameter and “C7” on one face.

Iclusig 45 mg film-coated tablets have approximately 9 mm in diameter and “AP4” on one face.

Iclusig is available in plastic bottles, each with a molecular sieve desiccant. The bottles are presented in a cardboard box.

Iclusig 15 mg bottles contain 30, 60 or 180 film-coated tablets.

Iclusig 30 mg bottles contain 30 film-coated tablets.

Iclusig 45 mg bottles contain 30 or 90 film-coated tablets.

Only some packaging sizes may be marketed.

Marketing Authorization Holder

Incyte Biosciences Distribution B.V.

Paasheuvelweg 25

1105 BP Amsterdam

Netherlands

Responsible for manufacturing

Incyte Biosciences Distribution B.V.

Paasheuvelweg 25

1105 BP Amsterdam

Netherlands

Tjoapack Netherlands B.V.

Nieuwe Donk 9

Etten-Leur, 4879 AC

Netherlands

Last review date of this leaflet: {MM/AAAA}.

Further information on this medicine is available on the European Medicines Agency website:http://www.ema.europa.eu.

There are also links to other websites on rare diseases and orphan medicines.

This leaflet is available in all languages of the European Union/European Economic Area on the European Medicines Agency website.