ICLUSIG 15 mg FILM-COATED TABLETS

Introduction

Package Leaflet: Information for the Patient

Iclusig 15 mg Film-Coated Tablets

Iclusig 30 mg Film-Coated Tablets

Iclusig 45 mg Film-Coated Tablets

ponatinib

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What is Iclusig and what is it used for
2. What you need to know before you take Iclusig
3. How to take Iclusig
4. Possible side effects
5. Storage of Iclusig
6. Contents of the pack and other information

1. What is Iclusig and what is it used for

Iclusig is used to treatadults with the following types of leukemiathat are no longer benefiting from treatment with other medicines or have a known genetic difference called T315I mutation:

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

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

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

2. What you need to know before you take Iclusig

Do not take Iclusig

allergicto ponatinib or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Tell your doctor or pharmacist before you start taking 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 previously had a heart attack or stroke.
• You have had blood clots in the blood vessels.
• You have had narrowing of the renal artery (narrowing of the blood vessels in one or both kidneys).
• You have heart problems, such as heart failure, irregular heartbeats, or prolonged QT interval.
• You have high blood pressure.
• You have had an aneurysm (a bulge 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 currently have a hepatitis B virus infection. This is because Iclusig could cause hepatitis B to become active again, which can be life-threatening in some cases. Your doctor will carefully check for signs of this infection before starting treatment.

Your doctor will:

• Assess your heart function and the condition of your arteries and veins.
• Perform a complete blood count.

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 will be measured every two weeks for the first two months and then periodically. If lipase increases, treatment may need to be interrupted or the dose reduced.

• Liver function tests.

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

A brain disorder called posterior reversible encephalopathy syndrome (PRES) has been reported in patients treated with ponatinib. Symptoms can include sudden severe headache, confusion, seizures, and vision changes. You should see your doctor immediately if you experience any of these symptoms during treatment with ponatinib, as it can be serious.

Children and adolescents

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

Other medicines and Iclusig

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

The following medicines may affect Iclusig or be affected by this medicine:

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

Taking Iclusig with food and drinks

Avoid grapefruit products, such as grapefruit juice.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

• Contraception in men and women

Womenof childbearing age treated with Iclusig should not become pregnant. It is recommended that mentreated with Iclusig do not father children during treatment. Effective contraception should be used during treatment.

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

• Breast-feeding

Breast-feeding should be interrupted during treatment with Iclusig. It is not known whether Iclusig passes into breast milk.

Driving and using machines

You should be careful when driving or using machines because patients taking Iclusig may experience visual disturbances, dizziness, drowsiness, and fatigue.

Iclusig contains lactose

If your doctor has told you that you have an intolerance to some sugars, contact them before taking this medicine.

3. How to take Iclusig

Always take this medicine exactly as your doctor or pharmacist has told you. If you are not sure, check with your doctor or pharmacist.

Treatment with Iclusig should be prescribed by a doctor with experience in treating leukemia.

Iclusig is available as:

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

The recommended starting dose isone 45 mg film-coated tablet once a day.

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

• a satisfactory response to treatment is achieved.
• the number of a type of white blood cell called neutrophils decreases.
• the number of platelets decreases.
• a severe side effect occurs that does not affect the blood:

• pancreatitis.
• increased levels of serum proteins lipase and amylase.

• you experience heart or blood vessel problems.
• you have liver disease.

Iclusig can be restarted at the same dose or a lower dose once the event is resolved or controlled.

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

Method of administration

Swallow the tablets whole, with a glass of water. The tablets can be taken with or without food. Do not crush or dissolve the tablets.

Do not swallow the desiccant container in the bottle.

Duration of treatment

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 forgotten doses. Take the next dose at the usual time.

If you stop taking Iclusig

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

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Patient over 65 years of age are more likely to be affected by side effects.

Seek medical attention immediately if you experience any of the following serious side effects.

If you receive abnormal results from blood tests, you should contact a doctor immediately.

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

• • pneumonia (can cause difficulty breathing).
• pancreatitis. Tell your doctor immediately if you get pancreatitis. Symptoms are severe pain in the stomach and back area.
• fever, often with other signs of infection due to a decrease in the number of white blood cells.
• heart attack (symptoms include: increased heart rate, chest pain, difficulty breathing).
• changes in blood levels:

• decrease in the number of red blood cells (symptoms include: weakness, dizziness, and fatigue).
• decrease in the number of blood platelets (symptoms include: increased tendency to bleed or bruise).
• decrease in the number of a type of white blood cell called neutrophils (symptoms include: increased tendency to get infections).
• increase in the level of a serum protein called lipase.

• abnormal heart rhythm, pulse abnormalities.
• heart failure (symptoms include: weakness, fatigue, and swelling of the legs).
• discomfort, feeling of fullness, tightness, or pain in the center of the chest (angina) and non-heart-related chest pain.
• high blood pressure.
• narrowing of the arteries in the brain.
• problems with the blood vessels of the heart.
• blood infection.
• swelling, redness of the skin that feels hot and tender (cellulitis).
• dehydration.
• difficulty breathing.
• fluid in the chest (can cause breathing difficulties).
• diarrhea.
• formation of a blood clot in a deep vein, sudden blockage of a vein, or blood clot in a blood vessel in the lung (symptoms include: redness, flushing, reddening of the face, and difficulty breathing).
• stroke (symptoms include: difficulty speaking or moving, drowsiness, migraine, and unusual sensation).
• problems with blood circulation (symptoms include: pain in the legs or arms and cooling of the hands and feet).
• blood clot in the main arteries that carry blood to the head or neck (carotid artery).
• constipation.
• low sodium levels in the blood.
• increased tendency to bleed or bruise.

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

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

• infection of the upper respiratory tract (can cause difficulty breathing).
• decreased appetite.
• insomnia.
• headache, dizziness.
• cough.
• diarrhea, vomiting, nausea.
• increased levels of several liver enzymes called:

• alanine aminotransferase.
• aspartate aminotransferase.

• rash, dry skin, itching.
• 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):

• inflammation of the hair follicles, swelling, redness of the skin or under the skin that feels hot and tender.
• reduced activity of the thyroid gland.
• fluid retention.
• low levels of calcium, phosphate, or potassium in the blood.
• increased levels of sugar or uric acid in the blood, high levels of triglycerides (fat) in the blood.
• weight loss.
• transient ischemic attack.
• nerve disorder in the arms or legs (often causing numbness and pain in the hands and feet).
• lethargy, migraines.
• increased or decreased sense of touch or sensitivity, abnormal sensation such as pins and needles, tingling, or itching.
• blurred vision, dry eyes, eye infection, visual disturbance.
• inflammation of the tissue 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.
• hot flushes, reddening.
• nosebleeds, difficulty speaking, pulmonary hypertension.
• increased levels of blood enzymes of the liver and pancreas:

• amylase.
• alkaline phosphatase.
• gamma-glutamyltransferase.

• heartburn caused by reflux of stomach juices, inflammation of the mouth, discomfort, indigestion, or abdominal bloating, dry mouth.
• stomach bleeding (symptoms include: stomach pain, vomiting blood).
• increased level of bilirubin in the blood, the yellow breakdown product of the blood pigment (symptoms include: dark-colored urine).
• pain in bones or neck.
• rash, skin peeling, thickening of the skin, reddening, bruising, skin pain, changes in skin color, hair loss.
• inflammation of the face due to fluid accumulation.
• night sweats, increased sweating.
• erectile dysfunction (inability to develop or maintain an erection).
• chills, flu-like illness.

Uncommon side effects(may affect up to 1 in 100 people):

• metabolic disorders caused by the breakdown products of cancer cells during destruction.
• bleeding in the brain.
• blockage of the blood vessels in the eye.
• heart problems, pain in the left side of the chest, dysfunction of the left heart chamber.
• narrowing of the blood vessels, poor blood circulation, sudden increase in blood pressure.
• narrowing of the renal artery (narrowing of the blood vessels in one or both kidneys).
• problems with blood circulation in the spleen.
• liver damage, jaundice (symptoms include: yellowing of the skin and eyes).
• headache, confusion, seizures, and vision loss, which can be symptoms related to a brain disorder called posterior reversible encephalopathy syndrome (PRES).

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

• painful red lumps, skin pain, reddening of the skin (inflammation of the fatty tissue under the skin).

Frequency not known(cannot be estimated from the available data):

• • reactivation (re-activation) of hepatitis B virus infection if you have had hepatitis B in the past (a liver infection).
• severe skin rashes that can include blistering or peeling and may affect the mouth, throat, and other areas of the body, as well as a high fever and feeling unwell. Tell your doctor immediately if you get these symptoms.
• weakening and bulging of the wall of a blood vessel or tear in the wall of a blood vessel (aneurysms and arterial dissections).

Reporting of side effects

If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Iclusig

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

Do not use this medicine after the expiry date which is stated on the outer packaging and on the label of the bottle after CAD. The expiry date is the last day of the month indicated.

Store in the original package to protect from light.

The bottle contains a plastic container with a molecular sieve desiccant. Keep the container in the bottle. Do not swallow the container with the desiccant.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines that are no longer needed. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Iclusig

• The active substance is ponatinib.

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

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

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

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

Appearance of Iclusig and Package Contents

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

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

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

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

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

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

The 30 mg Iclusig bottles contain 30 film-coated tablets.

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

Only some pack sizes may be marketed.

Marketing Authorisation Holder

Incyte Biosciences Distribution B.V.

Paasheuvelweg 25

1105 BP Amsterdam

Netherlands

Manufacturer

Incyte Biosciences Distribution B.V.

Paasheuvelweg 25

1105 BP Amsterdam

Netherlands

Tjoapack Netherlands B.V.

Nieuwe Donk 9

Etten-Leur, 4879 AC

Netherlands

Date of Last Revision of this Leaflet: {MM/YYYY}.

Detailed 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 can be found on the European Medicines Agency website in all languages of the European Union/European Economic Area.