Iclusig

Patient Information Leaflet

Iclusig 15 mg film-coated tablets, 30 mg film-coated tablets, 45 mg film-coated tablets

ponatinib
Please read this leaflet carefully before taking this medicine because it contains
important information for you.
Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, because it may be harmful.
If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.
Contents of this leaflet:

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

1. What Iclusig is and what it is used for

Iclusig is used as a treatment in adults with the following types of leukaemia who no longer benefit from treatment with other medicines, or who have a specific genetic alteration known as the T315I mutation:
chronic myeloid leukaemia (CML): a blood cancer leading to an excessive number of abnormal white blood cells in the blood and bone marrow (where blood cells are formed).
Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL): a type of leukaemia characterised by an excessive number of immature white blood cells in the blood and bone marrow that produces blood. In this type of leukaemia, part of the DNA (genetic material) has rearranged to form an abnormal chromosome, the Philadelphia chromosome.
Iclusig is also used as a treatment in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL), in combination with other anticancer medicines (chemotherapy).
Iclusig belongs to a group of medicines called tyrosine kinase inhibitors. In patients with CML and Ph+ ALL, changes in the DNA generate a signal that causes the body to produce abnormal white blood cells. Iclusig blocks this signal, thereby stopping the production of these cells.

2. What you should know before taking Iclusig

Do not take Iclusig
if you are allergic to ponatinib or to any of the other ingredients of this medicine
(listed in section 6).

Warnings and precautions
Talk to your doctor or pharmacist before taking Iclusig if you have:
a liver or pancreatic disorder, or reduced kidney function. Your doctor may wish to take additional precautions.
a history of alcohol abuse
a previous episode of heart attack or stroke
a history of blood clots in blood vessels
a previous history of renal artery stenosis (narrowing of the blood vessels in one or both kidneys)
heart problems, including heart failure, irregular heartbeat, and QT prolongation
high blood pressure
or have had an aneurysm (dilation and weakening of a blood vessel wall) or a tear in the wall of a blood vessel
a history of bleeding episodes
never had or may currently have a hepatitis B infection. This is because Iclusig could cause reactivation of hepatitis B, which in some cases may be fatal. Patients will be closely monitored by the doctor for signs of this infection before starting treatment.

Your doctor will perform:
assessments of heart function and the condition of arteries and veins
a full blood count
This will be repeated every 2 weeks for the first 3 months after starting treatment. Afterwards, monitoring will occur monthly, or as directed by your doctor.
checks of a serum protein called lipase
A serum protein called lipase will be checked every 2 weeks for the first 2 months, and periodically thereafter. If lipase levels increase, a treatment interruption or dose reduction may be necessary.
liver function tests
Liver function tests will be performed periodically, as directed by your doctor.

A neurological condition called reversible posterior leukoencephalopathy syndrome (PRES) has been reported in patients treated with ponatinib. Symptoms may include sudden onset of severe headache, confusion, seizures, and vision changes. Inform your doctor immediately if you experience any of these symptoms during treatment with ponatinib, as they could be serious.

Children and adolescents
Do not administer this medicine to children under 18 years of age due to lack of data.

Other medicines and Iclusig
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

The following medicines may interact with Iclusig or be affected by it:
ketoconazole, itraconazole, voriconazole: medicines used to treat fungal infections.
indinavir, nelfinavir, ritonavir, saquinavir: medicines used to treat HIV infection.
clarithromycin, telithromycin, troleandomycin: medicines used to treat bacterial infections.
nefazodone: a medicine used to treat depression.
St. John’s wort (Hypericum perforatum): a herbal preparation used to treat depression.
carbamazepine: a medicine used to treat epilepsy, manic/depressive episodes, and certain painful conditions.
phenobarbital, phenytoin: medicines used to treat epilepsy.
rifabutin, rifampicin: medicines used to treat tuberculosis or certain other infections.
digoxin: a medicine used to treat heart weakness.
dabigatran: a medicine used to prevent blood clots.
colchicine: a medicine used to treat gout attacks.
pravastatin, rosuvastatin: medicines used to reduce high cholesterol levels.
methotrexate: a medicine used to treat severe joint inflammation (rheumatoid arthritis), tumors, and the skin disease called psoriasis.
sulfasalazine: a medicine used to treat severe intestinal and joint inflammation of rheumatic origin.

Iclusig with food and drink
Avoid grapefruit-containing products such as grapefruit juice.

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.

Advice on male and female contraception
Women of childbearing potential treated with Iclusig must avoid pregnancy. Men treated with Iclusig must avoid fathering children during treatment. An effective method of contraception must be used during treatment.
Use Iclusig during pregnancy only if your doctor tells you it is absolutely necessary, as there are potential risks to the unborn child.

Breastfeeding
Discontinue breastfeeding during treatment with Iclusig. It is not known whether Iclusig passes into breast milk.

Driving and using machines
Exercise particular caution when driving or operating machinery, as patients taking Iclusig may experience vision disturbances, dizziness, drowsiness, and fatigue.

Iclusig contains lactose
If your doctor has diagnosed you with an intolerance to certain sugars, contact your doctor before taking this medicine.

3. How to take Iclusig

Take this medicine exactly as your doctor or pharmacist has told you. If you have any doubts, consult your doctor or pharmacist.
Treatment with Iclusig must be prescribed by a doctor experienced in the treatment of leukemia.
Iclusig is available as:
a 45 mg film-coated tablet and a 30 mg film-coated tablet for the recommended starting doses.
a 15 mg film-coated tablet for potential dose adjustments.
The recommended starting dose is one 45 mg film-coated tablet once daily.
The recommended starting dose in combination with chemotherapy is one 30 mg film-coated tablet once daily.
Your doctor may reduce your dose or ask you to temporarily stop taking Iclusig if:
an adequate response to treatment is achieved.
the number of white blood cells called neutrophils decreases.
the number of platelets decreases.
a serious non-hematological adverse effect occurs.

• inflammation of the pancreas.
• increased levels of serum lipase or amylase proteins. you develop heart or blood vessel problems. you have liver disease

Once this adverse effect has resolved or is under control, treatment with Iclusig may be resumed at the same dose or at a reduced dose. Your doctor may assess your response to treatment at regular intervals.
Instructions for use
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 ingest the desiccant container found inside the bottle.
Duration of treatment
Make sure to take Iclusig every day, for as long as prescribed. This is a long-term treatment.
If you take more Iclusig than you should
In this case, contact 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 stop taking Iclusig
Do not stop taking Iclusig without your doctor's approval.
If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Side effects are more likely to occur in patients aged 65 years and older.
Contact your doctor immediately if you experience any of the following serious side effects.
In case of abnormal blood test results, contact a doctor immediately.

Serious side effects (may affect up to 1 in 10 people):
lung infection (can cause breathing difficulties)
inflammation of the pancreas. If you have pancreatitis, inform your doctor immediately. Symptoms include severe stomach and back pain.
fever, often with other signs of infection, due to a reduced number of white blood cells
heart attack (symptoms include: sudden sensation of increased heartbeat, chest pain, shortness of breath)
changes in blood levels:

• reduction in the number of red blood cells (symptoms include: weakness, dizziness, fatigue)
• reduction in the number of platelets (symptoms include: increased tendency to bleed or bruise)
• reduction in the number of white blood cells called neutrophils (symptoms include: increased susceptibility to infections)
• increase in the level of a serum protein known as lipase
  heart rhythm disorder, heart rate abnormalities
  heart failure (symptoms include: weakness, fatigue, swelling of the legs)
  uncomfortable sensation of pressure, fullness, tightness, or pain in the center of the chest (angina pectoris) and non-cardiac chest pain
  high blood pressure
  narrowing of cerebral arteries, stroke caused by reduced blood flow to part of the brain
  problems in blood vessels of the heart muscle
  blood infection
  swelling or redness of areas of skin that are warm and tender to touch (cellulitis)
  dehydration
  breathing difficulties
  fluid in the chest (can cause breathing difficulties)
  diarrhea
  formation of a blood clot in a deep vein, sudden venous obstruction, formation of a blood clot in a blood vessel of the lung (symptoms include: hot flushes, redness, facial flushing, breathing difficulties)
  stroke (symptoms include: difficulty speaking or moving, drowsiness, headache, unusual sensations)
  blood circulation problems (symptoms include: leg or arm pain, cold extremities)
  formation of a blood clot in the main arteries carrying blood to the head or neck (carotid artery)
  constipation
  reduction in the amount of sodium in the blood
  increased tendency to bleed or bruise

Other possible side effects that may occur with the following frequencies are:

Very common side effects (may affect more than 1 in 10 people):
upper respiratory tract infection (can cause breathing difficulties)
loss of appetite
insomnia
headache, dizziness
cough
inflammation of the mouth
diarrhea, vomiting, nausea, constipation, abdominal pain
increased blood levels of several liver enzymes called:

• alanine aminotransferase
• aspartate aminotransferase

low levels of calcium, phosphate, or potassium in the blood
skin rash, dry skin, itching
bone, joint, muscle, back, arm, or leg pain, muscle spasms
nerve disorder in arms and/or legs (often causing numbness and pain in hands and feet)
increased or decreased sense of touch or sensitivity, unusual sensations such as tingling, prickling, and itching
fatigue, fluid accumulation in arms and/or legs, fever, pain
increased blood sugar or uric acid levels in the blood
elevated levels of fats (triglycerides) in the blood
increased cholesterol detectable in blood tests

Common side effects (may affect up to 1 in 10 people):
liver damage (symptoms may include: fatigue, yellowing of the skin and itchy skin, yellowing of the whites of the eyes, nausea or vomiting, loss of appetite, pain in the upper right abdomen, dark or brown urine, bleeding or bruising more easily than normal)
inflammation of hair and body hair follicles, swelling and redness of areas of skin or beneath the skin that are warm and tender to touch
reduced activity of the thyroid gland
fluid retention
weight loss
transient ischaemic attack
nerve disorder of the face (often causing numbness or weakness on one or both sides of the face)
lethargy, migraine
muscle weakness, musculoskeletal stiffness
blurred vision, dry eyes, eye infection, visual disturbances, eye pain
eyelid or periorbital edema due to excess fluid
palpitations
pain in one or both legs while walking or exercising, which disappears after a few minutes of rest
hot flushes, redness
nosebleeds, difficulty producing vocal sounds, pulmonary hypertension
increased levels of liver and pancreatic enzymes in the blood:

• amylase
• alkaline phosphatase
• gamma-glutamyl transferase

increase in the level of a protein in the serum called C-reactive protein, which rises in the presence of inflammation in the body
stomach burning caused by gastric acid reflux, peptic ulcer
sore throat or mouth, dry mouth, bleeding gums
abdominal swelling or discomfort or indigestion
stomach bleeding (symptoms include: stomach pain, vomiting blood)
increased level of bilirubin in the blood – the yellow breakdown product of blood pigment (symptoms include: dark amber-colored urine)
pain in the skeletal system or neck
pain caused by inflammation of the membrane surrounding tendons, usually in feet or hands
skin peeling, abnormal thickening of the skin, redness, bruising, skin pain, changes in skin color, flat discolored areas and small raised bumps on the skin, warts, acne-like skin disease, possible appearance of red, symmetrical, raised areas on the entire body, hair loss
facial swelling due to excess fluid
night sweats, increased sweating
inability to achieve or maintain an erection

chills, flu-like syndrome
herpes zoster
overactivity of the thyroid gland, leading to an accelerated metabolism; this may cause various symptoms such as weight loss, hand tremors, rapid or irregular heartbeat
weight gain
anxiety
heart problems, chest pain localized to the left side, dysfunction of the left ventricle, changes in heartbeat, rapid heartbeat, increased level of a serum protein called brain natriuretic peptide, which may rise when the heart does not pump blood properly
narrowing of blood vessels, inadequate blood circulation, sudden increase in blood pressure
blockage of eye veins
painful red nodules, skin pain, skin redness (inflammation of subcutaneous fat tissue)
metabolic disorders caused by breakdown products of dying tumor cells

Uncommon side effects (may affect up to 1 in 100 people):
renal artery stenosis (narrowing of blood vessels in one or both kidneys)
circulatory problems in the spleen
jaundice (symptoms include: yellowing of the skin and eyes)
headache, confusion, seizures, and loss of vision, which may be symptoms of a brain condition known as Posterior Reversible Encephalopathy Syndrome (PRES)

Not known (frequency cannot be estimated from available data):
recurrence (reactivation) of hepatitis B infection if you have previously had hepatitis B (a liver infection)
severe skin rashes with blistering or widespread skin peeling throughout the body, associated with fatigue. Inform your doctor immediately if you experience these symptoms.
dilation and weakening of the wall of a blood vessel or a tear in the wall of a blood vessel (aneurysms and arterial dissections).

Additional side effects reported when ponatinib was used in combination with chemotherapy in Philadelphia chromosome-positive ALL:

Very common side effects (may affect more than 1 in 10):
changes in blood levels:

• increase in the number of white blood cells
• increase in serum enzyme levels called lactate dehydrogenase, a possible indicator of tissue damage

Common side effects (may affect up to 1 in 10):
infection due to low number of white blood cells called neutrophils in the blood
changes in blood levels:

• reduction in the number of red blood cells, white blood cells, and platelets (myelosuppression, cytopenia)
• increase in the number of white blood cells called neutrophils
• increase in the number of platelets in the blood
• low number of white blood cells, increasing the risk of serious infections due to a compromised immune system
• reduction in the level of the serum protein called albumin in the blood
• increase in the level of the serum protein called creatinine in the blood, related to kidney function
• increase in the level of the serum protein called troponin I, which may indicate heart damage
• reduction in the level of fibrinogen, a protein that enables blood clotting, in the blood
• reduction in the level of total proteins in the blood
  rupture of a blood vessel with bleeding on the surface of the eye
  palpitations
  slow heartbeat, with a resting heart rate equal to or less than 60 beats per minute
  hoarseness
  inflammation of the inner lining of the stomach

Uncommon side effects (may affect up to 1 in 100):
cold sensation in arms and/or legs
blood clots
bleeding from the mouth
liver and biliary tract problems that may cause increases in amylase or lipase enzymes in the blood

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V.
Reporting side effects can help provide more information on the safety of this medicine.

5. How to store Iclusig

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the vial label and on the
packaging after "Exp". The expiry date refers to the last day of that month.
Store in the original packaging to protect the medicine from light.
The vial contains a sealed plastic container with a molecular sieve desiccant. Keep the container inside the vial. Do not ingest the desiccant container.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package contents and other information

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

Description of the appearance of Iclusig and contents of the pack
Iclusig film-coated tablets are white, round, and biconvex.
The 15 mg Iclusig film-coated tablets have a diameter of approximately 6 mm and are marked with “A5” on one side.
The 30 mg Iclusig film-coated tablets have a diameter of approximately 8 mm and are marked with “C7” on one side.
The 45 mg Iclusig film-coated tablets have a diameter of approximately 9 mm and are marked with “AP4” on one side.
Iclusig is available in plastic bottles, each containing a container 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.
Not all pack sizes may be marketed.

Marketing Authorization Holder
Incyte Biosciences Distribution B.V.
Paasheuvelweg 25
1105 BP Amsterdam
The Netherlands

Manufacturer
Incyte Biosciences Distribution B.V.
Paasheuvelweg 25
1105 BP Amsterdam
The Netherlands
Tjoapack Netherlands B.V.
Nieuwe Donk 9
4879 AC Etten-Leur
The Netherlands

More detailed information on this medicinal product is available on the website of the European Medicines Agency: https://www.ema.europa.eu.
In addition, links to other websites on rare diseases and their therapeutic treatments are provided.
This leaflet is available in all languages of the European Union/European Economic Area on the European Medicines Agency website.