Imatinib Koanaa 400 mg Film-coated Tablets

Ireland - English - HPRA (Health Products Regulatory Authority)

Active ingredient:
Imatinib mesylate
Available from:
Koanaa Healthcare Limited
ATC code:
L01XE; L01XE01
INN (International Name):
Imatinib mesylate
Dosage:
400 milligram(s)
Pharmaceutical form:
Film-coated tablet
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Protein kinase inhibitors; imatinib
Authorization status:
Not marketed
Authorization number:
PA2041/001/002
Authorization date:
2017-08-04

Read the complete document

Page 1 of 9

Package leaflet: Information for the user

Imatinib Koanaa 100 mg film-coated tablets

Imatinib Koanaa 400 mg film-coated tablets

Imatinib

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 or nurse.

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, pharmacist or nurse. This includes any

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Imatinib

Koanaa

film-coated tablets is and what it is used for

What you need to know before you take Imatinib Koanaa film-coated tablets

How to take Imatinib Koanaa film-coated tablets

Possible side effects

How to store Imatinib Koanaa film-coated tablets

Contents of the pack and other information

1.

What Imatinib Koanaa film-coated tablets is and what it is used for

Imatinib Koanaa film-coated tablets is a medicine containing an active substance called

imatinib. This medicine works by inhibiting the growth of abnormal cells in the diseases listed

below. These include some types of cancer.

Imatinib Koanaa film-coated tablets is a treatment for:

Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These

white cells usually help the body to fight infection. Chronic myeloid leukaemia is a form

of leukaemia in which certain abnormal white cells (named myeloid cells) start growing

out of control.

In adult patients Imatinib Koanaa film-coated tablets is used to treat a late stage of

chronic myeloid leukaemia called “blast crisis.” In children and adolescents however it

may be used to treat all stages of the illness.

Imatinib Koanaa film-coated tablets is a treatment for adults and children for:

Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive

ALL). Leukaemia is a cancer of white blood cells. These white cells usually help the

body to fight infection. Acute lymphoblastic leukaemia is a form of leukaemia in which

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certain abnormal white cells (named lymphoblasts) start growing out of control. Imatinib

Koanaa film-coated tablets inhibits the growth of these cells.

Imatinib Koanaa film-coated tablets is also a treatment for adults for:

Myelodysplastic/myeloproliferative diseases (MDS/MPD). These are a group of blood

diseases in which some blood cells start growing out of control. Imatinib Koanaa film-

coated tablets inhibits the growth of these cells in a certain subtype of these diseases.

Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL).

These are blood diseases in which some blood cells (named eosinophils) start growing

out of control. Imatinib Koanaa film-coated tablets inhibits the growth of these cells in a

certain subtype of these diseases.

Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the

skin in which some cells start growing out of control. Imatinib Koanaa film-coated

tablets inhibits the growth of these cells.

In the rest of this leaflet, we will use the abbreviations when talking about these diseases.

If you have any questions about how Imatinib Koanaa film-coated tablets works or why this

medicine has been prescribed for you, ask your doctor.

2.

What you need to know before you take Imatinib Koanaa film-coated tablets

Imatinib Koanaa film-coated tablets will only be prescribed to you by a doctor with experience

in medicines to treat blood cancers or solid tumours.

Follow all your doctor’s instructions carefully, even if they differ from the general information

contained in this leaflet.

Do not take Imatinib Koanaa film-coated tablets

if you are allergic to Imatinib Koanaa film-coated tablets or any of the other ingredients of

this medicine (listed in section (6).

If this applies to you, tell your doctor without taking Imatinib Koanaa film-coated tablets.

If you think you may be allergic but are not sure, ask your doctor for advice.

Warnings and precautions

Talk to your doctor or pharmacist before taking Imatinib Koanaa film-coated tablets

if you have or have ever had a liver, kidney or heart problem.

if you are taking the medicine levothyroxine because your thyroid has been removed.

if you have ever had or might now have a hepatitis B infection. This is because Imatinib

Koanaa film-coated tablets could cause hepatitis B to become active again, which can be

fatal in some cases. Patients will be carefully checked by their doctor for signs of this

infection before treatment is started.

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If any of these apply to you, tell your doctor before taking Imatinib Koanaa film-coated

tablets

During treatment with Imatinib Koanaa film-coated tablets, tell your doctor straight away

if you put on weight very quickly. Imatinib Koanaa film-coated tablets may cause your body to

retain water (severe fluid retention).

While you are taking Imatinib Koanaa film-coated tablets your doctor will regularly check

whether the medicine is working. You will also have blood tests and be weighed regularly.

Children and adolescents

Imatinib Koanaa film-coated tablets is also a treatment for children with CML. There is no

experience in children with CML below 2 years of age. There is limited experience in children

with Ph-positive ALL and very limited experience in children with MDS/MPD, DFSP and

HES/CEL.

Some children and adolescents taking Imatinib Koanaa film-coated tablets may have slower

than normal growth. The doctor will monitor the growth at regular visits.

Other medicines and Imatinib Koanaa film-coated tablets

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

medicines, including medicines obtained without a prescription (such as paracetamol) and

including herbal medicines (such as St. John’s Wort). Some medicines can interfere with the

effect of Imatinib Koanaa film-coated tablets when taken together. They may increase or

decrease the effect of Imatinib Koanaa film-coated tablets, either leading to increased side

effects or making Imatinib Koanaa film-coated tablets less effective. Imatinib Koanaa film-

coated tablets may do the same to some other medicines

Tell your doctor if you are using medicines that prevent the formation of blood clots.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a

baby, ask your doctor for advice before taking this medicine.

Imatinib Koanaa film-coated tablets is not recommended during pregnancy unless clearly

necessary as it may harm your baby. Your doctor will discuss with you the possible risks of

taking Imatinib Koanaa film-coated tablets during pregnancy.

Women who might become pregnant are advised to use effective contraception during

treatment.

Do not breast-feed during the treatment with Imatinib Koanaa film-coated tablets.

Patients who are concerned about their fertility while taking Imatinib Koanaa film-coated

tablets are advised to consult with their doctor.

Driving and using machines

You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens,

do not drive or use any tools or machines until you are feeling well again.

3.

How to take Imatinib Koanaa film-coated tablets

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Always take this medicine exactly as your doctor or pharmacist has told you. Check with your

doctor or pharmacist if you are not sure.

Your doctor has prescribed Imatinib Koanaa film-coated tablets because you suffer from a

serious condition. Imatinib Koanaa film-coated tablets can help you to fight this condition.

However, always take this medicine exactly as your doctor, pharmacist has told you. It is

important that you do this as long as your doctor, pharmacist tells you to. Check with your

doctor, pharmacist if you are not sure.

Do not stop taking Imatinib Koanaa film-coated tablets unless your doctor tells you to. If you

are not able to take the medicine as your doctor prescribed or you feel you do not need it

anymore, contact your doctor straight away.

How much Imatinib Koanaa film-coated tablets to take

Use in adults

Your doctor will tell you exactly how many tablets of Imatinib Koanaa film-coated tablets to

take.

If you are being treated for CML in blast crisis:

Depending on your condition the usual starting dose is 600 mg:

600 mg to be taken as 6 tablets of 100 mg or 1 tablet of 400 mg plus 2 tablets of

100 mg once a day.

Your doctor may prescribe a higher or lower dose depending on how you respond to the

treatment. If your daily dose is 800 mg (8 tablets of 100 mg), you should take 4 tablets in the

morning and 4 tablets in the evening.

Your doctor may prescribe a higher or lower dose depending on how you respond to the treatment. If

your daily dose is 800 mg (2 tablets of 400 mg), you should take one tablet in the morning and a second

tablet in the evening.

If you are being treated for Ph-positive ALL:

The starting dose is 600 mg to be taken as 6 tablets of 100mg or one tablet of 400mg

plus 2 tablets of 100mg once a day.

If you are being treated for MDS/MPD:

The starting

dose

is 400 mg to be taken as 4 tablets of 100 mg or one tablet of 400 mg once a

day.

If you are being treated for HES/CEL:

The starting dose is 100 mg, to be taken as one tablet of 100mg once a day. Your doctor

may decide to increase the dose to 400 mg, to be taken as 4 tablets of 100 mg or one

tablet of 400 mg once a day, depending on how you respond to treatment.

If you are being treated for DFSP:

The dose is 800 mg per day (to be taken as 4 tablets of 100 mg or 1 tablet of 400 mg in

the morning and 4 tablets of 100mg or 1 tablet of 400mg in the evening).

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Use in children and adolescents

The doctor will tell you how many tablets of Imatinib Koanaa film-coated tablets to give to your

child. The amount of Imatinib Koanaa film-coated tablets given will depend on your child’s

condition, body weight and height. The total daily dose in children must not exceed 800 mg with

CML and 600 mg with Ph+ALL. The treatment can either be given to your child as a once-daily

dose or alternatively the daily dose can be split into two administrations (half in the morning and

half in the evening).

When and how to take Imatinib Koanaa film-coated tablets

Take Imatinib Koanaa film-coated tablets with a meal. This will help protect you

from stomach problems when taking Imatinib Koanaa film-coated tablets

Swallow the tablets whole with a large glass of water.

If you are unable to swallow the tablets, you can dissolve them in a glass of still water or apple

juice:

Use about 50 ml for each 100 mg tablet or 200 ml for each 400 mg tablet.

Stir with a spoon until the tablets have completely dissolved.

Once the tablet has dissolved, drink everything in the glass straight away. Traces of the

dissolved tablets may be left behind in the glass.

The tablet can be divided into equal doses.

How long to take Imatinib Koanaa film-coated tablets

Keep taking Imatinib every day for as long as your doctor tells you.

If you take more Imatinib Koanaa film-coated tablets than you should

If you have accidentally taken too many tablets, talk to your doctor straight away. You may

require medical attention. Take the medicine pack with you.

If you forget to take Imatinib Koanaa film-coated tablets

If you forget a dose, take it as soon as you remember. However if it is nearly time for the

next dose, skip the missed dose.

Then continue with your normal schedule.

Do not take a double dose to make up a forgotten dose.

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

nurse.

4.

Possible side effects

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

They are usually mild to moderate.

Some side effects may be serious. Tell your doctor straight away if you get any of the

following:

Page 6 of 9

Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10

people):

Rapid weight gain. Imatinib Koanaa film-coated tablets may cause your body to retain

water (severe fluid retention).

Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib

Koanaa film-coated tablets can reduce the number of white blood cells, so you might get

infections more easily.

Unexpected bleeding or bruising (when you have not hurt yourself).

Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people):

Chest pain, irregular heart rhythm (signs of heart problems).

Cough, having difficulty breathing or painful breathing (signs of lung problems).

Feeling light-headed, dizzy or fainting (signs of low blood pressure).

Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes

(signs of liver problems).

Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised

red or purple skin patches, itching, burning sensation, pustular eruption (signs of skin

problems).

Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of

gastrointestinal disorders).

Severely

decreased urine output, feeling thirsty (signs of kidney problems).

Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of

bowel problems).

Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden

loss of consciousness (signs of nervous system problems such as bleeding or swelling in

skull/brain).

Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of

red blood cells).

Eye pain or deterioration in vision, bleeding in the eyes.

Pain in

your

hips or difficulty walking.

Numb or cold toes and fingers (signs of Raynaud’s syndrome).

Sudden swelling and redness of the skin (signs of a skin infection called cellulites).

Difficulty hearing.

Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the

amount of potassium in your blood).

Bruising.

Stomach pain with feeling sick (nausea).

Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs

of muscle problems).

Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding,

feeling dizzy or fainting due to low blood pressure (signs of problems with your ovaries

or womb).

Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint

discomfort associated with abnormal laboratory test results (eg. high potassium, uric

acid and calcium levels and low phosphorous levels in the blood).

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Not known (frequency cannot be estimated from the available data):

Combination of a widespread severe rash, feeling sick, fever, high level of certain white

blood cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest

pain/discomfort, severely decreased urine output and feeling thirsty etc. (signs of a

treatment-related allergic reaction).

Chronic renal failure.

Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the

past (a liver infection).

If you get any of the above, tell your doctor straight away.

Other side effects may include:

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

Headache or feeling tired.

Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion.

Rash.

Muscle cramps or joint, muscle or bone pain.

Swelling such as round your ankles or puffy eyes.

Weight gain

If any of these affects you severely, tell your doctor.

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

Anorexia, weight loss or a disturbed sense of taste.

Feeling dizzy or weak.

Difficulty in sleeping (insomnia).

Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes

or having blurred vision.

Nose bleeds.

Pain or swelling in your abdomen, flatulence, heartburn or constipation.

Itching.

Unusual hair loss or thinning.

Numbness of the hands or feet.

Mouth ulcers.

Joint pain with swelling.

Dry mouth, dry skin or dry eye.

Decreased or increased skin sensitivity.

Hot flushes, chills or night sweats.

If any of these affects you severely, tell your doctor.

Not known (frequency cannot be estimated from the available data):

Reddening and/or swelling on the palms of the hands and soles of the feet which may be

accompanied by tingling sensation and burning pain.

Slowing of growth in children and adolescents.

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If any of these affects you severely, tell your doctor.

Reporting of side effects

If you get 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:

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2,

Tel: +353 1 6764971; Fax: +353 1 6762517;

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Imatinib Koanaa film-coated tablets

This medicine does not require any special storage conditions.

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 Blister and carton after

EXP. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how

to throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Imatinib Koanaa film-coated tablets contains

The active substance is Imatinib (as mesilate). Each film-coated tablet contains 100 mg or

400 mg imatinib (as mesilate).

The other ingredients are

Tablet core: Povidone K30 and magnesium stearate (E572)

Tablet coat: Hypromellose (E464), Macrogol 3350, Talc (E553), Titanium dioxide (E171),

Iron oxide red (E172), Iron oxide yellow (E172)

What Imatinib looks like and contents of the pack

Imatinib Koanaa 100

mg

film-coated

Tablets; Dark yellow to brownish orange colored, film-

coated tablets, round (7.00 mm), biconvex with bevelled edges debossed with ’S’ and ‘1’ on

either side of break line on one side and plain on other side. The tablet can be divided into equal

doses.

Imatinib

400

m g

film-coated

Tablets: Dark yellow to brownish orange colored, film-coated

tablets, capsule shaped (8.5 mm x 16.00 mm), biconvex with bevelled edges debossed with ’S’

and ‘2’ on either side of break line on one side and plain on other side.

The tablet can be divided

into equal doses.

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Imatinib Koanaa film-coated tablets are available in clear PVC/PVDC/Aluminium foil blister

pack

Pack sizes:

Imatinib Koanaa 100 mg film-coated tablets

Blister pack: 20, 30, 60, 120 or 180 film-coated tablets

Imatinib 400 mg film-coated tablets

Blister pack: 10, 30 or 90 film-coated tablets

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Koanaa Healthcare Limited

4th Floor Cavendish House,

369 Burnt Oak Broadway,

Edgware, HA8 5AW Middlesex

United Kingdom.

Manufacturer:

Drehm Pharma GmbH

Hietzinger Hauptstrasse 37

A-1130 Vienna

Austria.

This medicinal product is authorised in the Member States of the EEA under the following

names:

Austria

Imatinib Koanaa 100 mg/400mg Filmtabletten

Belgium

Imatinib Koanaa Healthcare 100 mg/400mg filmcoated tablets

Czech Republic

Imatinib Koanaa 100 mg/400mg potahované tablety

Finland

Imatinib Koanaa 100 mg/400mg, kalvopäällysteiset tabletit

France

IMATINIB KOANAA 100 mg/400mg, comprimé pelliculé sécalble

Germany

Imatinib Koanaa 100 mg/400mg Filmtabletten

Ireland

Imatinib Koanaa 100 mg/400mg Film-coated Tablets

Lithuania

Imatinib Koanaa 100 mg/400mg plėvele dengtos tablets

Latvia

Imatinib Koanaa 100 mg/400mg apvalkotās tabletes

Malta

Imatinib Koanaa 100 mg/400mg Film-coated Tablets

Netherlands

Imatinib Koanaa, 100 mg/400mg, filmomhulde tabletten

Romania

Imatinib Koanaa 100 mg/400mg comprimate filmate

Sweden

Imatinib Koanaa 100 mg/400mg, filmdragerade tabletter

Slovenia

Imatinib Koanaa Healthcare 100 mg/400mg filmsko obložene tablete

United Kingdom

Imatinib 100 mg/400mg Film-coated Tablets

This leaflet was last revised in.

Read the complete document

Health Products Regulatory Authority

30 November 2020

CRN00C245

Page 1 of 26

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Imatinib Koanaa 400 mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 400 mg of Imatinib (as mesilate)

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet:

Dark yellow to brownish orange coloured, film-coated tablets, round (7.00 mm), biconvex with bevelled edges debossed with ’

S’ and ‘1’ on either side of break line on one side and plain on other side. The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Imatinib is indicated for the treatment of

paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) chronic myeloid

leukaemia (CML) for whom bone marrow transplantation is not considered as the first line of treatment.

paediatric patients with Ph+ CML in chronic phase after failure of interferon-alpha therapy, or in accelerated phase

or blast crisis.

adult patients with Ph+ CML in blast crisis.

adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute lymphoblastic

leukaemia (Ph+ ALL) integrated with chemotherapy.

adult patients with relapsed or refractory Ph+ ALL as monotherapy.

adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with platelet-derived

growth factor receptor (PDGFR) gene re-arrangements.

adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia (CEL) with

FIP1L1-PDGFRα rearrangement.

The effect of Imatinib on the outcome of bone marrow transplantation has not been determined.

Imatinib is indicated for

the treatment of adult patients with Kit (CD 117) positive unresectable and/or metastatic malignant gastrointestinal

stromal tumours (GIST).

the adjuvant treatment of adult patients who are at significant risk of relapse following resection of Kit

(CD117)-positive GIST. Patients who have a low or very low risk of recurrence should not receive adjuvant

treatment.

the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with

recurrent and/or metastatic DFSP who are not eligible for surgery.

In adult and paediatric patients, the effectiveness of imatinib is based on overall haematological and cytogenetic response

rates and progression-free survival in CML, on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on

haematological response rates in HES/CEL and on objective response rates in adult patients with unresectable and/or

metastatic GIST and DFSP and on recurrence free survival in adjuvant GIST. The experience with imatinib in patients with

MDS/MPD associated with PDGFR gene re-arrangements is very limited (see section 5.1). There are no controlled trials

demonstrating a clinical benefit or increased survival for these diseases.

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Page 2 of 26

4.2 Posology and method of administration

Therapy should be initiated by a physician experienced in the treatment of patients with haematological malignancies and

malignant sarcomas, as appropriate.

For doses of 400 mg and above (see dosage recommendation below) a 400 mg tablet is available.

For doses other than 400 mg and 800 mg (see dosage recommendation below) a 100 mg divisible tablet is available.

The prescribed dose should be administered orally with a meal and a large glass of water to minimise the risk of

gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, whereas a daily dose of 800 mg

should be administered as 400 mg twice a day, in the morning and in the evening.

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of still water or apple juice. The

required number of tablets should be placed in the appropriate volume of beverage (approximately 50 ml for a 100 mg tablet,

and 200 ml for a 400 mg tablet) and stirred with a spoon. The suspension should be administered immediately after complete

disintegration of the tablet(s).

Posology for CML in adult patients

The recommended dose of Imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis is defined as blasts ≥ 30% in

blood or bone marrow or extramedullary disease other than hepatosplenomegaly.

Treatment duration: In clinical trials, treatment with imatinib was continued until disease progression. The effect of stopping

treatment after the achievement of a complete cytogenetic response has not been investigated.

Dose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with blast crisis may be

considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or

thrombocytopenia in the following circumstances: disease progression (at any time); failure to achieve a satisfactory

haematological response after at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of

treatment; or loss of a previously achieved haematological and/or cytogenetic response. Patients should be monitored closely

following dose escalation given the potential for an increased incidence of adverse reactions at higher dosages.

Posology for CML in children

Dosing for children should be on the basis of body surface area (mg/m

). The dose of 340 mg/m

daily is recommended for

children with chronic phase CML and advanced phase CML (not to exceed the total dose of 800 mg). Treatment can be given

as a once daily dose or alternatively the daily dose may be split into two administrations – one in the morning and one in the

evening. The dose recommendation is currently based on a small number of paediatric patients (see sections 5.1 and 5.2).

There is no experience with the treatment of children below 2 years of age.

Dose increases from 340 mg/m

daily to 570 mg/m

daily (not to exceed the total dose of 800 mg) may be considered in

children in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia

in the following circumstances: disease progression (at any time); failure to achieve a satisfactory haematological response after

at least 3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously

achieved haematological and/or cytogenetic response. Patients should be monitored closely following dose escalation given

the potential for an increased incidence of adverse reactions at higher dosages.

Posology for Ph+ ALL in adult patients

The recommended dose of Imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological experts in the management

of this disease should supervise the therapy throughout all phases of care.

Treatment schedule: On the basis of the existing data, imatinib has been shown to be effective and safe when administered at

600 mg/day in combination with chemotherapy in the induction phase, the consolidation and maintenance phases of

chemotherapy (see section 5.1) for adult patients with newly diagnosed Ph+ ALL. The duration of imatinib therapy can vary

with the treatment programme selected, but generally longer exposures to imatinib have yielded better results.

Health Products Regulatory Authority

30 November 2020

CRN00C245

Page 3 of 26

For adult patients with relapsed or refractory Ph+ALL Imatinib monotherapy at 600 mg/day is safe, effective and can be given

until disease progression occurs.

Posology for Ph+ ALL in children

Dosing for children should be on the basis of body surface area (mg/m

). The dose of 340 mg/m

daily is recommended for

children with Ph+ ALL (not to exceed the total dose of 600 mg).

Posology for MDS/MPD

The recommended dose of Imatinib is 400 mg/day for adult patients with MDS/MPD.

Treatment duration: In the only clinical trial performed up to now, treatment with imatinib was continued until disease

progression (see section 5.1). At the time of analysis, the treatment duration was a median of 47 months (24 days - 60 months).

Posology for HES/CEL

The recommended dose of Imatinib is 100 mg/day for adult patients with HES/CEL.

Dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions if assessments

demonstrate an insufficient response to therapy.

Treatment should be continued as long as the patient continues to benefit.

Posology for GIST

The recommended dose of Imatinib is 400 mg/day for patients with unresectable and/or metastatic malignant GIST.

Limited data exist on the effect of dose increases from 400 mg to 600 mg or 800 mg in patients progressing at the lower dose

(see section 5.1).

Treatment duration: In clinical trials in GIST patients, treatment with Imatinib was continued until disease progression. At the

time of analysis, the treatment duration was a median of 7 months (7 days to 13 months). The effect of stopping treatment

after achieving a response has not been investigated.

The recommended dose of Imatinib is 400 mg/day for the adjuvant treatment of adult patients following resection of GIST.

Optimal treatment duration is not yet established. Length of

treatment in the clinical trial supporting this indication was 36 months (see section 5.1).

Posology for DFSP

The recommended dose of Imatinib is 800 mg/day for adult patients with DFSP.

Dose adjustment for adverse reactions

Non-haematological adverse reactions

If a severe non-haematological adverse reaction develops with imatinib use, treatment must be withheld until the event has

resolved. Thereafter, treatment can be resumed as appropriate depending on the initial severity of the event.

If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases > 5 x IULN occur, Imatinib

should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase levels to < 2.5 x IULN. Treatment with

imatinib may then be continued at a reduced daily dose. In adults the dose should be reduced from 400 to 300 mg or from 600

to 400 mg, or from 800 mg to 600 mg, and in children from 340 to 260 mg/m

/day.

Haematological adverse reactions

Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are recommended as indicated in the

table below.

Dose adjustments for neutropenia and thrombocytopenia:

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HES/CEL

(starting dose 100 mg)

ANC < 1.0 x 10

and/or

platelets < 50 x 10

1. Stop Imatinib until ANC ≥ 1.5 x 10

/l and

platelets ≥ 75 x 10

2. Resume treatment with Imatinib at previous

dose (i.e. before severe adverse reaction).

MDS/MPD and GIST (starting dose 400 mg) HES/CEL (at

dose 400 mg)

ANC < 1.0 x 10

and/or

platelets < 50 x 10

1. Stop Imatinib until ANC ≥ 1.5 x 10

/l and

platelets ≥ 75 x 10

2. Resume treatment with Imatinib at previous

dose (i.e. before severe adverse reaction).

3. In the event of recurrence of ANC< 1.0 x 10

and/or platelets < 50x 10

/l, repeat step 1 and

resume Imatinib at reduced dose of 300 mg.

Paediatric chronic phase CML

(at dose 340 mg/m

ANC < 1.0 x 10

and/or

platelets < 50 x 10

1. Stop Imatinib until ANC ≥ 1.5 x 10

/l and

platelets ≥ 75 x 10

2. Resume treatment with Imatinib at previous

dose (i.e. before severe adverse reaction).

3. In the event of recurrence of ANC <1.0 x 10

and/or platelets < 50 x10

/l, repeat step 1 and

resume Imatinib at reduced dose of 260 mg/m

CML in Blast crisis and Ph+ ALL

(starting dose 600 mg)

ANC< 0.5 x 10

and/or

platelets < 10 x 10

1. Check whether cytopenia is related to

leukaemia (marrow aspirate or biopsy).

2. If cytopenia is unrelated to leukaemia, reduce

dose of Imatinib to 400 mg.

3. If cytopenia persists for 2 weeks, reduce further

to 300 mg.

4. If cytopenia persists for 4 weeks and is still

unrelated to leukaemia, stop Imatinib until ANC ≥

1 x 10

/l and platelets ≥ 20 x 10

/l, then resume

treatment at 300 mg.

Paediatric accelerated phase CML and blast crisis

(starting dose 340 mg/m

ANC< 0.5 x 10

and/or

platelets < 10 x 10

1. Check whether cytopenia is related to

leukaemia (marrow aspirate or biopsy).

2. If cytopenia is unrelated to leukaemia, reduce

dose of Imatinib to 260 mg/m

3. If cytopenia persists for 2 weeks, reduce further

to 200 mg/m

4. If cytopenia persists for 4 weeks and is still

unrelated to leukaemia, stop Imatinib until ANC ≥

1 x 10

/l and platelets ≥ 20 x 10

/l, then resume

treatment at 200 mg/m

DFSP

(at dose 800 mg)

ANC < 1.0 x 10

and/or

platelets < 50 x 10

1. Stop Imatinib until ANC ≥ 1.5 x 10

/l and

platelets ≥ 75 x 10

2. Resume treatment with Imatinib at 600 mg.

3. In the event of recurrence of ANC < 1.0 x 10

and/or platelets < 50 x 10

/l, repeat step 1 and

resume Imatinib at reduced dose of 400 mg.

ANC = absolute neutrophil count

occurring after at least 1 month of treatment

Special populations

Paediatric use:There is no experience in children with CML below 2 years of age and with Ph+ALL below 1 year of age (see

section 5.1). There is very limited experience in children with MDS/MPD, DFSP, GIST and HES/CEL.

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The safety and efficacy of imatinib in children with MDS/MPD, DFSP, GIST and HES/CEL aged less than 18 years of age have not

been established in clinical trials. Currently available published data are summarised in section 5.1 but no recommendation on

a posology can be made.

Hepatic insufficiency:Imatinib is mainly metabolised through the liver. Patients with mild, moderate or severe liver dysfunction

should be given the minimum recommended dose of 400 mg daily. The dose can be reduced if not tolerated (see sections 4.4,

4.8 and 5.2).

Liver dysfunction classification:

Liver dysfunction

Liver function tests

Mild

Total bilirubin: = 1.5 ULN

AST: >ULN (can be normal or < ULN if total

bilirubin is > ULN)

Moderate

Total bilirubin: > 1.5-3.0 ULN

AST: any

Severe

Total bilirubin: > 3-10 ULN

AST: any

ULN = upper limit of normal for the institution

AST = asparate aminotransferase

Renal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimum recommended dose of 400 mg

daily as starting dose. However, in these patients caution is recommended. The dose can be reduced if not tolerated. If

tolerated, the dose can be increased for lack of efficacy (see sections 4.4 and 5.2).

Older people: Imatinib pharmacokinetics have not been specifically studied in older people. No significant age-related

pharmacokinetic differences have been observed in adult patients in clinical trials which included over 20% of patients age 65

and older. No specific dose recommendation is necessary in older people.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

When imatinib is co-administered with other medicinal products, there is a potential for drug interactions. Caution should be

used when taking imatinib with protease inhibitors, azole antifungals, certain macrolides (see section 4.5), CYP3A4 substrates

with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl,

alfentanil, terfenadine, bortezomib, docetaxel, quinidine) or warfarin and other coumarin derivatives (see section 4.5).

Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone, phenytoin, carbamazepine,

rifampicin, phenobarbital or Hypericumperforatum, also known as St. John's Wort) may significantly reduce exposure to

imatinib, potentially increasing the risk of therapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and

imatinib should be avoided (see section 4.5).

Hypothyroidism

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoing levothyroxine replacement during

treatment with imatinib (see section 4.5). Thyroid-stimulating hormone (TSH) levels should be closely monitored in such

patients.

Hepatotoxicity

Metabolism of imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. In patients with hepatic

dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should be carefully monitored (see sections

4.2, 4.8 and 5.2). It should be noted that GIST patients may have hepatic metastases which could lead to hepatic impairment.

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Cases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib. When imatinib is

combined with high dose chemotherapy regimens, an increase in serious hepatic reactions has been detected. Hepatic function

should be carefully monitored in circumstances where imatinib is combined with chemotherapy regimens also known to be

associated with hepatic dysfunction (see section 4.5 and 4.8).

Fluid retention

Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, superficial oedema) have been

reported in approximately 2.5% of newly diagnosed CML patients taking imatinib. Therefore, it is highly recommended that

patients be weighed regularly. An unexpected rapid weight gain should be carefully investigated and if necessary appropriate

supportive care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence of these

events in older people and those with a prior history of cardiac disease. Therefore, caution should be exercised in patients with

cardiac dysfunction

Patients with cardiac disease

Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be monitored carefully, and any

patient with signs or symptoms consistent with cardiac or renal failure should be evaluated and treated.

In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the myocardium, isolated cases of

cardiogenic shock/left ventricular dysfunction have been associated with HES cell degranulation upon the initiation of imatinib

therapy. The condition was reported to be reversible with the administration of systemic steroids, circulatory support measures

and temporarily withholding imatinib. As cardiac adverse events have been reported uncommonly with imatinib, a careful

assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL population before treatment initiation.

Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated with high eosinophil levels.

Evaluation by a cardiology specialist, performance of an echocardiogram and determination of serum troponin should

therefore be considered in patients with HES/CEL, and in patients with MDS/MPD associated with high eosinophil levels before

imatinib is administered. If either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic

steroids (1–2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of therapy.

Gastrointestinal haemorrhage

In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and intra-tumoural haemorrhages were

reported (see section 4.8). Based on the available data, no predisposing factors (e.g. tumour size, tumour location, coagulation

disorders) have been identified that place patients with GIST at a higher risk of either type of haemorrhage. Since increased

vascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard practices and procedures for

the monitoring and management of haemorrhage in all patients should be applied.

In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has been reported in

post-marketing experience in patients with CML, ALL and other diseases (see section 4.8). When needed, discontinuation of

imatinib treatment may be considered.

Tumour lysis syndrome

Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant dehydration and treatment of

high uric acid levels are recommended prior to initiation of imatinib (see section 4.8).

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL

tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or

a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with Imatinib. Experts in liver disease and in the

treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology

(including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who

require treatment with Imatinib should be closely monitored for signs and symptoms of active HBV infection throughout

therapy and for several months following termination of therapy (see section 4.8).

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Laboratory tests

Complete blood counts must be performed regularly during therapy with imatinib. Treatment of CML patients with imatinib

has been associated with neutropenia or thrombocytopenia. However, the occurrence of these cytopenias is likely to be related

to the stage of the disease being treated and they were more frequent in patients with accelerated phase CML or blast crisis as

compared to patients with chronic phase CML. Treatment with imatinib may be interrupted or the dose may be reduced, as

recommended in section 4.2.

Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in patients receiving imatinib.

In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in patients with normal renal

function, probably due to an elevated plasma level of alpha-acid glycoprotein (AGP), an imatinib-binding protein, in these

patients. Patients with renal impairment should be given the minimum starting dose. Patients with severe renal impairment

should be treated with caution. The dose can be reduced if not tolerated (see section 4.2 and 5.2).

Long-term treatment with imatinib may be associated with a clinically significant decline in renal function. Renal function

should, therefore, be evaluated prior to the start of imatinib therapy and closely monitored during therapy, with particular

attention to those patients exhibiting risk factors for renal dysfunction. If renal dysfunction is observed, appropriate

management and treatment should be prescribed in accordance with standard treatment guidelines.

Paediatric population

There have been case reports of growth retardation occurring in children and pre-adolescents receiving imatinib. The

long-term effects of prolonged treatment with imatinib on growth in children are unknown. Therefore, close monitoring of

growth in children under imatinib treatment is recommended (see section 4.8).

4.5 Interaction with other medicinal products and other forms of interactions

Active substances that may increase imatinib plasma concentrations

Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitors such as indinavir,

lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azole antifungals including ketoconazole, itraconazole,

posaconazole, voriconazole; certain macrolides such as erythromycin, clarithromycin and telithromycin) could decrease

metabolism and increase imatinib concentrations. There was a significant increase in exposure to imatinib (the mean C

AUC of imatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with a single dose of

ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administering imatinib with inhibitors of the CYP3A4 family.

Active substances that may decrease imatinib plasma concentrations

Substances that are inducers of CYP3A4 activity (e.g. dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital,

fosphenytoin, primidone or Hypericum perforatum, also known as St. John's Wort) may significantly reduce exposure to

imatinib, potentially increasing the risk of therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed

by a single 400 mg dose of imatinib resulted in decrease in C

and AUC

(0-∞)

by at least 54% and 74%, of the respective values

without rifampicin treatment. Similar results were observed in patients with malignant gliomas treated with imatinib while

taking enzyme-inducing anti-epileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC

for imatinib decreased by 73% compared to patients not on EIAEDs. Concomitant use of rifampicin or other strong CYP3A4

inducers and imatinib should be avoided.

Active substances that may have their plasma concentration altered by imatinib

Imatinib increases the mean C

and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, respectively, indicating an

inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended when administering imatinib with CYP3A4 substrates

with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl,

alfentanil, terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of other CYP3A4

metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel blockers, certain HMG-CoA reductase

inhibitors, i.e. statins, etc.).

Because of known increased risks of bleeding in conjunction with the use of imatinib (e.g. haemorrhage), patients who require

anticoagulation should receive low-molecular-weight or standard heparin, instead of coumarin derivatives such as warfarin.

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In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar to those that affect CYP3A4

activity. Imatinib at 400 mg twice daily had an inhibitory effect on CYP2D6-mediated metoprolol metabolism, with metoprolol

and AUC being increased by approximately 23% (90%CI [1.16-1.30]). Dose adjustments do not seem to be necessary when

imatinib is co-administrated with CYP2D6 substrates, however caution is advised for CYP2D6 substrates with a narrow

therapeutic window such as metoprolol. In patients treated with metoprolol clinical monitoring should be considered.

In vitro, imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/l. This inhibition has not been observed

in vivo after the administration of imatinib 400 mg and paracetamol 1000 mg. higher doses of imatinib and paracetamol have

not been studied.

Caution should therefore be exercised when using high doses of imatinib and paracetamol concomitantly.

In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be decreased when imatinib is

co-administered (see section 4.4). Caution is therefore recommended. However, the mechanism of the observed interaction is

presently unknown.

In Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy (see section 5.1), but

drug-drug interactions between imatinib and chemotherapy regimens are not well characterised. Imatinib adverse events, i.e.

hepatotoxicity, myelosuppression or others, may increase and it has been reported that concomitant use with L-asparaginase

could be associated with increased hepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination requires

special precaution.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential must be advised to use effective contraception during treatment.

Pregnancy

There are limited data on the use of imatinib in pregnant women. Studies in animals have however shown reproductive toxicity

(see section 5.3) and the potential risk for the foetus is unknown. imatinib should not be used during pregnancy unless clearly

necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding

There is limited information on imatinib distribution on human milk. Studies in two breast-feeding women revealed that both

imatinib and its active metabolite can be distributed into human milk. The milk plasma ratio studied in a single patient was

determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater distribution of the metabolite into the milk.

Considering the combined concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the

total exposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of low-dose exposure of

the infant to imatinib are unknown, women taking imatinib should not breast-feed.

Fertility

In non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies on patients receiving

imatinib and its effect on fertility and gametogenesis have not been performed. Patients concerned about their fertility on

imatinib treatment should consult with their physician.

4.7 Effects on ability to drive and use machines

Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision or somnolence during

treatment with imatinib. Therefore, caution should be recommended when driving a car or operating machinery.

4.8 Undesirable effects

Patients with advanced stages of malignancies may have numerous confounding medical conditions that make causality of

adverse reactions difficult to assess due to the variety of symptoms related to the underlying disease, its progression, and the

co-administration of numerous medicinal products.

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In clinical trials in CML, drug discontinuation for drug-related adverse reactions was observed in 2.4% of newly diagnosed

patients, 4% of patients in late chronic phase after failure of interferon therapy, 4% of patients in accelerated phase after failure

of interferon therapy and 5% of blast crisis patients after failure of interferon therapy. In GIST the study drug was discontinued

for drug-related adverse reactions in 4% of patients.

The adverse reactions were similar in all indications, with two exceptions. There was more myelosuppression seen in CML

patients than in GIST, which is probably due to the underlying disease. In the study in patients with unresectable and/or

metastatic GIST, 7 (5%) patients experienced CTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1

patient). GI tumour sites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be serious

and sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions in both settings were mild nausea,

vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps and rash. Superficial oedemas were a common finding in

all studies and were described primarily as periorbital or lower limb oedemas. However, these oedemas were rarely severe and

may be managed with diuretics, other supportive measures, or by reducing the dose of imatinib.

When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver toxicity in the form of

transaminase elevation and hyperbilirubinaemia were observed. Considering the limited safety database, the adverse events

thus far reported in children are consistent with the known safety profile in adult patients with Ph+ ALL. The safety database for

children with Ph+ALL is very limited though no new safety concerns have been identified.

Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight gain with or without

superficial oedema may be collectively described as “fluid retention”. These reactions can usually be managed by withholding

imatinib temporarily and with diuretics and other appropriate supportive care measures. However, some of these reactions may

be serious or life-threatening and several patients with blast crisis died with a complex clinical history of pleural effusion,

congestive heart failure and renal failure. There were no special safety findings in paediatric clinical trials.

Adverse reactions

Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequency

categories are defined using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon

(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available

data).

Within each frequency grouping, undesirable effects are presented in order of frequency, the most frequent first.

Adverse reactions and their frequencies are reported in Table 1.

Table 1 Tabulated summary of adverse reactions

Infections and infestations

Uncommon:

Herpes zoster, herpes simplex, nasopharyngitis, pneumonia

, sinusitis, cellulitis, upper respiratory tract infection,

influenza, urinary tract infection, gastroenteritis, sepsis

Rare:

Fungal infection

Not known

Hepatitis B reactivation*

Neoplasm benign, malignant and unspecified (including cysts and polyps)

Rare:

Tumour lysis syndrome

Not known:

Tumour haemorrhage/tumour necrosis*

Immune system disorders

Not known:

Anaphylactic shock*

Blood and lymphatic system disorders

Very common:

Neutropenia, thrombocytopenia, anaemia

Common:

Pancytopenia, febrile neutropenia

Uncommon:

Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia, lymphadenopathy

Rare:

Haemolytic anaemia

Metabolism and nutrition disorders

Common:

Anorexia

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Uncommon:

Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite, dehydration, gout, hyperuricaemia,

hypercalcaemia, hyperglycaemia, hyponatraemia

Rare:

Hyperkalaemia, hypomagnesaemia

Psychiatric disorders

Common:

Insomnia

Uncommon:

Depression, libido decreased, anxiety

Rare:

Confusional state

Nervous system disorders

Very common:

Headache

Common:

Dizziness, paraesthesia, taste disturbance, hypoaesthesia

Uncommon:

Migraine, somnolence, syncope, peripheral neuropathy, memory impairment, sciatica, restless leg syndrome,

tremor, cerebral haemorrhage

Rare:

Increased intracranial pressure, convulsions, optic neuritis

Not known:

Cerebral oedema*

Eye disorders

Common:

Eyelid oedema, lacrimation increased, conjunctival haemorrhage, conjunctivitis, dry eye, blurred vision

Uncommon:

Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinal haemorrhage, blepharitis, macular oedema

Rare:

Cataract, glaucoma, papilloedema

Not known:

Vitreous haemorrhage*

Ear and labyrinth disorders

Uncommon:

Vertigo, tinnitus, hearing loss

Cardiac disorders

Uncommon:

Palpitations, tachycardia, cardiac failure congestive

, pulmonary oedema

Rare:

Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, pericardial effusion

Not known:

Pericarditis*, cardiac tamponade*

Vascular disorders

4

Common:

Flushing, haemorrhage

Uncommon:

Hypertension, haematoma, subdural haematoma, peripheral coldness, hypotension, Raynaud's phenomenon

Not known:

Thrombosis/embolism*

Respiratory, thoracic and mediastinal disorders

Common:

Dyspnoea, epistaxis, cough

Uncommon:

Pleural effusion

, pharyngolaryngeal pain, pharyngitis

Rare:

Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage

Not known:

Acute respiratory failure

*, interstitial lung disease*

Gastrointestinal disorders

Very common:

Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain

Common:

Flatulence, abdominal distension, gastro-oesophageal reflux, constipation, dry mouth, gastritis

Uncommon:

Stomatitis, mouth ulceration, gastrointestinal haemorrhage

, eructation, melaena, oesophagitis, ascites, gastric

ulcer, haematemesis, cheilitis, dysphagia, pancreatitis

Rare:

Colitis, ileus, inflammatory bowel disease

Not known:

Ileus/intestinal obstruction*, gastrointestinal perforation*, diverticulitis*, gastric antral vascular ectasia (GAVE)*

Hepatobiliary disorders

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