Imatinib 400mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Imatinib mesilate
Available from:
Wockhardt UK Ltd
ATC code:
L01XE01
INN (International Name):
Imatinib mesilate
Dosage:
400mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 08010500; GTIN: 5012727912721 5012727913018
Authorization number:
PL 29831/0639

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CHANGE CONTROL : Version changes due to change in:

Size/Layout Regulatory Non-Regulatory

Changes in detail:

New regulatory text

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,

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

1. What Imatinib Tablets are and what they are used for

2. What you need to know before you take Imatinib Tablets

3. How to take Imatinib Tablets

4. Possible side effects

5. How to store Imatinib Tablets

6. Contents of the pack and other information

1. What Imatinib Tablets are and what they are used for

Imatinib 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 Tablets is a treatment for adults and children 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.

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 certain abnormal white cells (named

lymphoblasts) start growing out of control. Imatinib Tablets

inhibits the growth of these cells.

Imatinib 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

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 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 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 Tablets works or

why this medicine has been prescribed for you, ask your

doctor.

2. What you need to know before you take Imatinib

Tablets

Imatinib 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 Tablets:

if you are allergic to imatinib or any of the other ingredients

of this medicine (listed in section 6). If this applies to you,

tell your doctor without taking Imatinib Tablets.

If you think you may be allergic but are not sure, ask your

doctor for advice.

Warnings and precautions

Talk to your doctor before taking Imatinib 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 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.

If any of these apply to you, tell your doctor before taking

Imatinib Tablets.

During treatment with Imatinib Tablets, tell your doctor

straight away if you put on weight very quickly. Imatinib

Tablets may cause your body to retain water (severe fluid

retention).

While you are taking Imatinib 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 Tablets is also a treatment for children and

adolescents 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 Tablets may

have slower than normal growth. The doctor will monitor the

growth at regular visits.

Other medicines and Imatinib 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 Tablets

when taken together. They may increase or decrease the

effect of Imatinib Tablets, either leading to increased side

effects or making Imatinib Tablets less effective. Imatinib

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 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 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

Tablets.

Patients who are concerned about their fertility while taking

Imatinib 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 Tablets

Your doctor has prescribed Imatinib Tablets because you

suffer from a serious condition. Imatinib Tablets can help you

to fight this condition.

However, always take this medicine exactly as your doctor or

pharmacist has told you. It is important that you do this as

long as your doctor or pharmacist tells you to. Check with your

doctor or pharmacist if you are not sure.

Do not stop taking Imatinib 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 Tablets to take

Use in adults

Your doctor will tell you exactly how many Imatinib Tablets to

take.

If you are being treated for CML:

Depending on your condition the usual starting dose is

either 400mg or 600mg:

400mg to be taken as four tablets of 100mg or one tablet

of 400mg once a day

600mg to be taken as six tablets of 100mg or one 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

800mg (eight tablets of 100mg or 2 tablets of 400mg), you

should take four tablets of 100mg or one tablet of 400mg in

the morning and four tablets of 100mg or one tablet of 400mg

in the evening.

If you are being treated for Ph-positive ALL:

The starting dose is 600mg to be taken as six tablets of

100mg or one tablet of 400mg plus two tablets of 100mg

once a day.

If you are being treated for MDS/MPD: The starting dose

is 400 mg to be taken as four tablets of 100mg or one tablet

of 400mg once a day.

If you are being treated for HES/CEL:

The starting dose is 100mg, to be taken as one tablet of

100mg once a day. Your doctor may decide to increase the

dose to 400mg, to be taken as four tablets of 100mg or one

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

to treatment.

If you are being treated for DFSP:

The dose is 800mg per day (to be taken as four tablets of

100mg or one tablet of 400mg in the morning and four

tablets of 100mg or one tablet of 400mg in the evening).

Use in children and adolescents

The doctor will tell you how many tablets of Imatinib to give to

your child. The amount of Imatinib Tablets given will depend

on your child’s condition, body weight and height. The total

daily dose in children and adolescents must not exceed

800mg with CML and 600mg 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 Tablets

Take Imatinib Tablets with a meal. This will help protect

you from stomach problems when taking Imatinib 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 50ml for each 100mg tablet or 200ml for each

400mg tablet

Package leaflet: Information for the user

Imatinib 100mg Film-Coated tablets

Imatinib 400mg Film-Coated Tablets

Imatinib

(referred to as Imatinib Tablets in the remainder of this leaflet)

Artwork for UK submission only

ART WORK CHECK BOX

PRODUCT :

Imatinib 100mg & 400mg Film-Coated Tablets - 30 Tabs

CUSTOMER :

Wockhardt UK

FP CODE:

PLANT LOCATION :

For UK submission only

DIMENSIONS :

(w)180mm x (h)400mm

TEXT FONT SIZE

8 pt.

FILE NAME :

Imatinib_400mg_Leaflet_107941-5.ai

SOFTWARE :

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TYPEFACES :

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ARTWORK (DETAILS)

2nd December, 2016

RECEIVED ON :

PROOF REVISION :

R 1st PDF sent on

- 13TH DEC. 2016

R 2nd PDF sent on - 16TH DEC. 2016

R 3rd PDF sent on

- 20TH FEB. 2017

R 4th PDF sent on

- 1ST MARCH 2017

R 5th PDF sent on

- 29TH MARCH 2017

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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.

How long to take Imatinib Tablets

Keep taking Imatinib Tablets every day for as long as your

doctor tells you.

If you take more Imatinib 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 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:

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

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

rapid weight gain. Imatinib 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 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 cellulitis)

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).

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, during

Imatinib Tablets treatment or after you have stopped taking

Imatinib Tablets.

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.

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

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or

nurse. This includes any possible side effects not listed in this

leaflet. You can also report side effects directly via the national

reporting systems listed below:

United Kingdom:

Yellow Card Scheme

Website: http://www.mhra.gov.uk/yellowcard

Ireland:

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 Tablets

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 carton or bottle label after ‘EXP’. The expiry

date refers to the last day of the month.

Do not store above 25°C.

Do not use any pack that is damaged or shows signs of

tampering.

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 Tablets contain

The active substance is imatinib mesilate. Each 100mg

tablet contains 100mg imatinib (as mesilate). Each 400mg

tablet contains 400mg imatinib (as mesilate).

The other ingredients are sodium stearyl fumarate.

The tablet coating of the 100mg and 400mg tablets are

made of hydroxypropylmethyl cellulose, red iron oxide

(E172), yellow iron oxide (E172) and talc.

What Imatinib Tablets looks like and contents of the pack

Imatinib 100mg film-coated tablets are brownish, round,

biconvex, film-coated tablets embossed with "100" on one

side and a score line on the other side, with "N" on one side of

the score line and "I" on the other side of the score line.

Imatinib 400mg Film-Coated Tablets are brownish, oval,

biconvex, film-coated tablets embossed with “400” on one side

and “NI” on the other side.

They are supplied in Aluminium/aluminium (Alu/Alu) packs

containing 10, 20, 30, 60, 90, 120 and 180 film-coated tablets

or High density polyethylene (HDPE) bottles with a

polypropylene child-resistant closure containing 30, 60, 90,

120 and 180 film-coated tablets.

Not all pack sizes may be available.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder: Wockhardt UK Ltd,

Ash Road North, Wrexham, LL13 9UF, UK.

Manufacturer: CP Pharmaceuticals Ltd, Ash Road North,

Wrexham, LL13 9UF, UK.

This Medicinal Product is authorised in the Member

States under the following names:

UK & Ireland: Imatinib 100mg & 400mg Film-Coated Tablets

Other formats:

To listen to or request a copy of this leaflet in Braille, large

print or audio please call, free of charge:

0800 198 5000 (UK only)

Please be ready to give the following information:

Product name

Reference number

Imatinib 100mg Film-Coated Tablets

29831/0638

Imatinib 400mg Film-Coated Tablets

29831/0639

This is a service provided by the Royal National Institute of

Blind People.

For the Republic of Ireland please call +44 1978 661261

This leaflet was last revised in 02/2017

pg2/2

107941/5

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Object 1

Imatinib 400mg Film-Coated Tablets

Summary of Product Characteristics Updated 22-Aug-2017 | Wockhardt UK Ltd

1. Name of the medicinal product

Imatinib 400mg Film-Coated Tablets

2. Qualitative and quantitative composition

Each film-coated tablet contains 400mg imatinib (as mesilate).

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Film-coated tablet.

Brownish, oval, biconvex, film-coated tablets embossed with "400" on one side and "NI" on the other

side.

4. Clinical particulars

4.1 Therapeutic indications

Imatinib is indicated for the treatment of:

adult and 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.

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

in accelerated phase or 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.

adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and adult patients with

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

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

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 DFSP. The experience with imatinib in patients with MDS/MPD

associated with PDGFR gene re-arrangements is very limited (see section 5.1). Except in newly

diagnosed chronic phase CML, there are no controlled trials demonstrating a clinical benefit or increased

survival for these diseases.

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.

Method of administration

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 mineral

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 dosage of imatinib is 400 mg/day for adult patients in chronic phase CML. Chronic

phase CML is defined when all of the following criteria are met: blasts < 15% in blood and bone marrow,

peripheral blood basophils < 20%, platelets > 100 x 10

The recommended dosage of imatinib is 600 mg/day for adult patients in accelerated phase. Accelerated

phase is defined by the presence of any of the following: blasts ≥ 15% but < 30% in blood or bone

marrow, blasts plus promyelocytes ≥ 30% in blood or bone marrow (providing < 30% blasts), peripheral

blood basophils ≥ 20%, platelets < 100 x 10

/l unrelated to therapy.

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 400 mg to 600 mg or 800 mg in patients with chronic phase disease, or from 600 mg

to a maximum of 800 mg (given as 400 mg twice daily) in patients with accelerated phase or 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 paediatric patients

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.

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 paediatric patients

Dosing for children should be on 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 600mg).

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 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:

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).

Chronic phase CML,

MDS/MPD (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

/l and/or platelets < 50 x 10

/l, repeat step 1

and resume imatinib at reduced dose of 300 mg.

Paediatric chronic phase

(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

/l and/or platelets < 50 x 10

/l, repeat step 1

and resume imatinib at reduced dose of 260

mg/m

Accelerated phase CML

and 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

/l 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

and HES/CEL.

The safety and efficacy of imatinib in children with MDS/MPD, DFSP 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 = aspartate 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).

Elderly patients: Imatinib pharmacokinetics have not been specifically studied in the elderly. 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

the elderly.

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 Hypericum perforatum, 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.

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 Tablets

(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 (BCR-ABL TKIs). 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).

Laboratory tests

Complete blood counts must be performed regularly during therapy with Imatinib Tablets. 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 sections 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 interaction

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

and 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

Tablets 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.

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 C

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 Tablets 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. There have been post-marketing reports

of spontaneous abortions and infant congenital anomalies from women who have taken imatinib. 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.

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 Tablets.

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 Tablets 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

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

Common:

Increased hepatic enzymes

Uncommon:

Hyperbilirubinaemia, hepatitis, jaundice

Rare:

Hepatic failure

, hepatic necrosis

Skin and subcutaneous tissue disorders

Very common:

Periorbital oedema, dermatitis/eczema/rash

Common:

Pruritus, face oedema, dry skin, erythema, alopecia, night sweats, photosensitivity

reaction

Uncommon:

Rash pustular, contusion, sweating increased, urticaria, ecchymosis, increased

tendency to bruise, hypotrichosis, skin hypopigmentation, dermatitis exfoliative,

onychoclasis, folliculitis, petechiae, psoriasis, purpura, skin hyperpigmentation,

bullous eruptions

Rare:

Acute febrile neutrophilic dermatosis (Sweet's syndrome), nail discolouration,

angioneurotic oedema, rash vesicular, erythema multiforme, leucocytoclastic

vasculitis, Stevens-Johnson syndrome, acute generalised exanthematous

pustulosis (AGEP)

Not known:

Palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichen planus*,

toxic epidermal necrolysis*, drug rash with eosinophilia and systemic symptoms

(DRESS)*

Musculoskeletal and connective tissue disorders

Very common:

Muscle spasm and cramps, musculoskeletal pain including myalgia

, arthralgia,

bone pain

Common:

Joint swelling

Uncommon:

Joint and muscle stiffness

Rare:

Muscular weakness, arthritis, rhabdomyolysis/myopathy

Not known:

Avascular necrosis/hip necrosis*, growth retardation in children*

Renal and urinary disorders

Uncommon:

Renal pain, haematuria, renal failure acute, urinary frequency increased

Not known:

Renal failure chronic

Reproductive system and breast disorders

Uncommon:

Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular, sexual

dysfunction, nipple pain, breast enlargement, scrotal oedema

Rare:

Haemorrhagic corpus luteum/haemorrhagic ovarian cyst

General disorders and administration site conditions

Very common:

Fluid retention and oedema, fatigue

Common:

Weakness, pyrexia, anasarca, chills, rigors

Uncommon:

Chest pain, malaise

Investigations:

Very common:

Weight increased

Common:

Weight decreased

Uncommon:

Blood creatinine increased, blood creatine phosphokinase increased, blood lactate

dehydrogenase increased, blood alkaline phosphatase increased

Rare:

Blood amylase increased

*These types of reactions have been reported mainly from post-marketing experience with Imatinib

tablets. This includes spontaneous case reports as well as serious adverse events from ongoing studies, the

expanded access programmes, clinical pharmacology studies and exploratory studies in unapproved

indications. Because these reactions are reported from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal relationship to imatinib exposure.

1 Pneumonia was reported most commonly in patients with transformed CML and in patients with GIST.

2 Headache was the most common in GIST patients.

3 On a patient-year basis, cardiac events including congestive heart failure were more commonly

observed in patients with transformed CML than in patients with chronic CML.

4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was most

common in patients with GIST and with transformed CML (CML-AP and CML-BC).

5 Pleural effusion was reported more commonly in patients with GIST and in patients with transformed

CML (CML-AP and CML-BC) than in patients with chronic CML.

6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST patients.

8 Some fatal cases of hepatic failure and of hepatic necrosis have been reported.

9 Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed in post-

marketing.

10 Musculoskeletal pain and related events were more commonly observed in patients with CML than in

GIST patients.

11 Fatal cases have been reported in patients with advanced disease, severe infections, severe neutropenia

and other serious concomitant conditions.

Laboratory test abnormalities

Haematology

In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in all

studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study). However, the

occurrence of cytopenias was also clearly dependent on the stage of the disease, the frequency of grade 3

or 4 neutropenias (ANC < 1.0 x 10

/l) and thrombocytopenias (platelet count < 50 x 10

/l) being between

4 and 6 times higher in blast crisis and accelerated phase (59–64% and 44–63% for neutropenia and

thrombocytopenia, respectively) as compared to newly diagnosed patients in chronic phase CML (16.7%

neutropenia and 8.9% thrombocytopenia). In newly diagnosed chronic phase CML grade 4 neutropenia

(ANC < 0.5 x 10

/l) and thrombocytopenia (platelet count < 10 x 10

/l) were observed in 3.6% and < 1%

of patients, respectively. The median duration of the neutropenic and thrombocytopenic episodes usually

ranged from 2 to 3 weeks, and from 3 to 4 weeks, respectively. These events can usually be managed with

either a reduction of the dose or an interruption of treatment with Imatinib Tablets but can in rare cases

lead to permanent discontinuation of treatment. In paediatric CML patients the most frequent toxicities

observed were grade 3 or 4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These

generally occur within the first several months of therapy.

In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported in

5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra-tumoural

bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and 2.7% of

patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient developed grade 4

thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts occurred mainly

during the first six weeks of therapy, with values remaining relatively stable thereafter.

Biochemistry

Severe elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was usually

managed with dose reduction or interruption (the median duration of these episodes was approximately

one week). Treatment was discontinued permanently because of liver laboratory abnormalities in less

than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 ALT (alanine

aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) elevations were

observed. Bilirubin elevation was below 3%.

There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them outcome

was fatal, including one patient on high dose paracetamol.

Description of selected adverse reactions

Hepatitis B reactivation

Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in

acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section

4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions via the Yellow Card Scheme at

www.mhra.gov.uk/yellowcard.

4.9 Overdose

Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases of

imatinib overdose have been reported spontaneously and in the literature. In the event of overdose the

patient should be observed and appropriate symptomatic treatment given. Generally the reported outcome

in these cases was “improved” or “recovered”. Events that have been reported at different dose ranges are

as follows:

Adult population

1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, erythema,

oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal pain, headache,

decreased appetite.

1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine

phosphokinase, increased bilirubin, gastrointestinal pain.

6400 mg (single dose): One case reported in the literature of one patient who experienced nausea,

vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased transaminases.

8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

Paediatric population

One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia

and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood cell

count and diarrhoea.

In the event of overdose, the patient should be observed and appropriate supportive treatment given.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: protein-tyrosine kinase inhibitor, ATC code: L01XE01

Mechanism of action

Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-

Abl tyrosine kinase (TK), as well as several receptor TKs, the discoidin domain receptors (DDR1 and

DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors

alpha and beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by

activation of these receptor kinases.

Pharmacodynamic effects

Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at the in

vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces apoptosis in

Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia chromosome positive CML

and acute lymphoblastic leukaemia (ALL) patients.

In vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl

positive tumour cells.

Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF),

PDGF-R, and inhibits PDGF-mediated cellular events. Constitutive activation of the PDGF receptor or

the Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive

production of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP.

Imatinib inhibits signalling and proliferation of cells driven by dysregulated PDGFR and Abl kinase

activity.

Clinical studies in chronic myeloid leukaemia (CML)

The effectiveness of imatinib is based on overall haematological and cytogenetic response rates and

progression-free survival. Except in newly diagnosed chronic phase CML, there are no controlled trials

demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival.

Three large, international, open-label, non-controlled phase II studies were conducted in patients with

Philadelphia chromosome positive (Ph+) CML in advanced, blast or accelerated phase disease, other Ph+

leukaemias or with CML in the chronic phase but failing prior interferon-alpha (IFN) therapy.

One large, open-label, multicentre, international randomised phase III study has been conducted in

patients with newly diagnosed Ph+ CML.

In addition, children have been treated in two phase I studies (in patients with CML or Ph+ acute

leukaemia) and one phase II study.

In all clinical studies 38–40% of patients were ≥ 60 years of age and 10–12% of patients were ≥ 70 years

of age.

Chronic phase, newly diagnosed: This phase III study in adult patients compared treatment with either

single-agent imatinib or a combination of interferon-alpha (IFN) plus cytarabine (Ara-C).

Patients showing lack of response (lack of complete haematological response (CHR) at 6 months,

increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or

MCyR) or severe intolerance to treatment were allowed to cross over to the alternative treatment arm. In

the imatinib arm, patients were treated with 400 mg daily. In the IFN arm, patients were treated with a

target dose of IFN of 5 MIU/m

/day subcutaneously in combination with subcutaneous Ara-C 20

mg/m2/day for 10 days/month.

A total of 1.106 patients were randomised, 553 to each arm. Baseline characteristics were well balanced

between the two arms. Median age was 51 years (range 18–70 years), with 21.9% of patients ≥ 60 years

of age. There were 59% males and 41% females; 89.9% caucasian and 4.7% black patients. Seven years

after the last patient had been recruited, the median duration of first-line treatment was 82 and 8 months

in the imatinib and IFN arms, respectively. The median duration of second-line treatment with imatinib

was 64 months. Overall, in patients receiving first-line imatinib, the average daily dose delivered was 406

±76 mg. The primary efficacy endpoint of the study is progression-free survival.

Progression was defined as any of the following events: progression to accelerated phase or blast crisis,

death, loss of CHR or MCyR, or in patients not achieving a CHR an increasing WBC despite appropriate

therapeutic management. Major cytogenetic response, haematological response, molecular response

(evaluation of minimal residual disease), time to accelerated phase or blast crisis and survival are main

secondary endpoints. Response data are shown in Table 2.

Table 2 Response in newly diagnosed CML Study (84-month data)

(Best response rates)

Imatinib

n=553

IFN+Ara-C

n=553

Haematological response

CHR rate n (%)

534 (96.6%)*

313 (56.6%)*

[95% CI]

[94.7%, 97.9%]

[52.4%, 60.8%]

Cytogenetic response

Major response n (%)

490 (88.6%)*

129 (23.3%)*

[95% CI]

[85.7%, 91.1%]

[19.9%, 27.1%]

Complete CyR n (%)

456 (82.5%)*

64 (11.6%)*

Partial CyR n (%)

34 (6.1%)

65 (11.8%)

Molecular response**

Major response at 12 months (%)

153/305=50.2%

8/83=9.6%

Major response at 24 months (%)

73/104=70.2%

3/12=25%

Major response at 84 months (%)

102/116=87.9%

3/4=75%

* p<0.001, Fischer's exact test

** molecular response percentages are based on available samples

Haematological response criteria (all responses to be confirmed after ≥ 4 weeks):

WBC < 10 x 10

/l, platelet < 450 x 10

/l, myelocyte+metamyelocyte < 5% in blood, no blasts and

promyelocytes in blood, basophils < 20%, no extramedullary involvement

Cytogenetic response criteria: complete (0% Ph+ metaphases), partial (1–35%), minor (36–65%) or

minimal (66–95%). A major response (0–35%) combines both complete and partial responses.

Major molecular response criteria: in the peripheral blood reduction of ≥ 3 logarithms in the amount of

Bcr-Abl transcripts (measured by real-time quantitative reverse transcriptase PCR assay) over a

standardised baseline.

Rates of complete haematological response, major cytogenetic response and complete cytogenetic

response on first-line treatment were estimated using the Kaplan-Meier approach, for which non-

responses were censored at the date of last examination. Using this approach, the estimated cumulative

response rates for first-line treatment with imatinib improved from 12 months of therapy to 84 months of

therapy as follows: CHR from 96.4% to 98.4% and CCyR from 69.5% to 87.2%, respectively.

With 7 years follow-up, there were 93 (16.8%) progression events in the imatinib arm: 37 (6.7%)

involving progression to accelerated phase/blast crisis, 31 (5.6%) loss of MCyR, 15 (2.7%) loss of CHR

or increase in WBC, and 10 (1.8%) CML unrelated deaths. In contrast, there were 165 (29.8%) events in

the IFN+Ara-C arm, of which 130 occurred during first-line treatment with IFN+Ara-C.

The estimated rate of patients free of progression to accelerated phase or blast crisis at 84 months was

significantly higher in the imatinib arm compared to the IFN arm (92.5% versus 85.1%, p<0.001). The

annual rate of progression to accelerated phase or blast crisis decreased with time on therapy and was less

than 1% annually in the fourth and fifth years. The estimated rate of progression-free survival at 84

months was 81.2% in the imatinib arm and 60.6% in the control arm (p<0.001). The yearly rates of

progression of any type for imatinib also decreased over time.

A total of 71 (12.8%) and 85 (15.4%) patients died in the imatinib and IFN+Ara-C groups, respectively.

At 84 months the estimated overall survival is 86.4% (83, 90) vs. 83.3% (80, 87) in the randomised

imatinib and the IFN+Ara-C groups, respectively (p=0.073, log-rank test). This time-to-event endpoint is

strongly affected by the high crossover rate from IFN+Ara-C to imatinib.

The effect of imatinib treatment on survival in chronic phase, newly diagnosed CML has been further

examined in a retrospective analysis of the above reported imatinib data with the primary data from

another Phase III study using IFN+Ara-C (n=325) in an identical regimen. In this retrospective analysis,

the superiority of imatinib over IFN+Ara-C in overall survival was demonstrated (p<0.001); within 42

months, 47 (8.5%) imatinib patients and 63 (19.4%) IFN+Ara-C patients had died.

The degree of cytogenetic response and molecular response had a clear effect on long-term outcomes in

patients on imatinib. Whereas an estimated 96% (93%) of patients with CCyR (PCyR) at 12 months were

free of progression to accelerated phase/blast crisis at 84 months, only 81% of patients without MCyR at

12 months were free of progression to advanced CML at 84 months (p<0.001 overall, p=0.25 between

CCyR and PCyR). For patients with reduction in Bcr-Abl transcripts of at least 3 logarithms at 12 months,

the probability of remaining free from progression to accelerated phase/blast crisis was 99% at 84

months. Similar findings were found based on a 18-months landmark analysis.

In this study, dose escalations were allowed from 400 mg daily to 600 mg daily, then from 600 mg daily

to 800 mg daily. After 42 months of follow-up, 11 patients experienced a confirmed loss (within 4 weeks)

of their cytogenetic response. Of these 11 patients, 4 patients escalated up to 800 mg daily, 2 of whom

regained a cytogenetic response (1 partial and 1 complete, the latter also achieving a molecular response),

while of the 7 patients who did not escalate the dose, only one regained a complete cytogenetic response.

The percentage of some adverse reactions was higher in the 40 patients in whom the dose was increased

to 800 mg daily compared to the population of patients before dose increase (n=551). The more frequent

adverse reactions included gastrointestinal haemorrhages, conjunctivitis and elevation of transaminases or

bilirubin. Other adverse reactions were reported with lower or equal frequency.

Chronic phase, Interferon failure: 532 adult patients were treated at a starting dose of 400 mg. The

patients were distributed in three main categories: haematological failure (29%), cytogenetic failure

(35%), or intolerance to interferon (36%). Patients had received a median of 14 months of prior IFN

therapy at doses ≥ 25 x 10

IU/week and were all in late chronic phase, with a median time from

diagnosis of 32 months. The primary efficacy variable of the study was the rate of major cytogenetic

response (complete plus partial response, 0 to 35% Ph+ metaphases in the bone marrow).

In this study 65% of the patients achieved a major cytogenetic response that was complete in 53%

(confirmed 43%) of patients (Table 3). A complete haematological response was achieved in 95% of

patients.

Accelerated phase: 235 adult patients with accelerated phase disease were enrolled. The first 77 patients

were started at 400 mg, the protocol was subsequently amended to allow higher dosing and the remaining

158 patients were started at 600 mg.

The primary efficacy variable was the rate of haematological response, reported as either complete

haematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and the

blood, but without a full peripheral blood recovery as for complete responses), or return to chronic phase

CML. A confirmed haematological response was achieved in 71.5% of patients (Table 3). Importantly,

27.7% of patients also achieved a major cytogenetic response, which was complete in 20.4% (confirmed

16%) of patients. For the patients treated at 600 mg, the current estimates for median progression-free-

survival and overall survival were 22.9 and 42.5 months, respectively.

Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received prior

chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 165

(63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol was

subsequently amended to allow higher dosing and the remaining 223 patients were started at 600 mg.

The primary efficacy variable was the rate of haematological response, reported as either complete

haematological response, no evidence of leukaemia, or return to chronic phase CML using the same

criteria as for the study in accelerated phase. In this study, 31% of patients achieved a haematological

response (36% in previously untreated patients and 22% in previously treated patients). The rate of

response was also higher in the patients treated at 600 mg (33%) as compared to the patients treated at

400 mg (16%, p=0.0220). The current estimate of the median survival of the previously untreated and

treated patients was 7.7 and 4.7 months, respectively.

Lymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n=10). The rate of

haematological response was 70% with a duration of 2-3 months.

Table 3 Response in adult CML studies

Study 0110

37-month data

Chronic phase, IFN

failure

(n=532)

Study 0109

40.5-month data

Accelerated phase

(n=235)

Study 0102

38-month data

Myeloid blast crisis

(n=260)

% of patients (CI

Haematological

response

95% (92.3–96.3)

71% (65.3–77.2)

31% (25.2-36.8)

Complete

haematological

response (CHR)

No evidence of

leukaemia (NEL)

Not applicable

Return to chronic

phase (RTC)

Not applicable

Major cytogenetic

response

65% (61.2–69.5)

28% (22.0–33.9)

15% (11.2–20.4)

Complete

(Confirmed

) [95%

(43%) [38.6–47.2]

(16%) [11.3–21.0]

(2%) [0.6-4.4]

Partial

Haematological response criteria (all responses to be confirmed after ≥ 4 weeks):

CHR: Study 0110 [WBC < 10 x 10

/l, platelets < 450 x 10

/l, myelocyte+metamyelocyte < 5% in blood,

no blasts and promyelocytes in blood, basophils < 20%, no extramedullary involvement] and in studies

0102 and 0109 [ANC ≥ 1.5 x 10

/l, platelets ≥ 100 x 10

/l, no blood blasts, BM blasts < 5% and no

extramedullary disease]

NEL Same criteria as for CHR but ANC ≥ 1 x 10

/l and platelets ≥ 20 x 10

/l (0102 and 0109 only)

RTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in PB, no

extramedullary disease other than spleen and liver (only for 0102 and 0109).

BM = bone marrow, PB = peripheral blood

Cytogenetic response criteria:

A major response combines both complete and partial responses: complete (0% Ph+ metaphases), partial

(1–35%)

Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation performed at

least one month after the initial bone marrow study.

Paediatric patients: A total of 26 paediatric patients of age < 18 years with either chronic phase CML

(n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase I

trial. This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a

prior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m

/day (n=5), 340

mg/m

/day (n=9), 440 mg/m

/day (n=7) and 570 mg/m

/day (n=5). Out of 9 patients with chronic phase

CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial cytogenetic

response, respectively, for a rate of MCyR of 77%.

A total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been

enrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib 340

mg/m

/day, with no interruptions in the absence of dose limiting toxicity. Imatinib treatment induces a

rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after 8 weeks of therapy.

The high rate of CHR is accompanied by the development of a complete cytogenetic response (CCyR) of

65% which is comparable to the results observed in adults. Additionally, partial cytogenetic response

(PCyR) was observed in 16% for a MCyR of 81%. The majority of patients who achieved a CCyR

developed the CCyR between months 3 and 10 with a median time to response based on the Kaplan-

Meier estimate of 5.6 months.

The European Medicines Agency has waived the obligation to submit the results of studies with imatinib

in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)-positive

chronic myeloid leukaemia (see section 4.2 for information on paediatric use).

Clinical studies in Ph+ ALL

Newly diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy induction in

55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced a significantly

higher rate of complete haematological response than chemotherapy (96.3% vs. 50%; p=0.0001). When

salvage therapy with imatinib was administered in patients who did not respond or who responded poorly

to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving a complete haematological

response. This clinical effect was associated with a higher reduction in bcr-abl transcripts in the imatinib-

treated patients than in the chemotherapy arm after 2 weeks of therapy (p=0.02). All patients received

imatinib and consolidation chemotherapy (see Table 3) after induction and the levels of bcr-abl transcripts

were identical in the two arms at 8 weeks. As expected on the basis of the study design, no difference was

observed in remission duration, disease-free survival or overall survival, although patients with complete

molecular response and remaining in minimal residual disease had a better outcome in terms of both

remission duration (p=0.01) and disease-free survival (p=0.02).

The results observed in a population of 211 newly diagnosed Ph+ ALL patients in four uncontrolled

clinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above.

Imatinib in combination with chemotherapy induction (see Table 3) resulted in a complete haematological

response rate of 93% (147 out of 158 evaluable patients) and in a major cytogenetic response rate of 90%

(19 out of 21 evaluable patients). The complete molecular response rate was 48% (49 out of 102

evaluable patients). Disease-free survival (DFS) and overall survival (OS) constantly exceeded 1 year and

were superior to historical control (DFS p<0.001; OS p<0.0001) in two studies (AJP01 and AUS01).

Table 4 Chemotherapy regimen used in combination with imatinib

Study ADE10

Prephase

DEX 10 mg/m

oral, days 1-5;

CP 200 mg/m

i.v., days 3, 4, 5;

MTX 12 mg intrathecal, day 1

Remission induction

DEX 10 mg/m

oral, days 6-7, 13-16;

VCR 1 mg i.v., days 7, 14;

IDA 8 mg/m

i.v. (0.5 h), days 7, 8, 14, 15;

CP 500 mg/m

i.v.(1 h) day 1;

Ara-C 60 mg/m

i.v., days 22-25, 29-32

Consolidation therapy I, III, V

MTX 500 mg/m

i.v. (24 h), days 1, 15;

6-MP 25 mg/m

oral, days 1-20

Consolidation therapy II, IV

Ara-C 75 mg/m

i.v. (1 h), days 1-5;

VM26 60 mg/m

i.v. (1 h), days 1-5

Study AAU02

Induction therapy (de novo Ph+ ALL)

Daunorubicin 30 mg/m

i.v., days 1-3, 15-16;

VCR 2 mg total dose i.v., days 1, 8, 15, 22;

CP 750 mg/m

i.v., days 1, 8;

Prednisone 60 mg/m

oral, days 1-7, 15-21;

IDA 9 mg/m

oral, days 1-28;

MTX 15 mg intrathecal, days 1, 8, 15, 22;

Ara-C 40 mg intrathecal, days 1, 8, 15, 22;

Methylprednisolone 40 mg intrathecal, days 1, 8, 15, 22

Consolidation (de novo Ph+ ALL)

Ara-C 1,000 mg/m

/12 h i.v.(3 h), days 1-4;

Mitoxantrone 10 mg/m

i.v. days 3-5;

MTX 15 mg intrathecal, day 1;

Methylprednisolone 40 mg intrathecal, day 1

Study ADE04

Prephase

DEX 10 mg/m

oral, days 1-5;

CP 200 mg/m

i.v., days 3-5;

MTX 15 mg intrathecal, day 1

Induction therapy I

DEX 10 mg/m

oral, days 1-5;

VCR 2 mg i.v., days 6, 13, 20;

Daunorubicin 45 mg/m

i.v., days 6-7, 13-14

Induction therapy II

CP 1 g/m

i.v. (1 h), days 26, 46;

Ara-C 75 mg/m

i.v. (1 h), days 28-31, 35-38, 42-45;

6-MP 60 mg/m

oral, days 26-46

Consolidation therapy

DEX 10 mg/m

oral, days 1-5;

Vindesine 3 mg/m

i.v., day 1;

MTX 1.5 g/m

i.v. (24 h), day 1;

Etoposide 250 mg/m

i.v. (1 h) days 4-5;

Ara-C 2x 2 g/m

i.v. (3 h, q 12 h), day 5

Study AJP01

Induction therapy

CP 1.2 g/m

i.v. (3 h), day 1;

Daunorubicin 60 mg/m

i.v. (1 h), days 1-3;

Vincristine 1.3 mg/m

i.v., days 1, 8, 15, 21;

Prednisolone 60 mg/m

/day oral

Consolidation therapy

Alternating chemotherapy course: high dose chemotherapy

with MTX 1 g/m

i.v. (24 h), day 1, and Ara-C 2 g/m

i.v. (q

12 h), days 2-3, for 4 cycles

Maintenance

VCR 1.3 g/m

i.v., day 1;

Prednisolone 60 mg/m

oral, days 1-5

Study AUS01

Induction-consolidation therapy

Hyper-CVAD regimen: CP 300 mg/m

i.v. (3 h, q 12 h), days

1-3; Vincristine 2 mg i.v., days 4, 11;

Doxorubicine 50 mg/m

i.v. (24 h), day 4;

DEX 40 mg/day on days 1-4 and 11-14, alternated with MTX

1 g/m

i.v. (24 h), day 1, Ara-C 1 g/m

i.v. (2 h, q 12 h), days

2-3 (total of 8 courses)

Maintenance

VCR 2 mg i.v. monthly for 13 months;

Prednisolone 200 mg oral, 5 days per month for 13 months

All treatment regimens include administration of steroids for CNS prophylaxis.

Ara-C: cytosine arabinoside; CP: cyclophosphamide; DEX: dexamethasone; MTX: methotrexate; 6-

MP: 6-mercaptopurine VM26: Teniposide; VCR: vincristine; IDA: idarubicine; i.v.: intravenous

Paediatric patients: In study I2301, a total of 93 paediatric, adolescent and young adult patients (from 1

to 22 years old) with Ph+ ALL were enrolled in an open-label, multicentre, sequential cohort,

nonrandomized phase III trial, and were treated with imatinib (340 mg/m

/day) in combination with

intensive chemotherapy after induction therapy. Imatinib was administered intermittently in cohorts 1- 5,

with increasing duration and earlier start of imatinib from cohort to cohort; cohort 1 receiving the lowest

intensity and cohort 5 receiving the highest intensity of imatinib (longest duration in days with continuous

daily imatinib dosing during the first chemotherapy treatment courses). Continuous daily exposure to

imatinib early in the course of treatment in combination with chemotherapy in cohort 5-patients (n=50)

improved the 4-year event-free survival (EFS) compared to historical controls (n=120), who received

standard chemotherapy without imatinib (69.6% vs. 31.6%, respectively). The estimated 4-year OS in

cohort 5-patients was 83.6% compared to 44.8% in the historical controls. 20 out of the 50 (40%) patients

in cohort 5 received haematopoietic stem cell transplant.

Table 5 Chemotherapy regimen used in combination with imatinib in study I2301

Consolidation block 1

(3 weeks)

VP-16 (100 mg/m

/day, IV): days 1-5

Ifosfamide (1.8 g/m

/day, IV): days 1-5

MESNA (360 mg/m

/dose q3h, x 8 doses/day, IV): days 1-5

G-CSF (5 μg/kg, SC): days 6-15 or until ANC > 1500 post nadir

IT Methotrexate (age-adjusted): day 1 ONLY

Triple IT therapy (age-adjusted): day 8, 15

Consolidation block 2

(3 weeks)

Methotrexate (5 g/m

over 24 hours, IV): day 1

Leucovorin (75 mg/m

at hour 36, IV; 15 mg/m

IV or PO q6h x 6 doses)iii:

Days 2 and 3

Triple IT therapy (age-adjusted): day 1

ARA-C (3 g/m

/dose q 12 h x 4, IV): days 2 and 3

G-CSF (5 μg/kg, SC): days 4-13 or until ANC > 1500 post nadir

Reinduction block 1

(3 weeks)

VCR (1.5 mg/m

/day, IV): days 1, 8, and 15

DAUN (45 mg/m

/day bolus, IV): days 1 and 2

CPM (250 mg/m

/dose q12h x 4 doses, IV): days 3 and 4

PEG-ASP (2500 IUnits/m

, IM): day 4

G-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir

Triple IT therapy (age-adjusted): days 1 and 15

DEX (6 mg/m

/day, PO): days 1-7 and 15-21

Intensification block 1

(9 weeks)

Methotrexate (5 g/m

over 24 hours, IV): days 1 and 15

Leucovorin (75 mg/m

at hour 36, IV; 15 mg/m

IV or PO q6h x 6 doses)iii:

days 2, 3, 16, and 17

Triple IT therapy (age-adjusted): days 1 and 22

VP-16 (100 mg/m

/day, IV): days 22-26

CPM (300 mg/m

/day, IV): days 22-26

MESNA (150 mg/m

/day, IV): days 22-26

G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir

ARA-C (3 g/m

, q12h, IV): days 43, 44

L-ASP (6000 IUnits/m

, IM): day 44

Reinduction block 2

(3 weeks)

VCR (1.5 mg/m

/day, IV): days 1, 8 and 15

DAUN (45 mg/m

/day bolus, IV): days 1 and 2

CPM (250 mg/m

/dose q12h x 4 doses, iv): Days 3 and 4

PEG-ASP (2500 IUnits/m

, IM): day 4

G-CSF (5 μg/kg, SC): days 5-14 or until ANC > 1500 post nadir

Triple IT therapy (age-adjusted): days 1 and 15

DEX (6 mg/m

/day, PO): days 1-7 and 15-21

Intensification block 2

(9 weeks)

Methotrexate (5 g/m

over 24 hours, IV): days 1 and 15

Leucovorin (75 mg/m

at hour 36, IV; 15 mg/m

IV or PO q6h x 6 doses)iii:

days 2, 3, 16, and 17

Triple IT therapy (age-adjusted): days 1 and 22

VP-16 (100 mg/m

/day, IV): days 22-26

CPM (300 mg/m

/day, IV): days 22-26

MESNA (150 mg/m

/day, IV): days 22-26

G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir

ARA-C (3 g/m

, q12h, IV): days 43, 44

L-ASP (6000 IUnits/m

, IM): day 44

Maintenance

(8-week cycles)

Cycles 1–4

MTX (5 g/m

over 24 hours, IV): day 1

Leucovorin (75 mg/m

at hour 36, IV; 15 mg/m

IV or PO q6h x 6 doses)iii:

days 2 and 3

Triple IT therapy (age-adjusted): days 1, 29

VCR (1.5 mg/m

, IV): days 1, 29

DEX (6 mg/m

/day PO): days 1-5; 29-33

6-MP (75 mg/m

/day, PO): days 8-28

Methotrexate (20 mg/m

/week, PO): days 8, 15, 22

VP-16 (100 mg/m

, IV): days 29-33

CPM (300 mg/m

, IV): days 29-33

MESNA IV days 29-33

G-CSF (5 μg/kg, SC): days 34-43

Maintenance

(8-week cycles)

Cycle 5

Cranial irradiation (Block 5 only)

12 Gy in 8 fractions for all patients that are CNS1 and CNS2 at diagnosis

18 Gy in 10 fractions for patients that are CNS3 at diagnosis

VCR (1.5 mg/m

/day, IV): days 1, 29

DEX (6 mg/m

/day, PO): days 1-5; 29-33

6-MP (75 mg/m

/day, PO): days 11-56 (Withhold 6-MP during the 6-10 days

of cranial irradiation beginning on day 1 of Cycle 5. Start 6-MP the 1st day

after cranial irradiation completion.)

Methotrexate (20 mg/m

/week, PO): days 8, 15, 22, 29, 36, 43, 50

Maintenance

(8-week cycles)

Cycles 6-12

VCR (1.5 mg/m

/day, IV): days 1, 29

DEX (6 mg/m

/day, PO): days 1-5; 29-33

6-MP (75 mg/m

/day, PO): days 1-56

Methotrexate (20 mg/m

/week, PO): days 1, 8, 15, 22, 29, 36, 43, 50

G-CSF = granulocyte colony stimulating factor, VP-16 = etoposide, MTX = methotrexate, IV =

intravenous, SC = subcutaneous, IT = intrathecal, PO = oral, IM = intramuscular, ARA-C = cytarabine,

CPM = cyclophosphamide, VCR = vincristine, DEX = dexamethasone, DAUN = daunorubicin, 6-MP =

6-mercaptopurine, E.Coli L-ASP = L-asparaginase, PEG-ASP = PEG asparaginase, MESNA= 2-

mercaptoethane sulfonate sodium, iii= or until MTX level is < 0.1 μM, q6h = every 6 hours, Gy= Gray

Study AIT07 was a multicentre, open-label, randomised, phase II/III study that included 128 patients (1 to

< 18 years) treated with imatinib in combination with chemotherapy. Safety data from this study seem to

be in line with the safety profile of imatinib in Ph+ ALL patients.

Relapsed/refractory Ph+ ALL: When imatinib was used as single agent in patients with

relapsed/refractory Ph+ ALL, it resulted, in the 53 out of 411 patients evaluable for response, in a

haematological response rate of 30% (9% complete) and a major cytogenetic response rate of 23%. (Of

note, out of the 411 patients, 353 were treated in an expanded access program without primary response

data collected.) The median time to progression in the overall population of 411 patients with

relapsed/refractory Ph+ ALL ranged from 2.6 to 3.1 months, and median overall survival in the 401

evaluable patients ranged from 4.9 to 9 months. The data was similar when re-analysed to include only

those patients age 55 or older.

Clinical studies in MDS/MPD

Experience with imatinib in this indication is very limited and is based on haematological and cytogenetic

response rates. There are no controlled trials demonstrating a clinical benefit or increased survival. One

open label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in diverse

populations of patients suffering from life-threatening diseases associated with Abl, Kit or PDGFR

protein tyrosine kinases. This study included 7 patients with MDS/MPD who were treated with imatinib

400 mg daily. Three patients presented a complete haematological response (CHR) and one patient

experienced a partial haematological response (PHR). At the time of the original analysis, three of the

four patients with detected PDGFR gene rearrangements developed haematological response (2 CHR and

1 PHR). The age of these patients ranged from 20 to 72 years.

An observational registry (study L2401) was conducted to collect long-term safety and efficacy data in

patients suffering from myeloproliferative neoplasms with PDGFR- β rearrangement and who were

treated with imatinib. The 23 patients enrolled in this registry received imatinib at a median daily dose of

264 mg (range: 100 to 400 mg) for a median duration of 7.2 years (range 0.1 to 12.7 years). Due to the

observational nature of this registry, haematologist, cytogenetic and molecular assessment data were

available for 22, 9 and 17 of the 23 enrolled patients, respectively. When assuming conservatively that

patients with missing data were non-responders, CHR was observed in 20/23 (87%) patients, CCyR in

9/23 (39.1%) patients, and MR in 11/23 (47.8%) patients, respectively. When the response rate is

calculated from patients with at least one valid assessment, the response rate for CHR, CCyR and MR

was 20/22 (90.9%), 9/9 (100%) and 11/17 (64.7%), respectively.

In addition a further 24 patients with MDS/MPD were reported in 13 publications. 21 patients were

treated with imatinib 400 mg daily, while the other 3 patients received lower doses. In eleven patients

PDGFR gene rearrangements was detected, 9 of them achieved a CHR and 1 PHR. The age of these

patients ranged from 2 to 79 years. In a recent publication updated information from 6 of these 11 patients

revealed that all these patients remained in cytogenetic remission (range 32-38 months). The same

publication reported long term follow-up data from 12 MDS/MPD patients with PDGFR gene

rearrangements (5 patients from study B2225). These patients received imatinib for a median of 47

months (range 24 days – 60 months). In 6 of these patients follow-up now exceeds 4 years. Eleven

patients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease or

disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogenetic responses

have been sustained for a median of 49 months (range 19-60) and 47 months (range 16-59), respectively.

The overall survival is 65 months since diagnosis (range 25-234). Imatinib administration to patients

without the genetic translocation generally results in no improvement.

There are no controlled trials in paediatric patients with MDS/MPD. Five (5) patients with MDS/MPD

associated with PDGFR gene re-arrangements were reported in 4 publications. The age of these patients

ranged from 3 months to 4 years and imatinib was given at dose 50 mg daily or doses ranging from 92.5

to 340 mg/m

daily. All patients achieved complete haematological response, cytogenetic response and/or

clinical response.

Clinical studies in HES/CEL

One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib in

diverse populations of patients suffering from life-threatening diseases associated with Abl, Kit or

PDGFR protein tyrosine kinases. In this study, 14 patients with HES/CEL were treated with 100 mg to

1,000 mg of imatinib daily. A further 162 patients with HES/CEL, reported in 35 published case reports

and case series received imatinib at doses from 75 mg to 800 mg daily. Cytogenetic abnormalities were

evaluated in 117 of the total population of 176 patients. In 61 of these 117 patients FIP1L1-PDGFRα

fusion kinase was identified. An additional four HES patients were found to be FIP1L1-PDGFRα-positive

in other 3 published reports. All 65 FIP1L1-PDGFRα fusion kinase positive patients achieved a CHR

sustained for months (range from 1+ to 44+ months censored at the time of the reporting). As reported in

a recent publication 21 of these 65 patients also achieved complete molecular remission with a median

follow-up of 28 months (range 13-67 months). The age of these patients ranged from 25 to 72 years.

Additionally, improvements in symptomatology and other organ dysfunction abnormalities were reported

by the investigators in the case reports. Improvements were reported in cardiac, nervous,

skin/subcutaneous tissue, respiratory/thoracic/mediastinal, musculoskeletal/connective tissue/vascular,

and gastrointestinal organ systems.

There are no controlled trials in paediatric patients with HES/CEL. Three (3) patients with HES and CEL

associated with PDGFR gene re-arrangements were reported in 3 publications. The age of these patients

ranged from 2 to 16 years and imatinib was given at dose 300 mg/m

daily or doses ranging from 200 to

400 mg daily. All patients achieved complete haematological response, complete cytogenetic response

and/or complete molecular response.

Clinical studies in DFSP

One phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patients

with DFSP treated with imatinib 800 mg daily. The age of the DFSP patients ranged from 23 to 75 years;

DFSP was metastatic, locally recurrent following initial resective surgery and not considered amenable to

further resective surgery at the time of study entry. The primary evidence of efficacy was based on

objective response rates. Out of the 12 patients enrolled, 9 responded, one completely and 8 partially.

Three of the partial responders were subsequently rendered disease free by surgery. The median duration

of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months. A further 6 DFSP

patients treated with imatinib were reported in 5 published case reports, their ages ranging from 18

months to 49 years. The adult patients reported in the published literature were treated with either 400 mg

(4 cases) or 800 mg (1 case) imatinib daily. Five (5) patients responded, 3 completely and 2 partially. The

median duration of therapy in the published literature ranged between 4 weeks and more than 20 months.

The translocation t(17:22)[(q22:q13)], or its gene product, was present in nearly all responders to imatinib

treatment.

There are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and PDGFR

gene re-arrangements were reported in 3 publications. The age of these patients ranged from newborn to

14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to 520 mg/m

daily. All

patients achieved partial and/or complete response.

5.2 Pharmacokinetic properties

Pharmacokinetics of imatinib

The pharmacokinetics of imatinib have been evaluated over a dosage range of 25 to 1,000 mg. Plasma

pharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasma

concentrations had reached steady state.

Absorption

Mean absolute bioavailability for imatinib is 98%. There was high between-patient variability in plasma

imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate of absorption of

imatinib was minimally reduced (11% decrease in Cmax and prolongation of t

by 1.5 h), with a small

reduction in AUC (7.4%) compared to fasting conditions. The effect of prior gastrointestinal surgery on

drug absorption has not been investigated.

Distribution

At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% on

the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding to

lipoprotein.

Biotransformation

The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows

similar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16% of

the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to that of

the parent compound.

Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulating radioactivity

(AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor metabolites.

The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the

biotransformation of imatinib. Of a panel of potential comedications (acetaminophen, aciclovir,

allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, penicillin V)

only erythromycin (IC50 50 µM) and fluconazole (IC50 118 µM) showed inhibition of imatinib

metabolism which could have clinical relevance.

Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 and

CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/l, respectively. Maximal

plasma concentrations of imatinib in patients are 2–4 μmol/l, consequently an inhibition of CYP2D6

and/or CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib did not interfere

with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a result of

competitive inhibition of CYP2C8 (Ki = 34.7 µM). This Ki value is far higher than the expected plasma

levels of imatinib in patients, consequently no interaction is expected upon co-administration of either 5-

fluorouracil or paclitaxel and imatinib.

Elimination

Based on the recovery of compound(s) after an oral

C-labelled dose of imatinib, approximately 81% of

the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose). Unchanged

imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites.

Plasma pharmacokinetics

Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that once-

daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose

proportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in the

kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when dosed

once daily.

Population pharmacokinetics

Based on population pharmacokinetic analysis in CML patients, there was a small effect of age on the

volume of distribution (12% increase in patients > 65 years old). This change is not thought to be

clinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patient

weighing 50 kg the mean clearance is expected to be 8.5 l/h, while for a patient weighing 100 kg the

clearance will rise to 11.8 l/h. These changes are not considered sufficient to warrant dose adjustment

based on kg bodyweight. There is no effect of gender on the kinetics of imatinib.

Pharmacokinetics in paediatric population

As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in both

phase I and phase II studies. Dosing in children at 260 and 340 mg/m

/day achieved the same exposure,

respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC(0-24) on day 8

and day 1 at the 340 mg/m

/day dose level revealed a 1.7-fold drug accumulation after repeated once-

daily dosing.

Based on pooled population pharmacokinetic analysis in paediatric patients with haematological disorders

(CML, Ph+ALL, or other haematological disorders treated with imatinib), clearance of imatinib increases

with increasing body surface area (BSA). After correcting for the BSA effect, other demographics such as

age, body weight and body mass index did not have clinically significant effects on the exposure of

imatinib. The analysis confirmed that exposure of imatinib in paediatric patients receiving 260 mg/m

once daily (not exceeding 400 mg once daily) or 340 mg/m

once daily (not exceeding 600 mg once

daily) were similar to those in adult patients who received imatinib 400 mg or 600 mg once daily.

Organ function impairment

Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild and

moderate impairment of renal function appear to have a higher plasma exposure than patients with normal

renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold elevation of

plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is probably similar

between patients with renal impairment and those with normal renal function, since renal excretion

represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4).

Although the results of pharmacokinetic analysis showed that there is considerable inter-subject variation,

the mean exposure to imatinib did not increase in patients with varying degrees of liver dysfunction as

compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8).

5.3 Preclinical safety data

The preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits.

Multiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs and

monkeys, accompanied by bone marrow changes in rats and dogs.

The liver was a target organ in rats and dogs. Mild to moderate increases in transaminases and slight

decreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. No

histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated for 2

weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct hyperplasia.

Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of the

renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were observed in

several of these animals. In rats, hyperplasia of the transitional epithelium in the renal papilla and in the

urinary bladder was observed at doses ≥ 6 mg/kg in the 13-week study, without changes in serum or

urinary parameters. An increased rate of opportunistic infections was observed with chronic imatinib

treatment.

In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the lowest

dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based on body surface.

Treatment resulted in worsening of normally suppressed malarial infections in these animals.

Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in

vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive genotoxic

effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster ovary) for

clastogenicity (chromosome aberration) in the presence of metabolic activation. Two intermediates of the

manufacturing process, which are also present in the final product, are positive for mutagenesis in the

Ames assay. One of these intermediates was also positive in the mouse lymphoma assay.

In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights

and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical dose

of 800 mg/day, based on body surface area. This was not seen at doses ≤ 20 mg/kg. A slight to moderate

reduction in spermatogenesis was also observed in the dog at oral doses ≥ 30 mg/kg. When female rats

were dosed 14 days prior to mating and through to gestational day 6, there was no effect on mating or on

number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-implantation foetal

loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg.

In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 45

mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn pups

as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the same

dose level, mean body weights were reduced from birth until terminal sacrifice and the number of litters

achieving criterion for preputial separation was slightly decreased. F1 fertility was not affected, while an

increased number of resorptions and a decreased number of viable foetuses was noted at 45 mg/kg/day.

The no observed effect level (NOEL) for both the maternal animals and the F1 generation was 15

mg/kg/day (one quarter of the maximum human dose of 800 mg).

Imatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/kg,

approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area.

Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal

bones. These effects were not seen at doses ≤ 30 mg/kg.

No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70

postpartum) with respect to the known target organs in adult rats. In the juvenile toxicology study, effects

upon growth, delay in vaginal opening and preputial separation were observed at approximately 0.3 to 2

times the average paediatric exposure at the highest recommended dose of 340 mg/m

. In addition,

mortality was observed in juvenile animals (around weaning phase) at approximately 2 times the average

paediatric exposure at the highest recommended dose of 340 mg/m

In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted in a

statistically significant reduction in the longevity of males at 60 mg/kg/day and females at ≥30

mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic

progressive nephropathy (females) and preputial gland papilloma as principal causes of death or reasons

for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial

and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-glandular stomach.

Papilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, representing

approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day,

respectively, and 0.4 times the daily exposure in children (based on AUC) at 340 mg/m

/day. The no

observed effect level (NOEL) was 15 mg/kg/day. The renal adenoma/carcinoma, the urinary bladder and

urethra papilloma, the small intestine adenocarcinomas, the parathyroid glands adenomas, the benign and

malignant medullary tumours of the adrenal glands and the non-glandular stomach papillomas/carcinomas

were noted at 60 mg/kg/day, representing approximately 1.7 or 1 times the human daily exposure (based

on AUC) at 400 mg/day or 800 mg/day, respectively, and 1.2 times the daily exposure in children (based

on AUC) at 340 mg/m

/day. The no observed effect level (NOEL) was 30 mg/kg/day.

The mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet

clarified.

Non-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system,

pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and

dilatation, leading to signs of cardiac insufficiency in some animals.

The active substance imatinib demonstrates an environmental risk for sediment organisms.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core:

Sodium stearyl fumarate

Tablet coat:

Opadry Brown:

Hydroxypropylmethyl cellulose

Red iron oxide (E172)

Yellow iron oxide (E172)

Talc

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

High density polyethylene (HDPE) bottle with a polypropylene child-resistant closure or

Aluminium/aluminium (alu/alu) blister pack

Pack sizes alu/alu blister

10, 30, 60 and 90 film-coated tablets (for 400 mg).

Pack sizes HDPE bottles:

30 and 90 film-coated tablets (for 400 mg).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal products or waste material should be disposed of in accordance with local

requirements.

7. Marketing authorisation holder

Wockhardt UK Ltd

Ash Road North

Wrexham

LL13 9UF

8. Marketing authorisation number(s)

PL 29831/0639

9. Date of first authorisation/renewal of the authorisation

19/08/2015

10. Date of revision of the text

11/08/2017

Company Contact Details

Wockhardt UK Ltd

Address

Ash Road North, Wrexham Industrial Estate, Wrexham, LL13 9UF

+44 (0)1978 660 130

Telephone

+44 (0)1978 661 261

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