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IMATINIB DEVATIS 100 MG FILM-COATED TABLETS

Active substance(s): IMATINIB MESILATE / IMATINIB MESILATE / IMATINIB MESILATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Imatinib Devatis 100 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 100 mg imatinib (as mesilate)

3

PHARMACEUTICAL FORM
Film-coated tablet
Dark yellow to brownish-orange coloured, round, score on one side, biconvex filmcoated tablets and with a diameter of 10.1 mm. approximately.
The tablet can be divided into two equal doses.

4
4.1

CLINICAL PARTICULARS
Therapeutic indications
Imatinib is indicated for the treatment of
-

paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl)
positive (Ph+) chronic myeloid leukaemia (CML) for whom bone marrow
transplantation is not considered as the first line of treatment.

-

paediatric patients with Ph+ CML in chronic phase after failure of interferonalpha therapy, or in accelerated phase or blast crisis.

-

adult patients with Ph+ CML in blast crisis.

-

adult and paediatric patients with newly diagnosed Philadelphia chromosome
positive acute lymphoblastic leukaemia (Ph+ ALL) integrated with
chemotherapy.

-

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

-

adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD)
associated with platelet-derived growth factor receptor (PDGFR) gene rearrangements.

-

adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic
eosinophilic leukaemia (CEL) with FIP1L1-PDGFRα rearrangement.

The effect of imatinib on the outcome of bone marrow transplantation has not been
determined.
Imatinib is indicated for

-

the treatment of adult patients with unresectable dermatofibrosarcoma
protuberans (DFSP) and adult patients with recurrent and/or metastatic DFSP
who are not eligible for surgery.

In adult and paediatric patients, the effectiveness of Imatinib is based on overall
haematological and cytogenetic response rates and progression-free survival in CML,
on haematological and cytogenetic response rates in Ph+ ALL, MDS/MPD, on
haematological response rates in HES/CEL and on objective response rates in adult
patients with unresectable and/or metastatic DFSP. The experience with Imatinib in
patients with MDS/MPD associated with PDGFR gene re-arrangements is very
limited (see section 5.1). There are no controlled trials demonstrating a clinical
benefit or increased survival for these diseases.

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.
The prescribed dose should be administered orally with a meal and a large glass of
water to minimise the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg
should be administered once daily, whereas a daily dose of 800 mg should be
administered as 400 mg twice a day, in the morning and in the evening.
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in
a glass of still water or apple juice. The required number of tablets should be placed
in the appropriate volume of beverage (approximately 50 ml for a 100 mg tablet, and
200 ml for a 400 mg tablet) and stirred with a spoon. The suspension should be
administered immediately after complete disintegration of the tablet(s).
Posology for CML in adult patients in blast crisis
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 increase from 600 mg to a maximum of 800 mg (given as 400 mg twice daily)
in patients with blast crisis may be considered in the absence of severe adverse drug
reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the
following circumstances: failure to achieve a satisfactory haematological response
after at least 3 months of treatment; failure to achieve a cytogenetic response after 12
months of treatment; or loss of a previously achieved haematological and/or
cytogenetic response. Patients should be monitored closely following dose escalation
given the potential for an increased incidence of adverse reactions at higher dosages.
Posology for CML in children
Dosing for children should be on the basis of body surface area (mg/m2). The dose of
340 mg/m2 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/m2 daily to 570 mg/m2 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 children
Dosing for children should be on the basis of body surface area (mg/m2). The dose of
340 mg/m2 daily is recommended for children with Ph+ ALL (not to exceed the total
dose of 600 mg).
Posology for MDS/MPD
The recommended dose of imatinib is 400 mg/day for adult patients with MDS/MPD.
Treatment duration: In the only clinical trial performed up to now, treatment with
imatinib was continued until disease progression (see section 5.1). At the time of
analysis, the treatment duration was a median of 47 months (24 days - 60 months).
Posology for HES/CEL
The recommended dose of imatinib is 100 mg/day for adult patients with HES/CEL.
Dose increase from 100 mg to 400 mg may be considered in the absence of adverse
drug reactions if assessments demonstrate an insufficient response to therapy.
Treatment should be continued as long as the patient continues to benefit.
Posology for 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/m2/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)

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

ANC < 1.0 x 109/l
and/or
platelets < 50 x
109/l
ANC < 1.0 x 109/l
and/or
platelets < 50 x
109/l

Paediatric chronic
phase CML
(at dose 340 mg/m2)

ANC < 1.0 x 109/l
and/or
platelets < 50 x
109/l

Blast crisis CML and
Ph+ ALL (starting
dose 600 mg)

a

ANC < 0.5 x 109/l
and/or
platelets < 10 x
109/l

1.
Stop imatinib until ANC ≥ 1.5 x 109/l and
platelets ≥ 75 x 109/l.
2.
Resume treatment with imatinib at
previous dose (i.e. before severe adverse reaction).
1.
Stop imatinib until ANC ≥ 1.5 x 109/l and
platelets ≥ 75 x 109/l.
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
109/l and/or platelets < 50 x 109/l, repeat step 1
and resume imatinib at reduced dose of 300 mg.
1.
Stop imatinib until ANC ≥ 1.5 x 109/l and
platelets ≥ 75 x 109/l.
2.
Resume treatment with imatinib at
previous dose (i.e. before severe adverse reaction).
3.
In the event of recurrence of ANC < 1.0
9
x10 /l and/or platelets < 50 x109/l, repeat step 1
and resume imatinib at reduced dose of 260
mg/m2.
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 109/l and platelets ≥ 20 x 109/l, then
resume treatment at 300 mg.

Paediatric accelerated
phase CML and blast
crisis (starting dose
340 mg/m2)

a

ANC < 0.5 x 109/l
and/or
platelets < 10 x
109/l

DFSP
(at dose 800 mg)

ANC < 1.0 x 109/l
and/or
platelets < 50 x
109/l

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/m2.
3.
If cytopenia persists for 2 weeks, reduce
further to 200 mg/m2.
4.
If cytopenia persists for 4 weeks and is
still unrelated to leukaemia, stop imatinib until
ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l, then
resume treatment at 200 mg/m2.
1.
Stop imatinib until ANC ≥ 1.5 x 109/l and
platelets ≥ 75 x 109/l.
2.
Resume treatment with imatinib at 600
mg.
3.
In the event of recurrence of ANC < 1.0 x
109/l and/or platelets < 50 x 109/l, repeat step 1
and resume imatinib at reduced dose of 400 mg.

ANC = absolute neutrophil count
a

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
Mild

Liver function tests
Total bilirubin: = 1.5 ULN
AST: >ULN (can be normal or >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).
Older people: Imatinib pharmacokinetics have not been specifically studied in older
people. No significant age-related pharmacokinetic differences have been observed in
adult patients in clinical trials which included over 20% of patients age 65 and older.
No specific dose recommendation is necessary in older people.

4.3

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

4.4

Special warnings and precautions for use
When imatinib is co-administered with other medicinal products, there is a potential
for drug interactions. Caution should be used when taking imatinib with protease
inhibitors, azole antifungals, certain macrolides (see section 4.5), CYP3A4 substrates
with a narrow therapeutic window (e.g. cyclosporine, pimozide, tacrolimus,
sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib,
docetaxel, quinidine) or warfarin and other coumarin derivatives (see section 4.5).
Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g.
dexamethasone, phenytoin, carbamazepine, rifampicin, phenobarbital or 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.
Tumor lysis syndrome
Due to the possible occurrence of tumour lysis syndrome (TLS), correction of
clinically significant dehydration and treatment of high uric acid levels are
recommended prior to initiation of imatinib (see section 4.8).
Laboratory tests
Complete blood counts must be performed regularly during therapy with imatinib.
Treatment of CML patients with imatinib has been associated with neutropenia or

thrombocytopenia. However, the occurrence of these cytopenias is likely to be related
to the stage of the disease being treated and they were more frequent in patients with
accelerated phase CML or blast crisis as compared to patients with chronic phase
CML. Treatment with imatinib may be interrupted or the dose may be reduced, as
recommended in section 4.2.
Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored
regularly in patients receiving imatinib.
In patients with impaired renal function, imatinib plasma exposure seems to be higher
than that in patients with normal renal function, probably due to an elevated plasma
level of alpha-acid glycoprotein (AGP), an imatinib-binding protein, in these patients.
Patients with renal impairment should be given the minimum starting dose. Patients
with severe renal impairment should be treated with caution. The dose can be reduced
if not tolerated (see section 4.2 and 5.2).
Paediatric population
There have been case reports of growth retardation occurring in children and preadolescents 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
Cmax 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
resulted in decrease in Cmax 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 Cmax 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 lowmolecular-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 Cmax and AUC being increased by approximately 23% (90%CI [1.161.30]). Dose adjustments do not seem to be necessary when imatinib is coadministrated with CYP2D6 substrates, however caution is advised for CYP2D6
substrates with a narrow therapeutic window such as metoprolol. In patients treated
with metoprolol clinical monitoring should be considered.
In vitro, imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5
micromol/l. This inhibition has not been observed in vivo after the administration of
imatinib 400 mg and paracetamol 1000 mg. Higher doses of imatinib and paracetamol
have not been studied.
Caution should therefore be exercised when using high doses of imatinib and
paracetamol concomitantly.
In thyroidectomy patients receiving levothyroxine, the plasma exposure to
levothyroxine may be decreased when imatinib is co-administered (see section 4.4).
Caution is therefore recommended. However, the mechanism of the observed
interaction is presently unknown.
In Ph+ ALL patients, there is clinical experience of co-administering imatinib with
chemotherapy (see section 5.1), but drug-drug interactions between imatinib and
chemotherapy regimens are not well characterised. Imatinib adverse events, i.e.
hepatotoxicity, myelosuppression or others, may increase and it has been reported
that concomitant use with L-asparaginase could be associated with increased
hepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination
requires special precaution.

4.6

Fertility, Pregnancy and lactation
Women of childbearing potential
Women of childbearing potential must be advised to use effective contraception
during treatment.
Pregnancy
There are limited data on the use of imatinib in pregnant women. Studies in animals
have however shown reproductive toxicity (see section 5.3) and the potential risk for

the foetus is unknown. Imatinib should not be used during pregnancy unless clearly
necessary. If it is used during pregnancy, the patient must be informed of the potential
risk to the foetus.
Breast-feeding
There is limited information on imatinib distribution on human milk. Studies in two
breast-feeding women revealed that both imatinib and its active metabolite can be
distributed into human milk. The milk plasma ratio studied in a single patient was
determined to be 0.5 for imatinib and 0.9 for the metabolite, suggesting greater
distribution of the metabolite into the milk. Considering the combined concentration
of imatinib and the metabolite and the maximum daily milk intake by infants, the
total exposure would be expected to be low (~10% of a therapeutic dose). However,
since the effects of low-dose exposure of the infant to imatinib are unknown, women
taking imatinib should not breast-feed.
Fertility
In non-clinical studies, the fertility of male and female rats was not affected (see
section 5.3). Studies on patients receiving imatinib and its effect on fertility and
gametogenesis have not been performed. Patients concerned about their fertility on
imatinib treatment should consult with their physician.

4.7

Effects on ability to drive and use machines
Patients should be advised that they may experience undesirable effects such as
dizziness, blurred vision or somnolence during treatment with imatinib. Therefore,
caution should be recommended when driving a car or operating machinery.

4.8

Undesirable effects
Patients with advanced stages of malignancies may have numerous
confounding medical conditions that make causality of adverse reactions
difficult to assess due to the variety of symptoms related to the underlying
disease, its progression, and the co-administration of numerous medicinal
products.
In clinical trials in CML, drug discontinuation for drug-related adverse
reactions was observed in 2.4% of newly diagnosed patients, 4% of patients in
late chronic phase after failure of interferon therapy, 4% of patients in
accelerated phase after failure of interferon therapy and 5% of blast crisis
patients after failure of interferon therapy. In GIST the study drug was
discontinued for drug-related adverse reactions in 4% of patients.
The adverse reactions were similar in all indications, with two exceptions.
There was more myelosuppression seen in CML patients than in GIST, which
is probably due to the underlying disease. In the study in patients with
unresectable and/or metastatic GIST, 7 (5%) patients experienced CTC grade
3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1
patient). GI tumour sites may have been the source of the GI bleeds (see
section 4.4). GI and tumoural bleeding may be serious and sometimes fatal.

The most commonly reported (≥ 10%) drug-related adverse reactions in both
settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue,
myalgia, muscle cramps and rash. Superficial oedemas were a common
finding in all studies and were described primarily as periorbital or lower limb
oedemas. However, these oedemas were rarely severe and may be managed
with diuretics, other supportive measures, or by reducing the dose of imatinib.
When imatinib was combined with high dose chemotherapy in Ph+ ALL
patients, transient liver toxicity in the form of transaminase elevation and
hyperbilirubinaemia were observed. Considering the limited safety database,
the adverse events thus far reported in children are consistent with the known
safety profile in adult patients with Ph+ ALL. The safety database for children
with Ph+ALL is very limited though no new safety concerns have been
identified.
Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary
oedema and rapid weight gain with or without superficial oedema may be
collectively described as “fluid retention”. These reactions can usually be
managed by withholding imatinib temporarily and with diuretics and other
appropriate supportive care measures. However, some of these reactions may
be serious or life-threatening and several patients with blast crisis died with a
complex clinical history of pleural effusion, congestive heart failure and renal
failure. There were no special safety findings in paediatric clinical trials.
Adverse reactions
Adverse reactions reported as more than an isolated case are listed below, by
system organ class and by frequency. Frequency categories are defined using
the following convention: very common (≥1/10), common (≥1/100 to <1/10),
uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare
(<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of
frequency, the most frequent first.
Adverse reactions and their frequencies reported in Table 1 are based on the
main registration studies.
Table 1 Adverse reactions in clinical studies
Infections and infestations
Uncommon:
Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1,
sinusitis, cellulitis, upper respiratory tract infection,
influenza, urinary tract infection, gastroenteritis, sepsis
Rare:
Fungal infection
Neoplasm benign, malignant and unspecified (including cysts and polyps)
Rare:
Tumour lysis syndrome
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:
Headache2
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
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
Ear and labyrinth disorders
Uncommon:
Vertigo, tinnitus, hearing loss
Cardiac disorders
Uncommon:
Palpitations, tachycardia, cardiac failure congestive3,
pulmonary oedema
Rare:
Arrhythmia, atrial fibrillation, cardiac arrest, myocardial
infarction, angina pectoris, pericardial effusion
Vascular disorders4
Common:
Flushing, haemorrhage
Uncommon:
Hypertension, haematoma, subdural haematoma, peripheral
coldness, hypotension, Raynaud’s phenomenon
Respiratory, thoracic and mediastinal disorders
Common:
Dyspnoea, epistaxis, cough
Uncommon:
Pleural effusion5, pharyngolaryngeal pain, pharyngitis
Rare:
Pleuritic pain, pulmonary fibrosis, pulmonary hypertension,
pulmonary haemorrhage
Gastrointestinal disorders
Very common:
Nausea, diarrhoea, vomiting, dyspepsia, abdominal pain6
Common:
Flatulence, abdominal distension, gastro-oesophageal reflux,
constipation, dry mouth, gastritis
Uncommon:
Stomatitis, mouth ulceration, gastrointestinal haemorrhage7,
eructation, melaena, oesophagitis, ascites, gastric ulcer,
haematemesis, cheilitis, dysphagia, pancreatitis
Rare:
Colitis, ileus, inflammatory bowel disease
Hepatobiliary disorders
Common:
Increased hepatic enzymes

Uncommon:
Hyperbilirubinaemia, hepatitis, jaundice
Rare:
Hepatic failure8, 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, StevensJohnson syndrome, acute generalised exanthematous
pustulosis (AGEP)
Musculoskeletal and connective tissue disorders
Very common:
Muscle spasm and cramps, musculoskeletal pain including
myalgia, arthralgia, bone pain9
Common:
Joint swelling
Uncommon:
Joint and muscle stiffness
Rare:
Muscular weakness, arthritis, rhabdomyolysis/myopathy
Renal and urinary disorders
Uncommon:
Renal pain, haematuria, renal failure acute, urinary
frequency increased
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
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 and related events were more commonly
observed in patients with CML than in GIST patients.
The following types of reactions have been reported mainly from postmarketing experience with imatinib. 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.
Table 2 Adverse reactions from post-marketing reports
Neoplasm benign, malignant and unspecified (including cysts and
polyps)
Not known:
Tumour haemorrhage/tumour necrosis
Immune system disorders
Not known:
Anaphylactic shock
Nervous system disorders
Not known:
Cerebral oedema
Eye disorders
Not known:
Vitreous haemorrhage
Cardiac disorders
Not known:
Pericarditis, cardiac tamponade
Vascular disorders
Not known:
Thrombosis/embolism
Respiratory, thoracic and mediastinal disorders
Not known:
Acute respiratory failure1, interstitial lung disease
Gastrointestinal disorders
Not known:
Ileus/intestinal obstruction, gastrointestinal
perforation, diverticulitis
Skin and subcutaneous tissue disorders
Not known:
Palmoplantar erythrodysesthesia syndrome
Not known:
Lichenoid keratosis, lichen planus
Not known:
Toxic epidermal necrolysis
Not known:
Drug rash with eosinophilia and systemic symptoms
(DRESS)
.Musculoskeletal and connective tissue disorders
Not known:
.Avascular necrosis/hip necrosis

Not known:

Growth retardation in children

.1
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 109/l) and
thrombocytopenias (platelet count < 50 x 109/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 109/l) and thrombocytopenia (platelet count < 10 x
109/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, 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.

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, Website:
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 dose 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: Kit, the
receptor for stem cell factor (SCF) coded for by the c-Kit proto-oncogene, 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 stem cell factor (SCF), c-Kit, and inhibits
PDGF- and SCF-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
The effectiveness of imatinib is based on overall haematological and cytogenetic
response rates and progression-free survival. There are no controlled trials
demonstrating a clinical benefit, such as improvement in disease-related symptoms or
increased survival.
A large, international, open-label, non-controlled phase II study was conducted in
patients with Philadelphia chromosome positive (Ph+) CML in the blast phase
disease. In addition, children have been treated in two phase I studies and one phase
II study.
In the clinical study 38% of patients were ≥ 60 years of age and 12% of patients were
≥ 70 years of age.
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, (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. 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 2 Response in adult CML study

Study 0102
38-month data
Myeloid blast crisis
(n=260)
% of patients (CI95%)
31% (25.2–36.8)
8%

Haematological response1
Complete haematological response
(CHR)
No evidence of leukaemia (NEL)
5%
Return to chronic phase (RTC)
18%
Major cytogenetic response2
15% (11.2–20.4)
Complete
7%
(Confirmed3) [95% CI]
(2%) [0.6–4.4]
Partial
8%
1
Haematological response criteria (all responses to be confirmed after ≥ 4
weeks):
CHR In study 0102 [ANC ≥ 1.5 x 109/l, platelets ≥ 100 x 109/l, no blood blasts,
BM blasts < 5% and no extramedullary disease]
NEL Same criteria as for CHR but ANC ≥ 1 x 109/l and platelets ≥ 20 x 109/l
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.
BM = bone marrow, PB = peripheral blood
2
Cytogenetic response criteria:
A major response combines both complete and partial responses: complete (0%
Ph+ metaphases), partial (1–35%)
3
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/m2/day (n=5),
340 mg/m2/day (n=9), 440 mg/m2/day (n=7) and 570 mg/m2/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/m2/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, diseasefree 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 3 Chemotherapy regimen used in combination with imatinib
Study ADE10
Prephase

Remission induction

Consolidation therapy I, III, V
Consolidation therapy II, IV
Study AAU02
Induction therapy (de novo
Ph+ ALL)

Consolidation (de novo Ph+
ALL)

DEX 10 mg/m2 oral, days 1-5;
CP 200 mg/m2 i.v., days 3, 4, 5;
MTX 12 mg intrathecal, day 1
DEX 10 mg/m2 oral, days 6-7, 13-16;
VCR 1 mg i.v., days 7, 14;
IDA 8 mg/m2 i.v. (0.5 h), days 7, 8, 14, 15;
CP 500 mg/m2 i.v.(1 h) day 1;
Ara-C 60 mg/m2 i.v., days 22-25, 29-32
MTX 500 mg/m2 i.v. (24 h), days 1, 15;
6-MP 25 mg/m2 oral, days 1-20
Ara-C 75 mg/m2 i.v. (1 h), days 1-5;
VM26 60 mg/m2 i.v. (1 h), days 1-5
Daunorubicin 30 mg/m2 i.v., days 1-3, 15-16;
VCR 2 mg total dose i.v., days 1, 8, 15, 22;
CP 750 mg/m2 i.v., days 1, 8;
Prednisone 60 mg/m2 oral, days 1-7, 15-21;
IDA 9 mg/m2 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
Ara-C 1,000 mg/m2/12 h i.v.(3 h), days 1-4;
Mitoxantrone 10 mg/m2 i.v. days 3-5;
MTX 15 mg intrathecal, day 1;

Methylprednisolone 40 mg intrathecal, day 1
Study ADE04
Prephase

Induction therapy I

Induction therapy II

Consolidation therapy

Study AJP01
Induction therapy

Consolidation therapy

Maintenance

DEX 10 mg/m2 oral, days 1-5;
CP 200 mg/m2 i.v., days 3-5;
MTX 15 mg intrathecal, day 1
DEX 10 mg/m2 oral, days 1-5;
VCR 2 mg i.v., days 6, 13, 20;
Daunorubicin 45 mg/m2 i.v., days 6-7, 13-14
CP 1 g/m2 i.v. (1 h), days 26, 46;
Ara-C 75 mg/m2 i.v. (1 h), days 28-31, 35-38, 42-45;
6-MP 60 mg/m2 oral, days 26-46
DEX 10 mg/m2 oral, days 1-5;
Vindesine 3 mg/m2 i.v., day 1;
MTX 1.5 g/m2 i.v. (24 h), day 1;
Etoposide 250 mg/m2 i.v. (1 h) days 4-5;
Ara-C 2x 2 g/m2 i.v. (3 h, q 12 h), day 5
CP 1.2 g/m2 i.v. (3 h), day 1;
Daunorubicin 60 mg/m2 i.v. (1 h), days 1-3;
Vincristine 1.3 mg/m2 i.v., days 1, 8, 15, 21;
Prednisolone 60 mg/m2/day oral
Alternating chemotherapy course: high dose chemotherapy
with MTX 1 g/m2 i.v. (24 h), day 1, and Ara-C 2 g/m2 i.v.
(q 12 h), days 2-3, for 4 cycles
VCR 1.3 g/m2 i.v., day 1;
Prednisolone 60 mg/m2 oral, days 1-5

Study AUS01
Induction-consolidation
therapy

Hyper-CVAD regimen: CP 300 mg/m2 i.v. (3 h, q 12 h),
days 1-3; Vincristine 2 mg i.v., days 4, 11;
Doxorubicine 50 mg/m2 i.v. (24 h), day 4;
DEX 40 mg/day on days 1-4 and 11-14, alternated with
MTX 1 g/m2 i.v. (24 h), day 1, Ara-C 1 g/m2 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, non-randomised phase III trial, and were treated with
imatinib (340 mg/m2/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 4 Chemotherapy regimen used in combination with imatinib in study
I2301
Consolidation block 1
(3 weeks)

Consolidation block 2
(3 weeks)

Reinduction block 1
(3 weeks)

Intensification block 1
(9 weeks)

Reinduction block 2
(3 weeks)

Intensification block 2
(9 weeks)

VP-16 (100 mg/m2/day, IV): days 1-5
Ifosfamide (1.8 g/m2/day, IV): days 1-5
MESNA (360 mg/m2/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
Methotrexate (5 g/m2 over 24 hours, IV): day 1
Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii:
Days 2 and 3
Triple IT therapy (age-adjusted): day 1
ARA-C (3 g/m2/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
VCR (1.5 mg/m2/day, IV): days 1, 8, and 15
DAUN (45 mg/m2/day bolus, IV): days 1 and 2
CPM (250 mg/m2/dose q12h x 4 doses, IV): days 3 and 4
PEG-ASP (2500 IUnits/m2, 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/m2/day, PO): days 1-7 and 15-21
Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15
Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 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/m2/day, IV): days 22-26
CPM (300 mg/m2/day, IV): days 22-26
MESNA (150 mg/m2/day, IV): days 22-26
G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir
ARA-C (3 g/m2, q12h, IV): days 43, 44
L-ASP (6000 IUnits/m2, IM): day 44
VCR (1.5 mg/m2/day, IV): days 1, 8 and 15
DAUN (45 mg/m2/day bolus, IV): days 1 and 2
CPM (250 mg/m2/dose q12h x 4 doses, iv): Days 3 and 4
PEG-ASP (2500 IUnits/m2, 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/m2/day, PO): days 1-7 and 15-21
Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15
Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 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/m2/day, IV): days 22-26
CPM (300 mg/m2/day, IV): days 22-26
MESNA (150 mg/m2/day, IV): days 22-26
G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir
ARA-C (3 g/m2, q12h, IV): days 43, 44
L-ASP (6000 IUnits/m2, IM): day 44

Maintenance
(8-week cycles)
Cycles 1–4

Maintenance
(8-week cycles)
Cycle 5

Maintenance
(8-week cycles)
Cycles 6-12

MTX (5 g/m2 over 24 hours, IV): day 1
Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6 doses)iii:
days 2 and 3
Triple IT therapy (age-adjusted): days 1, 29
VCR (1.5 mg/m2, IV): days 1, 29
DEX (6 mg/m2/day PO): days 1-5; 29-33
6-MP (75 mg/m2/day, PO): days 8-28
Methotrexate (20 mg/m2/week, PO): days 8, 15, 22
VP-16 (100 mg/m2, IV): days 29-33
CPM (300 mg/m2, IV): days 29-33
MESNA IV days 29-33
G-CSF (5 μg/kg, SC): days 34-43
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/m2/day, IV): days 1, 29
DEX (6 mg/m2/day, PO): days 1-5; 29-33
6-MP (75 mg/m2/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/m2/week, PO): days 8, 15, 22, 29, 36, 43, 50
VCR (1.5 mg/m2/day, IV): days 1, 29
DEX (6 mg/m2/day, PO): days 1-5; 29-33
6-MP (75 mg/m2/day, PO): days 1-56
Methotrexate (20 mg/m2/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 LASP = 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 reanalysed 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. 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 1659), 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/m2 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/m2 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/m2 daily. All patients achieved partial
and/or complete response.

5.2

Pharmacokinetic properties
Pharmacokinetics of Imatinib tablets
The pharmacokinetics of Imatinib tablets 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 highfat meal, the rate of absorption of imatinib was minimally reduced (11% decrease in
Cmax and prolongation of tmax 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 alphaacid-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 CYP3A4/5mediated 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 14C-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 children
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/m2/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/m2/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/m2 once daily (not exceeding 400 mg once daily) or 340
mg/m2 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.
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/m2. 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/m2.
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 30mg/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/m2/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/m2/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:
Cellulose microcrystalline
Hypromellose
Crospovidone
Silica, colloidal, anhydrous
Magnesium stearate
Tablet coat:
Poly(vinyl alcohol)
Macrogol
Iron oxide, yellow (E172)
Iron oxide, red (E172)
Talcum
Titanium dioxide (E171)

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
24 months.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
PVC/PCTFE/aluminium blisters
Packs containing 15, 20, 24, 48, 60, 96, 120 and 180 film-coated tablets
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.

7

MARKETING AUTHORISATION HOLDER
Devatis GmbH
Spitalstr. 22
79539 Lörrach
Germany

8

MARKETING AUTHORISATION NUMBER(S)
PL 45736/0001

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
19/02/2015

10

DATE OF REVISION OF THE TEXT

23/11/2016

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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