Imatinib medac

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib medac 100 mg hard capsules 
Imatinib medac 400 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Imatinib medac 100 mg hard capsules 
Each hard capsule contains 100 mg of imatinib (as mesilate). 
 
Imatinib medac 400 mg hard capsules 
Each hard capsule contains 400 mg of imatinib (as mesilate). 
 
Excipient(s) with known effect: 
Imatinib medac 100 mg hard capsules 
Each hard capsule contains 12.518 mg lactose monohydrate. 
 
Imatinib medac 400 mg hard capsules 
Each hard capsule contains 50.072 mg lactose monohydrate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule 
 
Imatinib medac 100 mg hard capsules 
Size “3” hard capsules with orange body and cap. 
 
Imatinib medac 400 mg hard capsules 
Size “00” hard capsules with caramel body and cap. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Imatinib medac is indicated for the treatment of 
• paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) 

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

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

• adult and paediatric patients with Ph+ CML in blast crisis. 
• adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acute 

lymphoblastic leukaemia (Ph+ ALL) integrated with chemotherapy. 
• adult patients with relapsed or refractory Ph+ ALL as monotherapy. 
• adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with 

platelet-derived growth factor receptor (PDGFR) gene re-arrangements. 
• adult patients with advanced hypereosinophilic syndrome (HES) and/or chronic eosinophilic 

leukaemia (CEL) with FIP1L1-PDGFRα rearrangement. 
• 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. 

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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). 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.  
For doses of 400 mg and above (see dosage recommendation below) a 400 mg capsule (not divisible) 
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 capsules (e.g. paediatric patients), their content may be dispersed in 
a glass of still mineral water or apple juice. 
 
Posology for CML in adult patients 
The recommended dose of imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis is 
defined as blasts ≥ 30 % in blood or bone marrow or extramedullary disease other than 
hepatosplenomegaly. 
 
Treatment duration: In clinical trials, treatment with imatinib was continued until disease progression. 
The effect of stopping treatment after the achievement of a complete cytogenetic response has not 
been investigated. 
 
Dose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients with 
blast crisis may be considered in the absence of severe adverse drug reaction and severe 
non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease 
progression (at any time); failure to achieve a satisfactory haematological response after at least 3 
months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or loss of 
a previously achieved haematological and/or cytogenetic response. Patients should be monitored 
closely following dose escalation given the potential for an increased incidence of adverse reactions at 
higher dosages. 
 
Posology for CML in paediatric patients 
Dosing for paediatric patients should be on the basis of body surface area (mg/m2). The dose of 
340 mg/m2 daily is recommended for paediatric patients with chronic phase CML and accelerated 
phase CML (not to exceed the total dose of 800 mg). Accelerated phase is an intermediate phase 
among the chronic phase and the onset of the blast crisis; it is considered as the first manifestation of 
resistance to therapy. 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 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 

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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 patients with newly 
diagnosed Ph+ ALL. The duration of imatinib therapy can vary with the treatment program 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 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 in adult patients  
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 median treatment 
duration was 47 months (24 days - 60 months). 
 
Posology for HES/CEL in adult patients 
The recommended dose of imatinib is 100 mg/day for patients with HES/CEL. 
Dose increases 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 in adult patients  
The recommended dose of imatinib is 800 mg/day for patients with DFSP. 
 
Dose adjustment for adverse reactions in all indications in adults and paediatric patients 
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 mg to 300 mg or from 600 mg to 400 mg, or from 
800 mg to 600 mg, and in paediatric patients from 340 mg 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: 
 

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Therapeutic indication Neutropenia and 
thrombocytopenia toxicity 

Posology modification 

HES/CEL (starting dose 
100 mg)  

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

Chronic phase CML, 
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  

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.  

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

ANC < 1.0 x 109/l  
and/or  
platelets < 50 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).  
3. In the event of recurrence of 
ANC < 1.0 x109/l and/or 
platelets < 50 x109/l, repeat 
step 1 and resume imatinib at 
reduced dose of 260 mg/m2.  

Accelerated phase CML and 
blast crisis and Ph+ ALL 
(starting dose 600 mg)  

aANC < 0.5 x 109/l  
and/or  
platelets < 10 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 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)  

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

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Therapeutic indication Neutropenia and 
thrombocytopenia toxicity 

Posology modification 

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.  

DFSP 
(at dose 800 mg)  

ANC < 1.0 x 109/l  
and/or  
platelets < 50 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 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 
and DFSP. There is no experience in children or adolescents with 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).  
 
Older people: Imatinib pharmacokinetics have not been studied in older people. No significant 
age-related pharmacokinetic differences have been observed in patients in clinical trials which 

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included over 20 % of patients aged 65 and older. No specific dose recommendation is necessary in 
older people. 
 
Method of administration 
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. 
 
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). 
 
Hepatitis B reactivation 
Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these 
patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or 
fulminant hepatitis leading to liver transplantation or a fatal outcome. 
Patients should be tested for HBV infection before initiating treatment with imatinib. Experts in liver 
disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients 
with positive hepatitis B serology (including those with active disease) and for patients who test 
positive for HBV infection during treatment. Carriers of HBV who require treatment with imatinib 

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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). 
 
Fluid retention 
Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, 
superficial oedema) have been reported in approximately 2.5 % of newly diagnosed CML patients 
taking imatinib. Therefore, it is highly recommended that patients be weighed regularly. An 
unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive 
care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence 
of these events in older people and those with a prior history of cardiac disease. Therefore, caution 
should be exercised in patients with cardiac dysfunction. 
 
Patients with cardiac disease 
Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be 
monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure 
should be evaluated and treated. 
 
In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the 
myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated 
with HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be 
reversible with the administration of systemic steroids, circulatory support measures and temporarily 
withholding imatinib. As cardiac adverse events have been reported uncommonly with imatinib, a 
careful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL 
population before treatment initiation. 
 
Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated 
with high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram 
and determination of serum troponin should therefore be considered in patients with HES/CEL, and in 
patients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If 
either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids 
(1–2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation 
of therapy. 
 
Gastrointestinal haemorrhage 
In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and intra-
tumoural haemorrhages were reported (see section 4.8). Based on the available data, no predisposing 
factors (e.g. tumour size, tumour location, coagulation disorders) have been identified that place 
patients with GIST at a higher risk of either type of haemorrhage. Since increased vascularity and 
propensity for bleeding is a part of the nature and clinical course of GIST, standard practices and 
procedures for the monitoring and management of haemorrhage in all patients should be applied. 
 
In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has 
been reported in post-marketing experience in patients with CML, ALL and other diseases (see 
section 4.8). When needed, discontinuation of imatinib treatment may be considered. 
 
Tumour lysis syndrome  
Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant 
dehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib (see 
section 4.8). 
 
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. 

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Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in 
patients receiving imatinib. 
 
In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in 
patients with normal renal function, probably due to an elevated plasma level of alpha-acid 
glycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment 
should be given the minimum starting dose. Patients with severe renal impairment should be treated 
with caution. The dose can be reduced if not tolerated (see section 4.2 and 5.2). 
 
Long-term treatment with imatinib may be associated with a clinically significant decline in renal 
function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and 
closely monitored during therapy, with particular attention to those patients exhibiting risk factors for 
renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be 
prescribed in accordance with standard treatment guidelines. 
 
Paediatric population 
There have been case reports of growth retardation occurring in children and pre-adolescents receiving 
imatinib. In an observational study in the CML paediatric population, a statistically significant 
decrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and 
24 months of treatment was reported in two small subsets irrespective of pubertal status or gender. 
Close monitoring of growth in paediatric patients under treatment with imatinib is recommended (see 
section 4.8). 
 
Lactose 
Imatinib medac contains lactose. Patients with rare hereditary problems of galactose intolerance, the 
Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 
 
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 medicinal 
products (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. 
cyclosporin, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, 

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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 Cmax 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. Clinical monitoring should be 
considered when administering imatinib to patients treated with metoprolol. 
 
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). However, the mechanism of the 
observed interaction is presently unknown. Caution is recommended in thyroidectomy patients 
receiving levothyroxine and imatinib. 
 
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 with other 
chemotherapeutic agents requires special precaution. 
 
Paediatric population 
Interaction studies have only been performed in adults. 
 
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 

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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 on imatinib treatment who are concerned about their fertility 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 
 
Summary of the safety profile 
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, discontinuation of the investigational medicinal product for treatment-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 investigational 
medicinal product was discontinued for imatinib-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 %) 
treatment-related adverse reactions 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. 
 
Tabulated list of 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 

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(≥ 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, pneumonia1, 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: 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 
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 congestive3, pulmonary oedema 
Rare: Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, angina pectoris, 

pericardial effusion 

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Not known: Pericarditis*, cardiac tamponade* 
Vascular disorders4 
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 effusion5, pharyngolaryngeal pain, pharyngitis 
Rare: Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonary haemorrhage 
Not known: Acute respiratory failure11*, interstitial lung disease* 
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 
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 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, 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 myalgia9, arthralgia, bone 

pain10 
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 

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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. 
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. Transformed CML is the stage of the disease after its progression from chronic phase to 
accelerated phase (AP) or blast crisis (BC). 
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. 
 
Description of selected adverse reactions: 
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). 
 
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. 

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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 
intratumoural 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 national reporting system 
listed in Appendix V. 
 
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 mg 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 mg 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 g 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. 
 
 

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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: protein kinase inhibitor, ATC code: L01XE01 
 
Mechanism of action 
Imatinib is a small molecule protein 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 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 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 crisis phase of the disease.  In the clinical 
study 38 % of patients were ≥ 60 years of age and 12 % of patients were ≥ 70 years of age. 
 
In addition, paediatric patients have been treated in two phase I studies and one phase II study.  
 
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. 
 

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Table 2  Response in adult CML study 
 
 Study 0102 

38-month data 
Myeloid blast crisis 

(n = 260) 
 % of patients (CI95 %) 

Haematological response1  31 % (25.2–36.8) 
Complete haematological 
response (CHR)  

8 % 

No evidence of leukaemia (NEL)  5 % 
Return to chronic phase (RTC)  18 % 
Major cytogenetic response2  15 % (11.2–20.4) 
Complete  
(Confirmed3) [95 % CI]  

7 % 
(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. 
 
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. 

 
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 

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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 3  Chemotherapy regimen used in combination with imatinib 
 
Study ADE10  
Prephase  DEX 10 mg/m2 oral, days 1-5; 

CP 200 mg/m2 i.v., days 3, 4, 5; 
MTX 12 mg intrathecal, day 1  

Remission induction  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  

Consolidation therapy I, 
III, V  

MTX 500 mg/m2 i.v. (24 h), days 1, 15; 
6-MP 25 mg/m2 oral, days 1-20  

Consolidation therapy II, 
IV  

Ara-C 75 mg/m2 i.v. (1 h), days 1-5; 
VM26 60 mg/m2 i.v. (1 h), days 1-5  

Study AAU02  
Induction therapy (de 
novo Ph+ ALL)  

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 

Consolidation (de novo 
Ph+ ALL)  

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  DEX 10 mg/m2 oral, days 1-5; 

CP 200 mg/m2 i.v., days 3-5; 
MTX 15 mg intrathecal, day 1 

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Study ADE10  
Induction therapy I  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 

Induction therapy II  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 

Consolidation therapy  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 

Study AJP01  
Induction therapy  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 

Consolidation therapy  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 

Maintenance  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 intensitiy 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) 

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 

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Consolidation block 2 
(3 weeks) 

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 

Reinduction block 1 
(3 weeks) 

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 

Intensification block 1 
(9 weeks) 

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 

Reinduction block 2 
(3 weeks) 

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 

Intensification block 2 
(9 weeks) 

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 

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 

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/m2/day, IV): days 1, 29 
DEX (6 mg/m2/day, PO): days 1-5; 29-33 

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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 

Maintenance 
(8-week cycles) 
Cycles 6-12 

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 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, haematologic, 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 were 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 

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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/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. The paediatric patient received 
400 mg/m2/daily, subsequently increased to 520 mg/m2/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. 
 

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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 
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 tmax by 1.5 
h), with a small reduction in AUC (7.4 %) compared to fasting conditions. The effect of prior 
gastrointestinal surgery on imatinib 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 (see section 4.5). 
 
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 medicinal products 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. 
 

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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 patients 
As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in 
both phase I and phase II studies. Dosing in paediatric patients 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 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 

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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 at a 
concentration of 125 μg/ml.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/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. 
 

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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 paediatric patients (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 paediatric patients (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 
 
Imatinib medac 100 mg hard capsules 
Capsule content 
Crospovidone (type A) 
Lactose monohydrate 
Magnesium stearate 
 
Capsule shell 
Gelatin  
Yellow iron oxide  (E172) 
Titanium dioxide  (E171) 
Red iron oxide   (E172) 
 
Imatinib medac 400 mg hard capsules 
Capsule content 
Crospovidone (type A) 
Lactose monohydrate 
Magnesium stearate 
 
Capsule shell 
Gelatin  
Yellow iron oxide  (E172) 
Titanium dioxide  (E171) 
Red iron oxide   (E172) 
Black iron oxide  (E172)  
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 

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6.4 Special precautions for storage 
 
Do not store above 30 ºC. 
 
6.5 Nature and contents of container 
 
Imatinib medac 100 mg hard capsules 
PA-Aluminium/PVC//Aluminium blisters. 
Packs containing 60 hard capsules. 
 
Imatinib medac 400 mg hard capsules 
PA-Aluminium/PVC//Aluminium blisters. 
Packs containing 30 hard capsules. 
 
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 
 
medac 
Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
Imatinib medac 100 mg hard capsules 
EU/1/13/876/001 
 
Imatinib medac 400 mg hard capsules 
EU/1/13/876/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 25 September 2013 
 
 
10. DATE OF REVISION OF THE TEXT  
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

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ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 

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A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 

medac Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
GERMANY 
 
Pabianickie Zaklady Farmaceutyczne Polfa S.A. 
ul. Marszalka J. Pilsudskiego 5 
95-200 Pabianice 
Poland 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic Safety Update Reports 

 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
• Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
theagreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 

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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

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A. LABELLING 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON  
 
 
1.  NAME OF THE MEDICINAL PRODUCT  
 
Imatinib medac 100 mg hard capsules 
Imatinib  
 
 
2.  STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 100 mg of imatinib (as mesilate). 
 
 
 
3.  LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. 
See package leaflet for further information. 
 
 
4.  PHARMACEUTICAL FORM AND CONTENTS 
 
60 hard capsules. 
 
 
5.  METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6.  SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7.  OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8.  EXPIRY DATE 
 
EXP: 
 
 
9.  SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 ºC. 
 
 

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10.  SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11.  NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12.  MARKETING AUTHORISATION NUMBER (S) 
 
EU/1/13/876/001 
 
 
13.  BATCH NUMBER 
 
Lot: 
 
 
14.  GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription.  
 
 
15.  INSTRUCTIONS ON USE 
 
 
16.  INFORMATION IN BRAILLE 
 
Imatinib medac 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
{2D barcode carrying the unique identifier included.} 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
1.  NAME OF THE MEDICINAL PRODUCT 
 
Imatinib medac 100 mg hard capsules 
Imatinib 
 
 
2.  NAME OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
 
 
3.  EXPIRY DATE 
 
EXP: 
 
 
4.  BATCH NUMBER 
 
Lot: 
 
 
5.  OTHER 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON  
 
 
1.  NAME OF THE MEDICINAL PRODUCT 
 
Imatinib medac 400 mg hard capsules 
Imatinib 
 
 
2.  STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 400 mg of imatinib (as mesilate). 
 
 
3.  LIST OF EXCIPIENTS 
 
Contains lactose monohydrate. 
See package leaflet for further information. 
 
 
4.  PHARMACEUTICAL FORM AND CONTENTS 
 
30 hard capsules. 
 
 
5.  METHOD AND ROUTE(S) OF ADMINISTRATION  
 
Read the package leaflet before use. 
Oral use. 
 
 
6.  SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7.  OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8.  EXPIRY DATE 
 
EXP: 
 
 
9.  SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 ºC. 
 
 
10.  SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

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 36 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11.  NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
 
12.  MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/876/002 
 
 
13.  BATCH NUMBER  
 
Lot: 
 
 
14.  GENERAL CLASSIFICATION FOR SUPPLY  
 
Medicinal product subject to medical prescription. 
 
 
15.  INSTRUCTIONS ON USE  
 
 
16.  INFORMATION IN BRAILLE  
 
Imatinib medac 400 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
{2D barcode carrying the unique identifier included.} 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
1.  NAME OF THE MEDICINAL PRODUCT 
 
Imatinib medac 400 mg hard capsules 
Imatinib 
 
 
2.  NAME OF THE MARKETING AUTHORISATION HOLDER 
 
medac GmbH 
 
 
3.  EXPIRY DATE 
 
EXP: 
 
 
4.  BATCH NUMBER 
 
Lot: 
 
 
5.  OTHER 
 
 

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B. PACKAGE LEAFLET 

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 39 

 
 

Package leaflet: Information for the user 
 

Imatinib medac 100 mg hard capsules 
Imatinib medac 400 mg hard capsules 

Imatinib 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.  
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor, 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 medac is and what it is used for 
2. What you need to know before you take Imatinib medac 
3. How to take Imatinib medac 
4. Possible side effects 
5. How to store Imatinib medac 
6. Contents of the pack and other information 
 
 
1.  What Imatinib medac is and what it is used for 
 
Imatinib medac 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 medac is a treatment for adults and children and adolescents for: 
 
• Chronic myeloid leukaemia (CML) in blast crisis. 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. Imatinib medac inhibits the growth of these cells. Blast crisis is the most 
advanced stage of this disease.  

• 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 medac inhibits the 
growth of these cells.  

 
Imatinib medac is also a treatment for children and adolescents for: 
 
• Newly diagnosed CML for whom bone marrow transplantation is not considered as the first line 

of treatment; 
• CML in the chronic phase after failure of interferon-alpha therapy, or in the accelerated phase. 

Accelerated phase is an intermediate phase among the chronic phase and the onset of blast 
crisis; it is considered as the first manifestation of resistance to therapy. 

 

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Imatinib medac 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 medac 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 medac 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 medac 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 medac works or why this medicine has been prescribed 
for you, ask your doctor. 
 
 
2.  What you need to know before you take Imatinib medac 
 
Imatinib medac 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 medac: 
• 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 medac. 
 
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 medac: 
• 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 medac 

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 medac. 
 
During treatment with Imatinib medac, tell your doctor straight away if you put on weight very 
quickly. Imatinib medac may cause your body to retain water (severe fluid retention). 
 
While you are taking Imatinib medac, your doctor will regularly check whether the medicine is 
working. You will also have blood tests and be weighed regularly. 
 
Children and adolescents 
Imatinib medac 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 and adolescents with 
Ph-positive ALL. 
Some children and adolescents taking Imatinib medac may have slower than normal growth. The 
doctor will monitor the growth at regular visits. 
 

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Other medicines and Imatinib medac 
Tell your doctor, pharmacist or nurse 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 
medac when taken together. They may increase or decrease the effect of Imatinib medac, either 
leading to increased side effects or making Imatinib medac less effective. Imatinib medac 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 medac 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 medac during 
pregnancy. 

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

• Do not breast-feed during the treatment with Imatinib medac as there is limited information on 
the distribution of imatinib into the breast milk. 

• Patients who are concerned about their fertility while taking Imatinib medac 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. 
 
Imatinib medac contains lactose monohydrate 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
 
 
3.  How to take Imatinib medac  
 
Your doctor has prescribed Imatinib medac because you suffer from a serious condition. Imatinib 
medac can help you to fight this condition. 
However, always take this medicine exactly as your doctor, pharmacist or nurse has told you. It is 
important that you do this as long as your doctor, pharmacist or nurse tells you to. Check with your 
doctor, pharmacist or nurse if you are not sure. 
 
Do not stop taking Imatinib medac 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 medac to take 
 
Use in adults 
Your doctor will tell you exactly how many capsules of Imatinib medac to take. 
 
The usual starting dose in treatment in CML in blast crisis is 600 mg, to be taken as 6 capsules of 
100 mg (or 1 capsule of 400 mg plus 2 capsules of 100 mg) once a day. 
 
Your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your 
daily dose is 800 mg, you should take 1 capsule of 400 mg in the morning and 1 capsule of 400 mg in 
the evening. 
 

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• If you are being treated for Ph-positive ALL: 
The starting dose is 600 mg to be taken as 6 capsules of 100 mg (or 1 capsule of 400 mg plus 
2 capsules of 100 mg) once a day. 

 
• If you are being treated for MDS/MPD: 

The starting dose is 400 mg, to be taken as 1 capsule of 400 mg once a day. 
 
• If you are being treated for HES/CEL: 

The starting dose is 100 mg, to be taken as 1 capsule of 100 mg once a day. Your doctor may 
decide to increase the dose to 400 mg, to be taken as 1 capsule of 400 mg once a day, depending 
on how you respond to treatment. 
 

• If you are being treated for DFSP: 
The dose is 800 mg per day, to be taken as 1 capsule of 400 mg in the morning and 1 capsule of 
400 mg in the evening. 

 
Use in children and adolescents  
The doctor will tell you how many capsules of Imatinib medac to give to your child. The amount of 
Imatinib medac given will depend on your child’s condition, body weight and height. The total daily 
dose in children and adolescents must not exceed 800 mg with CML and 600 mg with Ph+ALL. The 
treatment can either be given to your child as a once-daily dose or alternatively the daily dose can be 
split into two administrations (half in the morning and half in the evening). 
 
When and how to take Imatinib medac  
• Take Imatinib medac with a meal. This will help protect you from stomach problems when 

taking Imatinib medac. 
• Swallow the capsules whole with a large glass of water. Do not open or crush the capsules 

unless you have difficulty in swallowing (e.g. in children). 
• If you are unable to swallow the capsules, you can open them up and pour the powder into a 

glass of still mineral water or apple juice. 
• If you are a woman who is pregnant or might get pregnant and are trying to open the capsules 

for your children or another patient unable to swallow, you should handle the contents with 
caution in order to avoid skin-eye contact or inhalation. You should wash your hands 
immediately after opening the capsules. 

 
How long to take Imatinib medac 
Keep taking Imatinib medac every day for as long as your doctor tells you. 
 
If you take more Imatinib medac than you should 
If you have accidentally taken too many capsules, talk to your doctor straight away. You may require 
medical attention. Take the medicine pack with you. 
 
If you forget to take Imatinib medac 
• 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.  
 

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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 medac may cause your body to retain water (severe fluid retention). 
• Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib medac 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 phosphorus 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. 
 
If you get any of the above, tell your doctor straight away.  
 

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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 medac treatment or after you have 

stopped taking Imatinib medac 
• 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. 
•  Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a 

liver infection). 
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 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5.  How to store Imatinib medac 
 
Keep this medicine out of the sight and reach of children. 
Do not use this medicine after the expiry date which is stated on the blister and carton after EXP. 
Do not store above 30 °C. 
Do not use any pack that is damaged or shows signs of tampering. 

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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 medac contains  
• The active substance is imatinib (as mesilate).  
 Each 100 mg hard capsule of Imatinib medac contains 100 mg imatinib (as mesilate). 
 Each 400 mg hard capsule of Imatinib medac contains 400 mg imatinib (as mesilate). 
 
• The other ingredients are crospovidone (type A), lactose monohydrate, magnesium stearate.  
 The capsule shell for 100 mg capsule is composed of gelatine, yellow iron oxide (E172), 

titanium dioxide (E171) and red iron oxide (E172).  
 The capsule shell for 400 mg capsule is composed of gelatine, yellow iron oxide (E172), 

titanium dioxide (E171), red iron oxide (E172) and black iron oxide (E172). 
 
What Imatinib medac looks like and contents of the pack  
Imatinib medac 100 mg hard capsules are gelatin capsules of size “3” with orange body and cap. 
Imatinib medac 400 mg hard capsules are gelatin capsules of size “00” with caramel body and cap. 
Imatinib medac 100 mg capsules are supplied in packs containing 60 capsules in blisters. 
Imatinib medac 400 mg capsules are supplied in packs containing 30 capsules in blisters. 
 
Marketing Authorisation Holder  
 
medac 
Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
Manufacturer 
 
Pabianickie Zakłady Farmaceutyczne Polfa S.A.  
Marszałka Józefa Piłsudskiego 5 
95-200 Pabianice 
Poland 
 
medac 
Gesellschaft für klinische Spezialpräparate mbH 
Theaterstr. 6 
22880 Wedel 
Germany 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu 
 

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	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET