Imatinib Actavis

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 50 mg hard capsules 
Imatinib Actavis 100 mg hard capsules 
Imatinib Actavis 400 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Imatinib Actavis 50 mg hard capsules 
Each hard capsule contains 50 mg imatinib (as mesilate). 
 
Imatinib Actavis 100 mg hard capsules 
Each hard capsule contains 100 mg imatinib (as mesilate). 
 
Imatinib Actavis 400 mg hard capsules 
Each hard capsule contains 400 mg imatinib (as mesilate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule (capsule). 
 
Imatinib Actavis 50 mg hard capsules 
Hard capsule of size 3 with light yellow cap and light yellow body imprinted with “50 mg” in black 
ink. 
 
Imatinib Actavis 100 mg hard capsules 
Hard capsule of size 1 with light orange cap and light orange body imprinted with “100 mg” in black 
ink. 
 
Imatinib Actavis 400 mg hard capsules 
Hard capsule of size 00 with orange opaque colour cap and body imprinted with “400 mg” in black 
ink. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Imatinib Actavis is indicated for the treatment of 
- paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) 

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

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

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

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

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

leukaemia (CEL) with FIP1L1-PDGFRα rearrangement. 
 

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The effect of imatinib on the outcome of bone marrow transplantation has not been determined. 
 
Imatinib Actavis is indicated for 
- the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and 

adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery. 
 
In adult and paediatric patients, the effectiveness of imatinib is based on overall haematological and 
cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic 
response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on 
objective response rates in adult patients with unresectable and/or metastatic DFSP. The experience 
with imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very 
limited (see section 5.1). There are no controlled trials demonstrating a clinical benefit or increased 
survival for these diseases. 
 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the treatment of patients with 
haematological malignancies and malignant sarcomas, as appropriate. 
 
Posology 
 
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 children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily 
is recommended for children with chronic phase CML and advanced phase CML (not to exceed the 
total dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose may 
be split into two administrations – one in the morning and one in the evening. The dose 
recommendation is currently based on a small number of paediatric patients (see sections 5.1 and 5.2). 
There is no experience with the treatment of children below 2 years of age. 
 
Dose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may 
be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia-
related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any 
time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; 
failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved 
haematological and/or cytogenetic response. Patients should be monitored closely following dose 
escalation given the potential for an increased incidence of adverse reactions at higher dosages. 
 
Posology for Ph+ ALL in adult patients 

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The recommended dose of imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological 
experts in the management of this disease should supervise the therapy throughout all phases of care. 
 
Treatment schedule: On the basis of the existing data, imatinib has been shown to be effective and safe 
when administered at 600 mg/day in combination with chemotherapy in the induction phase, the 
consolidation and maintenance phases of chemotherapy (see section 5.1) for adult patients with newly 
diagnosed Ph+ ALL. The duration of imatinib therapy can vary with the treatment programme 
selected, but generally longer exposures to imatinib have yielded better results. 
 
For adult patients with relapsed or refractory Ph+ALL imatinib monotherapy at 600 mg/day is safe, 
effective and can be given until disease progression occurs. 
 
Posology for Ph+ ALL in paediatric patients 
Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily 
is recommended for children with Ph+ ALL (not to exceed the total dose of 600 mg). 
 
Posology for MDS/MPD 
The recommended dose of imatinib is 400 mg/day for adult patients with MDS/MPD. 
 
Treatment duration: In the only clinical trial performed up to now, treatment with imatinib was 
continued until disease progression (see section 5.1). At the time of analysis, the treatment 
duration was a median of 47 months (24 days - 60 months). 
 
Posology for HES/CEL 
The recommended dose of imatinib is 100 mg/day for adult patients with HES/CEL. 
 
Dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions 
if assessments demonstrate an insufficient response to therapy. 
 
Treatment should be continued as long as the patient continues to benefit.  
 
Posology for DFSP 
The recommended dose of imatinib is 800 mg/day for adult patients with DFSP. 
 
Dose adjustment for adverse reactions 
Non-haematological adverse reactions 
If a severe non-haematological adverse reaction develops with imatinib use, treatment must be 
withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending 
on the initial severity of the event. 
 
If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases 
> 5 x IULN occur, imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN 
and transaminase levels to < 2.5 x IULN. Treatment with imatinib may then be continued at a reduced 
daily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from 
800 mg to 600 mg, and in children from 340 to 260 mg/m2/day. 
 
Haematological adverse reactions 
Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are 
recommended as indicated in the table below. 
 
Dose adjustments for neutropenia and thrombocytopenia: 
 
HES/CEL (starting dose 
100 mg) 

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). 

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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 x 109/L and/or platelets 
< 50 x 109/L, repeat step 1 and resume 
imatinib at reduced dose of 
260 mg/m2. 

CML in 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 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 
 

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Paediatric use: There is no experience in children with CML below 2 years of age and with Ph+ALL 
below 1 year of age (see section 5.1).There is very limited experience in children with MDS/MPD, 
DFSP, and HES/CEL. 
 
The safety and efficacy of imatinib in children with MDS/MPD, DFSP and HES/CEL aged less than 
18 years of age have not been established in clinical trials. Currently available published data are 
summarised in section 5.1 but no recommendation on a posology can be made. 
 
Hepatic insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate 
or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The 
dose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2). 
 
Liver dysfunction classification: 
 
Liver dysfunction Liver function tests 
Mild Total bilirubin: = 1.5 ULN 

AST: >ULN (can be normal or <ULN if total bilirubin is >ULN) 
Moderate Total bilirubin: >1.5-3.0 ULN 

AST: any 
Severe Total bilirubin: >3-10 ULN 

AST: any 
ULN = upper limit of normal for the institution 
AST = aspartate aminotransferase 
 
Renal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimum 
recommended dose of 400 mg daily as starting dose. However, in these patients caution is 
recommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack 
of efficacy (see sections 4.4 and 5.2). 
 
Elderly patients: Imatinib pharmacokinetics have not been specifically studied in older people. No 
significant age-related pharmacokinetic differences have been observed in adult patients in clinical 
trials which included over 20% of patients age 65 and older. No specific dose recommendation is 
necessary in older people. 
 
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 (children) unable to swallow the capsules, their content may be diluted in a glass of either 
still water or apple juice. Since studies in animals have shown reproductive toxicity, and the potential 
risk for the human foetus is unknown, women of child-bearing potential who open capsules should be 
advised to handle the contents with caution and avoid skin-eye contact or inhalation (see section 4.6). 
Hands should be washed immediately after handling open capsules. 
 
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, 

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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 sections 4.5 and 4.8). 
 
Fluid retention 
Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, 
superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients 
taking imatinib. Therefore, it is highly recommended that patients be weighed regularly. An 
unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive 
care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence 
of these events in elderly patients 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 

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In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and 
intra-tumoural haemorrhages were reported (see section 4.8). Based on the available data, no 
predisposing factors (e.g. tumour size, tumour location, coagulation disorders) have been identified 
that place patients with GIST at a higher risk of either type of haemorrhage. Since increased 
vascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard 
practices and procedures for the monitoring and management of haemorrhage in all patients should be 
applied. 
In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has 
been reported in post-marketing experience in patients with CML, ALL and other diseases (see 
section 4.8). When needed, discontinuation of imatinib treatment may be considered. 
 
Tumour lysis syndrome 
Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant 
dehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib (see 
section 4.8). 
 
Hepatitis B reactivation 
Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these 
patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or 
fulminant hepatitis leading to liver transplantation or a fatal outcome.  
Patients should be tested for HBV infection before initiating treatment with Imatinib Actavis. 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 
Actavis 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). 
 
Phototoxicity 
Exposure to direct sunlight should be avoided or minimised due to the risk of phototoxicity associated 
with imatinib treatment. Patients should be instructed to use measures such as protective clothing and 
sunscreen with high sun protection factor (SPF). 
 
Thrombotic microangiopathy 
BCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy 
(TMA), including individual case reports for Imatinib Actavis (see section 4.8). If laboratory or 
clinical findings associated with TMA occur in a patient receiving Imatinib Actavis, treatment should 
be discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-
ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated 
in conjunction with low ADAMTS13 activity, treatment with Imatinib Actavis should not be resumed. 
 
Laboratory tests 
Complete blood counts must be performed regularly during therapy with imatinib. Treatment of CML 
patients with imatinib has been associated with neutropenia or thrombocytopenia. However, the 
occurrence of these cytopenias is likely to be related to the stage of the disease being treated and they 
were more frequent in patients with accelerated phase CML or blast crisis as compared to patients with 
chronic phase CML. Treatment with imatinib may be interrupted or the dose may be reduced, as 
recommended in section 4.2. 
 
Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in 
patients receiving imatinib. 
 
In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in 
patients with normal renal function, probably due to an elevated plasma level of alpha-acid 
glycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment 
should be given the minimum starting dose. Patients with severe renal impairment should be treated 
with caution. The dose can be reduced if not tolerated (see sections 4.2 and 5.2). 
 

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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 children under imatinib treatment is recommended (see section 4.8). 
 
Excipients(s) 
 
Sodium 
This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say 
essentially ‘sodium-free’. 
 
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. 
cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, 
terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of 
other CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel 
blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.). 
 
Because of known increased risks of bleeding in conjunction with the use of imatinib (e.g. 
haemorrhage), patients who require anticoagulation should receive low-molecular-weight or standard 
heparin instead of coumarin derivatives such as warfarin. 
 

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In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similar 
to those that affect CYP3A4 activity. Imatinib at 400 mg twice daily had an inhibitory effect on 
CYP2D6-mediated metoprolol metabolism, with metoprolol 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. In patients treated with metoprolol 
clinical monitoring should be considered. 
 
In vitro, imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/L. This 
inhibition has not been observed in vivo after the administration of imatinib 400 mg and 
paracetamol 1000 mg. Higher doses of imatinib and paracetamol have not been studied. 
 
Caution should therefore be exercised when using high doses of imatinib and paracetamol 
concomitantly. 
 
In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be 
decreased when imatinib is co-administered (see section 4.4). Caution is therefore recommended. 
However, the mechanism of the observed interaction is presently unknown. 
 
In Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy (see 
section 5.1), but drug-drug interactions between imatinib and chemotherapy regimens are not well 
characterised. Imatinib adverse events, i.e. hepatotoxicity, myelosuppression or others, may increase 
and it has been reported that concomitant use with L-asparaginase could be associated with increased 
hepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination requires special 
precaution. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
Women of childbearing potential must be advised to use effective contraception during treatment. 
 
Pregnancy 
There are limited data on the use of imatinib in pregnant women. There have been post-marketing 
reports of spontaneous abortions and infant congenital anomalies from women who have taken 
imatinib. Studies in animals have however shown reproductive toxicity (see section 5.3) and the 
potential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearly 
necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the 
foetus. 
 
Breast-feeding 
There is limited information on imatinib distribution on human milk. Studies in two breast-feeding 
women revealed that both imatinib and its active metabolite can be distributed into human milk. The 
milk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the 
metabolite, suggesting greater distribution of the metabolite into the milk. Considering the combined 
concentration of imatinib and the metabolite and the maximum daily milk intake by infants, the total 
exposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of 
low-dose exposure of the infant to imatinib are unknown, women taking imatinib should not 
breast-feed. 
 
Fertility 
In non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies 
on patients receiving imatinib and its effect on fertility and gametogenesis have not been performed. 
Patients concerned about their fertility on imatinib treatment should consult with their physician. 
 
4.7 Effects on ability to drive and use machines 
 

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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 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, drug discontinuation for drug-related adverse reactions was observed in 2.4% 
of newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, 
4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients 
after failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse 
reactions in 4% of patients. 
 
The adverse reactions were similar in all indications, with two exceptions. There was more 
myelosuppression seen in CML patients than in GIST, which is probably due to the underlying 
disease. In the study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced 
CTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour 
sites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be 
serious and sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions in 
both settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps 
and rash. Superficial oedemas were a common finding in all studies and were described primarily as 
periorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed 
with diuretics, other supportive measures, or by reducing the dose of imatinib. 
 

When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver 
toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed. Considering the 
limited safety database, the adverse events thus far reported in children are consistent with the known 
safety profile in adult patients with Ph+ ALL. The safety database for children with Ph+ALL is very 
limited though no new safety concerns have been identified. 
 
Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight 
gain with or without superficial oedema may be collectively described as “fluid retention”. These 
reactions can usually be managed by withholding imatinib temporarily and with diuretics and other 
appropriate supportive care measures. However, some of these reactions may be serious or life-
threatening and several patients with blast crisis died with a complex clinical history of pleural 
effusion, congestive heart failure and renal failure. There were no special safety findings in paediatric 
clinical trials. 
 
Adverse reactions 
Adverse reactions reported as more than an isolated case are listed below, by system organ class and 
by frequency. Frequency categories are defined using the following convention: very common 
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), 
very rare (<1/10,000), not known (cannot be estimated from the available data). 
 
Within each frequency grouping, undesirable effects are presented in order of frequency, the most 
frequent first. 
 
Adverse reactions and their frequencies are reported in Table 1. 
 
Table 1 Tabulated summary of adverse reactions 
 
Infections and infestations 
Uncommon Herpes zoster, herpes simplex, nasopharyngitis, pneumonia1, sinusitis, 

11 



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, thrombotic microangiopathy 
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 
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 

12 



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)*, pseudoporphyria* 

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 
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 

13 



 
* 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. 

2 Headache was the most common in GIST patients. 
3 On a patient-year basis, cardiac events including congestive heart failure were more commonly 

observed in patients with transformed CML than in patients with chronic CML. 
4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was 

most common in patients with GIST and with transformed CML (CML-AP and CML-BC). 
5 Pleural effusion was reported more commonly in patients with GIST and in patients with 

transformed CML (CML-AP and CML-BC) than in patients with chronic CML. 
6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST 

patients. 
8 Some fatal cases of hepatic failure and of hepatic necrosis have been reported. 
9 Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed 

in post-marketing. 
10 Musculoskeletal pain and related events were more commonly observed in patients with CML 

than in GIST patients. 
11 Fatal cases have been reported in patients with advanced disease, severe infections, severe 

neutropenia and other serious concomitant conditions. 
 
Laboratory test abnormalities 
Haematology 
In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in 
all studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study). 
However, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the 
frequency of grade 3 or 4 neutropenias (ANC < 1.0 x 109/L) and thrombocytopenias (platelet 
count < 50 x 109/L) being between 4 and 6 times higher in blast crisis and accelerated phase (59–64% 
and 44–63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed 
patients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed 
chronic phase CML grade 4 neutropenia (ANC < 0.5 x 109/L) and thrombocytopenia (platelet count 
< 10 x 109/L) were observed in 3.6% and < 1% of patients, respectively. The median duration of the 
neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, 
respectively. These events can usually be managed with either a reduction of the dose or an 
interruption of treatment with imatinib, but can in rare cases lead to permanent discontinuation of 
treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 
4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the 
first several months of therapy. 
 
In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported 
in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra-
tumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and 
2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient 
developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts 
occurred mainly during the first six weeks of therapy, with values remaining relatively stable 
thereafter. 
 
Biochemistry 
Severe elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was 
usually managed with dose reduction or interruption (the median duration of these episodes was 
approximately one week). Treatment was discontinued permanently because of liver laboratory 
abnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 

14 



ALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) 
elevations were observed. Bilirubin elevation was below 3%. 
 
There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them 
outcome was fatal, including one patient on high dose paracetamol. 
 
Description of selected adverse reactions 
Hepatitis B reactivation 
Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in 
acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see 
section 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the 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 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, 
erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal 
pain, headache, decreased appetite. 
1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine 
phosphokinase, increased bilirubin, gastrointestinal pain. 
6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, 
vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased 
transaminases. 
8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. 
 
Paediatric population 
One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia 
and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood 
cell count and diarrhoea. 
 
In the event of overdose, the patient should be observed and appropriate supportive treatment given. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitor, ATC code: L01XE01 
 
Mechanism of action 
Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the 
Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor 
(SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the 
colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and 

15 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation 
of these receptor kinases. 
 
Pharmacodynamic effects 
Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at 
the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces 
apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia 
chromosome positive CML and acute lymphoblastic leukaemia (ALL) patients. 
 
In vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl 
positive tumour cells. 
 
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), 
PDGF-R, and inhibits PDGF-mediated cellular events. Constitutive activation of the PDGF receptor or 
the Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive 
production of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP. 
Imatinib inhibits signalling and proliferation of cells driven by dysregulated PDGFR and Abl kinase 
activity. 
 
Clinical studies in chronic myeloid leukaemia 
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 addition, 
children and adolescents have been treated in two phase I studies (in patients with CML or Ph+ acute 
leukaemia) and one phase II study. 
 
In the clinical study 38% of patients were ≥ 60 years of age and 12% of patients were ≥ 70 years of 
age. 
 
Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received prior 
chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 
165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol 
was subsequently amended to allow higher dosing and the remaining 223 patients were started at 
600 mg. 
 
The primary efficacy variable was the rate of haematological response, reported as either complete 
haematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and the 
blood, but without a full peripheral blood recovery as for complete responses), or return to chronic 
phase CML. In this study, 31% of patients achieved a haematological response (36% in previously 
untreated patients and 22% in previously treated patients) (Table 2). The rate of response was also 
higher in the patients treated at 600 mg (33%) as compared to the patients treated at 400 mg (16%, 
p=0.0220). The current estimate of the median survival of the previously untreated and treated patients 
was 7.7 and 4.7 months, respectively. 
 
Lymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n=10). The rate of 
haematological response was 70% with a duration of 2–3 months. 
 

16 



Table 2 Response in adult CML study 
 

 Study 0102 
38-month data 

Myeloid blast crisis 
(n=260) 

 % of patients (CI95%) 
Haematological response1 
 Complete haematological response (CHR) 
 
 No evidence of leukaemia (NEL) 
 
 Return to chronic phase (RTC) 

31% (25.2–36.8) 
8% 

 
5% 

 
18% 

Major cytogenetic response2 
 Complete 
 (Confirmed3) [95% CI] 
 Partial 

15% (11.2–20.4) 
7% 

(2%) [0.6–4.4] 
8% 

1 Haematological response criteria (all responses to be confirmed after ≥ 4 weeks): 
CHR: In study 0102 [ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, no blood blasts, BM blasts < 5% and 

no extramedullary disease] 
NEL Same criteria as for CHR but ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L 
RTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in PB, 

no extramedullary disease other than spleen and liver. 
BM = bone marrow, PB = peripheral blood 
2 Cytogenetic response criteria: 
A major response combines both complete and partial responses: complete (0% Ph+ metaphases), 
partial (1–35%) 
3 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation 
performed at least one month after the initial bone marrow study. 
 
Paediatric patients: A total of 26 paediatric patients of age < 18 years with either chronic phase CML 
(n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase 
I trial. This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a 
prior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m2/day (n=5), 
340 mg/m2/day (n=9), 440 mg/m2/day (n=7) and 570 mg/m2/day (n=5). Out of 9 patients with chronic 
phase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial 
cytogenetic response, respectively, for a rate of MCyR of 77%. 
 
A total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been 
enrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib 
340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Imatinib treatment 
induces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after 
8 weeks of therapy. The high rate of CHR is accompanied by the development of a complete 
cytogenetic response (CCyR) of 65% which is comparable to the results observed in adults. 
Additionally, partial cytogenetic response (PCyR) was observed in 16% for a MCyR of 81%. The 
majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a 
median time to response based on the Kaplan-Meier estimate of 5.6 months. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
imatinib in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)-
positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use). 
 
Clinical studies in Ph+ ALL 
Newly diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy induction 
in 55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced a 
significantly higher rate of complete haematological response than chemotherapy (96.3% vs. 50%; 

17 



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 

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 

18 



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 

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 

19 



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 
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 

20 



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 was detected, 9 of them achieved a CHR and 1 PHR. The age of these 
patients ranged from 2 to 79 years. In a recent publication updated information from 6 of these 
11 patients revealed that all these patients remained in cytogenetic remission (range 32-38 months). 
The same publication reported long term follow-up data from 12 MDS/MPD patients with PDGFR 
gene rearrangements (5 patients from study B2225). These patients received imatinib for a median of 
47 months (range 24 days – 60 months). In 6 of these patients follow-up now exceeds 4 years. Eleven 
patients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease 
or disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogenetic 
responses have been sustained for a median of 49 months (range 19-60) and 47 months (range 16-59), 

21 



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. 5 patients responded, 
3 completely and 2 partially. The median duration of therapy in the published literature ranged 
between 4 weeks and more than 20 months. The translocation t(17:22)[(q22:q13)], or its gene product, 
was present in nearly all responders to imatinib treatment. 
 
There are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and 
PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from 
newborn to 14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to 
520 mg/m2 daily. All patients achieved partial and/or complete response. 
 
5.2 Pharmacokinetic properties 
 
Pharmacokinetics of imatinib 

22 



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 drug absorption has not been investigated. 
 
Distribution 
At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% 
on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding 
to lipoprotein. 
 
Biotransformation 
The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows 
similar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16% 
of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to 
that of the parent compound. 
 
Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulating 
radioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor 
metabolites. 
 
The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the 
biotransformation of imatinib. Of a panel of potential comedications (acetaminophen, aciclovir, 
allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, 
penicillin V) only erythromycin (IC50 50 µM) and fluconazole (IC50 118 µM) showed inhibition of 
imatinib metabolism which could have clinical relevance. 
 
Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 
and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/L, respectively. 
Maximal plasma concentrations of imatinib in patients are 2–4 μmol/L, consequently an inhibition of 
CYP2D6 and/or CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib did 
not interfere with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a 
result of competitive inhibition of CYP2C8 (Ki - 34.7 µM). This Ki value is far higher than the 
expected plasma levels of imatinib in patients, consequently no interaction is expected upon co-
administration of either 5-fluorouracil or paclitaxel and imatinib. 
 
Elimination 
Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% 
of the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose). Unchanged 
imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites. 
 
Plasma pharmacokinetics 
Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that 
once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose 
proportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in 
the kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when 
dosed once daily. 
 
Population pharmacokinetics 
Based on population pharmacokinetic analysis in CML patients, there was a small effect of age on the 
volume of distribution (12% increase in patients > 65 years old). This change is not thought to be 
clinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patient 

23 



weighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg the 
clearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustment 
based on kg bodyweight. There is no effect of gender on the kinetics of imatinib. 
 
Pharmacokinetics in paediatric population 
As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in 
both phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved the same 
exposure, respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC(0-24) 
on day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after 
repeated once-daily dosing. 
 
Based on pooled population pharmacokinetic analysis in paediatric patients with haematological 
disorders (CML, Ph+ALL, or other haematological disorders treated with imatinib), clearance of 
imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other 
demographics such as age, body weight and body mass index did not have clinically significant effects 
on the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients 
receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not 
exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 
600 mg once daily. 
 
Organ function impairment 
Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild 
and moderate impairment of renal function appear to have a higher plasma exposure than patients with 
normal renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold 
elevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is 
probably similar between patients with renal impairment and those with normal renal function, since 
renal excretion represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4). 
 
Although the results of pharmacokinetic analysis showed that there is considerable inter-subject 
variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver 
dysfunction as compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8). 
 
5.3 Preclinical safety data 
 
The preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits. 
 
Multiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs and 
monkeys, accompanied by bone marrow changes in rats and dogs. 
 
The liver was a target organ in rats and dogs. Mild to moderate increases in transaminases and slight 
decreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. 
No histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated 
for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct 
hyperplasia. 
 
Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of 
the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were 
observed in several of these animals. In rats, hyperplasia of the transitional epithelium in the renal 
papilla and in the urinary bladder was observed at doses ≥ 6 mg/kg in the 13-week study, without 
changes in serum or urinary parameters. An increased rate of opportunistic infections was observed 
with chronic imatinib treatment. 
 
In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the 
lowest dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based on 
body surface. Treatment resulted in worsening of normally suppressed malarial infections in these 
animals. 
 

24 



Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in 
vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive 
genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster 
ovary) for clastogenicity (chromosome aberration) in the presence of metabolic activation. Two 
intermediates of the manufacturing process, which are also present in the final product, are positive for 
mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma 
assay. 
 
In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights 
and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical 
dose of 800 mg/day, based on body surface area. This was not seen at doses ≤ 20 mg/kg. A slight to 
moderate reduction in spermatogenesis was also observed in the dog at oral doses ≥ 30 mg/kg. When 
female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on 
mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-
implantation foetal loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg. 
 
In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 
45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn 
pups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the 
same dose level, mean body weights were reduced from birth until terminal sacrifice and the number 
of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not 
affected, while an increased number of resorptions and a decreased number of viable foetuses was 
noted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 
generation was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg). 
 
Imatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/kg, 
approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. 
Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal 
bones. These effects were not seen at doses ≤ 30 mg/kg. 
 
No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 
postpartum) with respect to the known target organs in adult rats. In the juvenile toxicology study, 
effects upon growth, delay in vaginal opening and preputial separation were observed at 
approximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of 
340 mg/m2. In addition, mortality was observed in juvenile animals (around weaning phase) at 
approximately 2 times the average paediatric exposure at the highest recommended dose of 
340 mg/m2. 
 
In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted 
in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at 
≥ 30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), 
chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death 
or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, 
urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-
glandular stomach. 
 
Papilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, 
representing approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day 
or 800 mg/day, respectively, and 0.4 times the daily exposure in children (based on AUC) at 
340 mg/m2/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renal 
adenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, 
the parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands 
and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representing 
approximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, 
respectively, and 1.2 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no 
observed effect level (NOEL) was 30 mg/kg/day. 
 

25 



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 Actavis 50 mg hard capsules 
Capsule content 
Cellulose microcrystalline 
Copovidone 
Crospovidone 
Sodium stearyl fumarate 
Silica, hydrophobic colloidal  
Silica, colloidal anhydrous 
 
Capsule shell 
Hypromellose 
Titanium dioxide (E171) 
Iron oxide yellow (E172) 
 
Printing ink 
Shellac 
Black iron oxide (E172) 
Propylene glycol 
Ammonia solution 
Potassium hydroxide 
 
Imatinib Actavis 100 mg hard capsules 
Capsule content 
Cellulose microcrystalline 
Copovidone 
Crospovidone 
Sodium stearyl fumarate 
Silica, hydrophobic colloidal  
Silica, colloidal anhydrous 
 
Capsule shell 
Hypromellose 
Titanium dioxide (E171) 
Iron oxide yellow (E172) 
Iron oxide red (E172)  
 
Printing ink 
Shellac 
Black iron oxide (E172) 
Propylene glycol 
Ammonia solution 
Potassium hydroxide 
 

26 



Imatinib Actavis 400 mg hard capsules 
Capsule content 
Cellulose microcrystalline 
Copovidone 
Crospovidone 
Sodium stearyl fumarate 
Silica, hydrophobic colloidal  
Silica, colloidal anhydrous 
 
Capsule shell 
Hypromellose 
Titanium dioxide (E171) 
Iron oxide yellow (E172) 
Iron oxide red (E172)  
Iron oxide black (E172) 
 
Printing ink 
Shellac Glaze-45% 
Black iron oxide (E172) 
Propylene glycol 
Ammonium Hydroxide 28% 
 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
Do not store above 25°C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Imatinib Actavis 50 mg hard capsules 
Al/PVC/Aclar blister. One blister contains 10 capsules. 
Pack containing either 30 or 90 capsules. 
 
Imatinib Actavis 100 mg hard capsules 
Al/PVC/Aclar blister. One blister contains either 8 or 10 capsules. 
Pack containing either 24, 48, 60, 96, 120 or 180 capsules 
 
Imatinib Actavis 400 mg hard capsules 
Al/PVC-PVDC blister. One blister contains 10 capsules. 
Pack containing either 10, 30, 60, or 90 capsules. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Handling of opened capsules by women of child-bearing potential 
Since studies in animals have shown reproductive toxicity, and the potential risk for the human foetus 
is unknown, women of child-bearing potential who open capsules should be advised to handle the 

27 



contents with caution and avoid skin-eye contact or inhalation (see section 4.6). Hands should be 
washed immediately after handling open capsules. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
Reykjavíkurvegur 76-78 
IS-220 Hafnarfjörður 
Iceland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
Imatinib Actavis 50 mg hard capsules 
EU/1/13/825/001 
EU/1/13/825/002 
 
Imatinib Actavis 100 mg hard capsules 
EU/1/13/825/003 
EU/1/13/825/004 
EU/1/13/825/005 
EU/1/13/825/006 
EU/1/13/825/007 
EU/1/13/825/019 
 
Imatinib Actavis 400 mg hard capsules 
EU/1/13/825/020 
EU/1/13/825/021 
EU/1/13/825/022 
EU/1/13/825/023 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 17 April 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 
 
 

28 

http://www.ema.europa.eu/


1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 100 mg film-coated tablets 
Imatinib Actavis 400 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Imatinib Actavis 100 mg film-coated tablets 
Each film-coated tablet contains 100 mg imatinib (as mesilate). 
 
Excipients with known effect: 
Each film-coated tablet contains 0.19 mg lecithin (soya) (E322) 
 
Imatinib Actavis 400 mg film-coated tablets 
Each film-coated tablet contains 400 mg imatinib (as mesilate). 
 
Excipients with known effect: 
Each film-coated tablet contains 0.75 mg lecithin (soya) (E322)  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Imatinib Actavis 100 mg film-coated tablets 
Round, 9.2 mm in diameter, biconvex dark yellow to brownish film-coated tablet, embossed with 
company logo on one side and “36” with score line on the other side. 
The tablet can be divided into equal doses. 
 
Imatinib Actavis 400 mg film-coated tablets 
Oval-shape, 18.6x6.6 mm, biconvex dark yellow to brownish film-coated tablet, embossed with 
company logo on one side and “37” with score line on the other side. 
The score line is not intended for breaking the tablet. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Imatinib Actavis is indicated for the treatment of 
- paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive (Ph+) 

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

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

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

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

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

leukaemia (CEL) with FIP1L1-PDGFRα rearrangement. 
 

29 



The effect of imatinib on the outcome of bone marrow transplantation has not been determined. 
 
Imatinib Actavis is indicated for 
- the treatment of adult patients with unresectable dermatofibrosarcoma protuberans (DFSP) and 

adult patients with recurrent and/or metastatic DFSP who are not eligible for surgery. 
 
In adult and paediatric patients, the effectiveness of imatinib is based on overall haematological and 
cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic 
response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on 
objective response rates in adult patients with unresectable and/or metastatic DFSP. The experience 
with imatinib in patients with MDS/MPD associated with PDGFR gene re-arrangements is very 
limited (see section 5.1). There are no controlled trials demonstrating a clinical benefit or increased 
survival for these diseases. 
 
4.2 Posology and method of administration 
 
Therapy should be initiated by a physician experienced in the treatment of patients with 
haematological malignancies and malignant sarcomas, as appropriate. 
 
Posology 
 
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 children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily 
is recommended for children with chronic phase CML and advanced phase CML (not to exceed the 
total dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose may 
be split into two administrations – one in the morning and one in the evening. The dose 
recommendation is currently based on a small number of paediatric patients (see sections 5.1 and 5.2). 
There is no experience with the treatment of children below 2 years of age. 
 
Dose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may 
be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia-
related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any 
time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; 
failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved 
haematological and/or cytogenetic response. Patients should be monitored closely following dose 
escalation given the potential for an increased incidence of adverse reactions at higher dosages. 
 
Posology for Ph+ ALL in adult patients 

30 



The recommended dose of imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematological 
experts in the management of this disease should supervise the therapy throughout all phases of care. 
 
Treatment schedule: On the basis of the existing data, imatinib has been shown to be effective and safe 
when administered at 600 mg/day in combination with chemotherapy in the induction phase, the 
consolidation and maintenance phases of chemotherapy (see section 5.1) for adult patients with newly 
diagnosed Ph+ ALL. The duration of imatinib therapy can vary with the treatment programme 
selected, but generally longer exposures to imatinib have yielded better results. 
 
For adult patients with relapsed or refractory Ph+ALL imatinib monotherapy at 600 mg/day is safe, 
effective and can be given until disease progression occurs. 
 
Posology for Ph+ ALL in paediatric patients 
Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily 
is recommended for children with Ph+ ALL (not to exceed the total dose of 600 mg). 
 
Posology for MDS/MPD 
The recommended dose of imatinib is 400 mg/day for adult patients with MDS/MPD. 
 
Treatment duration: In the only clinical trial performed up to now, treatment with imatinib was 
continued until disease progression (see section 5.1). At the time of analysis, the treatment 
duration was a median of 47 months (24 days - 60 months). 
 
Posology for HES/CEL 
The recommended dose of imatinib is 100 mg/day for adult patients with HES/CEL. 
 
Dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactions 
if assessments demonstrate an insufficient response to therapy. 
 
Treatment should be continued as long as the patient continues to benefit.  
 
Posology for DFSP 
The recommended dose of imatinib is 800 mg/day for adult patients with DFSP. 
 
Dose adjustment for adverse reactions 
Non-haematological adverse reactions 
If a severe non-haematological adverse reaction develops with imatinib use, treatment must be 
withheld until the event has resolved. Thereafter, treatment can be resumed as appropriate depending 
on the initial severity of the event. 
 
If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases 
> 5 x IULN occur, imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULN 
and transaminase levels to < 2.5 x IULN. Treatment with imatinib may then be continued at a reduced 
daily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from 
800 mg to 600 mg, and in children from 340 to 260 mg/m2/day. 
 
Haematological adverse reactions 
Dose reduction or treatment interruption for severe neutropenia and thrombocytopenia are 
recommended as indicated in the table below. 
 
Dose adjustments for neutropenia and thrombocytopenia: 
 
HES/CEL (starting dose 
100 mg) 

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). 

31 



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 x 109/L and/or platelets 
< 50 x 109/L, repeat step 1 and resume 
imatinib at reduced dose of 
260 mg/m2. 

CML in 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 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 
 

32 



Paediatric use: There is no experience in children with CML below 2 years of age and with Ph+ALL 
below 1 year of age (see section 5.1). There is very limited experience in children with MDS/MPD, 
DFSP, and HES/CEL. 
 
The safety and efficacy of imatinib in children with MDS/MPD, DFSP and HES/CEL aged less than 
18 years of age have not been established in clinical trials. Currently available published data are 
summarised in section 5.1 but no recommendation on a posology can be made. 
 
Hepatic insufficiency: Imatinib is mainly metabolised through the liver. Patients with mild, moderate 
or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The 
dose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2). 
 
Liver dysfunction classification: 
 
Liver dysfunction Liver function tests 
Mild Total bilirubin: = 1.5 ULN 

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

Moderate Total bilirubin: >1.5-3.0 ULN 
AST: any 

Severe Total bilirubin: >3-10 ULN 
AST: any 

ULN = upper limit of normal for the institution 
AST = aspartate aminotransferase 
 
Renal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimum 
recommended dose of 400 mg daily as starting dose. However, in these patients caution is 
recommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack 
of efficacy (see sections 4.4 and 5.2). 
 
Elderly patients: Imatinib pharmacokinetics have not been specifically studied in older people. No 
significant age-related pharmacokinetic differences have been observed in adult patients in clinical 
trials which included over 20% of patients age 65 and older. No specific dose recommendation is 
necessary in older people. 
 
Method of administration 
 
For doses of 400 mg and above (see dosage recommendation above) a 400 mg tablet (not divisible) is 
available. 
For doses other than 400 mg and 800 mg (see dosage recommendation above) a 100 mg divisible 
tablet is available. 
 
The prescribed dose should be administered orally with a meal and a large glass of water to minimise 
the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, 
whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in 
the evening.  
 
For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of still 
water or apple juice. The required number of tablets should be placed in the appropriate volume of 
beverage (approximately 50 ml for a 100 mg tablet, and 200 ml for a 400 mg tablet) and stirred with a 
spoon. The suspension should be administered immediately after complete disintegration of the 
tablet(s). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 

33 



Hypersensitivity to soya or peanut. 
 
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 sections 4.5 and 4.8). 
 
Fluid retention 
Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, 
superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients 
taking imatinib. Therefore, it is highly recommended that patients be weighed regularly. An 
unexpected rapid weight gain should be carefully investigated and if necessary appropriate supportive 
care and therapeutic measures should be undertaken. In clinical trials, there was an increased incidence 
of these events in elderly patients 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. 
 

34 



Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated 
with high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram 
and determination of serum troponin should therefore be considered in patients with HES/CEL, and in 
patients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If 
either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids 
(1-2 mg/kg) for one to two weeks concomitantly with imatinib should be considered at the initiation of 
therapy. 
 
Gastrointestinal haemorrhage 
In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal and 
intra-tumoural haemorrhages were reported (see section 4.8). Based on the available data, no 
predisposing factors (e.g. tumour size, tumour location, coagulation disorders) have been identified 
that place patients with GIST at a higher risk of either type of haemorrhage. Since increased 
vascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standard 
practices and procedures for the monitoring and management of haemorrhage in all patients should be 
applied. 
In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, has 
been reported in post-marketing experience in patients with CML, ALL and other diseases (see 
section 4.8). When needed, discontinuation of imatinib treatment may be considered. 
 
Tumour lysis syndrome 
Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significant 
dehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib (see 
section 4.8). 
 
Hepatitis B reactivation 
Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these 
patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or 
fulminant hepatitis leading to liver transplantation or a fatal outcome.  
Patients should be tested for HBV infection before initiating treatment with Imatinib Actavis. 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 
Actavis 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). 
 
Phototoxicity 
Exposure to direct sunlight should be avoided or minimised due to the risk of phototoxicity associated 
with imatinib treatment. Patients should be instructed to use measures such as protective clothing and 
sunscreen with high sun protection factor (SPF). 
 
Thrombotic microangiopathy 
BCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy 
(TMA), including individual case reports for Imatinib Actavis (see section 4.8). If laboratory or 
clinical findings associated with TMA occur in a patient receiving Imatinib Actavis, treatment should 
be discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-
ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevated 
in conjunction with low ADAMTS13 activity, treatment with Imatinib Actavis should not be resumed. 
 
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. 
 

35 



Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly in 
patients receiving imatinib. 
 
In patients with impaired renal function, imatinib plasma exposure seems to be higher than that in 
patients with normal renal function, probably due to an elevated plasma level of alpha-acid 
glycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment 
should be given the minimum starting dose. Patients with severe renal impairment should be treated 
with caution. The dose can be reduced if not tolerated (see sections 4.2 and 5.2). 
 
Long-term treatment with imatinib may be associated with a clinically significant decline in renal 
function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and 
closely monitored during therapy, with particular attention to those patients exhibiting risk factors for 
renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be 
prescribed in accordance with standard treatment guidelines. 
 
Paediatric population 
There have been case reports of growth retardation occurring in children and pre-adolescents receiving 
imatinib. 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 children under imatinib treatment is recommended (see section 4.8). 
 
Excipients 
 
Lecithin (soya) 
This medicinal product contains lecithin (soya). Patients, who are allergic to peanut or soya, may not 
use this medicinal product. 
 
Sodium 
This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say 
essentially ‘sodium-free’. 
 
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: 

36 



Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold, 
respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommended 
when administering imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g. 
cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, 
terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration of 
other CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channel 
blockers, certain HMG-CoA reductase inhibitors, i.e. statins, etc.). 
 
Because of known increased risks of bleeding in conjunction with the use of imatinib (e.g. 
haemorrhage), patients who require anticoagulation should receive 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. In patients treated with metoprolol 
clinical monitoring should be considered. 
 
In vitro, imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/L. This 
inhibition has not been observed in vivo after the administration of imatinib 400 mg and 
paracetamol 1000 mg. Higher doses of imatinib and paracetamol have not been studied. 
 
Caution should therefore be exercised when using high doses of imatinib and paracetamol 
concomitantly. 
 
In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be 
decreased when imatinib is co-administered (see section 4.4). Caution is therefore recommended. 
However, the mechanism of the observed interaction is presently unknown. 
 
In Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy (see 
section 5.1), but drug-drug interactions between imatinib and chemotherapy regimens are not well 
characterised. Imatinib adverse events, i.e. hepatotoxicity, myelosuppression or others, may increase 
and it has been reported that concomitant use with L-asparaginase could be associated with increased 
hepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination requires special 
precaution. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
Women of childbearing potential must be advised to use effective contraception during treatment. 
 
Pregnancy 
There are limited data on the use of imatinib in pregnant women. 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 

37 



exposure would be expected to be low (~10% of a therapeutic dose). However, since the effects of 
low-dose exposure of the infant to imatinib are unknown, women taking imatinib should not 
breast-feed. 
 
Fertility 
In non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies 
on patients receiving imatinib and its effect on fertility and gametogenesis have not been performed. 
Patients concerned about their fertility on imatinib treatment should consult with their physician. 
 
4.7 Effects on ability to drive and use machines 
 
Patients should be advised that they may experience undesirable effects such as dizziness,blurred 
vision or somnolence during treatment with imatinib. Therefore, caution should be recommended 
when driving a car or operating machinery. 
 
4.8 Undesirable effects 
 
Summary of 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, drug discontinuation for drug-related adverse reactions was observed in 2.4% 
of newly diagnosed patients, 4% of patients in late chronic phase after failure of interferon therapy, 
4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients 
after failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse 
reactions in 4% of patients. 
 
The adverse reactions were similar in all indications, with two exceptions. There was more 
myelosuppression seen in CML patients than in GIST, which is probably due to the underlying 
disease. In the study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced 
CTC grade 3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour 
sites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be 
serious and sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions in 
both settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps 
and rash. Superficial oedemas were a common finding in all studies and were described primarily as 
periorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managed 
with diuretics, other supportive measures, or by reducing the dose of imatinib. 
 

When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient liver 
toxicity in the form of transaminase elevation and hyperbilirubinaemia were observed. Considering the 
limited safety database, the adverse events thus far reported in children are consistent with the known 
safety profile in adult patients with Ph+ ALL. The safety database for children with Ph+ALL is very 
limited though no new safety concerns have been identified. 
 
Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weight 
gain with or without superficial oedema may be collectively described as “fluid retention”. These 
reactions can usually be managed by withholding imatinib temporarily and with diuretics and other 
appropriate supportive care measures. However, some of these reactions may be serious or life-
threatening and several patients with blast crisis died with a complex clinical history of pleural 
effusion, congestive heart failure and renal failure. There were no special safety findings in paediatric 
clinical trials. 
 
Adverse reactions 
Adverse reactions reported as more than an isolated case are listed below, by system organ class and 
by frequency. Frequency categories are defined using the following convention: very common 

38 



(≥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, thrombotic microangiopathy 
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 

39 



pectoris, pericardial effusion 
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)*, pseudoporphyria* 

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 

40 



General disorders and administration site conditions 
Very common Fluid retention and oedema, fatigue 
Common Weakness, pyrexia, anasarca, chills, rigors 
Uncommon Chest pain, malaise 
Investigations 
Very common Weight increased 
Common Weight decreased 
Uncommon Blood creatinine increased, blood creatine phosphokinase increased, blood 

lactate dehydrogenase increased, blood alkaline phosphatase increased 
Rare Blood amylase increased 

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

imatinib. This includes spontaneous case reports as well as serious adverse events from ongoing 
studies, the expanded access programmes, clinical pharmacology studies and exploratory 
studies in unapproved indications. Because these reactions are reported from a population of 
uncertain size, it is not always possible to reliably estimate their frequency or establish a causal 
relationship to imatinib exposure. 

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

2 Headache was the most common in GIST patients. 
3 On a patient-year basis, cardiac events including congestive heart failure were more commonly 

observed in patients with transformed CML than in patients with chronic CML. 
4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) was 

most common in patients with GIST and with transformed CML (CML-AP and CML-BC). 
5 Pleural effusion was reported more commonly in patients with GIST and in patients with 

transformed CML (CML-AP and CML-BC) than in patients with chronic CML. 
6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GIST 

patients. 
8 Some fatal cases of hepatic failure and of hepatic necrosis have been reported. 
9 Musculoskeletal pain during treatment with imatinib or after discontinuation has been observed 

in post-marketing. 
10 Musculoskeletal pain and related events were more commonly observed in patients with CML 

than in GIST patients. 
11 Fatal cases have been reported in patients with advanced disease, severe infections, severe 

neutropenia and other serious concomitant conditions. 
 
Laboratory test abnormalities 
Haematology 
In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding in 
all studies, with the suggestion of a higher frequency at high doses ≥ 750 mg (phase I study). 
However, the occurrence of cytopenias was also clearly dependent on the stage of the disease, the 
frequency of grade 3 or 4 neutropenias (ANC < 1.0 x 109/L) and thrombocytopenias (platelet 
count < 50 x 109/L) being between 4 and 6 times higher in blast crisis and accelerated phase (59–64% 
and 44–63% for neutropenia and thrombocytopenia, respectively) as compared to newly diagnosed 
patients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosed 
chronic phase CML grade 4 neutropenia (ANC < 0.5 x 109/L) and thrombocytopenia (platelet count 
< 10 x 109/L) were observed in 3.6% and < 1% of patients, respectively. The median duration of the 
neutropenic and thrombocytopenic episodes usually ranged from 2 to 3 weeks, and from 3 to 4 weeks, 
respectively. These events can usually be managed with either a reduction of the dose or an 
interruption of treatment with imatinib, but can in rare cases lead to permanent discontinuation of 
treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 
4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the 
first several months of therapy. 
 
In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reported 
in 5.4% and 0.7% of patients, respectively, and may have been related to gastrointestinal or intra-
tumoural bleeding in at least some of these patients. Grade 3 and 4 neutropenia was seen in 7.5% and 

41 



2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient 
developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts 
occurred mainly during the first six weeks of therapy, with values remaining relatively stable 
thereafter. 
 
Biochemistry 
Severe elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and was 
usually managed with dose reduction or interruption (the median duration of these episodes was 
approximately one week). Treatment was discontinued permanently because of liver laboratory 
abnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 
ALT (alanine aminotransferase) elevations and 4.8% of grade 3 or 4 AST (aspartate aminotransferase) 
elevations were observed. Bilirubin elevation was below 3%. 
 
There have been cases of cytolytic and cholestatic hepatitis and hepatic failure; in some of them 
outcome was fatal, including one patient on high dose paracetamol. 
 
Description of selected adverse reactions 
Hepatitis B reactivation 
Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in 
acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see 
section 4.4). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the 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 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash, 
erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal 
pain, headache, decreased appetite. 
1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatine 
phosphokinase, increased bilirubin, gastrointestinal pain. 
6400 mg (single dose): One case reported in the literature of one patient who experienced nausea, 
vomiting, abdominal pain, pyrexia, facial swelling, decreased neutrophil count, increased 
transaminases. 
8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported. 
 
Paediatric population 
One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexia 
and another 3-year-old male exposed to a single dose of 980 mg experienced decreased white blood 
cell count and diarrhoea. 
 
In the event of overdose, the patient should be observed and appropriate supportive treatment given. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 

42 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitor, ATC code: L01XE01 
 
Mechanism of action 
Imatinib is a small molecule protein-tyrosine kinase inhibitor that potently inhibits the activity of the 
Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor 
(SCF) coded for by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the 
colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and 
beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation 
of these receptor kinases. 
 
Pharmacodynamic effects 
Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase at 
the in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and induces 
apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia 
chromosome positive CML and acute lymphoblastic leukaemia (ALL) patients. 
 
In vivo the compound shows anti-tumour activity as a single agent in animal models using Bcr-Abl 
positive tumour cells. 
 
Imatinib is also an inhibitor of the receptor tyrosine kinases for platelet-derived growth factor (PDGF), 
PDGF-R, and inhibits PDGF-mediated cellular events. Constitutive activation of the PDGF receptor or 
the Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutive 
production of PDGF have been implicated in the pathogenesis of MDS/MPD, HES/CEL and DFSP. 
Imatinib inhibits signalling and proliferation of cells driven by dysregulated PDGFR and Abl kinase 
activity. 
 
Clinical studies in chronic myeloid leukaemia 
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 addition, 
children and adolescents have been treated in two phase I studies (in patients with CML or Ph+ acute 
leukaemia) and one phase II study. 
 
In the clinical study 38% of patients were ≥ 60 years of age and 12% of patients were ≥ 70 years of 
age. 
 
Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received prior 
chemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas 
165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol 
was subsequently amended to allow higher dosing and the remaining 223 patients were started at 
600 mg. 
 
The primary efficacy variable was the rate of haematological response, reported as either complete 
haematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and the 
blood, but without a full peripheral blood recovery as for complete responses), or return to chronic 
phase CML. In this study, 31% of patients achieved a haematological response (36% in previously 
untreated patients and 22% in previously treated patients) (Table 2). 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. 
 

43 



Lymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n=10). The rate of 
haematological response was 70% with a duration of 2–3 months. 
 
Table 2 Response in adult CML study 
 

 Study 0102 
38-month data 
Myeloid blast 

crisis 
(n=260) 

 % of patients (CI95%) 
Haematological response1 
 Complete haematological response (CHR) 
 
 No evidence of leukaemia (NEL) 
 
 Return to chronic phase (RTC) 

31% (25.2–36.8) 
8% 

 
5% 

 
18% 

Major cytogenetic response2 
 Complete 
 (Confirmed3) [95% CI] 
 Partial 

15% (11.2–20.4) 
7% 

(2%) [0.6–4.4] 
8% 

1 Haematological response criteria (all responses to be confirmed after ≥ 4 weeks): 
CHR: In study 0102 [ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, no blood blasts, BM blasts < 5% and 

no extramedullary disease] 
NEL Same criteria as for CHR but ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L 
RTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in PB, 

no extramedullary disease other than spleen and liver. 
BM = bone marrow, PB = peripheral blood 
2 Cytogenetic response criteria: 
A major response combines both complete and partial responses: complete (0% Ph+ metaphases), 
partial (1–35%) 
3 Complete cytogenetic response confirmed by a second bone marrow cytogenetic evaluation 
performed at least one month after the initial bone marrow study. 
 
Paediatric patients: A total of 26 paediatric patients of age < 18 years with either chronic phase CML 
(n=11) or CML in blast crisis or Ph+ acute leukaemias (n=15) were enrolled in a dose-escalation phase 
I trial. This was a population of heavily pretreated patients, as 46% had received prior BMT and 73% a 
prior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m2/day (n=5), 
340 mg/m2/day (n=9), 440 mg/m2/day (n=7) and 570 mg/m2/day (n=5). Out of 9 patients with chronic 
phase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partial 
cytogenetic response, respectively, for a rate of MCyR of 77%. 
 
A total of 51 paediatric patients with newly diagnosed and untreated CML in chronic phase have been 
enrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib 
340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Imatinib treatment 
induces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after 
8 weeks of therapy. The high rate of CHR is accompanied by the development of a complete 
cytogenetic response (CCyR) of 65% which is comparable to the results observed in adults. 
Additionally, partial cytogenetic response (PCyR) was observed in 16% for a MCyR of 81%. The 
majority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with a 
median time to response based on the Kaplan-Meier estimate of 5.6 months. 
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
imatinib in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)-
positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use). 
 
Clinical studies in Ph+ ALL 

44 



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 

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 

45 



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 

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 

46 



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 
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 

47 



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 was detected, 9 of them achieved a CHR and 1 PHR. The age of these 
patients ranged from 2 to 79 years. In a recent publication updated information from 6 of these 
11 patients revealed that all these patients remained in cytogenetic remission (range 32-38 months). 
The same publication reported long term follow-up data from 12 MDS/MPD patients with PDGFR 
gene rearrangements (5 patients from study B2225). These patients received imatinib for a median of 
47 months (range 24 days – 60 months). In 6 of these patients follow-up now exceeds 4 years. Eleven 
patients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decrease 
or disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogenetic 
responses have been sustained for a median of 49 months (range 19-60) and 47 months (range 16-59), 

48 



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. 5 patients responded, 
3 completely and 2 partially. The median duration of therapy in the published literature ranged 
between 4 weeks and more than 20 months. The translocation t(17:22)[(q22:q13)], or its gene product, 
was present in nearly all responders to imatinib treatment. 
 
There are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and 
PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged from 
newborn to 14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to 
520 mg/m2 daily. All patients achieved partial and/or complete response. 
 
5.2 Pharmacokinetic properties 
 
Pharmacokinetics of imatinib 

49 



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 drug absorption has not been investigated. 
 
Distribution 
At clinically relevant concentrations of imatinib, binding to plasma proteins was approximately 95% 
on the basis of in vitro experiments, mostly to albumin and alpha-acid-glycoprotein, with little binding 
to lipoprotein. 
 
Biotransformation 
The main circulating metabolite in humans is the N-demethylated piperazine derivative, which shows 
similar in vitro potency to the parent. The plasma AUC for this metabolite was found to be only 16% 
of the AUC for imatinib. The plasma protein binding of the N-demethylated metabolite is similar to 
that of the parent compound. 
 
Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulating 
radioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minor 
metabolites. 
 
The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing the 
biotransformation of imatinib. Of a panel of potential comedications (acetaminophen, aciclovir, 
allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, hydroxyurea, norfloxacin, 
penicillin V) only erythromycin (IC50 50 µM) and fluconazole (IC50 118 µM) showed inhibition of 
imatinib metabolism which could have clinical relevance. 
 
Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6 
and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/L, respectively. 
Maximal plasma concentrations of imatinib in patients are 2–4 μmol/L, consequently an inhibition of 
CYP2D6 and/or CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib did 
not interfere with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a 
result of competitive inhibition of CYP2C8 (Ki - 34.7 µM). This Ki value is far higher than the 
expected plasma levels of imatinib in patients, consequently no interaction is expected upon co-
administration of either 5-fluorouracil or paclitaxel and imatinib. 
 
Elimination 
Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% 
of the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose). Unchanged 
imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites. 
 
Plasma pharmacokinetics 
Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that 
once-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and dose 
proportional in the range of 25–1,000 mg imatinib after oral administration. There was no change in 
the kinetics of imatinib on repeated dosing, and accumulation was 1.5–2.5-fold at steady state when 
dosed once daily. 
 
Population pharmacokinetics 
Based on population pharmacokinetic analysis in CML patients, there was a small effect of age on the 
volume of distribution (12% increase in patients > 65 years old). This change is not thought to be 
clinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patient 

50 



weighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg the 
clearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustment 
based on kg bodyweight. There is no effect of gender on the kinetics of imatinib. 
 
Pharmacokinetics in paediatric population 
As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients in 
both phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved the same 
exposure, respectively, as doses of 400 mg and 600 mg in adult patients. The comparison of AUC(0-24) 
on day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after 
repeated once-daily dosing. 
 
Based on pooled population pharmacokinetic analysis in paediatric patients with haematological 
disorders (CML, Ph+ALL, or other haematological disorders treated with imatinib), clearance of 
imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other 
demographics such as age, body weight and body mass index did not have clinically significant effects 
on the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients 
receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not 
exceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or 
600 mg once daily. 
 
Organ function impairment 
Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mild 
and moderate impairment of renal function appear to have a higher plasma exposure than patients with 
normal renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-fold 
elevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib is 
probably similar between patients with renal impairment and those with normal renal function, since 
renal excretion represents only a minor elimination pathway for imatinib (see sections 4.2 and 4.4). 
 
Although the results of pharmacokinetic analysis showed that there is considerable inter-subject 
variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver 
dysfunction as compared to patients with normal liver function (see sections 4.2, 4.4 and 4.8). 
 
5.3 Preclinical safety data 
 
The preclinical safety profile of imatinib was assessed in rats, dogs, monkeys and rabbits. 
 
Multiple dose toxicity studies revealed mild to moderate haematological changes in rats, dogs and 
monkeys, accompanied by bone marrow changes in rats and dogs. 
 
The liver was a target organ in rats and dogs. Mild to moderate increases in transaminases and slight 
decreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. 
No histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated 
for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct 
hyperplasia. 
 
Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation of 
the renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine were 
observed in several of these animals. In rats, hyperplasia of the transitional epithelium in the renal 
papilla and in the urinary bladder was observed at doses ≥ 6 mg/kg in the 13-week study, without 
changes in serum or urinary parameters. An increased rate of opportunistic infections was observed 
with chronic imatinib treatment. 
 
In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at the 
lowest dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based on 
body surface. Treatment resulted in worsening of normally suppressed malarial infections in these 
animals. 
 

51 



Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an in 
vitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positive 
genotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamster 
ovary) for clastogenicity (chromosome aberration) in the presence of metabolic activation. Two 
intermediates of the manufacturing process, which are also present in the final product, are positive for 
mutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphoma 
assay. 
 
In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weights 
and percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinical 
dose of 800 mg/day, based on body surface area. This was not seen at doses ≤ 20 mg/kg. A slight to 
moderate reduction in spermatogenesis was also observed in the dog at oral doses ≥ 30 mg/kg. When 
female rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect on 
mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-
implantation foetal loss and a reduced number of live foetuses. This was not seen at doses ≤ 20 mg/kg. 
 
In an oral pre- and postnatal development study in rats, red vaginal discharge was noted in the 
45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillborn 
pups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at the 
same dose level, mean body weights were reduced from birth until terminal sacrifice and the number 
of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not 
affected, while an increased number of resorptions and a decreased number of viable foetuses was 
noted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 
generation was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg). 
 
Imatinib was teratogenic in rats when administered during organogenesis at doses ≥ 100 mg/kg, 
approximately equal to the maximum clinical dose of 800 mg/day, based on body surface area. 
Teratogenic effects included exencephaly or encephalocele, absent/reduced frontal and absent parietal 
bones. These effects were not seen at doses ≤ 30 mg/kg. 
 
No new target organs were identified in the rat juvenile development toxicology study (day 10 to 70 
postpartum) with respect to the known target organs in adult rats. In the juvenile toxicology study, 
effects upon growth, delay in vaginal opening and preputial separation were observed at 
approximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of 
340 mg/m2. In addition, mortality was observed in juvenile animals (around weaning phase) at 
approximately 2 times the average paediatric exposure at the highest recommended dose of 
340 mg/m2. 
 
In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resulted 
in a statistically significant reduction in the longevity of males at 60 mg/kg/day and females at 
≥ 30 mg/kg/day. Histopathological examination of decedents revealed cardiomyopathy (both sexes), 
chronic progressive nephropathy (females) and preputial gland papilloma as principal causes of death 
or reasons for sacrifice. Target organs for neoplastic changes were the kidneys, urinary bladder, 
urethra, preputial and clitoral gland, small intestine, parathyroid glands, adrenal glands and non-
glandular stomach. 
 
Papilloma/carcinoma of the preputial/clitoral gland were noted from 30 mg/kg/day onwards, 
representing approximately 0.5 or 0.3 times the human daily exposure (based on AUC) at 400 mg/day 
or 800 mg/day, respectively, and 0.4 times the daily exposure in children (based on AUC) at 
340 mg/m2/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renal 
adenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas, 
the parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glands 
and the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representing 
approximately 1.7 or 1 times the human daily exposure (based on AUC) at 400 mg/day or 800 mg/day, 
respectively, and 1.2 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no 
observed effect level (NOEL) was 30 mg/kg/day. 
 

52 



The mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yet 
clarified. 
 
Non-neoplastic lesions not identified in earlier preclinical studies were the cardiovascular system, 
pancreas, endocrine organs and teeth. The most important changes included cardiac hypertrophy and 
dilatation, leading to signs of cardiac insufficiency in some animals. 
 
The active substance imatinib demonstrates an environmental risk for sediment organisms. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Cellulose microcrystalline  
Copovidone 
Crospovidone 
Sodium stearyl fumarate 
Silica, hydrophobic colloidal  
Silica, colloidal anhydrous 
 
Tablet coat 
Polyvinyl alchol part. hydrolised 
Talc 
Iron oxide yellow (E172) 
Titanium dioxide (E171) 
Iron oxide red (E172)  
Lecithin (soya) (E322) 
Xanthan gum (E415) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Imatinib Actavis 100 mg film-coated tablets 
2 years 
 
Imatinib Actavis 400 mg film-coated tablets 
21 month 
 
6.4 Special precautions for storage 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
Al/PVC/Aclar blister. One blister contains 10 tablets. 
 
Imatinib Actavis 100 mg film-coated tablets 
Pack containing either 10, 20, 30, 60, 90, 120 or 180 film-coated tablets 
 
Imatinib Actavis 400 mg film-coated tablets 
Pack containing either 10, 30, 60 or 90 film-coated tablets 

53 



 
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 
 
Actavis Group PTC ehf. 
Reykjavíkurvegur 76-78 
IS-220 Hafnarfjörður 
Iceland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
Imatinib Actavis 100 mg film-coated tablets 
EU/1/13/825/008 
EU/1/13/825/009 
EU/1/13/825/010 
EU/1/13/825/011 
EU/1/13/825/012 
EU/1/13/825/013 
EU/1/13/825/014 
 
Imatinib Actavis 400 mg film-coated tablets 
EU/1/13/825/015 
EU/1/13/825/016 
EU/1/13/825/017 
EU/1/13/825/018 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 17 April 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 

  

54 

http://www.ema.europa.eu/


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER 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 
 

55 



A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
S.C. Sindan-Pharma S.R.L. 
11th Ion Mihalache Ave, The 1st district, 
RO-011171 Bucharest 
Romania 
 
 
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 
 
At the time of granting the marketing authorisation, the submission of periodic safety update reports 
is not required for this medicinal product. However, the marketing authorisation holder shall submit 
periodic safety update reports for this medicinal product if the product is included in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 
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) 
Not applicable. 
 

  

56 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  

57 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  

58 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 50 mg hard capsules 
imatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 50 mg of imatinib (as mesilate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 hard capsules 
90 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before 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 
 
Use only as directed by a doctor. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

59 



 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
220 Hafnarfjörður 
Iceland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/825/001 30 capsules 
EU/1/13/825/002 90 capsules 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Imatinib Actavis 50 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
  

60 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 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 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
24 hard capsules 
48 hard capsules 
60 hard capsules 
96 hard capsules 
120 hard capsules 
180 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before 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 
 
Use only as directed by a doctor. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original package in order to protect from moisture. 
 

61 



 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
220 Hafnarfjörður 
Iceland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/825/003 24 capsules 
EU/1/13/825/004 48 capsules 
EU/1/13/825/019 60 capsules 
EU/1/13/825/005 96 capsules 
EU/1/13/825/006 120 capsules 
EU/1/13/825/007 180 capsules 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Imatinib Actavis 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 

62 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 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 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 hard capsules 
30 hard capsules 
60 hard capsules 
90 hard capusles 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before 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 
 
Use only as directed by a doctor. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25°C. 
Store in the original package in order to protect from moisture. 
 
 

63 



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

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
220 Hafnarfjörður 
Iceland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/825/020 10 capsules 
EU/1/13/825/021 30 capsules 
EU/1/13/825/022 60 capsules 
EU/1/13/825/023 90 capsules 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Imatinib Actavis 400 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
  

64 



MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 50 mg capsules 
imatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
[Actavis logo] 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  

65 



MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 100 mg capsules 
imatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
[Actavis logo] 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 

66 



MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 400 mg capsules 
imatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
[Actavis logo] 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
  

67 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 100 mg film-coated tablets 
imatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg of imatinib (as mesilate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lecithin (soya) (E322). See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
20 film-coated tablets 
30 film-coated tablets 
60 film-coated tablets 
90 film-coated tablets 
120 film-coated tablets 
180 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before 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 
 
Use only as directed by a doctor. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 

68 



Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
220 Hafnarfjörður 
Iceland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/825/008 10 tablets 
EU/1/13/825/009 20 tablets 
EU/1/13/825/010 30 tablets 
EU/1/13/825/011 60 tablets 
EU/1/13/825/012 90 tablets 
EU/1/13/825/013 120 tablets 
EU/1/13/825/014 180 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Imatinib Actavis 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
  

69 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 400 mg film-coated tablets 
imatinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 400 mg of imatinib (as mesilate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lecithin (soya) (E322). See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
30 film-coated tablets 
60 film-coated tablets 
90 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before 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 
 
Use only as directed by a doctor. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30°C. 
Store in the original package in order to protect from moisture. 
 

70 



 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Actavis Group PTC ehf. 
220 Hafnarfjörður 
Iceland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/13/825/015 10 tablets 
EU/1/13/825/016 30 tablets 
EU/1/13/825/017 60 tablets 
EU/1/13/825/018 90 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Imatinib Actavis 400 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
<2D barcode carrying the unique identifier included.> 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC: {number} 
SN: {number} 
NN: {number} 
 
  

71 



MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 100 mg tablets 
imatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
[Actavis logo] 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  

72 



MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Imatinib Actavis 400 mg tablets 
imatinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
[Actavis logo] 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 

  

73 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 

74 



Package leaflet: Information for the user 
 

Imatinib Actavis 50 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 Actavis is and what it is used for 
2. What you need to know before you take Imatinib Actavis 
3. How to take Imatinib Actavis 
4. Possible side effects 
5. How to store Imatinib Actavis 
6. Contents of the pack and other information 
 
 
1. What Imatinib Actavis is and what it is used for 
 
Imatinib Actavis 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 Actavis is a treatment for: 
 
- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white 

cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia 
in which certain abnormal white cells (named myeloid cells) start growing out of control. 

 
In adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast 
crisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease 
(chronic, accelerated phase and blast crisis). 
 
- 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 Actavis inhibits the 
growth of these cells. 

 
Imatinib Actavis 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 Actavis 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 Actavis inhibits the growth of these cells in a certain subtype of these diseases.  

75 



- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin 
in which some cells start growing out of control. Imatinib Actavis 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 Actavis works or why this medicine has been prescribed 
for you, ask your doctor. 
 
 
2. What you need to know before you take Imatinib Actavis 
 
Imatinib Actavis 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 Actavis: 
- 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 Actavis. 
 
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 Actavis: 
- 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 Actavis 

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 you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, 
contact your doctor. This may be a sign of damage to blood vessels known as thrombotic 
microangiopathy (TMA). 

If any of these apply to you, tell your doctor before taking Imatinib Actavis. 
 
You may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun-
exposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are 
also applicable to children. 
 
During treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very 
quickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). 
 
While you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is 
working. You will also have blood tests and be weighed regularly. 
 
Children and adolescents 
Imatinib Actavis is also a treatment for children with CML. There is no experience in children with 
CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very 
limited experience in children with MDS/MPD, DFSP and HES/CEL. 
 
Some children and adolescents taking Imatinib Actavis may have slower than normal growth. The 
doctor will monitor the growth at regular visits. 
 
Other medicines and Imatinib Actavis 

76 



Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription (such as paracetamol) and including 
herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib 
Actavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either 
leading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis 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 Actavis 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 Actavis 
during pregnancy. 

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

- Do not breast-feed during the treatment with Imatinib Actavis. 
- Patients who are concerned about their fertility while taking Imatinib Actavis 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 Actavis contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 
‘sodium-free’. 
 
 
3. How to take Imatinib Actavis 
 
Your doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib 
Actavis can help you to fight this condition. 
 
However, always take this medicine exactly as your doctor or pharmacist has told you. It is important 
that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or 
pharmacist if you are not sure. 
 
Do not stop taking Imatinib Actavis 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 Actavis to take 
 
Use in adults 
Your doctor will tell you exactly how many capsules of Imatinib Actavis to take. 
 
- If you are being treated for CML: 

The usual starting dose is 600 mg to be taken as 12 capsules 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 (16 capsules), you should take 8 capsules in the morning and 8 capsules in the 
evening. 
 
- If you are being treated for Ph-positive ALL: 

The starting dose is 600 mg to be taken as 12 capsules once a day. 

77 



 
- If you are being treated for MDS/MPD: 

The starting dose is 400 mg, to be taken as 8 capsules once a day. 
 
- If you are being treated for HES/CEL: 

The starting dose is 100 mg, to be taken as 2 capsules once a day. Your doctor may decide to 
increase the dose to 400 mg, to be taken as 8 capsules once a day, depending on how you 
respond to treatment. 

 
- If you are being treated for DFSP: 

The dose is 800 mg per day (16 capsules), to be taken as 8 capsules in the morning and 
8 capsules in the evening. 

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

taking Imatinib Actavis. 
- 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 water or apple juice. 
- If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, 

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 Actavis 
Keep taking Imatinib Actavis every day for as long as your doctor tells you. 
 
If you take more Imatinib Actavis 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 Actavis 
- If you forget a dose, take it as soon as you remember. However if it is nearly time for the next 

dose, skip the missed dose. 
- Then continue with your normal schedule. 
- Do not take a double dose to make up a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. They are 
usually mild to moderate. 
 
Some side effects may be serious. Tell your doctor straight away if you get any of the following: 
 
Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): 
- Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid 

retention). 

78 



- Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can 
reduce the number of white blood cells, so you might get infections more easily. 

- Unexpected bleeding or bruising (when you have not hurt yourself). 
 
Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): 
- Chest pain, irregular heart rhythm (signs of heart problems). 
- Cough, having difficulty breathing or painful breathing (signs of lung problems). 
- Feeling light-headed, dizzy or fainting (signs of low blood pressure). 
- Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of 

liver problems). 
- Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or 

purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). 
- Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of 

gastrointestinal disorders). 
- Severely decreased urine output, feeling thirsty (signs of kidney problems). 
- Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel 

problems). 
- Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of 

consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). 
- Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red 

blood cells). 
- Eye pain or deterioration in vision, bleeding in the eyes. 
- Pain in your hips or difficulty walking. 
- Numb or cold toes and fingers (signs of Raynaud’s syndrome). 
- Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). 
- Difficulty hearing. 
- Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of 

potassium in your blood). 
- Bruising. 
- Stomach pain with feeling sick (nausea). 
- Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of 

muscle problems). 
- Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling 

dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). 
- Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint 

discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and 
calcium levels and low phosphorous levels in the blood). 

- Blood clots in small blood vessels (thrombotic microangiopathy). 
 
Not known (frequency cannot be estimated from the available data): 
- Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood 

cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, 
severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic 
reaction). 

- Chronic renal failure. 
- Recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a 

liver infection). 
 
If you get any of the above, tell your doctor straight away. 
 
Other side effects may include: 
 
Very common (may affect more than 1 in 10 people): 
- Headache or feeling tired. 
- Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. 
- Rash. 

79 



- Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have 
stopped taking imatinib. 

- Swelling such as round your ankles or puffy eyes. 
- Weight gain. 
If any of these affect 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 affect 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. 
- Painful and/or blistering skin lesions. 
- Slowing of growth in children and adolescents. 
- If any of these affect 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 Actavis 
 
Keep this medicine out of the sight and reach of children. 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 
expiry date refers to the last day of that month. 
Do not store above 25°C. Store in the original package in order to protect from moisture. 
Do not use any pack that is damaged or shows signs of tampering. 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Imatinib Actavis contains 
- The active substance is imatinib (as mesilate). Each capsule contains 50 mg imatinib (as 

mesilate). 
- The other ingredients are: Capsule content: cellulose microcrystalline, copovidone, 

crospovidone, sodium stearyl fumarate, silica (colloidal hydrophobe and colloidal anhydrous). 

80 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


Capsule shell: hypromellose, titanium dioxide (E171), yellow iron oxide (E172). Printing ink: 
shellac, black iron oxide (E172), propylene glycol, ammonia solution, potassium hydroxide. 

 
What Imatinib Actavis looks like and contents of the pack 
Hard capsule with light yellow cap and light yellow body imprinted with 50 mg in black ink. 
The capsule contains light yellow powder. 
 
Pack sizes: 
The capsules are supplied in aluminium blister packs of 30 or 90 capsules. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Actavis Group PTC ehf. 
Reykjavíkurvegur 76-78, 
Hafnarfjörður 
Iceland 
 
Manufacturer 
S.C. Sindan-Pharma S.R.L. 
11 Ion Mihalache Blvd 
Bucharest 
Romania 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Actavis Group PTC ehf. 
IJsland/Islande/Island 
Tél/Tel: +354 5503300 
 

Lietuva 
UAB Sicor Biotech 
Tel: +370 52660203 
 

България 
Актавис ЕАД 
Teл: +359 24899585 
 

Luxembourg/Luxemburg 
Actavis Group PTC ehf. 
Islande/Island 
Tél/Tel: +354 5503300 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251007111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel: +36 12886400 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44985511 
 

Malta 
Actavis Ltd. 
Tel: +356 21693533 
 

Deutschland 
Actavis Group PTC ehf. 
Island 
Tel: +354 5503300 
 

Nederland 
Actavis Group PTC ehf. 
IJsland 
Tel: +354 5503300 
 

Eesti 
UAB Sicor Biotech Eesti filiaal 
Tel: +372 6610801 
 

Norge 
Teva Norway AS 
Tlf: +47 66775590 
 

81 



Ελλάδα 
Specifar ABEE 
Τηλ: +30 2105401500 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1970070 
 

España 
Actavis Group PTC ehf. 
Islandia 
Tel: +354 5503300 
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel: +48 223459300 
 

France 
Actavis Group PTC ehf. 
Islande 
Tél: +354 5503300 
 

Portugal 
Actavis Group PTC ehf. 
Islândia 
Tel: +354 5503300 
 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel: +385 13720000 
 

România 
Teva Pharmaceuticals S.R.L. 
Tel: +40 212306524 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 (0)19630330 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 15890390 
 

Ísland 
Actavis Group PTC ehf. 
Sími: +354 5503300 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o. 
Tel: +421 257267911 
 

Italia 
Actavis Group PTC ehf. 
Islanda 
Tel: +354 5503300 
 

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 201805900 
 

Κύπρος 
Specifar ABEE 
Ελλάδα 
Τηλ: +30 2105401500 
 

Sverige 
Teva Sweden AB 
Tel: +46 42121100 
 

Latvija 
UAB Sicor Biotech filiāle Latvijā 
Tel: +371 67323666 
 

United Kingdom 
Actavis UK Limited 
Tel: +44 1271385257 
 

 
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 
 

82 

http://www.ema.europa.eu/


Package leaflet: Information for the user 
 

Imatinib Actavis 100 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 Actavis is and what it is used for 
2. What you need to know before you take Imatinib Actavis 
3. How to take Imatinib Actavis 
4. Possible side effects 
5. How to store Imatinib Actavis 
6. Contents of the pack and other information 
 
 
1. What Imatinib Actavis is and what it is used for 
 
Imatinib Actavis 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 Actavis is a treatment for: 
 
- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white 

cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia 
in which certain abnormal white cells (named myeloid cells) start growing out of control. 

 
In adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast 
crisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease 
(chronic, accelerated phase and blast crisis). 
 
- 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 Actavis inhibits the 
growth of these cells. 

 
Imatinib Actavis 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 Actavis 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 Actavis inhibits the growth of these cells in a certain subtype of these diseases. 

83 



- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin 
in which some cells start growing out of control. Imatinib Actavis 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 Actavis works or why this medicine has been prescribed 
for you, ask your doctor. 
 
 
2. What you need to know before you take Imatinib Actavis 
 
Imatinib Actavis 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 Actavis: 
- 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 Actavis. 
 
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 Actavis: 
- 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 Actavis 

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 you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, 
contact your doctor. This may be a sign of damage to blood vessels known as thrombotic 
microangiopathy (TMA). 

If any of these apply to you, tell your doctor before taking Imatinib Actavis. 
 
You may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun-
exposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are 
also applicable to children. 
 
During treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very 
quickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). 
 
While you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is 
working. You will also have blood tests and be weighed regularly. 
 
Children and adolescents 
Imatinib Actavis is also a treatment for children with CML. There is no experience in children with 
CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very 
limited experience in children with MDS/MPD, DFSP and HES/CEL. 
 
Some children and adolescents taking Imatinib Actavis may have slower than normal growth. The 
doctor will monitor the growth at regular visits. 
 
Other medicines and Imatinib Actavis 

84 



Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription (such as paracetamol) and including 
herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib 
Actavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either 
leading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis 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 Actavis 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 Actavis 
during pregnancy. 

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

- Do not breast-feed during the treatment with Imatinib Actavis. 
- Patients who are concerned about their fertility while taking Imatinib Actavis 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 Actavis contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 
‘sodium-free’. 
 
 
3. How to take Imatinib Actavis 
 
Your doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib 
Actavis can help you to fight this condition. 
 
However, always take this medicine exactly as your doctor or pharmacist has told you. It is important 
that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or 
pharmacist if you are not sure. 
 
Do not stop taking Imatinib Actavis 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 Actavis to take 
 
Use in adults 
Your doctor will tell you exactly how many capsules of Imatinib Actavis to take. 
 
- If you are being treated for CML:  

The usual starting dose is 600 mg to be taken as 6 capsules 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 (8 capsules), you should take 4 capsules in the morning and 4 capsules in the 
evening. 
 
- If you are being treated for Ph-positive ALL: 

The starting dose is 600 mg to be taken as 6 capsules once a day. 

85 



 
- If you are being treated for MDS/MPD: 

The starting dose is 400 mg to be taken as 4 capsules once a day. 
 
- If you are being treated for HES/CEL: 

The starting dose is 100 mg, to be taken as one capsule once a day. Your doctor may decide to 
increase the dose to 400 mg, to be taken as 4 capsules once a day, depending on how you 
respond to treatment. 

 
- If you are being treated for DFSP: 

The dose is 800 mg per day (8 capsules), to be taken as 4 capsules in the morning and 
4 capsules in the evening. 

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

taking Imatinib Actavis. 
- 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 water or apple juice. 
- If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, 

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 Actavis 
Keep taking Imatinib Actavis every day for as long as your doctor tells you. 
 
If you take more Imatinib Actavis 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 Actavis 
- If you forget a dose, take it as soon as you remember. However if it is nearly time for the next 

dose, skip the missed dose. 
- Then continue with your normal schedule. 
- Do not take a double dose to make up a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. They are 
usually mild to moderate. 
 
Some side effects may be serious. Tell your doctor straight away if you get any of the following: 
 
Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): 
- Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid 

retention). 

86 



- Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can 
reduce the number of white blood cells, so you might get infections more easily. 

- Unexpected bleeding or bruising (when you have not hurt yourself). 
 
Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): 
- Chest pain, irregular heart rhythm (signs of heart problems). 
- Cough, having difficulty breathing or painful breathing (signs of lung problems). 
- Feeling light-headed, dizzy or fainting (signs of low blood pressure). 
- Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of 

liver problems). 
- Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or 

purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). 
- Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of 

gastrointestinal disorders). 
- Severely decreased urine output, feeling thirsty (signs of kidney problems). 
- Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel 

problems). 
- Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of 

consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). 
- Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red 

blood cells). 
- Eye pain or deterioration in vision, bleeding in the eyes. 
- Pain in your hips or difficulty walking. 
- Numb or cold toes and fingers (signs of Raynaud’s syndrome). 
- Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). 
- Difficulty hearing. 
- Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of 

potassium in your blood). 
- Bruising. 
- Stomach pain with feeling sick (nausea). 
- Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of 

muscle problems). 
- Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling 

dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). 
- Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint 

discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and 
calcium levels and low phosphorous levels in the blood). 

- Blood clots in small blood vessels (thrombotic microangiopathy). 
 
Not known (frequency cannot be estimated from the available data): 
- Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood 

cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, 
severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic 
reaction). 

- Chronic renal failure. 
- Recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a 

liver infection). 
 
If you get any of the above, tell your doctor straight away. 
 
Other side effects may include: 
 
Very common (may affect more than 1 in 10 people): 
- Headache or feeling tired. 
- Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. 
- Rash. 

87 



- Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have 
stopped taking imatinib. 

- Swelling such as round your ankles or puffy eyes. 
- Weight gain. 
If any of these affect 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 affect 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. 
- Painful and/or blistering skin lesions. 
- Slowing of growth in children and adolescents. 
-  
If any of these affect 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 Actavis 
 
Keep this medicine out of the sight and reach of children. 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 
expiry date refers to the last day of that month. 
Do not store above 25°C. Store in the original package in order to protect from moisture. 
Do not use any pack that is damaged or shows signs of tampering. 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Imatinib Actavis contains 
- The active substance is imatinib (as mesilate). Each capsule contains 100 mg imatinib (as 

mesilate). 
- The other ingredients are: Capsule content: cellulose microcrystalline, copovidone, 

crospovidone, sodium stearyl fumarate, silica (colloidal hydrophobe and colloidal anhydrous). 

88 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


Capsule shell: hypromellose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide 
(E172). Printing ink: shellac, black iron oxide (E172), propylene glycol, ammonia solution, 
potassium hydroxide. 

 
What Imatinib Actavis looks like and contents of the pack 
Hard capsule with light orange cap and light orange body imprinted with 100 mg in black ink. 
The capsule contains light yellow powder. 
 
Pack sizes: 
The capsules are supplied in aluminium blister packs of 24, 48, 60, 96, 120 or 180 capsules. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Actavis Group PTC ehf. 
Reykjavíkurvegur 76-78, 
Hafnarfjörður 
Iceland 
 
Manufacturer 
S.C. Sindan-Pharma S.R.L. 
11 Ion Mihalache Blvd 
Bucharest 
Romania 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Actavis Group PTC ehf. 
IJsland/Islande/Island 
Tél/Tel: +354 5503300 
 

Lietuva 
UAB Sicor Biotech 
Tel: +370 52660203 
 

България 
Актавис ЕАД 
Teл: +359 24899585 
 

Luxembourg/Luxemburg 
Actavis Group PTC ehf. 
Islande/Island 
Tél/Tel: +354 5503300 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251007111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel: +36 12886400 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44985511 
 

Malta 
Actavis Ltd. 
Tel: +356 21693533 
 

Deutschland 
Actavis Group PTC ehf. 
Island 
Tel: +354 5503300 
 

Nederland 
Actavis Group PTC ehf. 
IJsland 
Tel: +354 5503300 
 

Eesti 
UAB Sicor Biotech Eesti filiaal 
Tel: +372 6610801 
 

Norge 
Teva Norway AS 
Tlf: +47 66775590 
 

89 



Ελλάδα 
Specifar ABEE 
Τηλ: +30 2105401500 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1970070 
 

España 
Actavis Group PTC ehf. 
Islandia 
Tel: +354 5503300 
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel: +48 223459300 
 

France 
Actavis Group PTC ehf. 
Islande 
Tél: +354 5503300 
 

Portugal 
Actavis Group PTC ehf. 
Islândia 
Tel: +354 5503300 
 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel: +385 13720000 
 

România 
Teva Pharmaceuticals S.R.L. 
Tel: +40 212306524 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 (0)19630330 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 15890390 
 

Ísland 
Actavis Group PTC ehf. 
Sími: +354 5503300 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o. 
Tel: +421 257267911 
 

Italia 
Actavis Group PTC ehf. 
Islanda 
Tel: +354 5503300 
 

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 201805900 
 

Κύπρος 
Specifar ABEE 
Ελλάδα 
Τηλ: +30 2105401500 
 
 

Sverige 
Teva Sweden AB 
Tel: +46 42121100 
 

Latvija 
UAB Sicor Biotech filiāle Latvijā 
Tel: +371 67323666 
 

United Kingdom 
Actavis UK Limited 
Tel: +44 1271385257 
 

 
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 

90 

http://www.ema.europa.eu/


Package leaflet: Information for the user 
 

Imatinib Actavis 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 Actavis is and what it is used for 
2. What you need to know before you take Imatinib Actavis 
3. How to take Imatinib Actavis 
4. Possible side effects 
5. How to store Imatinib Actavis 
6. Contents of the pack and other information 
 
 
1. What Imatinib Actavis is and what it is used for 
 
Imatinib Actavis 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 Actavis is a treatment for: 
 
- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white 

cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia 
in which certain abnormal white cells (named myeloid cells) start growing out of control.  

 
In adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast 
crisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease 
(chronic, accelerated phase and blast crisis). 
 
- 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 Actavis inhibits the 
growth of these cells. 

 
Imatinib Actavis 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 Actavis 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 Actavis inhibits the growth of these cells in a certain subtype of these diseases.  

91 



- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin 
in which some cells start growing out of control. Imatinib Actavis 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 Actavis works or why this medicine has been prescribed 
for you, ask your doctor. 
 
 
2. What you need to know before you take Imatinib Actavis 
 
Imatinib Actavis 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 Actavis: 
- 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 Actavis. 
 
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 Actavis: 
- 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 Actavis 

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 you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, 
contact your doctor. This may be a sign of damage to blood vessels known as thrombotic 
microangiopathy (TMA). 

If any of these apply to you, tell your doctor before taking Imatinib Actavis. 
 
You may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun-
exposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are 
also applicable to children. 
 
During treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very 
quickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). 
 
While you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is 
working. You will also have blood tests and be weighed regularly. 
 
Children and adolescents 
Imatinib Actavis is also a treatment for children with CML. There is no experience in children with 
CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very 
limited experience in children with MDS/MPD, DFSP and HES/CEL. 
 
Some children and adolescents taking Imatinib Actavis may have slower than normal growth. The 
doctor will monitor the growth at regular visits. 
 
Other medicines and Imatinib Actavis 

92 



Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription (such as paracetamol) and including 
herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib 
Actavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either 
leading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis 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 Actavis 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 Actavis 
during pregnancy. 

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

- Do not breast-feed during the treatment with Imatinib Actavis. 
- Patients who are concerned about their fertility while taking Imatinib Actavis 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 Actavis contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per hard capsule, that is to say essentially 
‘sodium-free’. 
 
 
3. How to take Imatinib Actavis 
 
Your doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib 
Actavis can help you to fight this condition. 
 
However, always take this medicine exactly as your doctor or pharmacist has told you. It is important 
that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or 
pharmacist if you are not sure. 
 
Do not stop taking Imatinib Actavis 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 Actavis to take 
 
Use in adults 
Your doctor will tell you exactly how many capsules of Imatinib Actavis to take. 
 
- If you are being treated for CML:  

The usual starting dose is 600 mg to be taken as one 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 the treatment. If 
your daily dose is 800 mg (2 capsules), you should take one capsule in the morning and a second 
capsule in the evening. 
 
- If you are being treated for Ph-positive ALL: 

93 



The starting dose is 600 mg to be taken as one 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 one capsule once a day. 
 
- If you are being treated for HES/CEL: 

The starting dose is 100 mg, to be taken as one capsule of 100 mg once a day. Your doctor may 
decide to increase the dose to 400 mg, to be taken as one 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 (2 capsules), to be taken as one capsule in the morning and a second 
capsule in the evening. 

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

taking Imatinib Actavis. 
- 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 water or apple juice.  
- If you are a woman who is pregnant or might get pregnant and are trying to open the capsules, 

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 Actavis 
Keep taking Imatinib Actavis every day for as long as your doctor tells you. 
 
If you take more Imatinib Actavis 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 Actavis 
- If you forget a dose, take it as soon as you remember. However if it is nearly time for the next 

dose, skip the missed dose. 
- Then continue with your normal schedule. 
- Do not take a double dose to make up a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. They are 
usually mild to moderate. 
 
Some side effects may be serious. Tell your doctor straight away if you get any of the following: 
 

94 



Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): 
- Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid 

retention). 
- Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can 

reduce the number of white blood cells, so you might get infections more easily. 
- Unexpected bleeding or bruising (when you have not hurt yourself). 
 
Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): 
- Chest pain, irregular heart rhythm (signs of heart problems). 
- Cough, having difficulty breathing or painful breathing (signs of lung problems). 
- Feeling light-headed, dizzy or fainting (signs of low blood pressure). 
- Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of 

liver problems). 
- Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or 

purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). 
- Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of 

gastrointestinal disorders). 
- Severely decreased urine output, feeling thirsty (signs of kidney problems). 
- Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel 

problems). 
- Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of 

consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). 
- Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red 

blood cells). 
- Eye pain or deterioration in vision, bleeding in the eyes. 
- Pain in your hips or difficulty walking. 
- Numb or cold toes and fingers (signs of Raynaud’s syndrome). 
- Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). 
- Difficulty hearing. 
- Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of 

potassium in your blood). 
- Bruising. 
- Stomach pain with feeling sick (nausea). 
- Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of 

muscle problems). 
- Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling 

dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). 
- Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint 

discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and 
calcium levels and low phosphorous levels in the blood). 

- Blood clots in small blood vessels (thrombotic microangiopathy). 
 
Not known (frequency cannot be estimated from the available data): 
- Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood 

cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, 
severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic 
reaction). 

- Chronic renal failure. 
- Recurrence (reactivation) of Hepatitis B infection when you have had hepatitis B in the past (a 

liver infection). 
 
If you get any of the above, tell your doctor straight away. 
 
Other side effects may include: 
 
Very common (may affect more than 1 in 10 people): 
- Headache or feeling tired. 

95 



- Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. 
- Rash. 
- Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have 

stopped taking imatinib. 
- Swelling such as round your ankles or puffy eyes. 
- Weight gain. 
If any of these affect 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 affect 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. 
- Painful and/or blistering skin lesions. 
- Slowing of growth in children and adolescents. 
-  
If any of these affect 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 Actavis 
 
Keep this medicine out of the sight and reach of children. 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 
expiry date refers to the last day of that month. 
Do not store above 25°C. Store in the original package in order to protect from moisture. 
Do not use any pack that is damaged or shows signs of tampering. 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Imatinib Actavis contains 
- The active substance is imatinib (as mesilate). Each capsule contains 400 mg imatinib (as 

mesilate). 

96 

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- The other ingredients are: 
Capsule content: cellulose microcrystalline, copovidone, crospovidone, sodium stearyl 
fumarate, silica (colloidal hydrophobic and colloidal anhydrous). 
Capsule shell: hypromellose, titanium dioxide (E171), yellow iron oxide (E172), red iron oxide 
(E172), black iron oxide (E172). 
Printing ink: shellac glaze-45%, black iron oxide (E172), propylene glycol, ammonium 
Hydroxide 28%. 

 
What Imatinib Actavis looks like and contents of the pack 
Hard capsule with orange opaque cap and body imprinted with 400 mg in black ink. 
The capsule contains light yellow powder. 
 
Pack sizes: 
The capsules are supplied in aluminium blister packs of 10, 30, 60, or 90 capsules. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Actavis Group PTC ehf. 
Reykjavíkurvegur 76-78, 
Hafnarfjörður 
Iceland 
 
Manufacturer 
S.C. Sindan-Pharma S.R.L. 
11 Ion Mihalache Blvd 
Bucharest 
Romania 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Actavis Group PTC ehf. 
IJsland/Islande/Island 
Tél/Tel: +354 5503300 
 

Lietuva 
UAB Sicor Biotech 
Tel: +370 52660203 
 

България 
Актавис ЕАД 
Teл: +359 24899585 
 

Luxembourg/Luxemburg 
Actavis Group PTC ehf. 
Islande/Island 
Tél/Tel: +354 5503300 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251007111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel: +36 12886400 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44985511 
 

Malta 
Actavis Ltd. 
Tel: +356 21693533 
 

Deutschland 
Actavis Group PTC ehf. 
Island 
Tel: +354 5503300 
 

Nederland 
Actavis Group PTC ehf. 
IJsland 
Tel: +354 5503300 
 

97 



Eesti 
UAB Sicor Biotech Eesti filiaal 
Tel: +372 6610801 
 

Norge 
Teva Norway AS 
Tlf: +47 66775590 
 

Ελλάδα 
Specifar ABEE 
Τηλ: +30 2105401500 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1970070 
 

España 
Actavis Group PTC ehf. 
Islandia 
Tel: +354 5503300 
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel: +48 223459300 
 

France 
Actavis Group PTC ehf. 
Islande 
Tél: +354 5503300 
 

Portugal 
Actavis Group PTC ehf. 
Islândia 
Tel: +354 5503300 
 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel: +385 13720000 
 

România 
Teva Pharmaceuticals S.R.L. 
Tel: +40 212306524 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 (0)19630330 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 15890390 
 

Ísland 
Actavis Group PTC ehf. 
Sími: +354 5503300 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o. 
Tel: +421 257267911 
 

Italia 
Actavis Group PTC ehf. 
Islanda 
Tel: +354 5503300 
 

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 201805900 
 

Κύπρος 
Specifar ABEE 
Ελλάδα 
Τηλ: +30 2105401500 
 
 

Sverige 
Teva Sweden AB 
Tel: +46 42121100 
 

Latvija 
UAB Sicor Biotech filiāle Latvijā 
Tel: +371 67323666 
 

United Kingdom 
Actavis UK Limited 
Tel: +44 1271385257 
 

 
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 
 

98 

http://www.ema.europa.eu/


Package leaflet: Information for the user 
 

Imatinib Actavis 100 mg film-coated tablets 
imatinib 

 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, 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 Actavis is and what it is used for 
2. What you need to know before you take Imatinib Actavis 
3. How to take Imatinib Actavis 
4. Possible side effects 
5. How to store Imatinib Actavis 
6. Contents of the pack and other information 
 
 
1. What Imatinib Actavis is and what it is used for 
 
Imatinib Actavis 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 Actavis is a treatment for: 
 
- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white 

cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia 
in which certain abnormal white cells (named myeloid cells) start growing out of control. 

 
In adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast 
crisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease 
(chronic, accelerated phase and blast crisis). 
 
- 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 Actavis inhibits the 
growth of these cells. 

 
Imatinib Actavis 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 Actavis 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 Actavis inhibits the growth of these cells in a certain subtype of these diseases. 

99 



- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin 
in which some cells start growing out of control. Imatinib Actavis 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 Actavis works or why this medicine has been prescribed 
for you, ask your doctor. 
 
 
2. What you need to know before you take Imatinib Actavis 
 
Imatinib Actavis 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 Actavis: 
- if you are allergic to imatinib, soya, peanut or any of the other ingredients of this medicine 

(listed in section 6). 
 
If this applies to you, tell your doctor without taking Imatinib Actavis. 
 
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 Actavis: 
- 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 Actavis 

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 you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, 
contact your doctor. This may be a sign of damage to blood vessels known as thrombotic 
microangiopathy (TMA). 

If any of these apply to you, tell your doctor before taking Imatinib Actavis. 
 
You may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun-
exposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are 
also applicable to children. 
 
During treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very 
quickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). 
 
While you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is 
working. You will also have blood tests and be weighed regularly. 
 
Children and adolescents 
Imatinib Actavis is also a treatment for children with CML. There is no experience in children with 
CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very 
limited experience in children with MDS/MPD, DFSP and HES/CEL. 
 
Some children and adolescents taking Imatinib Actavis may have slower than normal growth. The 
doctor will monitor the growth at regular visits. 
 
Other medicines and Imatinib Actavis 

100 



Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription (such as paracetamol) and including 
herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib 
Actavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either 
leading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis 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 Actavis 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 Actavis 
during pregnancy. 

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

- Do not breast-feed during the treatment with Imatinib Actavis. 
- Patients who are concerned about their fertility while taking Imatinib Actavis 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 Actavis contains lecithin (soya) 
If you are allergic to peanut or soya, do not use this medicinal product. 
 
Imatinib Actavis contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say 
essentially ‘sodium-free’. 
 
 
3. How to take Imatinib Actavis 
 
Your doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib 
Actavis can help you to fight this condition. 
 
However, always take this medicine exactly as your doctor or pharmacist has told you. It is important 
that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or 
pharmacist if you are not sure. 
 
Do not stop taking Imatinib Actavis 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 Actavis to take 
 
Use in adults 
Your doctor will tell you exactly how many tablets of Imatinib Actavis to take. 
 
- If you are being treated for CML:  

The usual starting dose is 600 mg to be taken as 6 tablets 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 (8 tablets), you should take 4 tablets in the morning and 4 tablets in the evening. 
 

101 



- If you are being treated for Ph-positive ALL: 
The starting dose is 600 mg to be taken as 6 tablets once a day.  

 
- If you are being treated for MDS/MPD: 

The starting dose is 400 mg to be taken as 4 tablets once a day. 
 
- If you are being treated for HES/CEL: 

The starting dose is 100 mg, to be taken as one tablet once a day. Your doctor may decide to 
increase the dose to 400 mg, to be taken as 4 tablets once a day, depending on how you respond 
to treatment. 

 
- If you are being treated for DFSP: 

The dose is 800 mg per day (8 tablets), to be taken as 4 tablets in the morning and 4 tablets in 
the evening. 

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

taking Imatinib Actavis. 
 
- Swallow the tablets whole with a large glass of water. 
 The tablet can be divided into equal doses. 
 
If you are unable to swallow the tablets, you can dissolve them in a glass of still or mineral water or 
apple juice: 
- Use about 50 ml for each 100 mg tablet. 
- Stir with a spoon until the tablets have completely dissolved. 
- Once the tablet has dissolved, drink everything in the glass straight away. Traces of the 

dissolved tablets may be left behind in the glass. 
 
How long to take Imatinib Actavis 
Keep taking Imatinib Actavis every day for as long as your doctor tells you. 
 
If you take more Imatinib Actavis than you should 
If you have accidentally taken too many tablets, talk to your doctor straight away. You may require 
medical attention. Take the medicine pack with you. 
 
If you forget to take Imatinib Actavis 
- 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. 

102 



 
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 Actavis may cause your body to retain water (severe fluid 

retention). 
- Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can 

reduce the number of white blood cells, so you might get infections more easily. 
- Unexpected bleeding or bruising (when you have not hurt yourself). 
 
Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): 
- Chest pain, irregular heart rhythm (signs of heart problems). 
- Cough, having difficulty breathing or painful breathing (signs of lung problems). 
- Feeling light-headed, dizzy or fainting (signs of low blood pressure). 
- Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of 

liver problems). 
- Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or 

purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). 
- Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of 

gastrointestinal disorders). 
- Severely decreased urine output, feeling thirsty (signs of kidney problems). 
- Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel 

problems). 
- Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of 

consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). 
- Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red 

blood cells). 
- Eye pain or deterioration in vision, bleeding in the eyes. 
- Pain in your hips or difficulty walking. 
- Numb or cold toes and fingers (signs of Raynaud’s syndrome). 
- Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). 
- Difficulty hearing. 
- Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of 

potassium in your blood). 
- Bruising. 
- Stomach pain with feeling sick (nausea). 
- Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of 

muscle problems). 
- Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling 

dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). 
- Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint 

discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and 
calcium levels and low phosphorous levels in the blood). 

- Blood clots in small blood vessels (thrombotic microangiopathy). 
 
Not known (frequency cannot be estimated from the available data): 
- Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood 

cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, 
severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic 
reaction). 

- Chronic renal failure. 
- Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a 

liver infection). 
 
If you get any of the above, tell your doctor straight away. 
 
Other side effects may include: 

103 



 
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 treatment or after you have 

stopped taking imatinib. 
- Swelling such as round your ankles or puffy eyes. 
- Weight gain. 
If any of these affect 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 affect 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. 
- Painful and/or blistering skin lesions 
- Slowing of growth in children and adolescents. 
If any of these affect 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 Actavis 
 
Keep this medicine out of the sight and reach of children. 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 
expiry date refers to the last day of that month. 
Do not store above 30°C. Store in the original package in order to protect from moisture. 
Do not use any pack that is damaged or shows signs of tampering. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 

104 

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What Imatinib Actavis contains 
- The active substance is imatinib (as mesilate). Each tablet contains 100 mg imatinib (as 

mesilate). 
- The other ingredients are cellulose microcrystalline, copovidone, crospovidone, sodium stearyl 

fumarate, silica (colloidal hydrophobe and colloidal anhydrous), polyvinyl alcohol partly 
hydrolysed, talc, yellow iron oxide (E172), titanium dioxide (E171), red iron oxide (E172), 
lecithin (soya) (E322), xanthan gum (E415). 

 
What Imatinib Actavis looks like and contents of the pack 
Round, biconvex dark yellow to brownish film-coated tablet, embossed with company logo on one 
side and “36” with score line on the other side. 
 
Pack sizes: 
The tablets are supplied in aluminium blister packs of 10, 20, 30, 60, 90, 120 or 180 film-coated 
tablets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Actavis Group PTC ehf. 
Reykjavíkurvegur 76-78, 
Hafnarfjörður 
Iceland 
 
Manufacturer 
S.C. Sindan-Pharma S.R.L. 
11 Ion Mihalache Blvd 
Bucharest 
Romania 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Actavis Group PTC ehf. 
IJsland/Islande/Island 
Tél/Tel: +354 5503300 
 

Lietuva 
UAB Sicor Biotech 
Tel: +370 52660203 
 

България 
Актавис ЕАД 
Teл: +359 24899585 
 

Luxembourg/Luxemburg 
Actavis Group PTC ehf. 
Islande/Island 
Tél/Tel: +354 5503300 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251007111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel: +36 12886400 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44985511 
 

Malta 
Actavis Ltd. 
Tel: +356 21693533 
 

Deutschland 
Actavis Group PTC ehf. 
Island 
Tel: +354 5503300 
 

Nederland 
Actavis Group PTC ehf. 
IJsland 
Tel: +354 5503300 
 

105 



Eesti 
UAB Sicor Biotech Eesti filiaal 
Tel: +372 6610801 
 

Norge 
Teva Norway AS 
Tlf: +47 66775590 
 

Ελλάδα 
Specifar ABEE 
Τηλ: +30 2105401500 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1970070 
 

España 
Actavis Group PTC ehf. 
Islandia 
Tel: +354 5503300 
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel: +48 223459300 
 

France 
Actavis Group PTC ehf. 
Islande 
Tél: +354 5503300 
 

Portugal 
Actavis Group PTC ehf. 
Islândia 
Tel: +354 5503300 
 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel: +385 13720000  
 

România 
Teva Pharmaceuticals S.R.L. 
Tel: +40 212306524 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 (0)19630330 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 15890390 
 

Ísland 
Actavis Group PTC ehf. 
Sími: +354 5503300 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o. 
Tel: +421 257267911 
 

Italia 
Actavis Group PTC ehf. 
Islanda 
Tel: +354 5503300 
 

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 201805900 
 

Κύπρος 
Specifar ABEE  
Ελλάδα 
Τηλ: +30 2105401500 
 
 

Sverige 
Teva Sweden AB 
Tel: +46 42121100 
 

Latvija 
UAB Sicor Biotech filiāle Latvijā 
Tel: +371 67323666 
 

United Kingdom 
Actavis UK Limited 
Tel: +44 1271385257 
 

 
This leaflet was last revised in 
 
Other source of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu 
 
 

106 

http://www.ema.europa.eu/


Package leaflet: Information for the user 
 

Imatinib Actavis 400 mg film-coated tablets 
imatinib 

 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, 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 Actavis is and what it is used for 
2. What you need to know before you take Imatinib Actavis 
3. How to take Imatinib Actavis 
4. Possible side effects 
5. How to store Imatinib Actavis 
6. Contents of the pack and other information 
 
 
1. What Imatinib Actavis is and what it is used for 
 
Imatinib Actavis 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 Actavis is a treatment for: 
 
- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white 

cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia 
in which certain abnormal white cells (named myeloid cells) start growing out of control. 

 
In adult patients, Imatinib Actavis is intended for use in the most advanced phase of the disease (blast 
crisis). In children and adolescents, Imatinib Actavis can be used in different phases of the disease 
(chronic, accelerated phase and blast crisis). 
 
- 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 Actavis inhibits the 
growth of these cells. 

 
Imatinib Actavis 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 Actavis 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 Actavis inhibits the growth of these cells in a certain subtype of these diseases. 

107 



- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin 
in which some cells start growing out of control. Imatinib Actavis 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 Actavis works or why this medicine has been prescribed 
for you, ask your doctor. 
 
 
2. What you need to know before you take Imatinib Actavis 
 
Imatinib Actavis 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 Actavis: 
- if you are allergic to imatinib, soya, peanut or any of the other ingredients of this medicine 

(listed in section 6). 
 
If this applies to you, tell your doctor without taking Imatinib Actavis. 
 
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 Actavis: 
- 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 Actavis 

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 you experience bruising, bleeding, fever, fatigue and confusion when taking Imatinib Actavis, 
contact your doctor. This may be a sign of damage to blood vessels known as thrombotic 
microangiopathy (TMA). 

If any of these apply to you, tell your doctor before taking Imatinib Actavis. 
 
You may become more sensitive to the sun while taking Imatinib Actavis. It is important to cover sun-
exposed areas of skin and use sunscreen with high sun protection factor (SPF). These precautions are 
also applicable to children. 
 
During treatment with Imatinib Actavis, tell your doctor straight away if you put on weight very 
quickly. Imatinib Actavis may cause your body to retain water (severe fluid retention). 
 
While you are taking Imatinib Actavis, your doctor will regularly check whether the medicine is 
working. You will also have blood tests and be weighed regularly. 
 
Children and adolescents 
Imatinib Actavis is also a treatment for children with CML. There is no experience in children with 
CML below 2 years of age. There is limited experience in children with Ph-positive ALL and very 
limited experience in children with MDS/MPD, DFSP and HES/CEL. 
 
Some children and adolescents taking Imatinib Actavis may have slower than normal growth. The 
doctor will monitor the growth at regular visits. 
 
Other medicines and Imatinib Actavis 

108 



Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription (such as paracetamol) and including 
herbal medicines (such as St. John’s Wort). Some medicines can interfere with the effect of Imatinib 
Actavis when taken together. They may increase or decrease the effect of Imatinib Actavis, either 
leading to increased side effects or making Imatinib Actavis less effective. Imatinib Actavis 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 Actavis 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 Actavis 
during pregnancy. 

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

- Do not breast-feed during the treatment with Imatinib Actavis. 
- Patients who are concerned about their fertility while taking Imatinib Actavis 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 Actavis contains lecithin (soya) 
If you are allergic to peanut or soya, do not use this medicinal product. 
 
Imatinib Actavis contains sodium 
This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say 
essentially ‘sodium-free’. 
 
 
3. How to take Imatinib Actavis 
 
Your doctor has prescribed Imatinib Actavis because you suffer from a serious condition. Imatinib 
Actavis can help you to fight this condition. 
 
However, always take this medicine exactly as your doctor or pharmacist has told you. It is important 
that you do this as long as your doctor or pharmacist tells you to. Check with your doctor or 
pharmacist if you are not sure. 
 
Do not stop taking Imatinib Actavis 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 Actavis to take 
 
Use in adults 
Your doctor will tell you exactly how many tablets of Imatinib Actavis to take. 
 
- If you are being treated for CML: 

The recommended starting dose is 600 mg to be taken as one tablet of 400 mg plus 2 tablets of 
100 mg once a day.  

 

109 



Your doctor may prescribe a higher or lower dose depending on how you respond to treatment. If your 
daily dose is 800 mg (2 tablets), you should take one tablet in the morning and a second in the 
evening. 
 
- If you are being treated for Ph-positive ALL: 

The starting dose is 600 mg to be taken as one tablet of 400 mg plus 2 tablets of 100 mg once a 
day.  

 
- If you are being treated for MDS/MPD: 

The starting dose is 400 mg to be taken as one tablet once a day. 
 
- If you are being treated for HES/CEL: 

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

 
- If you are being treated for DFSP: 

The dose is 800 mg per day (2 tablets), to be taken as one tablet in the morning and a second 
tablet in the evening. 

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

taking Imatinib Actavis. 
 
- Swallow the tablets whole with a large glass of water.  
 The score line is not intended for breaking the tablet. 
 
If you are unable to swallow the tablets, you can dissolve them in a glass of still or mineral water or 
apple juice: 
 Use about 200 ml for each 400 mg tablet. 
- Stir with a spoon until the tablets have completely dissolved. 
- Once the tablet has dissolved, drink everything in the glass straight away. Traces of the 

dissolved tablets may be left behind in the glass. 
 
How long to take Imatinib Actavis 
Keep taking Imatinib Actavis every day for as long as your doctor tells you. 
 
If you take more Imatinib Actavis than you should 
If you have accidentally taken too many tablets, talk to your doctor straight away. You may require 
medical attention. Take the medicine pack with you. 
 
If you forget to take Imatinib Actavis 
- 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. 
 
 

110 



4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. They are 
usually mild to moderate. 
 
Some side effects may be serious. Tell your doctor straight away if you get any of the following: 
 
Very common (may affect more than 1 in 10 people) or common (may affect up to 1 in 10 people): 
- Rapid weight gain. Imatinib Actavis may cause your body to retain water (severe fluid 

retention). 
- Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Imatinib Actavis can 

reduce the number of white blood cells, so you might get infections more easily. 
- Unexpected bleeding or bruising (when you have not hurt yourself). 
 
Uncommon (may affect up to 1 in 100 people) or rare (may affect up to 1 in 1,000 people): 
- Chest pain, irregular heart rhythm (signs of heart problems). 
- Cough, having difficulty breathing or painful breathing (signs of lung problems). 
- Feeling light-headed, dizzy or fainting (signs of low blood pressure). 
- Feeling sick (nausea), with loss of appetite, dark-coloured urine, yellow skin or eyes (signs of 

liver problems). 
- Rash, red skin with blisters on the lips, eyes, skin or mouth, peeling skin, fever, raised red or 

purple skin patches, itching, burning sensation, pustular eruption (signs of skin problems). 
- Severe abdominal pain, blood in your vomit, stools or urine, black stools (signs of 

gastrointestinal disorders). 
- Severely decreased urine output, feeling thirsty (signs of kidney problems). 
- Feeling sick (nausea) with diarrhoea and vomiting, abdominal pain or fever (signs of bowel 

problems). 
- Severe headache, weakness or paralysis of limbs or face, difficulty speaking, sudden loss of 

consciousness (signs of nervous system problems such as bleeding or swelling in skull/brain). 
- Pale skin, feeling tired and breathlessness and having dark urine (signs of low levels of red 

blood cells). 
- Eye pain or deterioration in vision, bleeding in the eyes. 
- Pain in your hips or difficulty walking. 
- Numb or cold toes and fingers (signs of Raynaud’s syndrome). 
- Sudden swelling and redness of the skin (signs of a skin infection called cellulitis). 
- Difficulty hearing. 
- Muscle weakness and spasms with an abnormal heart rhythm (signs of changes in the amount of 

potassium in your blood). 
- Bruising. 
- Stomach pain with feeling sick (nausea). 
- Muscle spasms with a fever, red-brown urine, pain or weakness in your muscles (signs of 

muscle problems). 
- Pelvic pain sometimes with nausea and vomiting, with unexpected vaginal bleeding, feeling 

dizzy or fainting due to low blood pressure (signs of problems with your ovaries or womb). 
- Nausea, shortness of breath, irregular heartbeat, clouding of urine, tiredness and/or joint 

discomfort associated with abnormal laboratory test results (eg. high potassium, uric acid and 
calcium levels and low phosphorous levels in the blood). 

- Blood clots in small blood vessels (thrombotic microangiopathy). 
 
Not known (frequency cannot be estimated from the available data): 
- Combination of a widespread severe rash, feeling sick, fever, high level of certain white blood 

cells or yellow skin or eyes (signs of jaundice) with breathlessness, chest pain/discomfort, 
severely decreased urine output and feeling thirsty etc. (signs of a treatment-related allergic 
reaction). 

- Chronic renal failure. 
- Recurrence (reactivation) of hepatitis B infection when you have had hepatitis B in the past (a 

liver infection). 

111 



 
If you get any of the above, tell your doctor straight away. 
 
Other side effects may include: 
 
Very common (may affect more than 1 in 10 people): 
- Headache or feeling tired. 
- Feeling sick (nausea), being sick (vomiting), diarrhoea or indigestion. 
- Rash. 
- Muscle cramps or joint, muscle or bone pain, during imatinib treatment or after you have 

stopped taking imatinib. 
- Swelling such as round your ankles or puffy eyes. 
- Weight gain. 
If any of these affect 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 affect 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. 
- Painful and/or blistering skin lesions 
- Slowing of growth in children and adolescents. 
If any of these affect 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 Actavis 
 
Keep this medicine out of the sight and reach of children. 
Do not use this medicine after the expiry date which is stated on the carton and blister after EXP. The 
expiry date refers to the last day of that month. 
Do not store above 30°C. Store in the original package in order to protect from moisture. 
Do not use any pack that is damaged or shows signs of tampering. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 

112 

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6. Contents of the pack and other information 
 
What Imatinib Actavis contains 
- The active substance is imatinib (as mesilate). Each tablet contains 400 mg imatinib (as 

mesilate). 
- The other ingredients are cellulose microcrystalline, copovidone, crospovidone, sodium stearyl 

fumarate, silica (colloidal hydrophobe and colloidal anhydrous), polyvinyl alcohol partly 
hydrolysed, talc, yellow iron oxide (E172), titanium dioxide (E171), red iron oxide (E172), 
lecithin (soya) (E322), xanthan gum (E415). 

 
What Imatinib Actavis looks like and contents of the pack 
Oval-shape, biconvex dark yellow to brownish film-coated tablet, embossed with company logo on 
one side and “37” with score line on the other side. 
 
Pack sizes: 
The tablets are supplied in aluminium blister packs of 10, 30, 60 or 90 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
Actavis Group PTC ehf. 
Reykjavíkurvegur 76-78, 
Hafnarfjörður 
Iceland 
 
Manufacturer 
S.C. Sindan-Pharma S.R.L. 
11 Ion Mihalache Blvd 
Bucharest 
Romania 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
Actavis Group PTC ehf. 
IJsland/Islande/Island 
Tél/Tel: +354 5503300 
 

Lietuva 
UAB Sicor Biotech 
Tel: +370 52660203 
 

България 
Актавис ЕАД 
Teл: +359 24899585 
 

Luxembourg/Luxemburg 
Actavis Group PTC ehf. 
Islande/Island 
Tél/Tel: +354 5503300 
 

Česká republika 
Teva Pharmaceuticals CR, s.r.o. 
Tel: +420 251007111 
 

Magyarország 
Teva Gyógyszergyár Zrt. 
Tel: +36 12886400 
 

Danmark 
Teva Denmark A/S 
Tlf: +45 44985511 
 

Malta 
Actavis Ltd. 
Tel: +356 21693533 
 

113 



Deutschland 
Actavis Group PTC ehf. 
Island 
Tel: +354 5503300 
 

Nederland 
Actavis Group PTC ehf. 
IJsland 
Tel: +354 5503300 
 

Eesti 
UAB Sicor Biotech Eesti filiaal 
Tel: +372 6610801 
 

Norge 
Teva Norway AS 
Tlf: +47 66775590 
 

Ελλάδα 
Specifar ABEE 
Τηλ: +30 2105401500 
 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1970070 
 

España 
Actavis Group PTC ehf. 
Islandia 
Tel: +354 5503300 
 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel: +48 223459300 
 

France 
Actavis Group PTC ehf. 
Islande 
Tél: +354 5503300 
 

Portugal 
Actavis Group PTC ehf. 
Islândia 
Tel: +354 5503300 
 

Hrvatska 
Pliva Hrvatska d.o.o. 
Tel: +385 13720000 
 

România 
Teva Pharmaceuticals S.R.L. 
Tel: +40 212306524 
 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 (0)19630330 
 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 15890390 
 

Ísland 
Actavis Group PTC ehf. 
Sími: +354 5503300 
 

Slovenská republika 
TEVA Pharmaceuticals Slovakia s.r.o. 
Tel: +421 257267911 
 

Italia 
Actavis Group PTC ehf. 
Islanda 
Tel: +354 5503300 
 

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +358 201805900 
 

Κύπρος 
Specifar ABEE  
Ελλάδα 
Τηλ: +30 2105401500 
 
 

Sverige 
Teva Sweden AB 
Tel: +46 42121100 
 

Latvija 
UAB Sicor Biotech filiāle Latvijā 
Tel: +371 67323666 
 

United Kingdom 
Actavis UK Limited 
Tel: +44 1271385257 
 

 
This leaflet was last revised in 
 
Other source of information 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu 

114 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER 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