Glivec

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

Glivec 50 mg hard capsules 

Glivec 100 mg hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

Glivec 50 mg hard capsules 

Each capsule contains 50 mg imatinib (as mesilate). 

 

Glivec 100 mg hard capsules 

Each capsule contains 100 mg imatinib (as mesilate). 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Hard capsule 

 

Glivec 50 mg hard capsulesweh 

White to yellow powder in a light yellow to orange-yellow opaque capsule, marked “NVR SH”. 

 

Glivec 100 mg hard capsules 

White to yellow powder in an orange to greyish-orange opaque capsule, marked “NVR SI”. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Glivec is indicated for the treatment of 

 adult and paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive 
(Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not 

considered as the first line of treatment. 

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

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

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

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

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

leukaemia (CEL) with FIP1L1-PDGFR rearrangement. 

 

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

 

Glivec is indicated for 

 the treatment of adult patients with Kit (CD 117) positive unresectable and/or metastatic 
malignant gastrointestinal stromal tumours (GIST). 



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 the adjuvant treatment of adult patients who are at significant risk of relapse following resection 
of Kit (CD117)-positive GIST. Patients who have a low or very low risk of recurrence should 

not receive adjuvant treatment. 

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

 

In adult and paediatric patients, the effectiveness of Glivec is based on overall haematological and 

cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic 

response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on 

objective response rates in adult patients with unresectable and/or metastatic GIST and DFSP and on 

recurrence-free survival in adjuvant GIST. The experience with Glivec in patients with MDS/MPD 

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

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

increased survival for these diseases. 

 

4.2 Posology and method of administration 
 

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

haematological malignancies and malignant sarcomas, as appropriate. 

 

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. 

 

Posology for CML in adult patients 

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

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

marrow, peripheral blood basophils < 20%, platelets > 100 x 109/l. 

 

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

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

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

peripheral blood basophils  20%, platelets < 100 x 109/l unrelated to therapy. 

 

The recommended dose of Glivec 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 Glivec was continued until disease progression. 

The effect of stopping treatment after the achievement of a complete cytogenetic response has not 

been investigated. 

 

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

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

blast crisis may be considered in the absence of severe adverse drug reaction and severe non-

leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease 

progression (at any time); failure to achieve a satisfactory haematological response after at least 

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

of a previously achieved haematological and/or cytogenetic response. Patients should be monitored 

closely following dose escalation given the potential for an increased incidence of adverse reactions at 

higher dosages. 

 



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Posology for CML in children 

Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily 

is recommended for children with chronic phase CML and advanced phase CML (not to exceed the 

total dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose may 

be split into two administrations – one in the morning and one in the evening. The dose 

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

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

 

Dose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may 

be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia-

related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any 

time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; 

failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved 

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

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

 

Posology for Ph+ ALL in adult patients 

The recommended dose of Glivec 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, Glivec 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 Glivec therapy can vary with the treatment programme selected, 

but generally longer exposures to Glivec have yielded better results. 

 

For adult patients with relapsed or refractory Ph+ALL Glivec monotherapy at 600 mg/day is safe, 

effective and can be given until disease progression occurs. 

 

Posology for Ph+ ALL in children 

Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily 

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

 

Posology for MDS/MPD 

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

 

Treatment duration: In the only clinical trial performed up to now, treatment with Glivec 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 Glivec is 100 mg/day for adult patients with HES/CEL. 

 

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

assessments demonstrate an insufficient response to therapy. 

 

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

 

Posology for GIST 

The recommended dose of Glivec is 400 mg/day for adult patients with unresectable and/or metastatic 

malignant GIST. 

 

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

progressing at the lower dose (see section 5.1). 

 

  



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Treatment duration: In clinical trials in GIST patients, treatment with Glivec was continued until 

disease progression. At the time of analysis, the treatment duration was a median of 7 months (7 days 

to 13 months). The effect of stopping treatment after achieving a response has not been investigated. 

 

The recommended dose of Glivec is 400 mg/day for the adjuvant treatment of adult patients following 

resection of GIST. Optimal treatment duration is not yet established. Length of treatment in the 

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

Posology for DFSP 

The recommended dose of Glivec 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 Glivec 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, Glivec should be withheld until bilirubin levels have returned to < 1.5 x IULN and 

transaminase levels to < 2.5 x IULN. Treatment with Glivec 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 Glivec until ANC  1.5 x 109/l and 

platelets  75 x 109/l. 

2. Resume treatment with Glivec at previous 

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

Chronic phase CML, 

MDS/MPD and GIST 

(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 Glivec until ANC  1.5 x 109/l and 

platelets  75 x 109/l. 

2. Resume treatment with Glivec 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 Glivec 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 Glivec until ANC  1.5 x 109/l and 

platelets  75 x 109/l. 

2. Resume treatment with Glivec at previous 

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

3. In the event of recurrence of ANC 

< 1.0 x109/l and/or platelets < 50 x109/l, 

repeat step 1 and resume Glivec at 

reduced dose of 260 mg/m2. 



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Accelerated phase CML 

and blast crisis and Ph+ 

ALL (starting dose 

600 mg) 

aANC < 0.5 x 109/l 

and/or 

platelets < 10 x 109/l 

1. Check whether cytopenia is related to 

leukaemia (marrow aspirate or biopsy). 

2. If cytopenia is unrelated to leukaemia, 

reduce dose of Glivec 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 Glivec 

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 Glivec 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 Glivec 

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 Glivec until ANC  1.5 x 109/l and 

platelets  75 x 109/l. 

2. Resume treatment with Glivec 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 Glivec at 

reduced dose of 400 mg. 

ANC = absolute neutrophil count 
a occurring after at least 1 month of treatment 

 

Special populations 

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

below 1 year of age (see section 5.1). There is very limited experience in children with MDS/MPD, 

DFSP, GIST and HES/CEL. 

 

The safety and efficacy of imatinib in children with MDS/MPD, DFSP, GIST and HES/CEL aged less 

than 18 years of age have not been established in clinical trials. Currently available published data are 

summarised in section 5.1 but no recommendation on a posology can be made. 

 

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

or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The 

dose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2). 

 



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Liver dysfunction classification: 

 

Liver dysfunction Liver function tests 

Mild Total bilirubin: = 1.5 ULN 

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

>ULN) 

Moderate Total bilirubin: >1.5–3.0 ULN 

AST: any  

Severe Total bilirubin: >3–10 ULN 

AST: any 

ULN = upper limit of normal for the institution 

AST = aspartate aminotransferase 

 

Renal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimum 

recommended dose of 400 mg daily as starting dose. However, in these patients caution is 

recommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack 

of efficacy (see sections 4.4 and 5.2). 

 

Older people: Imatinib pharmacokinetics have not been specifically studied in older people. No 

significant age-related pharmacokinetic differences have been observed in adult patients in clinical 

trials which included over 20% of patients age 65 and older. No specific dose recommendation is 

necessary in older people. 

 

4.3 Contraindications 
 

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

 

4.4 Special warnings and precautions for use 
 

When Glivec is co-administered with other medicinal products, there is a potential for drug 

interactions. Caution should be used when taking Glivec 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 Glivec, 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 Glivec (see section 4.5). Thyroid-stimulating 

hormone (TSH) levels should be closely monitored in such patients. 

 

Hepatotoxicity 

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

with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liver enzymes should 

be carefully monitored (see sections 4.2, 4.8 and 5.2). It should be noted that GIST patients may have 

hepatic metastases which could lead to hepatic impairment. 

 

  



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

When imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic 

reactions has been detected. Hepatic function should be carefully monitored in circumstances where 

imatinib is combined with chemotherapy regimens also known to be associated with hepatic 

dysfunction (see section 4.5 and 4.8). 

 

Fluid retention 

Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, 

superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients 

taking Glivec. Therefore, it is highly recommended that patients be weighed regularly. An unexpected 

rapid weight gain should be carefully investigated and if necessary appropriate supportive care and 

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

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

exercised in patients with cardiac dysfunction. 

 

Patients with cardiac disease 

Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be 

monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure 

should be evaluated and treated. 

 

In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the 

myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated 

with HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be 

reversible with the administration of systemic steroids, circulatory support measures and temporarily 

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

careful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL 

population before treatment initiation. 

 

Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated 

with high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram 

and determination of serum troponin should therefore be considered in patients with HES/CEL, and in 

patients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If 

either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids 

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

of therapy. 

 

Gastrointestinal haemorrhage 

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

tumoural haemorrhages were reported (see section 4.8). Based on the available data, no predisposing 

factors (e.g. tumour size, tumour location, coagulation disorders) have been identified that place 

patients with GIST at a higher risk of either type of haemorrhage. Since increased vascularity and 

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

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

 

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

been reported in post-marketing experience in patients with CML, ALL and other diseases (see section 

4.8). When needed, discontinuation of Glivec 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 Glivec (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. 



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Patients should be tested for HBV infection before initiating treatment with Glivec. 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 Glivec 

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 Glivec (see section 4.8). If laboratory or clinical findings 

associated with TMA occur in a patient receiving Glivec, 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 Glivec should not be resumed. 

 

Laboratory tests 

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

patients with Glivec 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 Glivec 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 Glivec. 

 

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

patients with normal renal function, probably due to an elevated plasma level of alpha-acid 

glycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment 

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

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

 

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

function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and 

closely monitored during therapy, with particular attention to those patients exhibiting risk factors for 

renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be 

prescribed in accordance with standard treatment guidelines. 

 

Paediatric population 

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

imatinib. In an observational study in the CML paediatric population, a statistically significant 

decrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and 

24 months of treatment was reported in two small subsets irrespective of pubertal status or gender. 

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

 

  



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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 

Glivec 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 Glivec, potentially increasing the risk of 

therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 

400 mg dose of Glivec 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 Glivec while taking enzyme-inducing anti-epileptic drugs (EIAEDs) 

such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC for imatinib decreased by 

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

inducers and imatinib should be avoided. 

 

Active substances that may have their plasma concentration altered by Glivec 

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 Glivec with CYP3A4 substrates with a narrow therapeutic window (e.g. 

cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, 

terfenadine, bortezomib, docetaxel and quinidine). Glivec 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 Glivec 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, Glivec inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/l. This 

inhibition has not been observed in vivo after the administration of Glivec 400 mg and paracetamol 

1000 mg. Higher doses of Glivec and paracetamol have not been studied. 

 

Caution should therefore be exercised when using high doses of Glivec and paracetamol 

concomitantly. 

 

In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be 

decreased when Glivec is co-administered (see section 4.4). Caution is therefore recommended. 

However, the mechanism of the observed interaction is presently unknown. 

 

  



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In Ph+ ALL patients, there is clinical experience of co-administering Glivec 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 Glivec 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 and 

for at least 15 days after stopping treatment with Glivec. 

 

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 Glivec. 

Studies in animals have however shown reproductive toxicity (see section 5.3) and the potential risk 

for the foetus is unknown. Glivec 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 should not breast-feed during 

treatment and for at least 15 days after stopping treatment with Glivec. 

 

Fertility 

In non-clinical studies, the fertility of male and female rats was not affected, although effects on 

reproductive parameters were observed (see section 5.3). Studies on patients receiving Glivec and its 

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

on Glivec treatment should consult with their physician. 

 

4.7 Effects on ability to drive and use machines 
 

Patients should be advised that they may experience undesirable effects such as dizziness, blurred 

vision or somnolence during treatment with imatinib. Therefore, caution should be recommended 

when driving a car or operating machinery. 

 

4.8 Undesirable effects 

 

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

that make causality of adverse reactions difficult to assess due to the variety of symptoms related to 

the underlying disease, its progression, and the co-administration of numerous medicinal products. 

 

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

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

4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients 

after failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse 

reactions in 4% of patients. 

 

  



12 

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 Glivec. 

 

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 Glivec 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, 

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 



13 

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 

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)* 



14 

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 

 

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

Glivec. 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. 

  



15 

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 Glivec, but can in rare cases lead to permanent discontinuation of 

treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 4 

cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the 

first several months of therapy. 

 

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

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

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

2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient 

developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts 

occurred mainly during the first six weeks of therapy, with values remaining relatively stable 

thereafter. 

 

Biochemistry 

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

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

approximately one week). Treatment was discontinued permanently because of liver laboratory 

abnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 

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

elevations were observed. Bilirubin elevation was below 3%. 

 

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

outcome was fatal, including one patient on high dose paracetamol. 

 

  



16 

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 

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

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

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

dose ranges are as follows: 

 

Adult population 

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

erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal 

pain, headache, decreased appetite. 

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

phosphokinase, increased bilirubin, gastrointestinal pain. 

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

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

transaminases. 

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

 

Paediatric population 

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

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

cell count and diarrhoea. 

 

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

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

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

 

Mechanism of action 

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

Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: 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. 

 

  

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


17 

Pharmacodynamic effects 

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

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

apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia 

chromosome positive CML and acute lymphoblastic leukaemia (ALL) patients. 

 

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

positive tumour cells. 

 

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

PDGF-R, and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In 

vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumour (GIST) 

cells, which express an activating kit mutation. 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 Glivec is based on overall haematological and cytogenetic response rates and 

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

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

survival. 

 

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

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

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

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

patients with newly diagnosed Ph+ CML. In addition, children have been treated in two phase I studies 

and one phase II study. 

 

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

 70 years of age. 

 

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

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

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

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

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

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

target dose of IFN of 5 MIU/m2/day subcutaneously in combination with subcutaneous Ara-C 

20 mg/m2/day for 10 days/month. 

 

A total of 1,106 patients were randomised, 553 to each arm. Baseline characteristics were well 

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

≥ 60 years of age. There were 59% males and 41% females; 89.9% caucasian and 4.7% black patients. 

Seven years after the last patient had been recruited, the median duration of first-line treatment was 82 

and 8 months in the Glivec and IFN arms, respectively. The median duration of second-line treatment 

with Glivec was 64 months. Overall, in patients receiving first-line Glivec, the average daily dose 

delivered was 406 ± 76 mg. The primary efficacy endpoint of the study is progression-free survival. 

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

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

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

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

are main secondary endpoints. Response data are shown in Table 2. 

 



18 

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

 

 Glivec IFN+Ara-C 

(Best response rates) n=553 n=553 

Haematological response   

CHR rate n (%) 534 (96.6%)* 313 (56.6%)* 

 [95% CI] [94.7%, 97.9%] [52.4%, 60.8%] 

   

Cytogenetic response   

Major response n (%) 490 (88.6%)* 129 (23.3%)* 

 [95% CI] [85.7%, 91.1%] [19.9%, 27.1%] 

 Complete CyR n (%) 456 (82.5%)* 64 (11.6%)* 

 Partial CyR n (%) 34 (6.1%) 65 (11.8%) 

   

Molecular response**   

Major response at 12 months (%) 153/305=50.2% 8/83=9.6% 

Major response at 24 months (%) 73/104=70.2% 3/12=25% 

Major response at 84 months (%) 102/116=87.9% 3/4=75% 

* p<0.001, Fischer’s exact test 

** molecular response percentages are based on available samples 

Haematological response criteria (all responses to be confirmed after  4 weeks): 
WBC < 10 x 109/l, platelet < 450 x 109/l, myelocyte+metamyelocyte < 5% in blood, no blasts and 

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

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

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

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

amount of Bcr-Abl transcripts (measured by real-time quantitative reverse transcriptase PCR assay) 

over a standardised baseline. 

 

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

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

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

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

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

 

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

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

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

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

 

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

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

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

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

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

progression of any type for Glivec also decreased over time. 

 

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

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

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

is strongly affected by the high crossover rate from IFN+Ara-C to Glivec. The effect of Glivec 

treatment on survival in chronic phase, newly diagnosed CML has been further examined in a 

retrospective analysis of the above reported Glivec data with the primary data from another Phase III 

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

of Glivec over IFN+Ara-C in overall survival was demonstrated (p<0.001); within 42 months, 47 

(8.5%) Glivec patients and 63 (19.4%) IFN+Ara-C patients had died. 

 



19 

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

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

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

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

p=0.25 between CCyR and PCyR). For patients with reduction in Bcr-Abl transcripts of at least 

3 logarithms at 12 months, the probability of remaining free from progression to accelerated 

phase/blast crisis was 99% at 84 months. Similar findings were found based on a 18-months landmark 

analysis. 

 

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

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

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

of whom regained a cytogenetic response (1 partial and 1 complete, the latter also achieving a 

molecular response), while of the 7 patients who did not escalate the dose, only one regained a 

complete cytogenetic response. The percentage of some adverse reactions was higher in the 

40 patients in whom the dose was increased to 800 mg daily compared to the population of patients 

before dose increase (n=551). The more frequent adverse reactions included gastrointestinal 

haemorrhages, conjunctivitis and elevation of transaminases or bilirubin. Other adverse reactions were 

reported with lower or equal frequency. 

 

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

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

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

therapy at doses  25 x 106 IU/week and were all in late chronic phase, with a median time from 

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

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

 

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

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

patients. 

 

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

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

the remaining 158 patients were started at 600 mg. 

 

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

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

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

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

Importantly, 27.7% of patients also achieved a major cytogenetic response, which was complete in 

20.4% (confirmed 16%) of patients. For the patients treated at 600 mg, the current estimates for 

median progression-free-survival and overall survival were 22.9 and 42.5 months, respectively. 

 

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

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

165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol 

was subsequently amended to allow higher dosing and the remaining 223 patients were started at 

600 mg. 

 

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

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

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

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

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

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

treated patients was 7.7 and 4.7 months, respectively. 

 



20 

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

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

 

Table 3 Response in adult CML studies 
 

 Study 0110 

37-month data 

Chronic phase, 

IFN failure 

(n=532) 

Study 0109 

40.5-month data 

Accelerated phase 

(n=235) 

Study 0102 

38-month data 

Myeloid blast 

crisis 

(n=260) 

 % of patients (CI95%) 

Haematological response1 95% (92.3–96.3) 71% (65.3–77.2) 31% (25.2–36.8) 

Complete haematological 

response (CHR) 

95% 42% 8% 

No evidence of leukaemia 

(NEL) 

Not applicable 12% 5% 

Return to chronic phase (RTC) Not applicable 17% 18% 

Major cytogenetic response2 65% (61.2–69.5) 28% (22.0–33.9) 15% (11.2–20.4) 

Complete 53% 20% 7% 

(Confirmed3) [95% CI] (43%) [38.6–47.2] (16%) [11.3–21.0] (2%) [0.6–4.4] 

Partial 12% 7% 8% 
1 Haematological response criteria (all responses to be confirmed after  4 weeks): 
CHR: Study 0110 [WBC < 10 x 109/l, platelets < 450 x 109/l, myelocyte+metamyelocyte < 5% in 

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

involvement] and in studies 0102 and 0109 [ANC  1.5 x 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 (0102 and 0109 only) 

RTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in 

PB, no extramedullary disease other than spleen and liver (only for 0102 and 0109). 

BM = bone marrow, PB = peripheral blood 
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 Glivec 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 Glivec 

340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Glivec 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 

Glivec 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). 



21 

 

Clinical studies in Ph+ ALL 

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

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

significantly higher rate of complete haematological response than chemotherapy (96.3% vs. 50%; 

p=0.0001). When salvage therapy with imatinib was administered in patients who did not respond or 

who responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving a 

complete haematological response. This clinical effect was associated with a higher reduction in bcr-

abl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy 

(p=0.02). All patients received imatinib and consolidation chemotherapy (see Table 4) 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 4) resulted in a complete 

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

response rate of 90% (19 out of 21 evaluable patients). The complete molecular response rate was 

48% (49 out of 102 evaluable patients). Disease-free survival (DFS) and overall survival (OS) 

constantly exceeded 1 year and were superior to historical control (DFS p<0.001; OS p<0.0001) in 

two studies (AJP01 and AUS01). 

 

Table 4 Chemotherapy regimen used in combination with imatinib 

 

Study ADE10  

Prephase DEX 10 mg/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 



22 

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 

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 Glivec (340 mg/m2/day) in combination with 

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

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

intensitiy and cohort 5 receiving the highest intensity of Glivec (longest duration in days with 

continuous daily Glivec dosing during the first chemotherapy treatment courses). Continuous daily 

exposure to Glivec 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 Glivec (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. 

 



23 

Table 5 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 

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 



24 

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 

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 Glivec 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 

Glivec 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 Glivec 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. 

 

  



25 

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 Glivec. The 23 patients enrolled in this registry received Glivec 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 Glivec 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 Glivec for a median of 

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

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

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

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

respectively. The overall survival is 65 months since diagnosis (range 25-234). Glivec 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 Glivec 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 Glivec daily. A further 162 patients with HES/CEL, reported in 35 published case reports 

and case series received Glivec 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. 

 

  



26 

Clinical studies in unresectable and/or metastatic GIST 

One phase II, open-label, randomised, uncontrolled multinational study was conducted in patients with 

unresectable or metastatic malignant gastrointestinal stromal tumours (GIST). In this study 

147 patients were enrolled and randomised to receive either 400 mg or 600 mg orally once daily for up 

to 36 months. These patients ranged in age from 18 to 83 years old and had a pathologic diagnosis of 

Kit-positive malignant GIST that was unresectable and/or metastatic. Immunohistochemistry was 

routinely performed with Kit antibody (A-4502, rabbit polyclonal antiserum, 1:100; DAKO 

Corporation, Carpinteria, CA) according to analysis by an avidin-biotin-peroxidase complex method 

after antigen retrieval. 

 

The primary evidence of efficacy was based on objective response rates. Tumours were required to be 

measurable in at least one site of disease, and response characterisation based on Southwestern 

Oncology Group (SWOG) criteria. Results are provided in Table 6. 

 

Table 6 Best tumour response in trial STIB2222 (GIST) 

 

 

 

 

Best response 

All doses (n=147) 

400 mg (n=73) 

600 mg (n=74) 

n (%) 

Complete response 1 (0.7) 

Partial response 98 (66.7) 

Stable disease 23 (15.6) 

Progressive disease 18 (12.2) 

Not evaluable 5 (3.4) 

Unknown 2 (1.4) 

 

There were no differences in response rates between the two dose groups. A significant number of 

patients who had stable disease at the time of the interim analysis achieved a partial response with 

longer treatment (median follow-up 31 months). Median time to response was 13 weeks (95% C.I. 12–

23). Median time to treatment failure in responders was 122 weeks (95% C.I 106–147), while in the 

overall study population it was 84 weeks (95% C.I 71–109). The median overall survival has not been 

reached. The Kaplan-Meier estimate for survival after 36-month follow-up is 68%. 

 

In two clinical studies (study B2222 and an intergroup study S0033) the daily dose of Glivec was 

escalated to 800 mg in patients progressing at the lower daily doses of 400 mg or 600 mg. The daily 

dose was escalated to 800 mg in a total of 103 patients; 6 patients achieved a partial response and 21 

stabilisation of their disease after dose escalation for an overall clinical benefit of 26%. From the 

safety data available, escalating the dose to 800 mg daily in patients progressing at lower doses of 

400 mg or 600 mg daily does not seem to affect the safety profile of Glivec. 

 

Clinical studies in adjuvant GIST 

In the adjuvant setting, Glivec was investigated in a multicentre, double-blind, long-term, placebo-

controlled phase III study (Z9001) involving 773 patients. The ages of these patients ranged from 18 

to 91 years. Patients were included who had a histological diagnosis of primary GIST expressing Kit 

protein by immunochemistry and a tumour size ≥ 3 cm in maximum dimension, with complete gross 

resection of primary GIST within 14-70 days prior to registration. After resection of primary GIST, 

patients were randomised to one of the two arms: Glivec at 400 mg/day or matching placebo for one 

year. 

 

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from date 

of randomisation to the date of recurrence or death from any cause. 

 

  



27 

Glivec significantly prolonged RFS, with 75% of patients being recurrence-free at 38 months in the 

Glivec group vs. 20 months in the placebo group (95% CIs, [30 - non-estimable]; [14 - non-estimable], 

respectively); (hazard ratio = 0.398 [0.259-0.610], p<0.0001). At one year the overall RFS was 

significantly better for Glivec (97.7%) vs. placebo (82.3%), (p<0.0001). The risk of recurrence was 

thus reduced by approximately 89% as compared with placebo (hazard ratio = 0.113 [0.049-0.264]). 

 

The risk of recurrence in patients after surgery of their primary GIST was retrospectively assessed 

based on the following prognostic factors: tumour size, mitotic index, tumour location. Mitotic index 

data were available for 556 of the 713 intention-to-treat (ITT) population. The results of subgroup 

analyses according to the United States National Institutes of Health (NIH) and the Armed Forces 

Institute of Pathology (AFIP) risk classifications are shown in Table 7. No benefit was observed in the 

low and very low risk groups. No overall survival benefit has been observed. 

 
Table 7 Summary of Z9001 trial RFS analyses by NIH and AFIP risk classifications 

 

Risk 

criteria 

Risk Level 

 

% of 

patients 

No. of events / 

No. of patients 

Overall hazard 

ratio (95%CI)* 

RFS rates (%) 

12 month 24 month 

Glivec vs placebo Glivec vs 

placebo 

Glivec vs 

placebo 

NIH Low 29.5 0/86 vs. 2/90 N.E. 100 vs. 98.7 100 vs. 95.5 

Intermediate 25.7 4/75 vs. 6/78 0.59 (0.17; 2.10) 100 vs. 94.8 97.8 vs. 89.5 

High 44.8 21/140 vs. 51/127 0.29 (0.18; 0.49) 94.8 vs. 64.0 80.7 vs. 46.6 

AFIP Very Low 20.7 0/52 vs. 2/63 N.E. 100 vs. 98.1 100 vs. 93.0 

Low 25.0 2/70 vs. 0/69 N.E. 100 vs. 100 97.8 vs. 100 

Moderate 24.6 2/70 vs. 11/67 0.16 (0.03; 0.70) 97.9 vs. 90.8 97.9 vs. 73.3 

High 29.7 16/84 vs. 39/81 0.27 (0.15; 0.48) 98.7 vs. 56.1 79.9 vs. 41.5 

* Full follow-up period; NE – Not estimable 

 

A second multicentre, open label phase III study (SSG XVIII/AIO) compared 400 mg/day Glivec 

12 months treatment vs. 36 months treatment in patients after surgical resection of GIST and one of 

the following: tumour diameter > 5 cm and mitotic count > 5/50 high power fields (HPF); or tumour 

diameter > 10 cm and any mitotic count or tumour of any size with mitotic count > 10/50 HPF or 

tumours ruptured into the peritoneal cavity. There were a total of 397 patients consented and 

randomised to the study (199 patients on 12-month arm and 198 patients on 36-month arm), median 

age was 61 years (range 22 to 84 years). The median time of follow-up was 54 months (from date of 

randomisation to data cut-off), with a total of 83 months between the first patient randomised and the 

cut-off date. 

 

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from date 

of randomisation to the date of recurrence or death from any cause. 

 

Thirty-six (36) months of Glivec treatment significantly prolonged RFS compared to 12 months of 

Glivec treatment (with overall Hazard Ratio (HR) = 0.46 [0.32, 0.65], p<0.0001) (Table 8, Figure 1). 

 

In addition, thirty-six (36) months of Glivec treatment significantly prolonged overall survival (OS) 

compared to 12 months of Glivec treatment (HR = 0.45 [0.22, 0.89], p=0.0187) (Table 8, Figure 2). 

 

Longer duration of the treatment (> 36 months) may delay the onset of further recurrences; however 

the impact of this finding on the overall survival remains unknown. 

 

The total number of deaths were 25 for the 12-month treatment arm and 12 for the 36-month treatment 

arm. 

 

  



28 

Treatment with imatinib for 36 months was superior to treatment for 12 months in the ITT analysis, 

i.e. including the entire study population. In a planned subgroup analysis by mutation type, the HR for 

RFS for 36 months of treatment for patients with mutations of exon 11 was 0.35 [95% CI: 0.22, 0.56]. 

No conclusions can be drawn for other less common mutation subgroups due to the low number of 

observed events. 

 

Table 8 12-month and 36-month Glivec treatment (SSGXVIII/AIO Trial) 
 

 12-month treatment arm 36-month treatment arm 

RFS %(CI) %(CI) 

12 months 93.7 (89.2-96.4) 95.9 (91.9-97.9) 

24 months 75.4 (68.6-81.0) 90.7 (85.6-94.0) 

36 months 60.1 (52.5-66.9) 86.6 (80.8-90.8) 

48 months 52.3 (44.0-59.8) 78.3 (70.8-84.1) 

60 months 47.9 (39.0-56.3) 65.6 (56.1-73.4) 

Survival   

36 months 94.0 (89.5-96.7) 96.3 (92.4-98.2) 

48 months 87.9 (81.1-92.3) 95.6 (91.2-97.8) 

60 months 81.7 (73.0-87.8) 92.0 (85.3-95.7) 

 

Figure 1 Kaplan-Meier estimates for primary recurrence-free survival endpoint (ITT 

population) 

 

 
 

 
At-risk : Events 
(1) 199:0 182:8 177:12 163:25 137:46 105:65 88:72 61:77 49:81 36:83 27:84 14:84 10:84 2:84 0:84 

(2) 198:0 189:5 184:8 181:11 173:18 152:22 133:25 102:29 82:35 54:46 39:47 21:49 8:50 0:50  

 

P
ro

b
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b
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ty
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f 
re

c
u
rr

e
n
c
e

-f
re

e
 s

u
rv

iv
a
l 

 

P < 0.0001 

Hazard ratio 0.46 

(95% Cl, 0.32-0.65) 

  N Evt Cen 

—— (1) Imatinib 12 MO: 199 84 115 

----- (2) Imatinib 36 MO: 198 50 148 

│││ Censored observations    

 

 

Survival time in months 



29 

Figure 2 Kaplan-Meier estimates for overall survival (ITT population) 

 

 
 

 

 
At-risk : Events 
(1) 199:0 190:2 188:2 183:6 176:8 156:10 140:11 105:14 87:18 64:22 46:23 27:25 20:25 2:25 0:25 

(2) 198:0 196:0 192:0 187:4 184:5 164:7 152:7 119:8 100:8 76:10 56:11 31:11 13:12 0:12  

 

There are no controlled trials in paediatric patients with c-Kit positive GIST. Seventeen (17) patients 

with GIST (with or without Kit and PDGFR mutations) were reported in 7 publications. The age of 

these patients ranged from 8 to 18 years and imatinib was given in both adjuvant and metastatic 

settings at doses ranging from 300 to 800 mg daily. The majority of paediatric patients treated for 

GIST lacked data confirming c-kit or PDGFR mutations which may have led to mixed clinical 

outcomes. 

 

Clinical studies in DFSP 

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

with DFSP treated with Glivec 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 Glivec 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) Glivec daily. Five (5) patients responded, 3 

completely and 2 partially. The median duration of therapy in the published literature ranged between 

4 weeks and more than 20 months. The translocation t(17:22)[(q22:q13)], or its gene product, was 

present in nearly all responders to Glivec 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. 

 

  

P
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f 
o
v
e
ra

ll 
s
u
rv

iv
a
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P = 0.019 

Hazard ratio 0.45 

(95% Cl, 0.22-0.89) 

  N Evt Cen 

—— (1) Imatinib 12 MO: 199 25 174 

----- (2) Imatinib 36 MO: 198 12 186 

│││ Censored observations    

 

 

Survival time in months 



30 

5.2 Pharmacokinetic properties 
 

Pharmacokinetics of Glivec 

The pharmacokinetics of Glivec 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 the capsule formulation 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 mol/l, respectively. 

Maximal plasma concentrations of imatinib in patients are 2–4 mol/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. 

 



31 

Pharmacokinetics in GIST patients 

In patients with GIST steady-state exposure was 1.5-fold higher than that observed for CML patients 

for the same dosage (400 mg daily). Based on preliminary population pharmacokinetic analysis in 

GIST patients, there were three variables (albumin, WBC and bilirubin) found to have a statistically 

significant relationship with imatinib pharmacokinetics. Decreased values of albumin caused a 

reduced clearance (CL/f); and higher levels of WBC led to a reduction of CL/f. However, these 

associations are not sufficiently pronounced to warrant dose adjustment. In this patient population, the 

presence of hepatic metastases could potentially lead to hepatic insufficiency and reduced metabolism. 

 

Population pharmacokinetics 

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

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

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

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

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

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

 

Pharmacokinetics in children 

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

both phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved the same 

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

on day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after 

repeated once-daily dosing. 

 

Based on pooled population pharmacokinetic analysis in paediatric patients with haematological 

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

imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other 

demographics such as age, body weight and body mass index did not have clinically significant effects 

on the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients 

receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not 

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

600 mg once daily. 

 

Organ function impairment 

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

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

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

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

probably similar between patients with renal impairment and those with normal renal function, since 

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

 

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

variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver 

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

 

  



32 

5.3 Preclinical safety data 
 

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

 

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

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

 

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

decreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. 

No histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated 

for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct 

hyperplasia. 

 

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

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

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

papilla and in the urinary bladder was observed at doses  6 mg/kg in the 13-week study, without 

changes in serum or urinary parameters. An increased rate of opportunistic infections was observed 

with chronic imatinib treatment. 

 

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

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

body surface. Treatment resulted in worsening of normally suppressed malarial infections in these 

animals. 

 

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

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

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

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

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

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

assay. 

 

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

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

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

moderate reduction in spermatogenesis was also observed in the dog at oral doses  30 mg/kg. When 

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

mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-

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

 

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

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

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

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

of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not 

affected, while an increased number of resorptions and a decreased number of viable foetuses was 

noted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 

generation was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg). 

 

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

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

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

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

 

  



33 

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. 

 

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 
 

Glivec 50 mg hard capsules 

Capsule content: Cellulose microcrystalline 

Crospovidone 

Magnesium stearate 

Silica colloidal, anhydrous 

 

Capsule shell: Gelatin 

Iron oxide, yellow (E172) 

Titanium dioxide (E171) 

 

Printing ink: Iron oxide, red (E172) 

Shellac 

Soya lecithin 

 



34 

Glivec 100 mg hard capsules 

Capsule content: Cellulose microcrystalline 

Crospovidone 

Magnesium stearate 

Silica colloidal, anhydrous 

 

Capsule shell: Gelatin 

Iron oxide, red (E172) 

Iron oxide, yellow (E172) 

Titanium dioxide (E171) 

 

Printing ink: Iron oxide, red (E172) 

Shellac 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

2 years 

 

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 
 

PVC/aluminium blisters 

 

Glivec 50 mg hard capsules 

Packs containing 30 capsules. 

 

Glivec 100 mg hard capsules 

Packs containing 24, 48, 96, 120 and 180 capsules. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal 
 

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

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 



35 

8. MARKETING AUTHORISATION NUMBER(S) 

 

Glivec 50 mg hard capsules 

EU/1/01/198/001 

 

Glivec 100 mg hard capsules 

EU/1/01/198/002-006 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 07 November 2001 

Date of latest renewal: 07 November 2006 

 

 

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 



36 

This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

1. NAME OF THE MEDICINAL PRODUCT 
 

Glivec 100 mg film-coated tablets 

Glivec 400 mg film-coated tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

Glivec 100 mg film-coated tablets 

Each film-coated tablet contains 100 mg imatinib (as mesilate). 

 

Glivec 400 mg film-coated tablets 

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

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 
 

Film-coated tablet 

 

Glivec 100 mg film-coated tablets 

Very dark yellow to brownish-orange film-coated tablet, round with “NVR” on one side and “SA” and 

score on the other side. 

 

Glivec 400 mg film-coated tablets 

Very dark yellow to brownish-orange, ovaloid, biconvex film-coated tablet with bevelled edges, 

debossed with “glivec” on one side. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Glivec is indicated for the treatment of 

 adult and paediatric patients with newly diagnosed Philadelphia chromosome (bcr-abl) positive 
(Ph+) chronic myeloid leukaemia (CML) for whom bone marrow transplantation is not 

considered as the first line of treatment. 

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

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

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

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

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

leukaemia (CEL) with FIP1L1-PDGFR rearrangement. 

 

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

 



37 

Glivec is indicated for 

 the treatment of adult patients with Kit (CD 117) positive unresectable and/or metastatic 
malignant gastrointestinal stromal tumours (GIST). 

 the adjuvant treatment of adult patients who are at significant risk of relapse following resection 
of Kit (CD117)-positive GIST. Patients who have a low or very low risk of recurrence should 

not receive adjuvant treatment. 

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

 

In adult and paediatric patients, the effectiveness of Glivec is based on overall haematological and 

cytogenetic response rates and progression-free survival in CML, on haematological and cytogenetic 

response rates in Ph+ ALL, MDS/MPD, on haematological response rates in HES/CEL and on 

objective response rates in adult patients with unresectable and/or metastatic GIST and DFSP and on 

recurrence-free survival in adjuvant GIST. The experience with Glivec in patients with MDS/MPD 

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

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

increased survival for these diseases. 

 

4.2 Posology and method of administration 
 

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

haematological malignancies and malignant sarcomas, as appropriate. 

 

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

tablet is available. 

For doses of 400 mg and above (see dosage recommendation below) a 400 mg tablet (not divisible) is 

available. 

 

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

the risk of gastrointestinal irritations. Doses of 400 mg or 600 mg should be administered once daily, 

whereas a daily dose of 800 mg should be administered as 400 mg twice a day, in the morning and in 

the evening. 

 

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of still 

water or apple juice. The required number of tablets should be placed in the appropriate volume of 

beverage (approximately 50 ml for a 100 mg tablet, and 200 ml for a 400 mg tablet) and stirred with a 

spoon. The suspension should be administered immediately after complete disintegration of the 

tablet(s). 

 

Posology for CML in adult patients 

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

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

marrow, peripheral blood basophils < 20%, platelets > 100 x 109/l. 

 

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

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

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

peripheral blood basophils  20%, platelets < 100 x 109/l unrelated to therapy. 

 

The recommended dose of Glivec 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 Glivec was continued until disease progression. 

The effect of stopping treatment after the achievement of a complete cytogenetic response has not 

been investigated. 

 

  



38 

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

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

blast crisis may be considered in the absence of severe adverse drug reaction and severe non-

leukaemia-related neutropenia or thrombocytopenia in the following circumstances: disease 

progression (at any time); failure to achieve a satisfactory haematological response after at least 

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

of a previously achieved haematological and/or cytogenetic response. Patients should be monitored 

closely following dose escalation given the potential for an increased incidence of adverse reactions at 

higher dosages. 

 

Posology for CML in children 

Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily 

is recommended for children with chronic phase CML and advanced phase CML (not to exceed the 

total dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose may 

be split into two administrations – one in the morning and one in the evening. The dose 

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

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

 

Dose increases from 340 mg/m2 daily to 570 mg/m2 daily (not to exceed the total dose of 800 mg) may 

be considered in children in the absence of severe adverse drug reaction and severe non-leukaemia-

related neutropenia or thrombocytopenia in the following circumstances: disease progression (at any 

time); failure to achieve a satisfactory haematological response after at least 3 months of treatment; 

failure to achieve a cytogenetic response after 12 months of treatment; or loss of a previously achieved 

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

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

 

Posology for Ph+ ALL in adult patients 

The recommended dose of Glivec 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, Glivec 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 Glivec therapy can vary with the treatment programme selected, 

but generally longer exposures to Glivec have yielded better results. 

 

For adult patients with relapsed or refractory Ph+ALL Glivec monotherapy at 600 mg/day is safe, 

effective and can be given until disease progression occurs. 

 

Posology for Ph+ ALL in children 

Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 daily 

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

 

Posology for MDS/MPD 

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

 

Treatment duration: In the only clinical trial performed up to now, treatment with Glivec 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 Glivec 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. 



39 

 

Posology for GIST 

The recommended dose of Glivec is 400 mg/day for adult patients with unresectable and/or metastatic 

malignant GIST. 

 

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

progressing at the lower dose (see section 5.1). 

 

Treatment duration: In clinical trials in GIST patients, treatment with Glivec was continued until 

disease progression. At the time of analysis, the treatment duration was a median of 7 months (7 days 

to 13 months). The effect of stopping treatment after achieving a response has not been investigated. 

 

The recommended dose of Glivec is 400 mg/day for the adjuvant treatment of adult patients following 

resection of GIST. Optimal treatment duration is not yet established. Length of treatment in the 

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

Posology for DFSP 

The recommended dose of Glivec 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 Glivec 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, Glivec should be withheld until bilirubin levels have returned to < 1.5 x IULN and 

transaminase levels to < 2.5 x IULN. Treatment with Glivec 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 Glivec until ANC  1.5 x 109/l and 

platelets  75 x 109/l. 

2. Resume treatment with Glivec at previous 

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

Chronic phase CML, 

MDS/MPD and GIST 

(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 Glivec until ANC  1.5 x 109/l and 

platelets  75 x 109/l. 

2. Resume treatment with Glivec 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 Glivec 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 Glivec until ANC  1.5 x 109/l and 

platelets  75 x 109/l. 

2. Resume treatment with Glivec at previous 

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

3. In the event of recurrence of ANC 

< 1.0 x109/l and/or platelets < 50 x109/l, 

repeat step 1 and resume Glivec at 

reduced dose of 260 mg/m2. 



40 

Accelerated phase CML 

and blast crisis and Ph+ 

ALL (starting dose 

600 mg) 

aANC < 0.5 x 109/l 

and/or 

platelets < 10 x 109/l 

1. Check whether cytopenia is related to 

leukaemia (marrow aspirate or biopsy). 

2. If cytopenia is unrelated to leukaemia, 

reduce dose of Glivec 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 Glivec 

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 Glivec 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 Glivec 

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 Glivec until ANC  1.5 x 109/l and 

platelets  75 x 109/l. 

2. Resume treatment with Glivec 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 Glivec at 

reduced dose of 400 mg. 

ANC = absolute neutrophil count 
a occurring after at least 1 month of treatment 

 

Special populations 

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

below 1 year of age (see section 5.1). There is very limited experience in children with MDS/MPD, 

DFSP, GIST and HES/CEL. 

 

The safety and efficacy of imatinib in children with MDS/MPD, DFSP, GIST and HES/CEL aged less 

than 18 years of age have not been established in clinical trials. Currently available published data are 

summarised in section 5.1 but no recommendation on a posology can be made. 

 

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

or severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. The 

dose can be reduced if not tolerated (see sections 4.4, 4.8 and 5.2). 

 



41 

Liver dysfunction classification: 

 

Liver dysfunction Liver function tests 

Mild Total bilirubin: = 1.5 ULN 

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

>ULN) 

Moderate Total bilirubin: >1.5–3.0 ULN 

AST: any  

Severe Total bilirubin: >3–10 ULN 

AST: any 

ULN = upper limit of normal for the institution 

AST = aspartate aminotransferase 

 

Renal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimum 

recommended dose of 400 mg daily as starting dose. However, in these patients caution is 

recommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lack 

of efficacy (see sections 4.4 and 5.2). 

 

Older people: Imatinib pharmacokinetics have not been specifically studied in older people. No 

significant age-related pharmacokinetic differences have been observed in adult patients in clinical 

trials which included over 20% of patients age 65 and older. No specific dose recommendation is 

necessary in older people. 

 

4.3 Contraindications 
 

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

 

4.4 Special warnings and precautions for use 
 

When Glivec is co-administered with other medicinal products, there is a potential for drug 

interactions. Caution should be used when taking Glivec 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 Glivec, 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 Glivec (see section 4.5). Thyroid-stimulating 

hormone (TSH) levels should be closely monitored in such patients. 

 

Hepatotoxicity 

Metabolism of Glivec 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. 

 

  



42 

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

When imatinib is combined with high dose chemotherapy regimens, an increase in serious hepatic 

reactions has been detected. Hepatic function should be carefully monitored in circumstances where 

imatinib is combined with chemotherapy regimens also known to be associated with hepatic 

dysfunction (see section 4.5 and 4.8). 

 

Fluid retention 

Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites, 

superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patients 

taking Glivec. Therefore, it is highly recommended that patients be weighed regularly. An unexpected 

rapid weight gain should be carefully investigated and if necessary appropriate supportive care and 

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

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

exercised in patients with cardiac dysfunction. 

 

Patients with cardiac disease 

Patients with cardiac disease, risk factors for cardiac failure or history of renal failure should be 

monitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failure 

should be evaluated and treated. 

 

In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within the 

myocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associated 

with HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to be 

reversible with the administration of systemic steroids, circulatory support measures and temporarily 

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

careful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CEL 

population before treatment initiation. 

 

Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associated 

with high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogram 

and determination of serum troponin should therefore be considered in patients with HES/CEL, and in 

patients with MDS/MPD associated with high eosinophil levels before imatinib is administered. If 

either is abnormal, follow-up with a cardiology specialist and the prophylactic use of systemic steroids 

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

of therapy. 

 

Gastrointestinal haemorrhage 

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

tumoural haemorrhages were reported (see section 4.8). Based on the available data, no predisposing 

factors (e.g. tumour size, tumour location, coagulation disorders) have been identified that place 

patients with GIST at a higher risk of either type of haemorrhage. Since increased vascularity and 

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

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

 

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

been reported in post-marketing experience in patients with CML, ALL and other diseases (see section 

4.8). When needed, discontinuation of Glivec 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 Glivec (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. 



43 

 

Patients should be tested for HBV infection before initiating treatment with Glivec. 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 Glivec 

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 Glivec (see section 4.8). If laboratory or clinical findings 

associated with TMA occur in a patient receiving Glivec, 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 Glivec should not be resumed. 

 

Laboratory tests 

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

patients with Glivec 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 Glivec 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 Glivec. 

 

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

patients with normal renal function, probably due to an elevated plasma level of alpha-acid 

glycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairment 

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

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

 

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

function. Renal function should, therefore, be evaluated prior to the start of imatinib therapy and 

closely monitored during therapy, with particular attention to those patients exhibiting risk factors for 

renal dysfunction. If renal dysfunction is observed, appropriate management and treatment should be 

prescribed in accordance with standard treatment guidelines. 

 

Paediatric population 

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

imatinib. In an observational study in the CML paediatric population, a statistically significant 

decrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and 

24 months of treatment was reported in two small subsets irrespective of pubertal status or gender. 

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

 

  



44 

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 

Glivec 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 Glivec, potentially increasing the risk of 

therapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single 

400 mg dose of Glivec 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 Glivec while taking enzyme-inducing anti-epileptic drugs (EIAEDs) 

such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC for imatinib decreased by 

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

inducers and imatinib should be avoided. 

 

Active substances that may have their plasma concentration altered by Glivec 

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 Glivec with CYP3A4 substrates with a narrow therapeutic window (e.g. 

cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, 

terfenadine, bortezomib, docetaxel and quinidine). Glivec 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 Glivec 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, Glivec inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/l. This 

inhibition has not been observed in vivo after the administration of Glivec 400 mg and paracetamol 

1000 mg. Higher doses of Glivec and paracetamol have not been studied. 

 

Caution should therefore be exercised when using high doses of Glivec and paracetamol 

concomitantly. 

 

In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may be 

decreased when Glivec is co-administered (see section 4.4). Caution is therefore recommended. 

However, the mechanism of the observed interaction is presently unknown. 

 

  



45 

In Ph+ ALL patients, there is clinical experience of co-administering Glivec 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 Glivec 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 and 

for at least 15 days after stopping treatment with Glivec. 

 

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 Glivec. 

Studies in animals have however shown reproductive toxicity (see section 5.3) and the potential risk 

for the foetus is unknown. Glivec 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 should not breast-feed during 

treatment and for at least 15 days after stopping treatment with Glivec. 

 

Fertility 

In non-clinical studies, the fertility of male and female rats was not affected, although effects on 

reproductive parameters were observed (see section 5.3). Studies on patients receiving Glivec and its 

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

on Glivec treatment should consult with their physician. 

 

4.7 Effects on ability to drive and use machines 
 

Patients should be advised that they may experience undesirable effects such as dizziness, blurred 

vision or somnolence during treatment with imatinib. Therefore, caution should be recommended 

when driving a car or operating machinery. 

 

4.8 Undesirable effects 

 

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

that make causality of adverse reactions difficult to assess due to the variety of symptoms related to 

the underlying disease, its progression, and the co-administration of numerous medicinal products. 

 

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

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

4% of patients in accelerated phase after failure of interferon therapy and 5% of blast crisis patients 

after failure of interferon therapy. In GIST the study drug was discontinued for drug-related adverse 

reactions in 4% of patients. 

 

  



46 

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 Glivec. 

 

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 Glivec 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, 

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 



47 

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 

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)* 



48 

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 

 

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

Glivec. 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. 

  



49 

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 Glivec, but can in rare cases lead to permanent discontinuation of 

treatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or 4 

cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within the 

first several months of therapy. 

 

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

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

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

2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patient 

developed grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil counts 

occurred mainly during the first six weeks of therapy, with values remaining relatively stable 

thereafter. 

 

Biochemistry 

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

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

approximately one week). Treatment was discontinued permanently because of liver laboratory 

abnormalities in less than 1% of CML patients. In GIST patients (study B2222), 6.8% of grade 3 or 4 

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

elevations were observed. Bilirubin elevation was below 3%. 

 

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

outcome was fatal, including one patient on high dose paracetamol. 

 

  



50 

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 

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

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

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

dose ranges are as follows: 

 

Adult population 

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

erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominal 

pain, headache, decreased appetite. 

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

phosphokinase, increased bilirubin, gastrointestinal pain. 

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

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

transaminases. 

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

 

Paediatric population 

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

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

cell count and diarrhoea. 

 

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

 

 

5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

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

 

Mechanism of action 

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

Bcr-Abl tyrosine kinase (TK), as well as several receptor TKs: 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. 

 

  

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


51 

Pharmacodynamic effects 

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

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

apoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphia 

chromosome positive CML and acute lymphoblastic leukaemia (ALL) patients. 

 

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

positive tumour cells. 

 

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

PDGF-R, and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. In 

vitro, imatinib inhibits proliferation and induces apoptosis in gastrointestinal stromal tumour (GIST) 

cells, which express an activating kit mutation. 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 Glivec is based on overall haematological and cytogenetic response rates and 

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

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

survival. 

 

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

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

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

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

patients with newly diagnosed Ph+ CML. In addition, children have been treated in two phase I studies 

and one phase II study. 

 

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

 70 years of age. 

 

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

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

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

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

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

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

target dose of IFN of 5 MIU/m2/day subcutaneously in combination with subcutaneous Ara-C 

20 mg/m2/day for 10 days/month. 

 

A total of 1,106 patients were randomised, 553 to each arm. Baseline characteristics were well 

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

≥ 60 years of age. There were 59% males and 41% females; 89.9% caucasian and 4.7% black patients. 

Seven years after the last patient had been recruited, the median duration of first-line treatment was 82 

and 8 months in the Glivec and IFN arms, respectively. The median duration of second-line treatment 

with Glivec was 64 months. Overall, in patients receiving first-line Glivec, the average daily dose 

delivered was 406 ± 76 mg. The primary efficacy endpoint of the study is progression-free survival. 

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

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

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

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

are main secondary endpoints. Response data are shown in Table 2. 

 



52 

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

 

 Glivec IFN+Ara-C 

(Best response rates) n=553 n=553 

Haematological response   

CHR rate n (%) 534 (96.6%)* 313 (56.6%)* 

 [95% CI] [94.7%, 97.9%] [52.4%, 60.8%] 

   

Cytogenetic response   

Major response n (%) 490 (88.6%)* 129 (23.3%)* 

 [95% CI] [85.7%, 91.1%] [19.9%, 27.1%] 

 Complete CyR n (%) 456 (82.5%)* 64 (11.6%)* 

 Partial CyR n (%) 34 (6.1%) 65 (11.8%) 

   

Molecular response**   

Major response at 12 months (%) 153/305=50.2% 8/83=9.6% 

Major response at 24 months (%) 73/104=70.2% 3/12=25% 

Major response at 84 months (%) 102/116=87.9% 3/4=75% 

* p<0.001, Fischer’s exact test 

** molecular response percentages are based on available samples 

Haematological response criteria (all responses to be confirmed after  4 weeks): 
WBC < 10 x 109/l, platelet < 450 x 109/l, myelocyte+metamyelocyte < 5% in blood, no blasts and 

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

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

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

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

amount of Bcr-Abl transcripts (measured by real-time quantitative reverse transcriptase PCR assay) 

over a standardised baseline. 

 

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

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

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

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

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

 

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

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

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

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

 

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

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

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

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

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

progression of any type for Glivec also decreased over time. 

 

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

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

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

is strongly affected by the high crossover rate from IFN+Ara-C to Glivec. The effect of Glivec 

treatment on survival in chronic phase, newly diagnosed CML has been further examined in a 

retrospective analysis of the above reported Glivec data with the primary data from another Phase III 

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

of Glivec over IFN+Ara-C in overall survival was demonstrated (p<0.001); within 42 months, 47 

(8.5%) Glivec patients and 63 (19.4%) IFN+Ara-C patients had died. 

 



53 

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

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

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

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

p=0.25 between CCyR and PCyR). For patients with reduction in Bcr-Abl transcripts of at least 

3 logarithms at 12 months, the probability of remaining free from progression to accelerated 

phase/blast crisis was 99% at 84 months. Similar findings were found based on a 18-months landmark 

analysis. 

 

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

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

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

of whom regained a cytogenetic response (1 partial and 1 complete, the latter also achieving a 

molecular response), while of the 7 patients who did not escalate the dose, only one regained a 

complete cytogenetic response. The percentage of some adverse reactions was higher in the 

40 patients in whom the dose was increased to 800 mg daily compared to the population of patients 

before dose increase (n=551). The more frequent adverse reactions included gastrointestinal 

haemorrhages, conjunctivitis and elevation of transaminases or bilirubin. Other adverse reactions were 

reported with lower or equal frequency. 

 

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

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

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

therapy at doses  25 x 106 IU/week and were all in late chronic phase, with a median time from 

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

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

 

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

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

patients. 

 

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

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

the remaining 158 patients were started at 600 mg. 

 

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

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

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

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

Importantly, 27.7% of patients also achieved a major cytogenetic response, which was complete in 

20.4% (confirmed 16%) of patients. For the patients treated at 600 mg, the current estimates for 

median progression-free-survival and overall survival were 22.9 and 42.5 months, respectively. 

 

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

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

165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocol 

was subsequently amended to allow higher dosing and the remaining 223 patients were started at 

600 mg. 

 

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

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

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

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

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

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

treated patients was 7.7 and 4.7 months, respectively. 

 



54 

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

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

 

Table 3 Response in adult CML studies 
 

 Study 0110 

37-month data 

Chronic phase, 

IFN failure 

(n=532) 

Study 0109 

40.5-month data 

Accelerated phase 

(n=235) 

Study 0102 

38-month data 

Myeloid blast 

crisis 

(n=260) 

 % of patients (CI95%) 

Haematological response1 95% (92.3–96.3) 71% (65.3–77.2) 31% (25.2–36.8) 

Complete haematological 

response (CHR) 

95% 42% 8% 

No evidence of leukaemia 

(NEL) 

Not applicable 12% 5% 

Return to chronic phase (RTC) Not applicable 17% 18% 

Major cytogenetic response2 65% (61.2–69.5) 28% (22.0–33.9) 15% (11.2–20.4) 

Complete 53% 20% 7% 

(Confirmed3) [95% CI] (43%) [38.6–47.2] (16%) [11.3–21.0] (2%) [0.6–4.4] 

Partial 12% 7% 8% 
1 Haematological response criteria (all responses to be confirmed after  4 weeks): 
CHR: Study 0110 [WBC < 10 x 109/l, platelets < 450 x 109/l, myelocyte+metamyelocyte < 5% in 

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

involvement] and in studies 0102 and 0109 [ANC  1.5 x 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 (0102 and 0109 only) 

RTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in 

PB, no extramedullary disease other than spleen and liver (only for 0102 and 0109). 

BM = bone marrow, PB = peripheral blood 
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 Glivec 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 Glivec 

340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Glivec 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 

Glivec 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). 



55 

 

Clinical studies in Ph+ ALL 

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

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

significantly higher rate of complete haematological response than chemotherapy (96.3% vs. 50%; 

p=0.0001). When salvage therapy with imatinib was administered in patients who did not respond or 

who responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving a 

complete haematological response. This clinical effect was associated with a higher reduction in bcr-

abl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy 

(p=0.02). All patients received imatinib and consolidation chemotherapy (see Table 4) 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 4) resulted in a complete 

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

response rate of 90% (19 out of 21 evaluable patients). The complete molecular response rate was 

48% (49 out of 102 evaluable patients). Disease-free survival (DFS) and overall survival (OS) 

constantly exceeded 1 year and were superior to historical control (DFS p<0.001; OS p<0.0001) in 

two studies (AJP01 and AUS01). 

 

Table 4 Chemotherapy regimen used in combination with imatinib 

 

Study ADE10  

Prephase DEX 10 mg/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 



56 

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 

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 Glivec (340 mg/m2/day) in combination with 

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

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

intensitiy and cohort 5 receiving the highest intensity of Glivec (longest duration in days with 

continuous daily Glivec dosing during the first chemotherapy treatment courses). Continuous daily 

exposure to Glivec 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 Glivec (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. 

 



57 

Table 5 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 

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 



58 

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 

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 Glivec 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 

Glivec 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 Glivec 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. 

 

  



59 

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 Glivec. The 23 patients enrolled in this registry received Glivec 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 Glivec 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 Glivec for a median of 

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

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

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

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

respectively. The overall survival is 65 months since diagnosis (range 25-234). Glivec 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 Glivec 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 Glivec daily. A further 162 patients with HES/CEL, reported in 35 published case reports 

and case series received Glivec 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. 

 

  



60 

Clinical studies in unresectable and/or metastatic GIST 

One phase II, open-label, randomised, uncontrolled multinational study was conducted in patients with 

unresectable or metastatic malignant gastrointestinal stromal tumours (GIST). In this study 

147 patients were enrolled and randomised to receive either 400 mg or 600 mg orally once daily for up 

to 36 months. These patients ranged in age from 18 to 83 years old and had a pathologic diagnosis of 

Kit-positive malignant GIST that was unresectable and/or metastatic. Immunohistochemistry was 

routinely performed with Kit antibody (A-4502, rabbit polyclonal antiserum, 1:100; DAKO 

Corporation, Carpinteria, CA) according to analysis by an avidin-biotin-peroxidase complex method 

after antigen retrieval. 

 

The primary evidence of efficacy was based on objective response rates. Tumours were required to be 

measurable in at least one site of disease, and response characterisation based on Southwestern 

Oncology Group (SWOG) criteria. Results are provided in Table 6. 

 

Table 6 Best tumour response in trial STIB2222 (GIST) 

 

 

 

 

Best response 

All doses (n=147) 

400 mg (n=73) 

600 mg (n=74) 

n (%) 

Complete response 1(0.7) 

Partial response 98 (66.7) 

Stable disease 23 (15.6) 

Progressive disease 18 (12.2) 

Not evaluable 5 (3.4) 

Unknown 2 (1.4) 

 

There were no differences in response rates between the two dose groups. A significant number of 

patients who had stable disease at the time of the interim analysis achieved a partial response with 

longer treatment (median follow-up 31 months). Median time to response was 13 weeks (95% C.I. 12–

23). Median time to treatment failure in responders was 122 weeks (95% C.I 106–147), while in the 

overall study population it was 84 weeks (95% C.I 71–109). The median overall survival has not been 

reached. The Kaplan-Meier estimate for survival after 36-month follow-up is 68%. 

 

In two clinical studies (study B2222 and an intergroup study S0033) the daily dose of Glivec was 

escalated to 800 mg in patients progressing at the lower daily doses of 400 mg or 600 mg. The daily 

dose was escalated to 800 mg in a total of 103 patients; 6 patients achieved a partial response and 21 

stabilisation of their disease after dose escalation for an overall clinical benefit of 26%. From the 

safety data available, escalating the dose to 800 mg daily in patients progressing at lower doses of 

400 mg or 600 mg daily does not seem to affect the safety profile of Glivec. 

 

Clinical studies in adjuvant GIST 

In the adjuvant setting, Glivec was investigated in a multicentre, double-blind, long-term, placebo-

controlled phase III study (Z9001) involving 773 patients. The ages of these patients ranged from 18 

to 91 years. Patients were included who had a histological diagnosis of primary GIST expressing Kit 

protein by immunochemistry and a tumour size ≥ 3 cm in maximum dimension, with complete gross 

resection of primary GIST within 14-70 days prior to registration. After resection of primary GIST, 

patients were randomised to one of the two arms: Glivec at 400 mg/day or matching placebo for one 

year. 

 

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from date 

of randomisation to the date of recurrence or death from any cause. 

 

  



61 

Glivec significantly prolonged RFS, with 75% of patients being recurrence-free at 38 months in the 

Glivec group vs. 20 months in the placebo group (95% CIs, [30 - non-estimable]; [14 - non-estimable], 

respectively); (hazard ratio = 0.398 [0.259-0.610], p<0.0001). At one year the overall RFS was 

significantly better for Glivec (97.7%) vs. placebo (82.3%), (p<0.0001). The risk of recurrence was 

thus reduced by approximately 89% as compared with placebo (hazard ratio = 0.113 [0.049-0.264]). 

 

The risk of recurrence in patients after surgery of their primary GIST was retrospectively assessed 

based on the following prognostic factors: tumour size, mitotic index, tumour location. Mitotic index 

data were available for 556 of the 713 intention-to-treat (ITT) population. The results of subgroup 

analyses according to the United States National Institutes of Health (NIH) and the Armed Forces 

Institute of Pathology (AFIP) risk classifications are shown in Table 7. No benefit was observed in the 

low and very low risk groups. No overall survival benefit has been observed. 

 
Table 7 Summary of Z9001 trial RFS analyses by NIH and AFIP risk classifications 

 

Risk 

criteria 

Risk Level 

 

% of 

patients 

No. of events / 

No. of patients 

Overall hazard 

ratio (95%CI)* 

RFS rates (%) 

12 month 24 month 

Glivec vs placebo Glivec vs 

placebo 

Glivec vs 

placebo 

NIH Low 29.5 0/86 vs. 2/90 N.E. 100 vs. 98.7 100 vs. 95.5 

Intermediate 25.7 4/75 vs. 6/78 0.59 (0.17; 2.10) 100 vs. 94.8 97.8 vs. 89.5 

High 44.8 21/140 vs. 51/127 0.29 (0.18; 0.49) 94.8 vs. 64.0 80.7 vs. 46.6 

AFIP Very Low 20.7 0/52 vs. 2/63 N.E. 100 vs. 98.1 100 vs. 93.0 

Low 25.0 2/70 vs. 0/69 N.E. 100 vs. 100 97.8 vs. 100 

Moderate 24.6 2/70 vs. 11/67 0.16 (0.03; 0.70) 97.9 vs. 90.8 97.9 vs. 73.3 

High 29.7 16/84 vs. 39/81 0.27 (0.15; 0.48) 98.7 vs. 56.1 79.9 vs. 41.5 

* Full follow-up period; NE – Not estimable 

 

A second multicentre, open label phase III study (SSG XVIII/AIO) compared 400 mg/day Glivec 

12 months treatment vs. 36 months treatment in patients after surgical resection of GIST and one of 

the following: tumour diameter > 5 cm and mitotic count > 5/50 high power fields (HPF); or tumour 

diameter > 10 cm and any mitotic count or tumour of any size with mitotic count > 10/50 HPF or 

tumours ruptured into the peritoneal cavity. There were a total of 397 patients consented and 

randomised to the study (199 patients on 12-month arm and 198 patients on 36-month arm), median 

age was 61 years (range 22 to 84 years). The median time of follow-up was 54 months (from date of 

randomisation to data cut-off), with a total of 83 months between the first patient randomised and the 

cut-off date. 

 

The primary endpoint of the study was recurrence-free survival (RFS), defined as the time from date 

of randomisation to the date of recurrence or death from any cause. 

 

Thirty-six (36) months of Glivec treatment significantly prolonged RFS compared to 12 months of 

Glivec treatment (with overall Hazard Ratio (HR) = 0.46 [0.32, 0.65], p<0.0001) (Table 8, Figure 1). 

 

In addition, thirty-six (36) months of Glivec treatment significantly prolonged overall survival (OS) 

compared to 12 months of Glivec treatment (HR = 0.45 [0.22, 0.89], p=0.0187) (Table 8, Figure 2). 

 

Longer duration of the treatment (> 36 months) may delay the onset of further recurrences; however 

the impact of this finding on the overall survival remains unknown. 

 

The total number of deaths were 25 for the 12-month treatment arm and 12 for the 36-month treatment 

arm. 

  



62 

 

Treatment with imatinib for 36 months was superior to treatment for 12 months in the ITT analysis, 

i.e. including the entire study population. In a planned subgroup analysis by mutation type, the HR for 

RFS for 36 months of treatment for patients with mutations of exon 11 was 0.35 [95% CI: 0.22, 0.56]. 

No conclusions can be drawn for other less common mutation subgroups due to the low number of 

observed events. 

 

Table 8 12-month and 36-month Glivec treatment (SSGXVIII/AIO Trial) 
 

 12-month treatment arm 36-month treatment arm 

RFS %(CI) %(CI) 

12 months 93.7 (89.2-96.4) 95.9 (91.9-97.9) 

24 months 75.4 (68.6-81.0) 90.7 (85.6-94.0) 

36 months 60.1 (52.5-66.9) 86.6 (80.8-90.8) 

48 months 52.3 (44.0-59.8) 78.3 (70.8-84.1) 

60 months 47.9 (39.0-56.3) 65.6 (56.1-73.4) 

Survival   

36 months 94.0 (89.5-96.7) 96.3 (92.4-98.2) 

48 months 87.9 (81.1-92.3) 95.6 (91.2-97.8) 

60 months 81.7 (73.0-87.8) 92.0 (85.3-95.7) 

 

Figure 1 Kaplan-Meier estimates for primary recurrence-free survival endpoint (ITT 

population) 

 

 
 

 
At-risk : Events 
(1) 199:0 182:8 177:12 163:25 137:46 105:65 88:72 61:77 49:81 36:83 27:84 14:84 10:84 2:84 0:84 

(2) 198:0 189:5 184:8 181:11 173:18 152:22 133:25 102:29 82:35 54:46 39:47 21:49 8:50 0:50  

 

P
ro

b
a

b
ili

ty
 o

f 
re

c
u
rr

e
n
c
e

-f
re

e
 s

u
rv

iv
a
l 

 

P < 0.0001 

Hazard ratio 0.46 

(95% Cl, 0.32-0.65) 

  N Evt Cen 

—— (1) Imatinib 12 MO: 199 84 115 

----- (2) Imatinib 36 MO: 198 50 148 

│││ Censored observations    

 

 

Survival time in months 



63 

Figure 2 Kaplan-Meier estimates for overall survival (ITT population) 

 

 
 

 

 
At-risk : Events 
(1) 199:0 190:2 188:2 183:6 176:8 156:10 140:11 105:14 87:18 64:22 46:23 27:25 20:25 2:25 0:25 

(2) 198:0 196:0 192:0 187:4 184:5 164:7 152:7 119:8 100:8 76:10 56:11 31:11 13:12 0:12  

 

There are no controlled trials in paediatric patients with c-Kit positive GIST. Seventeen (17) patients 

with GIST (with or without Kit and PDGFR mutations) were reported in 7 publications. The age of 

these patients ranged from 8 to 18 years and imatinib was given in both adjuvant and metastatic 

settings at doses ranging from 300 to 800 mg daily. The majority of paediatric patients treated for 

GIST lacked data confirming c-kit or PDGFR mutations which may have led to mixed clinical 

outcomes. 

 

Clinical studies in DFSP 

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

with DFSP treated with Glivec 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 Glivec 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) Glivec daily. Five (5) patients responded, 3 

completely and 2 partially. The median duration of therapy in the published literature ranged between 

4 weeks and more than 20 months. The translocation t(17:22)[(q22:q13)], or its gene product, was 

present in nearly all responders to Glivec 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. 

 

  

P
ro

b
a

b
ili

ty
 o

f 
o
v
e
ra

ll 
s
u
rv

iv
a
l 

 

 

P = 0.019 

Hazard ratio 0.45 

(95% Cl, 0.22-0.89) 

  N Evt Cen 

—— (1) Imatinib 12 MO: 199 25 174 

----- (2) Imatinib 36 MO: 198 12 186 

│││ Censored observations    

 

 

Survival time in months 



64 

5.2 Pharmacokinetic properties 
 

Pharmacokinetics of Glivec 

The pharmacokinetics of Glivec 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 mol/l, respectively. 

Maximal plasma concentrations of imatinib in patients are 2–4 mol/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. 

 



65 

Pharmacokinetics in GIST patients 

In patients with GIST steady-state exposure was 1.5-fold higher than that observed for CML patients 

for the same dosage (400 mg daily). Based on preliminary population pharmacokinetic analysis in 

GIST patients, there were three variables (albumin, WBC and bilirubin) found to have a statistically 

significant relationship with imatinib pharmacokinetics. Decreased values of albumin caused a 

reduced clearance (CL/f); and higher levels of WBC led to a reduction of CL/f. However, these 

associations are not sufficiently pronounced to warrant dose adjustment. In this patient population, the 

presence of hepatic metastases could potentially lead to hepatic insufficiency and reduced metabolism. 

 

Population pharmacokinetics 

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

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

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

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

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

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

 

Pharmacokinetics in children 

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

both phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved the same 

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

on day 8 and day 1 at the 340 mg/m2/day dose level revealed a 1.7-fold drug accumulation after 

repeated once-daily dosing. 

 

Based on pooled population pharmacokinetic analysis in paediatric patients with haematological 

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

imatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, other 

demographics such as age, body weight and body mass index did not have clinically significant effects 

on the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patients 

receiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (not 

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

600 mg once daily. 

 

Organ function impairment 

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

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

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

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

probably similar between patients with renal impairment and those with normal renal function, since 

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

 

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

variation, the mean exposure to imatinib did not increase in patients with varying degrees of liver 

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

 

5.3 Preclinical safety data 
 

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

 

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

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

 

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

decreases in cholesterol, triglycerides, total protein and albumin levels were observed in both species. 

No histopathological changes were seen in rat liver. Severe liver toxicity was observed in dogs treated 

for 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile duct 

hyperplasia. 



66 

 

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

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

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

papilla and in the urinary bladder was observed at doses  6 mg/kg in the 13-week study, without 

changes in serum or urinary parameters. An increased rate of opportunistic infections was observed 

with chronic imatinib treatment. 

 

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

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

body surface. Treatment resulted in worsening of normally suppressed malarial infections in these 

animals. 

 

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

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

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

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

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

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

assay. 

 

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

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

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

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

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

mating or on number of pregnant females. At a dose of 60 mg/kg, female rats had significant post-

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

 

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

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

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

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

of litters achieving criterion for preputial separation was slightly decreased. F1 fertility was not 

affected, while an increased number of resorptions and a decreased number of viable foetuses was 

noted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1 

generation was 15 mg/kg/day (one quarter of the maximum human dose of 800 mg). 

 

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

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

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

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

 

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

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

effects upon growth, delay in vaginal opening and preputial separation were observed at 

approximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of 

340 mg/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. 

 

  



67 

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. 

 

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 

Crospovidone 

Hypromellose 

Magnesium stearate 

Silica, colloidal anhydrous 

 

Tablet coat: 

Iron oxide, red (E172) 

Iron oxide, yellow (E172) 

Macrogol 

Talc 

Hypromellose 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

3 years 

 



68 

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 
 

Glivec 100 mg film-coated tablets 

PVC/alu blisters 

Packs containing 20, 60, 120 or 180 film-coated tablets 

 

PVDC/alu blisters 

Packs containing 60, 120 or 180 film-coated tablets 

 

Glivec 400 mg film-coated tablets 

PVDC/alu blisters 

Packs containing 10, 30 or 90 film-coated tablets 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal 
 

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

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

Glivec 100 mg film-coated tablets 

EU/1/01/198/007 

EU/1/01/198/008 

EU/1/01/198/011 

EU/1/01/198/012 

EU/1/01/198/014 

EU/1/01/198/015 

EU/1/01/198/016 

 

Glivec 400 mg film-coated tablets 

EU/1/01/198/009 

EU/1/01/198/010 

EU/1/01/198/013 

 

  



69 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 07 November 2001 

Date of latest renewal: 07 November 2006 

 

 

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 

 

  



70 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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 



71 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

Name and address of the manufacturer responsible for batch release 

 

Lek d.d, PE PROIZVODNJA LENDAVA 

Trimlini 2D 

Lendava, 9220 

Slovenia 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic Safety Update Reports 
The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 

 Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 

the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 

subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

 Obligation to conduct post-authorisation measures 
 

The MAH shall complete, within the stated timeframe, the below measures: 

 

Description Due date 

To conduct an observational registry collecting efficacy and safety data in newly 

diagnosed paediatric Ph+ Acute Lymphoblastic Leukaemia (ALL) patients 

treated with chemotherapy + imatinib ± HSCT. Submission of final study report. 

30/06/2022 

  



72 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



73 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
  



74 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Glivec 50 mg hard capsules 

imatinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 50 mg of imatinib (as mesilate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

30 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 30C. Store in the original package in order to protect from moisture. 

 

 



75 

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 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/198/001 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Glivec 50 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



76 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Glivec 50 mg capsules 

imatinib 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



77 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Glivec 100 mg hard capsules 

imatinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 100 mg of imatinib (as mesilate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

24 hard capsules 

48 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 30C. Store in the original package in order to protect from moisture. 

 

 



78 

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 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/198/002 24 capsules 

EU/1/01/198/003 48 capsules 

EU/1/01/198/004 96 capsules 

EU/1/01/198/005 120 capsules 

EU/1/01/198/006 180 capsules 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Glivec 100 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



79 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Glivec 100 mg capsules 

imatinib 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



80 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Glivec 100 mg film-coated tablets 

imatinib 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each film-coated tablet contains 100 mg imatinib (as mesilate). 

 

 

3. LIST OF EXCIPIENTS 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

20 film-coated tablets 

60 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 

 

Do not store above 30C. Store in the original package in order to protect from moisture. 

 

 



81 

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 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/198/007 20 tablets (PVC/alu blisters) 

EU/1/01/198/008 60 tablets (PVC/alu blisters) 

EU/1/01/198/011 120 tablets (PVC/alu blisters) 

EU/1/01/198/012 180 tablets (PVC/alu blisters) 

EU/1/01/198/014 60 tablets (PVDC/alu blisters) 

EU/1/01/198/015 120 tablets (PVDC/alu blisters) 

EU/1/01/198/016 180 tablets (PVDC/alu blisters) 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Glivec 100 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



82 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Glivec 100 mg tablets 

imatinib 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



83 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Glivec 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 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

10 film-coated tablets 

30 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. 

 

 



84 

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 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/01/198/009 10 tablets 

EU/1/01/198/010 30 tablets 

EU/1/01/198/013 90 tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Glivec 400 mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



85 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTERS 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Glivec 400 mg tablets 

imatinib 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



86 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



87 

Package leaflet: Information for the user 

 

Glivec 50 mg hard capsules 
imatinib 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects 

 

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 Glivec is and what it is used for 

2. What you need to know before you take Glivec 

3. How to take Glivec 

4. Possible side effects 

5. How to store Glivec 

6. Contents of the pack and other information 

 

 

1. What Glivec is and what it is used for 
 

Glivec 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. 

 

Glivec is a treatment for adults and children for: 

 

- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white 
cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia 

in which certain abnormal white cells (named myeloid cells) start growing out of control. 

- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). 
Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight 

infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal 

white cells (named lymphoblasts) start growing out of control. Glivec inhibits the growth of 

these cells. 

 

Glivec 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. Glivec 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. 

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

- Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It 
arises from uncontrolled cell growth of the supporting tissues of these organs. 

- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin 
in which some cells start growing out of control. Glivec inhibits the growth of these cells. 

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



88 

 

If you have any questions about how Glivec works or why this medicine has been prescribed for you, 

ask your doctor. 

 

 

2. What you need to know before you take Glivec 

 

Glivec 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 Glivec: 
- 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 Glivec. 

 

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 Glivec: 

- 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 Glivec 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 Glivec, 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 Glivec. 

 

You may become more sensitive to the sun while taking Glivec. 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 Glivec, tell your doctor straight away if you put on weight very quickly. 

Glivec may cause your body to retain water (severe fluid retention). 

 

While you are taking Glivec, your doctor will regularly check whether the medicine is working. You 

will also have blood tests and be weighed regularly. 

 

Children and adolescents 

Glivec 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, GIST and HES/CEL. 

 

Some children and adolescents taking Glivec may have slower than normal growth. The doctor will 

monitor the growth at regular visits. 

 

Other medicines and Glivec 

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 Glivec 

when taken together. They may increase or decrease the effect of Glivec, either leading to increased 

side effects or making Glivec less effective. Glivec may do the same to some other medicines. 

 



89 

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. 

- Glivec 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 Glivec during pregnancy. 

- Women who might become pregnant are advised to use effective contraception during treatment 
and for 15 days after ending treatment. 

- Do not breast-feed during the treatment with Glivec and for 15 days after ending treatment, as it 
may harm your baby. 

- Patients who are concerned about their fertility while taking Glivec are advised to consult with 
their doctor. 

 

Driving and using machines 
You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not 

drive or use any tools or machines until you are feeling well again. 

 

 

3. How to take Glivec 
 

Your doctor has prescribed Glivec because you suffer from a serious condition. Glivec 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 Glivec 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 Glivec to take 

 

Use in adults 
Your doctor will tell you exactly how many capsules of Glivec to take. 

 

 If you are being treated for CML: 
Depending on your condition the usual starting dose is either 400 mg or 600 mg: 

- 400 mg to be taken as 8 capsules once a day. 
- 600 mg to be taken as 12 capsules once a day. 

 

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

 

For CML and GIST, 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. 

 

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

  



90 

 

 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 Glivec to give to your child. The amount of Glivec 

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 Glivec 

- Take Glivec with a meal. This will help protect you from stomach problems when taking 
Glivec. 

- 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 Glivec 

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

 

If you take more Glivec 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 Glivec 

- 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. Glivec may cause your body to retain water (severe fluid retention). 

 Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Glivec 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). 
 



91 

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. 

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

 Swelling such as round your ankles or puffy eyes. 



92 

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

 

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

 Anorexia, weight loss or a disturbed sense of taste. 

 Feeling dizzy or weak. 

 Difficulty in sleeping (insomnia). 

 Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or 
having blurred vision. 

 Nose bleeds. 

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

 Itching. 

 Unusual hair loss or thinning. 

 Numbness of the hands or feet. 

 Mouth ulcers. 

 Joint pain with swelling. 

 Dry mouth, dry skin or dry eye. 

 Decreased or increased skin sensitivity. 

 Hot flushes, chills or night sweats. 
If any of these affects you severely, tell your doctor. 

 

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

 Reddening and/or swelling on the palms of the hands and soles of the feet which may be 
accompanied by tingling sensation and burning pain. 

 Painful and/or blistering skin lesions. 

 Slowing of growth in children and adolescents. 
If any of these affects you severely, tell your doctor. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

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 Glivec 
 

 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 after EXP. 

 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 
 

What Glivec contains 

- The active substance is imatinib mesilate. Each capsule of Glivec contains 50 mg imatinib (as 
mesilate). 

- The other ingredients are microcrystalline cellulose, crospovidone, magnesium stearate and 
anhydrous colloidal silica. The capsule shell is composed of gelatin, yellow iron oxide (E172) 

and titanium dioxide (E171). The printing ink is composed of red iron oxide (E172), shellac, 

soya lecithin. 

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


93 

 

What Glivec looks like and contents of the pack 

Glivec 50 mg capsules are light yellow to orange-yellow and marked “NVR SH”. They contain a 

white to yellow powder. 

 

They are supplied in packs containing 30 capsules. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder. 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „Novartis Baltics“ Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 



94 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

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 

 



95 

Package leaflet: Information for the user 

 

Glivec 100 mg hard capsules 

imatinib 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects 

 

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 Glivec is and what it is used for 

2. What you need to know before you take Glivec 

3. How to take Glivec 

4. Possible side effects 

5. How to store Glivec 

6. Contents of the pack and other information 

 

 

1. What Glivec is and what it is used for 
 

Glivec 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. 

 

Glivec is a treatment for adults and children for: 

 

- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white 
cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia 

in which certain abnormal white cells (named myeloid cells) start growing out of control. 

- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). 
Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight 

infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal 

white cells (named lymphoblasts) start growing out of control. Glivec inhibits the growth of 

these cells. 

 

Glivec 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. Glivec 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. 

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

- Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It 
arises from uncontrolled cell growth of the supporting tissues of these organs. 

- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin 
in which some cells start growing out of control. Glivec inhibits the growth of these cells. 

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



96 

 

If you have any questions about how Glivec works or why this medicine has been prescribed for you, 

ask your doctor. 

 

 

2. What you need to know before you take Glivec 

 

Glivec 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 Glivec: 
- 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 Glivec. 

 

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 Glivec: 

- 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 Glivec 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 Glivec, 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 Glivec. 

 

You may become more sensitive to the sun while taking Glivec. 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 Glivec, tell your doctor straight away if you put on weight very quickly. 

Glivec may cause your body to retain water (severe fluid retention). 

 

While you are taking Glivec, your doctor will regularly check whether the medicine is working. You 

will also have blood tests and be weighed regularly. 

 

Children and adolescents 

Glivec 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, GIST and HES/CEL. 

 

Some children and adolescents taking Glivec may have slower than normal growth. The doctor will 

monitor the growth at regular visits. 

 

Other medicines and Glivec 

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 Glivec 

when taken together. They may increase or decrease the effect of Glivec, either leading to increased 

side effects or making Glivec less effective. Glivec may do the same to some other medicines. 

 



97 

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. 

- Glivec 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 Glivec during pregnancy. 

- Women who might become pregnant are advised to use effective contraception during treatment 
and for 15 days after ending treatment. 

- Do not breast-feed during the treatment with Glivec and for 15 days after ending treatment, as it 
may harm your baby. 

- Patients who are concerned about their fertility while taking Glivec are advised to consult with 
their doctor. 

 

Driving and using machines 
You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not 

drive or use any tools or machines until you are feeling well again. 

 

 

3. How to take Glivec 
 

Your doctor has prescribed Glivec because you suffer from a serious condition. Glivec 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 Glivec 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 Glivec to take 

 

Use in adults 
Your doctor will tell you exactly how many capsules of Glivec to take. 

 

 If you are being treated for CML: 
Depending on your condition the usual starting dose is either 400 mg or 600 mg: 

- 400 mg to be taken as 4 capsules once a day. 
- 600 mg to be taken as 6 capsules once a day. 

 

 If you are being treated for GIST: 
The starting dose is 400 mg, to be taken as 4 capsules once a day. 

 

For CML and GIST, 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. 

 

 If you are being treated for MDS/MPD: 
The starting dose is 400 mg, to be taken as 4 capsules once a day. 

  



98 

 

 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 Glivec to give to your child. The amount of Glivec 

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 Glivec 

- Take Glivec with a meal. This will help protect you from stomach problems when taking 
Glivec. 

- 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 Glivec 

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

 

If you take more Glivec 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 Glivec 

- 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. Glivec may cause your body to retain water (severe fluid retention). 

 Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Glivec 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). 
 



99 

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. 

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

 Swelling such as round your ankles or puffy eyes. 



100 

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

 

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

 Anorexia, weight loss or a disturbed sense of taste. 

 Feeling dizzy or weak. 

 Difficulty in sleeping (insomnia). 

 Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or 
having blurred vision. 

 Nose bleeds. 

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

 Itching. 

 Unusual hair loss or thinning. 

 Numbness of the hands or feet. 

 Mouth ulcers. 

 Joint pain with swelling. 

 Dry mouth, dry skin or dry eye. 

 Decreased or increased skin sensitivity. 

 Hot flushes, chills or night sweats. 
If any of these affects you severely, tell your doctor. 

 

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

 Reddening and/or swelling on the palms of the hands and soles of the feet which may be 
accompanied by tingling sensation and burning pain. 

 Painful and/or blistering skin lesions. 

 Slowing of growth in children and adolescents. 
If any of these affects you severely, tell your doctor. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

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 Glivec 
 

 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 after EXP. 

 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 
 

What Glivec contains 

- The active substance is imatinib mesilate. Each capsule of Glivec contains 100 mg imatinib (as 
mesilate). 

- The other ingredients are microcrystalline cellulose, crospovidone, magnesium stearate and 
anhydrous colloidal silica. The capsule shell is composed of gelatin, red iron oxide (E172), 

yellow iron oxide (E172) and titanium dioxide (E171). The printing ink is composed of red iron 

oxide (E172) and shellac. 

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


101 

 

What Glivec looks like and contents of the pack 

Glivec 100 mg capsules are orange to greyish-orange and marked “NVR SI”. They contain a white to 

yellow powder. 

 

They are supplied in packs containing 24, 48, 96, 120 or 180 capsules, but these may not all be 

available in your country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder. 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „Novartis Baltics“ Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 



102 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

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 

 



103 

Package leaflet: Information for the user 

 

Glivec 100 mg film-coated tablets 
imatinib 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects 

 

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 Glivec is and what it is used for 

2. What you need to know before you take Glivec 

3. How to take Glivec 

4. Possible side effects 

5. How to store Glivec 

6. Contents of the pack and other information 

 

 

1. What Glivec is and what it is used for 
 

Glivec 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. 

 

Glivec is a treatment for adults and children for: 

 

- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white 
cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia 

in which certain abnormal white cells (named myeloid cells) start growing out of control. 

- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). 
Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight 

infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal 

white cells (named lymphoblasts) start growing out of control. Glivec inhibits the growth of 

these cells. 

 

Glivec 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. Glivec 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. 

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

- Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It 
arises from uncontrolled cell growth of the supporting tissues of these organs. 

- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin 
in which some cells start growing out of control. Glivec inhibits the growth of these cells. 

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



104 

 

If you have any questions about how Glivec works or why this medicine has been prescribed for you, 

ask your doctor. 

 

 

2. What you need to know before you take Glivec 

 

Glivec 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 Glivec: 
- 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 Glivec. 

 

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 Glivec: 

- 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 Glivec 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 Glivec, 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 Glivec. 

 

You may become more sensitive to the sun while taking Glivec. 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 Glivec, tell your doctor straight away if you put on weight very quickly. 

Glivec may cause your body to retain water (severe fluid retention). 

 

While you are taking Glivec, your doctor will regularly check whether the medicine is working. You 

will also have blood tests and be weighed regularly. 

 

Children and adolescents 

Glivec 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, GIST and HES/CEL. 

 

Some children and adolescents taking Glivec may have slower than normal growth. The doctor will 

monitor the growth at regular visits. 

 

Other medicines and Glivec 

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 Glivec 

when taken together. They may increase or decrease the effect of Glivec, either leading to increased 

side effects or making Glivec less effective. Glivec may do the same to some other medicines. 

 



105 

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. 

- Glivec 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 Glivec during pregnancy. 

- Women who might become pregnant are advised to use effective contraception during treatment 
and for 15 days after ending treatment. 

- Do not breast-feed during the treatment with Glivec and for 15 days after ending treatment, as it 
may harm your baby. 

- Patients who are concerned about their fertility while taking Glivec are advised to consult with 
their doctor. 

 

Driving and using machines 
You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not 

drive or use any tools or machines until you are feeling well again. 

 

 

3. How to take Glivec 
 

Your doctor has prescribed Glivec because you suffer from a serious condition. Glivec 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 Glivec 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 Glivec to take 

 

Use in adults 

Your doctor will tell you exactly how many tablets of Glivec to take. 

 

- If you are being treated for CML: 
Depending on your condition the usual starting dose is either 400 mg or 600 mg: 

- 400 mg to be taken as 4 tablets once a day, 
- 600 mg to be taken as 6 tablets once a day. 

 

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

 

For CML and GIST, your doctor may prescribe a higher or lower dose depending on how you respond 

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

4 tablets in the evening. 

 

- 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. 

  



106 

 

- 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 Glivec to give to your child. The amount of Glivec 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 Glivec 

- Take Glivec with a meal. This will help protect you from stomach problems when taking 
Glivec. 

- Swallow the tablets whole with a large glass of water. 
 

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

 Use about 50 ml for each 100 mg tablet. 

 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 Glivec 

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

 

If you take more Glivec 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 Glivec 

- 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. Glivec may cause your body to retain water (severe fluid retention). 

 Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Glivec 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). 
 



107 

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. 

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

 Swelling such as round your ankles or puffy eyes. 



108 

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

 

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

 Anorexia, weight loss or a disturbed sense of taste. 

 Feeling dizzy or weak. 

 Difficulty in sleeping (insomnia). 

 Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or 
having blurred vision. 

 Nose bleeds. 

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

 Itching. 

 Unusual hair loss or thinning. 

 Numbness of the hands or feet. 

 Mouth ulcers. 

 Joint pain with swelling. 

 Dry mouth, dry skin or dry eye. 

 Decreased or increased skin sensitivity. 

 Hot flushes, chills or night sweats. 
If any of these affects you severely, tell your doctor. 

 

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

 Reddening and/or swelling on the palms of the hands and soles of the feet which may be 
accompanied by tingling sensation and burning pain. 

 Painful and/or blistering skin lesions. 

 Slowing of growth in children and adolescents. 
If any of these affects you severely, tell your doctor. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

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 Glivec 
 

 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 after EXP. 

 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 
 

What Glivec contains 

- The active substance is imatinib mesilate. Each tablet of Glivec contains 100 mg imatinib (as 
mesilate). 

- The other ingredients are microcrystalline cellulose, crospovidone, hypromellose, magnesium 
stearate and anhydrous colloidal silica. 

- The tablet coating is made of red iron oxide (E172), yellow iron oxide (E172), macrogol, talc 
and hypromellose. 

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


109 

 

What Glivec looks like and contents of the pack 

Glivec 100 mg film-coated tablets are very dark yellow to brownish-orange round tablets. They have 

“NVR” on one side and “SA” and a score line on the other side. 

 

They are supplied in packs containing 20, 60, 120 or 180 tablets, but these may not all be available in 

your country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Lek d.d, PE PROIZVODNJA LENDAVA 

Trimlini 2D 

Lendava, 9220 

Slovenia 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder. 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „Novartis Baltics“ Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 



110 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

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 

 



111 

Package leaflet: Information for the user 

 

Glivec 400 mg film-coated tablets 
imatinib 

 

This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 

for how to report side effects 

 

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 Glivec is and what it is used for 

2. What you need to know before you take Glivec 

3. How to take Glivec 

4. Possible side effects 

5. How to store Glivec 

6. Contents of the pack and other information 

 

 

1. What Glivec is and what it is used for 
 

Glivec 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. 

 

Glivec is a treatment for adults and children for: 

 

- Chronic myeloid leukaemia (CML). Leukaemia is a cancer of white blood cells. These white 
cells usually help the body to fight infection. Chronic myeloid leukaemia is a form of leukaemia 

in which certain abnormal white cells (named myeloid cells) start growing out of control. 

- Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph-positive ALL). 
Leukaemia is a cancer of white blood cells. These white cells usually help the body to fight 

infection. Acute lymphoblastic leukaemia is a form of leukaemia in which certain abnormal 

white cells (named lymphoblasts) start growing out of control. Glivec inhibits the growth of 

these cells. 

 

Glivec 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. Glivec 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. 

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

- Gastrointestinal stromal tumours (GIST). GIST is a cancer of the stomach and bowels. It 
arises from uncontrolled cell growth of the supporting tissues of these organs. 

- Dermatofibrosarcoma protuberans (DFSP). DFSP is a cancer of the tissue beneath the skin 
in which some cells start growing out of control. Glivec inhibits the growth of these cells. 

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



112 

 

If you have any questions about how Glivec works or why this medicine has been prescribed for you, 

ask your doctor. 

 

 

2. What you need to know before you take Glivec 

 

Glivec 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 Glivec: 
- 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 Glivec. 

 

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 Glivec: 

- 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 Glivec 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 Glivec, 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 Glivec. 

 

You may become more sensitive to the sun while taking Glivec. 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 Glivec, tell your doctor straight away if you put on weight very quickly. 

Glivec may cause your body to retain water (severe fluid retention). 

 

While you are taking Glivec, your doctor will regularly check whether the medicine is working. You 

will also have blood tests and be weighed regularly. 

 

Children and adolescents 

Glivec 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, GIST and HES/CEL. 

 

Some children and adolescents taking Glivec may have slower than normal growth. The doctor will 

monitor the growth at regular visits. 

 

Other medicines and Glivec 

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 Glivec 

when taken together. They may increase or decrease the effect of Glivec, either leading to increased 

side effects or making Glivec less effective. Glivec may do the same to some other medicines. 

 



113 

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. 

- Glivec 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 Glivec during pregnancy. 

- Women who might become pregnant are advised to use effective contraception during treatment 
and for 15 days after ending treatment. 

- Do not breast-feed during the treatment with Glivec and for 15 days after ending treatment, as it 
may harm your baby. 

- Patients who are concerned about their fertility while taking Glivec are advised to consult with 
their doctor. 

 

Driving and using machines 
You may feel dizzy or drowsy or get blurred vision while taking this medicine. If this happens, do not 

drive or use any tools or machines until you are feeling well again. 

 

 

3. How to take Glivec 
 

Your doctor has prescribed Glivec because you suffer from a serious condition. Glivec 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 Glivec 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 Glivec to take 

 

Use in adults 
Your doctor will tell you exactly how many tablets of Glivec to take. 

 

 If you are being treated for CML: 
Depending on your condition the usual starting dose is either 400 mg or 600 mg: 

- 400 mg to be taken as one tablet once a day, 
- 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 GIST: 
The starting dose is 400 mg, to be taken as one tablet once a day. 

 

For CML and GIST, your doctor may prescribe a higher or lower dose depending on how you respond 

to the treatment. If your daily dose is 800 mg (2 tablets), you should take one tablet in the morning and 

a second tablet in the evening. 

 

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

  



114 

 

- 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 Glivec to give to your child. The amount of Glivec 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 Glivec 

- Take Glivec with a meal. This will help protect you from stomach problems when taking 
Glivec. 

- Swallow the tablets whole with a large glass of water. 
 

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

 Use about 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 Glivec 

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

 

If you take more Glivec 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 Glivec 

- 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. Glivec may cause your body to retain water (severe fluid retention). 

 Signs of infection such as fever, severe chills, sore throat or mouth ulcers. Glivec 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). 
 



115 

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. 

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

 Swelling such as round your ankles or puffy eyes. 



116 

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

 

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

 Anorexia, weight loss or a disturbed sense of taste. 

 Feeling dizzy or weak. 

 Difficulty in sleeping (insomnia). 

 Discharge from the eye with itching, redness and swelling (conjunctivitis), watery eyes or 
having blurred vision. 

 Nose bleeds. 

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

 Itching. 

 Unusual hair loss or thinning. 

 Numbness of the hands or feet. 

 Mouth ulcers. 

 Joint pain with swelling. 

 Dry mouth, dry skin or dry eye. 

 Decreased or increased skin sensitivity. 

 Hot flushes, chills or night sweats. 
If any of these affects you severely, tell your doctor. 

 

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

 Reddening and/or swelling on the palms of the hands and soles of the feet which may be 
accompanied by tingling sensation and burning pain. 

 Painful and/or blistering skin lesions. 

 Slowing of growth in children and adolescents. 
If any of these affects you severely, tell your doctor. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

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 Glivec 
 

 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 after EXP. 

 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 
 

What Glivec contains 

- The active substance is imatinib mesilate. Each tablet of Glivec contains 400 mg imatinib (as 
mesilate). 

- The other ingredients are microcrystalline cellulose, crospovidone, hypromellose, magnesium 
stearate and anhydrous colloidal silica. 

- The tablet coating is made of red iron oxide (E172), yellow iron oxide (E172), macrogol, talc 
and hypromellose. 

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


117 

 

What Glivec looks like and contents of the pack 

Glivec 400 mg film-coated tablets are very dark yellow to brownish-orange oval tablets. They have 

“glivec” on one side. 

 

They are supplied in packs containing 10, 30 or 90 tablets, but these may not all be available in your 

country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Lek d.d, PE PROIZVODNJA LENDAVA 

Trimlini 2D 

Lendava, 9220 

Slovenia 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder. 

 

België/Belgique/Belgien 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 

SIA „Novartis Baltics“ Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 

Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 

Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 

Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 

Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 

Novartis Pharma B.V. 

Tel: +31 26 37 82 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 

Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 

Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 

Novartis Pharma GmbH 

Tel: +43 1 86 6570 



118 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 

Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 

Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 

Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 

Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 

Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA “Novartis Baltics” 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

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 

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