Mavec 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 plateletderived growth factor receptor (PDGFR) gene re-arrangements.

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

(CEL) with FIP1L1-PDGFRα rearrangement.

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

Mavec 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 Mavec 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 recurrencefree survival in adjuvant GIST. The experience with Mavec 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.

administration

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

malignancies and malignant sarcomas, as appropriate.

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

available.

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

is available.

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

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

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

For patients unable to swallow the film-coated tablets, the tablets may be dispersed in a glass of 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 Mavec 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 Mavec 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 Mavec 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 Mavec was continued until disease progression. The

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

investigated.

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

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

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

neutropenia or thrombocytopenia in the following circumstances: disease progression (at any time);

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

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

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

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

Posology for CML in 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 Mavec 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, Mavec 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 Mavec therapy can vary with the treatment programme selected, but

generally longer exposures to Mavec have yielded better results.

For adult patients with relapsed or refractory Ph+ALL Mavec 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 Mavec is 400 mg/day for adult patients with MDS/MPD.

Treatment duration: In the only clinical trial performed up to now, treatment with Mavec 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 Mavec 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 Mavec 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 Mavec 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 Mavec 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 Mavec 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 Mavec 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, Mavec should be withheld until bilirubin levels have returned to < 1.5 x IULN and transaminase

levels to < 2.5 x IULN. Treatment with Mavec 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.

When Mavec is co-administered with other medicinal products, there is a potential for drug interactions.

Caution should be used when taking Mavec 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 Mavec, 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 Mavec (see section 4.5). Thyroid-stimulating hormone (TSH) levels

should be closely monitored in such patients.

Hepatotoxicity

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

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

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

hepatic metastases which could lead to hepatic impairment.

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

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

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

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

(see section 4.5 and 4.8).

Fluid retention

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

oedema) have been reported in approximately 2.5% of newly diagnosed CML patients taking Mavec.

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 Mavec 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 Mavec (see

section 4.8).

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these

patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or

fulminant hepatitis leading to liver transplantation or a fatal outcome.

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

monitored for signs and symptoms of active HBV infection throughout therapy and for several months

following termination of therapy (see section 4.8).

Laboratory tests

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

patients with Mavec 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 Mavec 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 Mavec.

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. The long-term effects of prolonged treatment with imatinib on growth in children are unknown.

Therefore, close monitoring of growth in children under imatinib treatment is recommended (see section

4.8)

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 Mavec

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 Mavec, potentially increasing the risk of therapeutic failure.

Pretreatment with multiple doses of rifampicin 600 mg followed by a single 400 mg dose of Mavec

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 Mavec

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 Mavec

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 Mavec with CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine,

pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil, terfenadine, bortezomib,

docetaxel and quinidine). Mavec 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 Mavec 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, Mavec inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/l. This inhibition has

not been observed in vivo after the administration of Mavec 400 mg and paracetamol 1000 mg. Higher

doses of Mavec and paracetamol have not been studied.

Caution should therefore be exercised when using high doses of Mavec and paracetamol concomitantly.

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

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

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

In Ph+ ALL patients, there is clinical experience of co-administering Mavec 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 Mavec in combination requires special precaution.

Pregnancy Category: D

Women of childbearing potential

Women of childbearing potential must be advised to use effective contraception during treatment.

Pregnancy

There are limited data on the use of imatinib in pregnant women. There have been post-marketing reports

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

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

is unknown. Mavec should not be used during pregnancy unless clearly necessary. If it is used during

pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding

There is limited information on imatinib distribution on human milk. Studies in two breast-feeding women

revealed that both imatinib and its active metabolite can be distributed into human milk. The milk plasma

ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for the metabolite,

suggesting greater distribution of the metabolite into the milk. Considering the combined concentration of

imatinib and the metabolite and the maximum daily milk intake by infants, the total exposure would be

expected to be low (~10% of a therapeutic dose). However, since the effects of low-dose exposure of the

infant to imatinib are unknown, women taking imatinib should not breast-feed.

Fertility

In non-clinical studies, the fertility of male and female rats was not affected (see section 5.3). Studies on

patients receiving Mavec and its effect on fertility and gametogenesis have not been performed. Patients

concerned about their fertility on Mavec treatment should consult with their physician.

a. Summary of the safety profile

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

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

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

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

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

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

of interferon therapy. In GIST the study drug was discontinued for drug-related adverse reactions in 4% of

patients.

The adverse reactions were similar in all indications, with two exceptions. There was more

myelosuppression seen in CML patients than in GIST, which is probably due to the underlying disease. In

the study in patients with unresectable and/or metastatic GIST, 7 (5%) patients experienced CTC grade

3/4 GI bleeds (3 patients), intra-tumoural bleeds (3 patients) or both (1 patient). GI tumour sites may have

been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may be serious and

sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions in both settings

were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle cramps and rash.

Superficial oedemas were a common finding in all studies and were described primarily as periorbital or

lower limb oedemas. However, these oedemas were rarely severe and may be managed with diuretics,

other supportive measures, or by reducing the dose of Mavec.

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 Mavec 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).

b. Tabulated summary of adverse reactions

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.

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 Mavec, 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.

c. 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).

d. Paediatric population

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.

e. Other special populations

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).

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.

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

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.

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

Mechanism of action

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

tyrosine kinase (TK), as well as several receptor TKs: Kit, the receptor for stem cell factor (SCF) coded for

by the c-Kit proto-oncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating

factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha

and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation of these receptor

kinases.

Pharmacodynamic effects

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

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

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

and acute lymphoblastic leukaemia (ALL) patients.

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

positive tumour cells.

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

PDGF-R, and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. 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 Mavec 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 Mavec 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 Mavec 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 Mavec and IFN arms, respectively. The median duration of second-line treatment with

Mavec was 64 months. Overall, in patients receiving first-line Mavec, 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.

Pharmacokinetics of Mavec
The pharmacokinetics of Mavec 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 vitroexperiments, 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. Kivalues in human liver microsomes were 27, 7.5 and 7.9 μmol/l, respectively. Maximal
plasma concentrations of imatinib in patients are 2–4 μmol/l, consequently an inhibition of CYP2D6 and/or
CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib did not interfere with the
biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as a result of competitive
inhibition of CYP2C8 (Ki = 34.7 µM). This Ki value is far higher than the expected plasma levels of
imatinib in patients, consequently no interaction is expected upon co-administration of either 5-fluorouracil
or paclitaxel and imatinib.
Elimination
Based on the recovery of compound(s) after an oral 14C-labelled dose of imatinib, approximately 81% of
the dose was recovered within 7 days in faeces (68% of dose) and urine (13% of dose). Unchanged
imatinib accounted for 25% of the dose (5% urine, 20% faeces), the remainder being metabolites.
Plasma pharmacokinetics
Following oral administration in healthy volunteers, the t½ was approximately 18 h, suggesting that oncedaily 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.
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)
 

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. F1fertility was not affected, while an

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

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

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

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

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

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

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

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

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

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

times the average paediatric exposure at the highest recommended dose of 340 mg/m2. In addition,

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

paediatric exposure at the highest recommended dose of 340 mg/m2.

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

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

Histopathological examination of decedents revealed cardiomyopathy (both sexes), chronic progressive

nephropathy (females) and preputial gland papilloma as principal causes of death or reasons for sacrifice.

Target organs for neoplastic changes were the kidneys, urinary bladder, urethra, preputial and clitoral

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

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

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

respectively, and 0.4 times the daily exposure in children (based on AUC) at 340 mg/m2/day. The no

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

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

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

papillomas/carcinomas were noted at 60 mg/kg/day, representing approximately 1.7 or 1 times the human

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

exposure in children (based on AUC) at 340 mg/m2/day. The no observed effect level (NOEL) was 30

mg/kg/day.

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.

Core Tablet:

• Sodium stearyl fumarate

Film Coating (Opadry Brown):

• Talc

• Hydroxypropyl cellulose

• Iron oxide yellow

• Iron oxide red

Not Applicable

Do not store above 30o C
Store in the original package in order to protect from moisture

MAVEC tablets are packed in Aluminum/ Aluminum blisters in pack of 30 tablets

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