IMATINIB ACTAVIS 100mg capsules medication leaflet

Imatinib Actavis 50 mg hard capsules

Imatinib Actavis 100 mg hard capsules

Imatinib Actavis 400 mg hard capsules

Imatinib Actavis 50 mg hard capsules

Each hard capsule contains 50 mg imatinib (as mesilate).

Imatinib Actavis 100 mg hard capsules

Each hard capsule contains 100 mg imatinib (as mesilate).

Imatinib Actavis 400 mg hard capsules

Each hard capsule contains 400 mg imatinib (as mesilate).

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Imatinib Actavis 50 mg hard capsules

Hard capsule of size 3 with light yellow cap and light yellow body imprinted with “50 mg” in blackink.

Imatinib Actavis 100 mg hard capsules

Hard capsule of size 1 with light orange cap and light orange body imprinted with “100 mg” in blackink.

Imatinib Actavis 400 mg hard capsules

Hard capsule of size 00 with orange opaque colour cap and body imprinted with “400 mg” in blackink.

Imatinib Actavis is indicated for the treatment of

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

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

- adult patients with Ph+ CML in blast crisis.

- adult and paediatric patients with newly diagnosed Philadelphia chromosome positive acutelymphoblastic 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 withplatelet-derived growth factor receptor (PDGFR) gene re-arrangements.

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

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

Imatinib Actavis is indicated for

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

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

Therapy should be initiated by a physician experienced in the treatment of patients withhaematological malignancies and malignant sarcomas, as appropriate.

Posology for CML in adult patients

The recommended dose of imatinib is 600 mg/day for adult patients in blast crisis. Blast crisis isdefined as blasts ≥ 30% in blood or bone marrow or extramedullary disease other thanhepatosplenomegaly.

Treatment duration: In clinical trials, treatment with imatinib was continued until disease progression.

The effect of stopping treatment after the achievement of a complete cytogenetic response has notbeen investigated.

Dose increases from 600 mg to a maximum of 800 mg (given as 400 mg twice daily) in patients withblast crisis may be considered in the absence of severe adverse drug reaction and severe non-leukaemia-related neutropenia or thrombocytopenia in the following circumstances: diseaseprogression (at any time); failure to achieve a satisfactory haematological response after at least3 months of treatment; failure to achieve a cytogenetic response after 12 months of treatment; or lossof a previously achieved haematological and/or cytogenetic response. Patients should be monitoredclosely following dose escalation given the potential for an increased incidence of adverse reactions athigher dosages.

Posology for CML in paediatric patients

Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 dailyis recommended for children with chronic phase CML and advanced phase CML (not to exceed thetotal dose of 800 mg). Treatment can be given as a once daily dose or alternatively the daily dose maybe split into two administrations - one in the morning and one in the evening. The doserecommendation 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) maybe 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 anytime); 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 achievedhaematological and/or cytogenetic response. Patients should be monitored closely following doseescalation given the potential for an increased incidence of adverse reactions at higher dosages.

Posology for Ph+ ALL in adult patients

The recommended dose of imatinib is 600 mg/day for adult patients with Ph+ ALL. Haematologicalexperts in the management of this disease should supervise the therapy throughout all phases of care.

Treatment schedule: On the basis of the existing data, imatinib has been shown to be effective and safewhen administered at 600 mg/day in combination with chemotherapy in the induction phase, theconsolidation and maintenance phases of chemotherapy (see section 5.1) for adult patients with newlydiagnosed Ph+ ALL. The duration of imatinib therapy can vary with the treatment programmeselected, but generally longer exposures to imatinib have yielded better results.

For adult patients with relapsed or refractory Ph+ALL imatinib monotherapy at 600 mg/day is safe,effective and can be given until disease progression occurs.

Posology for Ph+ ALL in paediatric patients

Dosing for children should be on the basis of body surface area (mg/m2). The dose of 340 mg/m2 dailyis recommended for children with Ph+ ALL (not to exceed the total dose of 600 mg).

Posology for MDS/MPD

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

Treatment duration: In the only clinical trial performed up to now, treatment with imatinib wascontinued until disease progression (see section 5.1). At the time of analysis, the treatmentduration was a median of 47 months (24 days - 60 months).

Posology for HES/CEL

The recommended dose of imatinib is 100 mg/day for adult patients with HES/CEL.

Dose increase from 100 mg to 400 mg may be considered in the absence of adverse drug reactionsif assessments demonstrate an insufficient response to therapy.

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

Posology for DFSP

The recommended dose of imatinib is 800 mg/day for adult patients with DFSP.

Dose adjustment for adverse reactions

Non-haematological adverse reactions

If a severe non-haematological adverse reaction develops with imatinib use, treatment must bewithheld until the event has resolved. Thereafter, treatment can be resumed as appropriate dependingon the initial severity of the event.

If elevations in bilirubin > 3 x institutional upper limit of normal (IULN) or in liver transaminases> 5 x IULN occur, imatinib should be withheld until bilirubin levels have returned to < 1.5 x IULNand transaminase levels to < 2.5 x IULN. Treatment with imatinib may then be continued at a reduceddaily dose. In adults the dose should be reduced from 400 to 300 mg or from 600 to 400 mg, or from800 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 arerecommended as indicated in the table below.

Dose adjustments for neutropenia and thrombocytopenia:

HES/CEL (starting dose ANC < 1.0 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/L100 mg) and/or and platelets ≥ 75 x 109/L.

platelets < 50 x 109/L 2. Resume treatment with imatinib atprevious dose (i.e. before severeadverse reaction).

MDS/MPD (starting ANC < 1.0 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/Ldose 400 mg) and/or and platelets ≥ 75 x 109/L.

HES/CEL (at dose platelets < 50 x 109/L 2. Resume treatment with imatinib at400 mg) previous dose (i.e. before severeadverse reaction).3. In the event of recurrence of ANC< 1.0 x 109/L and/or platelets< 50 x 109/L, repeat step 1 andresume imatinib at reduced dose of300 mg.

Paediatric chronic phase ANC < 1.0 x 109/L 1. Stop imatinib until ANC

CML (at dose and/or ≥ 1.5 x 109/L and platelets340 mg/m2) platelets < 50 x 109/L ≥ 75 x 109/L.

2. Resume treatment with imatinib atprevious dose (i.e. before severeadverse reaction).

3. In the event of recurrence of ANC< 1.0 x 109/L and/or platelets< 50 x 109/L, repeat step 1 andresume imatinib at reduced dose of260 mg/m2.

CML in blast crisis and aANC < 0.5 x 109/L 1. Check whether cytopenia is related

Ph+ ALL (starting dose and/or to leukaemia (marrow aspirate or600 mg) platelets < 10 x 109/L biopsy).

2. If cytopenia is unrelated toleukaemia, reduce dose of imatinibto 400 mg.

3. If cytopenia persists for 2 weeks,reduce further to 300 mg.

4. If cytopenia persists for 4 weeks andis still unrelated to leukaemia, stopimatinib until ANC ≥ 1 x 109/L andplatelets ≥ 20 x 109/L, then resumetreatment at 300 mg.

Paediatric accelerated aANC < 0.5 x 109/L 1. Check whether cytopenia is relatedphase CML and blast and/or to leukaemia (marrow aspirate orcrisis (starting dose platelets < 10 x 109/L biopsy).340 mg/m2) 2. If cytopenia is unrelated toleukaemia, reduce dose of imatinibto 260 mg/m2.

3. If cytopenia persists for 2 weeks,reduce further to 200 mg/m2.

4. If cytopenia persists for 4 weeks andis still unrelated to leukaemia, stopimatinib until ANC ≥ 1 x 109/L andplatelets ≥ 20 x 109/L, then resumetreatment at 200 mg/m2.

DFSP (at dose 800 mg) ANC < 1.0 x 109/L 1. Stop imatinib until ANC ≥ 1.5 x 109/Land/or and platelets ≥ 75 x 109/L.platelets < 50 x 109/L 2. Resume treatment with imatinib at600 mg.3. In the event of recurrence of ANC< 1.0 x 109/L and/or platelets< 50 x 109/L, repeat step 1 andresume imatinib at reduced dose of400 mg.

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

Paediatric use: There is no experience in children with CML below 2 years of age and with Ph+ALLbelow 1 year of age (see section 5.1).There is very limited experience in children with MDS/MPD,

DFSP, and HES/CEL.

The safety and efficacy of imatinib in children with MDS/MPD, DFSP and HES/CEL aged less than18 years of age have not been established in clinical trials. Currently available published data aresummarised 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, moderateor severe liver dysfunction should be given the minimum recommended dose of 400 mg daily. Thedose can be reduced if not tolerated (see sections 4.4, pct. 4.8 and 5.2).

Liver dysfunction classification:

Liver dysfunction Liver function tests

Mild Total bilirubin: = 1.5 ULN

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

Moderate Total bilirubin: >1.5-3.0 ULN

AST: any

Severe Total bilirubin: >3-10 ULN

AST: any

ULN = upper limit of normal for the institution

AST = aspartate aminotransferase

Renal insufficiency: Patients with renal dysfunction or on dialysis should be given the minimumrecommended dose of 400 mg daily as starting dose. However, in these patients caution isrecommended. The dose can be reduced if not tolerated. If tolerated, the dose can be increased for lackof efficacy (see sections 4.4 and 5.2).

Elderly patients: Imatinib pharmacokinetics have not been specifically studied in older people. Nosignificant age-related pharmacokinetic differences have been observed in adult patients in clinicaltrials which included over 20% of patients age 65 and older. No specific dose recommendation isnecessary in older people.

The prescribed dose should be administered orally with a meal and a large glass of water to minimisethe 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 inthe evening.

For patients (children) unable to swallow the capsules, their content may be diluted in a glass of eitherstill water or apple juice. Since studies in animals have shown reproductive toxicity, and the potentialrisk for the human foetus is unknown, women of child-bearing potential who open capsules should beadvised 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.

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

When imatinib is co-administered with other medicinal products, there is a potential for druginteractions. Caution should be used when taking imatinib with protease inhibitors, azole antifungals,certain macrolides (see section 4.5), CYP3A4 substrates with a narrow therapeutic window (e.g.cyclosporine, pimozide tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil,terfenadine, bortezomib, docetaxel, quinidine) or warfarin and other coumarin derivatives (seesection 4.5).

Concomitant use of imatinib and medicinal products that induce CYP3A4 (e.g. dexamethasone,phenytoin, carbamazepine, rifampicin, phenobarbital or Hypericum perforatum, also known as St.

John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk oftherapeutic failure. Therefore, concomitant use of strong CYP3A4 inducers and imatinib should beavoided (see section 4.5).

Clinical cases of hypothyroidism have been reported in thyroidectomy patients undergoinglevothyroxine replacement during treatment with imatinib (see section 4.5). Thyroid stimulatinghormone (TSH) levels should be closely monitored in such patients.

Metabolism of imatinib is mainly hepatic, and only 13% of excretion is through the kidneys. Inpatients with hepatic dysfunction (mild, moderate or severe), peripheral blood counts and liverenzymes should be carefully monitored (see sections 4.2, pct. 4.8 and 5.2). It should be noted that GISTpatients 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 hepaticreactions has been detected. Hepatic function should be carefully monitored in circumstances whereimatinib is combined with chemotherapy regimens also known to be associated with hepaticdysfunction (see sections 4.5 and 4.8).

Fluid retention

Occurrences of severe fluid retention (pleural effusion, oedema, pulmonary oedema, ascites,superficial oedema) have been reported in approximately 2.5% of newly diagnosed CML patientstaking imatinib. Therefore, it is highly recommended that patients be weighed regularly. Anunexpected rapid weight gain should be carefully investigated and if necessary appropriate supportivecare and therapeutic measures should be undertaken. In clinical trials, there was an increased incidenceof these events in elderly patients and those with a prior history of cardiac disease. Therefore, cautionshould 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 bemonitored carefully, and any patient with signs or symptoms consistent with cardiac or renal failureshould be evaluated and treated.

In patients with hypereosinophilic syndrome (HES) with occult infiltration of HES cells within themyocardium, isolated cases of cardiogenic shock/left ventricular dysfunction have been associatedwith HES cell degranulation upon the initiation of imatinib therapy. The condition was reported to bereversible with the administration of systemic steroids, circulatory support measures and temporarilywithholding imatinib. As cardiac adverse events have been reported uncommonly with imatinib, acareful assessment of the benefit/risk of imatinib therapy should be considered in the HES/CELpopulation before treatment initiation.

Myelodysplastic/myeloproliferative diseases with PDGFR gene re-arrangements could be associatedwith high eosinophil levels. Evaluation by a cardiology specialist, performance of an echocardiogramand determination of serum troponin should therefore be considered in patients with HES/CEL, and inpatients with MDS/MPD associated with high eosinophil levels before imatinib is administered. Ifeither 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 oftherapy.

Gastrointestinal haemorrhage

In the study in patients with unresectable and/or metastatic GIST, both gastrointestinal andintra-tumoural haemorrhages were reported (see section 4.8). Based on the available data, nopredisposing factors (e.g. tumour size, tumour location, coagulation disorders) have been identifiedthat place patients with GIST at a higher risk of either type of haemorrhage. Since increasedvascularity and propensity for bleeding is a part of the nature and clinical course of GIST, standardpractices and procedures for the monitoring and management of haemorrhage in all patients should beapplied.

In addition, gastric antral vascular ectasia (GAVE), a rare cause of gastrointestinal haemorrhage, hasbeen reported in post-marketing experience in patients with CML, ALL and other diseases (seesection 4.8). When needed, discontinuation of imatinib treatment may be considered.

Due to the possible occurrence of tumour lysis syndrome (TLS), correction of clinically significantdehydration and treatment of high uric acid levels are recommended prior to initiation of imatinib (seesection 4.8).

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after thesepatients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure orfulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with Imatinib Actavis. Expertsin liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated inpatients with positive hepatitis B serology (including those with active disease) and for patients whotest positive for HBV infection during treatment. Carriers of HBV who require treatment with Imatinib

Actavis should be closely monitored for signs and symptoms of active HBV infection throughouttherapy and for several months following termination of therapy (see section 4.8).

Exposure to direct sunlight should be avoided or minimised due to the risk of phototoxicity associatedwith imatinib treatment. Patients should be instructed to use measures such as protective clothing andsunscreen with high sun protection factor (SPF).

Thrombotic microangiopathy

BCR-ABL tyrosine kinase inhibitors (TKIs) have been associated with thrombotic microangiopathy(TMA), including individual case reports for Imatinib Actavis (see section 4.8). If laboratory orclinical findings associated with TMA occur in a patient receiving Imatinib Actavis, treatment shouldbe discontinued and thorough evaluation for TMA, including ADAMTS13 activity and anti-

ADAMTS13-antibody determination, should be completed. If anti-ADAMTS13-antibody is elevatedin conjunction with low ADAMTS13 activity, treatment with Imatinib Actavis should not be resumed.

Complete blood counts must be performed regularly during therapy with imatinib. Treatment of CMLpatients with imatinib has been associated with neutropenia or thrombocytopenia. However, theoccurrence of these cytopenias is likely to be related to the stage of the disease being treated and theywere more frequent in patients with accelerated phase CML or blast crisis as compared to patients withchronic phase CML. Treatment with imatinib may be interrupted or the dose may be reduced, asrecommended in section 4.2.

Liver function (transaminases, bilirubin, alkaline phosphatase) should be monitored regularly inpatients receiving imatinib.

In patients with impaired renal function, imatinib plasma exposure seems to be higher than that inpatients with normal renal function, probably due to an elevated plasma level of alpha-acidglycoprotein (AGP), an imatinib-binding protein, in these patients. Patients with renal impairmentshould be given the minimum starting dose. Patients with severe renal impairment should be treatedwith caution. The dose can be reduced if not tolerated (see sections 4.2 and 5.2).

Long-term treatment with imatinib may be associated with a clinically significant decline in renalfunction. Renal function should, therefore, be evaluated prior to the start of imatinib therapy andclosely monitored during therapy, with particular attention to those patients exhibiting risk factors forrenal dysfunction. If renal dysfunction is observed, appropriate management and treatment should beprescribed in accordance with standard treatment guidelines.

There have been case reports of growth retardation occurring in children and pre-adolescents receivingimatinib. In an observational study in the CML paediatric population, a statistically significantdecrease (but of uncertain clinical relevance) in median height standard deviation scores after 12 and24 months of treatment was reported in two small subsets irrespective of pubertal status or gender.

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

Excipients(s)

This medicinal product contains less than 1 mmol sodium (23 mg) per hard capsule, that is to sayessentially ‘sodium-free’.

Active substances that may increase imatinib plasma concentrations:

Substances that inhibit the cytochrome P450 isoenzyme CYP3A4 activity (e.g. protease inhibitorssuch as indinavir, lopinavir/ritonavir, ritonavir, saquinavir, telaprevir, nelfinavir, boceprevir; azoleantifungals including ketoconazole, itraconazole, posaconazole, voriconazole; certain macrolides suchas erythromycin, clarithromycin and telithromycin) could decrease metabolism and increase imatinibconcentrations. There was a significant increase in exposure to imatinib (the mean Cmax and AUC ofimatinib rose by 26% and 40%, respectively) in healthy subjects when it was co-administered with asingle dose of ketoconazole (a CYP3A4 inhibitor). Caution should be taken when administeringimatinib with inhibitors of the CYP3A4 family.

Active substances that may decrease imatinib plasma concentrations:

Substances that are inducers of CYP3A4 activity e.g. dexamethasone, phenytoin, carbamazepine,rifampicin, phenobarbital, fosphenytoin, primidone or Hypericum perforatum, also known as

St. John’s Wort) may significantly reduce exposure to imatinib, potentially increasing the risk oftherapeutic failure. Pretreatment with multiple doses of rifampicin 600 mg followed by a single400 mg dose of imatinib resulted in decrease in Cmax and AUC(0-∞) by at least 54% and 74%, of therespective values without rifampicin treatment. Similar results were observed in patients withmalignant gliomas treated with imatinib while taking enzyme-inducing anti-epileptic medicinalproducts (EIAEDs) such as carbamazepine, oxcarbazepine and phenytoin. The plasma AUC forimatinib decreased by 73% compared to patients not on EIAEDs. Concomitant use of rifampicin orother strong CYP3A4 inducers and imatinib should be avoided.

Active substances that may have their plasma concentration altered by imatinib

Imatinib increases the mean Cmax and AUC of simvastatin (CYP3A4 substrate) 2- and 3.5-fold,respectively, indicating an inhibition of the CYP3A4 by imatinib. Therefore, caution is recommendedwhen administering imatinib with CYP3A4 substrates with a narrow therapeutic window (e.g.cyclosporine, pimozide, tacrolimus, sirolimus, ergotamine, diergotamine, fentanyl, alfentanil,terfenadine, bortezomib, docetaxel and quinidine). Imatinib may increase plasma concentration ofother CYP3A4 metabolised drugs (e.g. triazolo-benzodiazepines, dihydropyridine calcium channelblockers, 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 standardheparin instead of coumarin derivatives such as warfarin.

In vitro imatinib inhibits the cytochrome P450 isoenzyme CYP2D6 activity at concentrations similarto 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 byapproximately 23% (90%CI [1.16-1.30]). Dose adjustments do not seem to be necessary whenimatinib is co-administrated with CYP2D6 substrates, however caution is advised for CYP2D6substrates with a narrow therapeutic window such as metoprolol. In patients treated with metoprololclinical monitoring should be considered.

In vitro, imatinib inhibits paracetamol O-glucuronidation with Ki value of 58.5 micromol/L. Thisinhibition has not been observed in vivo after the administration of imatinib 400 mg andparacetamol 1000 mg. Higher doses of imatinib and paracetamol have not been studied.

Caution should therefore be exercised when using high doses of imatinib and paracetamolconcomitantly.

In thyroidectomy patients receiving levothyroxine, the plasma exposure to levothyroxine may bedecreased when imatinib is co-administered (see section 4.4). Caution is therefore recommended.

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

In Ph+ ALL patients, there is clinical experience of co-administering imatinib with chemotherapy (seesection 5.1), but drug-drug interactions between imatinib and chemotherapy regimens are not wellcharacterised. Imatinib adverse events, i.e. hepatotoxicity, myelosuppression or others, may increaseand it has been reported that concomitant use with L-asparaginase could be associated with increasedhepatotoxicity (see section 4.8). Therefore, the use of imatinib in combination requires specialprecaution.

Women of childbearing potential must be advised to use effective contraception during treatment andfor at least 15 days after stopping treatment with Imatinib Actavis.

There are limited data on the use of imatinib in pregnant women. There have been post-marketingreports of spontaneous abortions and infant congenital anomalies from women who have takenimatinib. Studies in animals have however shown reproductive toxicity (see section 5.3) and thepotential risk for the foetus is unknown. Imatinib should not be used during pregnancy unless clearlynecessary. If it is used during pregnancy, the patient must be informed of the potential risk to thefoetus.

There is limited information on imatinib distribution on human milk. Studies in two breast-feedingwomen revealed that both imatinib and its active metabolite can be distributed into human milk. Themilk plasma ratio studied in a single patient was determined to be 0.5 for imatinib and 0.9 for themetabolite, suggesting greater distribution of the metabolite into the milk. Considering the combinedconcentration of imatinib and the metabolite and the maximum daily milk intake by infants, the totalexposure would be expected to be low (~10% of a therapeutic dose). However, since the effects oflow-dose exposure of the infant to imatinib are unknown, women should not breast-feed duringtreatment and for at least 15 days after stopping treatment with Imatinib Actavis.

In non-clinical studies, the fertility of male and female rats was not affected, although effects onreproductive parameters were observed (see section 5.3). Studies on patients receiving imatinib and itseffect on fertility and gametogenesis have not been performed. Patients concerned about their fertilityon imatinib treatment should consult with their physician.

Patients should be advised that they may experience undesirable effects such as dizziness,blurredvision or somnolence during treatment with imatinib. Therefore, caution should be recommendedwhen driving a car or operating machinery.

Patients with advanced stages of malignancies may have numerous confounding medical conditionsthat make causality of adverse reactions difficult to assess due to the variety of symptoms related tothe 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 patientsafter failure of interferon therapy. In GIST the study drug was discontinued for drug-related adversereactions in 4% of patients.

The adverse reactions were similar in all indications, with two exceptions. There was moremyelosuppression seen in CML patients than in GIST, which is probably due to the underlyingdisease. 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 tumoursites may have been the source of the GI bleeds (see section 4.4). GI and tumoural bleeding may beserious and sometimes fatal. The most commonly reported (≥ 10%) drug-related adverse reactions inboth settings were mild nausea, vomiting, diarrhoea, abdominal pain, fatigue, myalgia, muscle crampsand rash. Superficial oedemas were a common finding in all studies and were described primarily asperiorbital or lower limb oedemas. However, these oedemas were rarely severe and may be managedwith diuretics, other supportive measures, or by reducing the dose of imatinib.

When imatinib was combined with high dose chemotherapy in Ph+ ALL patients, transient livertoxicity in the form of transaminase elevation and hyperbilirubinaemia were observed. Considering thelimited safety database, the adverse events thus far reported in children are consistent with the knownsafety profile in adult patients with Ph+ ALL. The safety database for children with Ph+ALL is verylimited though no new safety concerns have been identified.

Miscellaneous adverse reactions such as pleural effusion, ascites, pulmonary oedema and rapid weightgain with or without superficial oedema may be collectively described as “fluid retention”. Thesereactions can usually be managed by withholding imatinib temporarily and with diuretics and otherappropriate 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 pleuraleffusion, congestive heart failure and renal failure. There were no special safety findings in paediatricclinical trials.

Adverse reactions

Adverse reactions reported as more than an isolated case are listed below, by system organ class andby 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 mostfrequent first.

Adverse reactions and their frequencies are reported in Table 1.

Table 1 Tabulated summary of adverse reactions

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*

Not known Anaphylactic shock*

Very common Neutropenia, thrombocytopenia, anaemia

Common Pancytopenia, febrile neutropenia

Uncommon Thrombocythaemia, lymphopenia, bone marrow depression, eosinophilia,lymphadenopathy

Rare Haemolytic anaemia, thrombotic microangiopathy

Common Anorexia

Uncommon Hypokalaemia, increased appetite, hypophosphataemia, decreased appetite,dehydration, gout, hyperuricaemia, hypercalcaemia, hyperglycaemia,hyponatraemia

Rare Hyperkalaemia, hypomagnesaemia

Common Insomnia

Uncommon Depression, libido decreased, anxiety

Rare Confusional state

Very common Headache2

Common Dizziness, paraesthesia, taste disturbance, hypoaesthesia

Uncommon Migraine, somnolence, syncope, peripheral neuropathy, memoryimpairment, sciatica, restless leg syndrome, tremor, cerebral haemorrhage

Rare Increased intracranial pressure, convulsions, optic neuritis

Not known Cerebral oedema*

Common Eyelid oedema, lacrimation increased, conjunctival haemorrhage,conjunctivitis, dry eye, blurred vision

Uncommon Eye irritation, eye pain, orbital oedema, scleral haemorrhage, retinalhaemorrhage, blepharitis, macular oedema

Rare Cataract, glaucoma, papilloedema

Not known Vitreous haemorrhage*

Ear and labyrinth disorders

Uncommon Vertigo, tinnitus, hearing loss

Uncommon Palpitations, tachycardia, cardiac failure congestive3, pulmonary oedema

Rare Arrhythmia, atrial fibrillation, cardiac arrest, myocardial infarction, anginapectoris, 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*

Common Dyspnoea, epistaxis, cough

Uncommon Pleural effusion5, pharyngolaryngeal pain, pharyngitis

Rare Pleuritic pain, pulmonary fibrosis, pulmonary hypertension, pulmonaryhaemorrhage

Not known Acute respiratory failure11*, interstitial lung disease*

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)*

Common Increased hepatic enzymes

Uncommon Hyperbilirubinaemia, hepatitis, jaundice

Rare Hepatic failure8, hepatic necrosis

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), naildiscolouration, angioneurotic oedema, rash vesicular, erythema multiforme,leucocytoclastic vasculitis, Stevens-Johnson syndrome, acute generalisedexanthematous pustulosis (AGEP)

Not known Palmoplantar erythrodysesthesia syndrome*, lichenoid keratosis*, lichenplanus*, toxic epidermal necrolysis*, drug rash with eosinophilia andsystemic symptoms (DRESS)*, pseudoporphyria*

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*

Uncommon Renal pain, haematuria, renal failure acute, urinary frequency increased

Not known Renal failure chronic

Uncommon Gynaecomastia, erectile dysfunction, menorrhagia, menstruation irregular,sexual dysfunction, nipple pain, breast enlargement, scrotal oedema

Rare Haemorrhagic corpus luteum/haemorrhagic ovarian cyst

Very common Fluid retention and oedema, fatigue

Common Weakness, pyrexia, anasarca, chills, rigors

Uncommon Chest pain, malaise

Very common Weight increased

Common Weight decreased

Uncommon Blood creatinine increased, blood creatine phosphokinase increased, bloodlactate dehydrogenase increased, blood alkaline phosphatase increased

Rare Blood amylase increased

* These types of reactions have been reported mainly from post-marketing experience withimatinib. This includes spontaneous case reports as well as serious adverse events from ongoingstudies, the expanded access programmes, clinical pharmacology studies and exploratorystudies in unapproved indications. Because these reactions are reported from a population ofuncertain size, it is not always possible to reliably estimate their frequency or establish a causalrelationship 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 commonlyobserved in patients with transformed CML than in patients with chronic CML.4 Flushing was most common in GIST patients and bleeding (haematoma, haemorrhage) wasmost 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 withtransformed CML (CML-AP and CML-BC) than in patients with chronic CML.6+7 Abdominal pain and gastrointestinal haemorrhage were most commonly observed in GISTpatients.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 observedin post-marketing.10 Musculoskeletal pain and related events were more commonly observed in patients with CMLthan in GIST patients.11 Fatal cases have been reported in patients with advanced disease, severe infections, severeneutropenia and other serious concomitant conditions.

Laboratory test abnormalities

In CML, cytopenias, particularly neutropenia and thrombocytopenia, have been a consistent finding inall 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, thefrequency of grade 3 or 4 neutropenias (ANC < 1.0 x 109/L) and thrombocytopenias (plateletcount < 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 diagnosedpatients in chronic phase CML (16.7% neutropenia and 8.9% thrombocytopenia). In newly diagnosedchronic 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 theneutropenic 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 aninterruption of treatment with imatinib, but can in rare cases lead to permanent discontinuation oftreatment. In paediatric CML patients the most frequent toxicities observed were grade 3 or4 cytopenias involving neutropenia, thrombocytopenia and anaemia. These generally occur within thefirst several months of therapy.

In the study in patients with unresectable and/or metastatic GIST, grade 3 and 4 anaemia was reportedin 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% and2.7% of patients, respectively, and grade 3 thrombocytopenia in 0.7% of patients. No patientdeveloped grade 4 thrombocytopenia. The decreases in white blood cell (WBC) and neutrophil countsoccurred mainly during the first six weeks of therapy, with values remaining relatively stablethereafter.

Biochemistry

Severe elevation of transaminases (<5%) or bilirubin (<1%) was seen in CML patients and wasusually managed with dose reduction or interruption (the median duration of these episodes wasapproximately one week). Treatment was discontinued permanently because of liver laboratoryabnormalities 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 themoutcome was fatal, including one patient on high dose paracetamol.

Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted inacute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (seesection 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Experience with doses higher than the recommended therapeutic dose is limited. Isolated cases ofimatinib overdose have been reported spontaneously and in the literature. In the event of overdose thepatient should be observed and appropriate symptomatic treatment given. Generally the reportedoutcome in these cases was “improved” or “recovered”. Events that have been reported at differentdose ranges are as follows:

Adult population1200 to 1600 mg (duration varying between 1 to 10 days): Nausea, vomiting, diarrhoea, rash,erythema, oedema, swelling, fatigue, muscle spasms, thrombocytopenia, pancytopenia, abdominalpain, headache, decreased appetite.1800 to 3200 mg (as high as 3200 mg daily for 6 days): Weakness, myalgia, increased creatinephosphokinase, 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, increasedtransaminases.8 to 10 g (single dose): Vomiting and gastrointestinal pain have been reported.

One 3-year-old male exposed to a single dose of 400 mg experienced vomiting, diarrhoea and anorexiaand another 3-year-old male exposed to a single dose of 980 mg experienced decreased white bloodcell count and diarrhoea.

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

Pharmacotherapeutic group: Antineoplastic agents, BCR-ABL tyrosine kinase inhibitors, ATC code:

L01EA01

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), thecolony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha andbeta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activationof these receptor kinases.

Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Bcr-Abl tyrosine kinase atthe in vitro, cellular and in vivo levels. The compound selectively inhibits proliferation and inducesapoptosis in Bcr-Abl positive cell lines as well as fresh leukaemic cells from Philadelphiachromosome 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-Ablpositive tumour cells.

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

PDGF-R, and inhibits PDGF-mediated cellular events. Constitutive activation of the PDGF receptor orthe Abl protein tyrosine kinases as a consequence of fusion to diverse partner proteins or constitutiveproduction 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 kinaseactivity.

Clinical studies in chronic myeloid leukaemia

The effectiveness of imatinib is based on overall haematological and cytogenetic response rates andprogression-free survival. There are no controlled trials demonstrating a clinical benefit, such asimprovement in disease-related symptoms or increased survival.

A large, international, open-label, non-controlled phase II study was conducted in patients with

Philadelphia chromosome positive (Ph+) CML in the blast crisis phase of the disease. In addition,children and adolescents have been treated in two phase I studies (in patients with CML or Ph+ acuteleukaemia) and one phase II study.

In the clinical study 38% of patients were ≥ 60 years of age and 12% of patients were ≥ 70 years ofage.

Myeloid blast crisis: 260 patients with myeloid blast crisis were enrolled. 95 (37%) had received priorchemotherapy for treatment of either accelerated phase or blast crisis (“pretreated patients”) whereas165 (63%) had not (“untreated patients”). The first 37 patients were started at 400 mg, the protocolwas subsequently amended to allow higher dosing and the remaining 223 patients were started at600 mg.

The primary efficacy variable was the rate of haematological response, reported as either completehaematological response, no evidence of leukaemia (i.e. clearance of blasts from the marrow and theblood, but without a full peripheral blood recovery as for complete responses), or return to chronicphase CML. In this study, 31% of patients achieved a haematological response (36% in previouslyuntreated patients and 22% in previously treated patients) (Table 2). The rate of response was alsohigher 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 patientswas 7.7 and 4.7 months, respectively.

Lymphoid blast crisis: a limited number of patients were enrolled in phase I studies (n=10). The rate ofhaematological response was 70% with a duration of 2-3 months.

Table 2 Response in adult CML study

Study 010238-month data

Myeloid blast crisis(n=260)% of patients (CI95%)

Haematological response1 31% (25.2-36.8)

Complete haematological response (CHR) 8%

No evidence of leukaemia (NEL) 5%

Return to chronic phase (RTC) 18%

Major cytogenetic response2 15% (11.2-20.4)

Complete 7%(Confirmed3) [95% CI] (2%) [0.6-4.4]

Partial 8%1 Haematological response criteria (all responses to be confirmed after ≥ 4 weeks):

CHR: In study 0102 [ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, no blood blasts, BM blasts < 5% andno extramedullary disease]

NEL Same criteria as for CHR but ANC ≥ 1 x 109/L and platelets ≥ 20 x 109/L

RTC < 15% blasts BM and PB, < 30% blasts+promyelocytes in BM and PB, < 20% basophils in PB,no extramedullary disease other than spleen and liver.

BM = bone marrow, PB = peripheral blood2 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 evaluationperformed 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% aprior multi-agent chemotherapy. Patients were treated at doses of imatinib of 260 mg/m2/day (n=5),340 mg/m2/day (n=9), 440 mg/m2/day (n=7) and 570 mg/m2/day (n=5). Out of 9 patients with chronicphase CML and cytogenetic data available, 4 (44%) and 3 (33%) achieved a complete and partialcytogenetic 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 beenenrolled in an open-label, multicentre, single-arm phase II trial. Patients were treated with imatinib340 mg/m2/day, with no interruptions in the absence of dose limiting toxicity. Imatinib treatmentinduces a rapid response in newly diagnosed paediatric CML patients with a CHR of 78% after8 weeks of therapy. The high rate of CHR is accompanied by the development of a completecytogenetic 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%. Themajority of patients who achieved a CCyR developed the CCyR between months 3 and 10 with amedian 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 withimatinib in all subsets of the paediatric population in Philadelphia chromosome (bcr-abl translocation)-positive chronic myeloid leukaemia (see section 4.2 for information on paediatric use).

Clinical studies in Ph+ ALL

Newly diagnosed Ph+ ALL: In a controlled study (ADE10) of imatinib versus chemotherapy inductionin 55 newly diagnosed patients aged 55 years and over, imatinib used as single agent induced asignificantly 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 orwho responded poorly to chemotherapy, it resulted in 9 patients (81.8%) out of 11 achieving acomplete haematological response. This clinical effect was associated with a higher reduction in bcr-abl transcripts in the imatinib-treated patients than in the chemotherapy arm after 2 weeks of therapy(p=0.02). All patients received imatinib and consolidation chemotherapy (see Table 3) after inductionand the levels of bcr-abl transcripts were identical in the two arms at 8 weeks. As expected on thebasis of the study design, no difference was observed in remission duration, disease-free survival oroverall survival, although patients with complete molecular response and remaining in minimalresidual disease had a better outcome in terms of both remission duration (p=0.01) and disease-freesurvival (p=0.02).

The results observed in a population of 211 newly diagnosed Ph+ ALL patients in four uncontrolledclinical studies (AAU02, ADE04, AJP01 and AUS01) are consistent with the results described above.

Imatinib in combination with chemotherapy induction (see Table 3) resulted in a completehaematological response rate of 93% (147 out of 158 evaluable patients) and in a major cytogeneticresponse rate of 90% (19 out of 21 evaluable patients). The complete molecular response rate was48% (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) intwo studies (AJP01 and AUS01).

Table 3 Chemotherapy regimen used in combination with imatinib

Study ADE10

Prephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3, 4, 5; MTX12 mg intrathecal, day 1

Remission induction DEX 10 mg/m2 oral, days 6-7, 13-16; VCR 1 mg i.v., days 7, 14; IDA8 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 MTX 500 mg/m2 i.v. (24 h), days 1, 15; 6-MP 25 mg/m2 oral, days 1-20therapy I, III, V

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

Study AAU02

Induction therapy Daunorubicin 30 mg/m2 i.v., days 1-3, 15-16; VCR 2 mg total dose i.v.,(de novo Ph+ ALL) days 1, 8, 15, 22; CP 750 mg/m2 i.v., days 1, 8; prednisone60 mg/m2 oral, days 1-7, 15-21; IDA 9 mg/m2 oral, days 1-28; MTX15 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 Ara-C 1,000 mg/m2 /12 h i.v.(3 h), days 1-4; mitoxantronenovo Ph+ ALL) 10 mg/m2 i.v. days 3-5; MTX 15 mg intrathecal, day 1;methylprednisolone 40 mg intrathecal, day 1

Study ADE04

Prephase DEX 10 mg/m2 oral, days 1-5; CP 200 mg/m2 i.v., days 3-5; MTX 15 mgintrathecal, 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 DEX 10 mg/m2 oral, days 1-5; vindesine 3 mg/m2 i.v., day 1; MTXtherapy 1.5 g/m2 i.v. (24 h), day 1; etoposide 250 mg/m2 i.v. (1 h) days 4-5; Ara- C2x 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/dayoral

Consolidation Alternating chemotherapy course: high dose chemotherapy with MTXtherapy 1 g/m2 i.v. (24 h), day 1, and Ara-C 2 g/m2 i.v. (q 12 h), days 2-3, for4 cycles

Maintenance VCR 1.3 g/m2 i.v., day 1; prednisolone 60 mg/m2 oral, days 1-5

Study AUS01

Induction- Hyper-CVAD regimen: CP 300 mg/m2 i.v. (3 h, q 12 h), days 1-3;consolidation therapy 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 daysper 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 (from1 to 22 years old) with Ph+ ALL were enrolled in an open-label, multicentre, sequential cohort,non-randomised phase III trial, and were treated with imatinib (340 mg/m2/day) in combination withintensive chemotherapy after induction therapy. Imatinib was administered intermittently in cohorts1-5, with increasing duration and earlier start of imatinib from cohort to cohort; cohort 1 receiving thelowest intensitiy and cohort 5 receiving the highest intensity of imatinib (longest duration in days withcontinuous daily imatinib dosing during the first chemotherapy treatment courses). Continuous dailyexposure to imatinib early in the course of treatment in combination with chemotherapy incohort 5-patients (n=50) improved the 4-year event-free survival (EFS) compared to historical controls(n=120), who received standard chemotherapy without imatinib (69.6% vs. 31.6%, respectively). Theestimated 4-year OS in cohort 5-patients was 83.6% compared to 44.8% in the historical controls. 20out of the 50 (40%) patients in cohort 5 received haematopoietic stem cell transplant.

Table 4 Chemotherapy regimen used in combination with imatinib in study I2301

Consolidation block 1 VP-16 (100 mg/m2/day, IV): days 1-5(3 weeks) 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 Methotrexate (5 g/m2 over 24 hours, IV): day 1(3 weeks) Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x6 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 VCR (1.5 mg/m2/day, IV): days 1, 8, and 15(3 weeks) 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 Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15(9 weeks) Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x6 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 VCR (1.5 mg/m2/day, IV): days 1, 8 and 15(3 weeks) 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 Methotrexate (5 g/m2 over 24 hours, IV): days 1 and 15(9 weeks) Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x6 doses)iii: days 2, 3, 16, and 17

Triple IT therapy (age-adjusted): days 1 and 22

VP-16 (100 mg/m2/day, IV): days 22-26

CPM (300 mg/m2/day, IV): days 22-26

MESNA (150 mg/m2/day, IV): days 22-26

G-CSF (5 μg/kg, SC): days 27-36 or until ANC > 1500 post nadir

ARA-C (3 g/m2, q12h, IV): days 43, 44

L-ASP (6000 IUnits/m2, IM): day 44

Maintenance MTX (5 g/m2 over 24 hours, IV): day 1(8-week cycles) Leucovorin (75 mg/m2 at hour 36, IV; 15 mg/m2 IV or PO q6h x 6

Cycles 1-4 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; 29-336-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 Cranial irradiation (Block 5 only)(8-week cycles) 12 Gy in 8 fractions for all patients that are CNS1 and CNS2 at diagnosis

Cycle 5 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; 29-336-MP (75 mg/m2/day, PO): days 11-56 (Withhold 6-MP during the6-10 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 VCR (1.5 mg/m2/day, IV): days 1, 29(8-week cycles) DEX (6 mg/m2/day, PO): days 1-5; 29-33

Cycles 6-12 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 = PEGasparaginase, 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 studyseem 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 withrelapsed/refractory Ph+ ALL, it resulted, in the 53 out of 411 patients evaluable for response, in ahaematological 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 primaryresponse data collected.) The median time to progression in the overall population of 411 patients withrelapsed/refractory Ph+ ALL ranged from 2.6 to 3.1 months, and median overall survival in the401 evaluable patients ranged from 4.9 to 9 months. The data was similar when re-analysed to includeonly those patients age 55 or older.

Clinical studies in MDS/MPD

Experience with imatinib in this indication is very limited and is based on haematological andcytogenetic response rates. There are no controlled trials demonstrating a clinical benefit or increasedsurvival. One open label, multicentre, phase II clinical trial (study B2225) was conducted testingimatinib 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 weretreated with imatinib 400 mg daily. Three patients presented a complete haematological response(CHR) and one patient experienced a partial haematological response (PHR). At the time of theoriginal analysis, three of the four patients with detected PDGFR gene rearrangements developedhaematological response (2 CHR and 1 PHR). The age of these patients ranged from 20 to 72 years.

An observational registry (study L2401) was conducted to collect long-term safety and efficacy data inpatients suffering from myeloproliferative neoplasms with PDGFR- β rearrangement and who weretreated with imatinib. The 23 patients enrolled in this registry received imatinib at a median daily doseof 264 mg (range: 100 to 400 mg) for a median duration of 7.2 years (range 0.1 to 12.7 years). Due tothe observational nature of this registry, haematologic, cytogenetic and molecular assessment datawere available for 22, 9 and 17 of the 23 enrolled patients, respectively. When assumingconservatively 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. Whenthe 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 weretreated with imatinib 400 mg daily, while the other 3 patients received lower doses. In eleven patients

PDGFR gene rearrangements was detected, 9 of them achieved a CHR and 1 PHR. The age of thesepatients ranged from 2 to 79 years. In a recent publication updated information from 6 of these11 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 PDGFRgene rearrangements (5 patients from study B2225). These patients received imatinib for a median of47 months (range 24 days - 60 months). In 6 of these patients follow-up now exceeds 4 years. Elevenpatients achieved rapid CHR; ten had complete resolution of cytogenetic abnormalities and a decreaseor disappearance of fusion transcripts as measured by RT-PCR. Haematological and cytogeneticresponses have been sustained for a median of 49 months (range 19-60) and 47 months (range 16-59),respectively. The overall survival is 65 months since diagnosis (range 25-234). Imatinib administrationto 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/MPDassociated with PDGFR gene re-arrangements were reported in 4 publications. The age of thesepatients ranged from 3 months to 4 years and imatinib was given at dose 50 mg daily or doses rangingfrom 92.5 to 340 mg/m2 daily. All patients achieved complete haematological response, cytogeneticresponse and/or clinical response.

Clinical studies in HES/CEL

One open-label, multicentre, phase II clinical trial (study B2225) was conducted testing imatinib indiverse 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 to1,000 mg of imatinib daily. A further 162 patients with HES/CEL, reported in 35 published casereports and case series received imatinib at doses from 75 mg to 800 mg daily. Cytogeneticabnormalities 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 kinasepositive patients achieved a CHR sustained for months (range from 1+ to 44+ months censored at thetime of the reporting). As reported in a recent publication 21 of these 65 patients also achievedcomplete molecular remission with a median follow-up of 28 months (range 13-67 months). The ageof these patients ranged from 25 to 72 years. Additionally, improvements in symptomatology andother 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 gastrointestinalorgan 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 thesepatients ranged from 2 to 16 years and imatinib was given at dose 300 mg/m2 daily or doses rangingfrom 200 to 400 mg daily. All patients achieved complete haematological response, completecytogenetic response and/or complete molecular response.

Clinical studies in DFSP

One phase II, open label, multicentre clinical trial (study B2225) was conducted including 12 patientswith DFSP treated with imatinib 800 mg daily. The age of the DFSP patients ranged from 23 to75 years; DFSP was metastatic, locally recurrent following initial resective surgery and not consideredamenable to further resective surgery at the time of study entry. The primary evidence of efficacy wasbased on objective response rates. Out of the 12 patients enrolled, 9 responded, one completely and8 partially. Three of the partial responders were subsequently rendered disease free by surgery. Themedian duration of therapy in study B2225 was 6.2 months, with a maximum duration of 24.3 months.

A further 6 DFSP patients treated with imatinib were reported in 5 published case reports, their agesranging from 18 months to 49 years. The adult patients reported in the published literature weretreated with either 400 mg (4 cases) or 800 mg (1 case) imatinib daily. 5 patients responded,3 completely and 2 partially. The median duration of therapy in the published literature rangedbetween 4 weeks and more than 20 months. The translocation t(17:22)[(q22:q13)], or its gene product,was present in nearly all responders to imatinib treatment.

There are no controlled trials in paediatric patients with DFSP. Five (5) patients with DFSP and

PDGFR gene re-arrangements were reported in 3 publications. The age of these patients ranged fromnewborn to 14 years and imatinib was given at dose 50 mg daily or doses ranging from 400 to520 mg/m2 daily. All patients achieved partial and/or complete response.

Pharmacokinetics of imatinib

The pharmacokinetics of imatinib have been evaluated over a dosage range of 25 to 1,000 mg. Plasmapharmacokinetic profiles were analysed on day 1 and on either day 7 or day 28, by which time plasmaconcentrations had reached steady state.

Mean absolute bioavailability for imatinib is 98%. There was high between-patient variability inplasma imatinib AUC levels after an oral dose. When given with a high-fat meal, the rate ofabsorption of imatinib was minimally reduced (11% decrease in Cmax and prolongation of tmax by1.5 h), with a small reduction in AUC (7.4%) compared to fasting conditions. The effect of priorgastrointestinal surgery on drug absorption has not been investigated.

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 bindingto lipoprotein.

The main circulating metabolite in humans is the N-demethylated piperazine derivative, which showssimilar 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 tothat of the parent compound.

Imatinib and the N-demethyl metabolite together accounted for about 65% of the circulatingradioactivity (AUC(0-48h)). The remaining circulating radioactivity consisted of a number of minormetabolites.

The in vitro results showed that CYP3A4 was the major human P450 enzyme catalysing thebiotransformation 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 ofimatinib metabolism which could have clinical relevance.

Imatinib was shown in vitro to be a competitive inhibitor of marker substrates for CYP2C9, CYP2D6and CYP3A4/5. Ki values in human liver microsomes were 27, 7.5 and 7.9 μmol/L, respectively.

Maximal plasma concentrations of imatinib in patients are 2-4 μmol/L, consequently an inhibition of

CYP2D6 and/or CYP3A4/5-mediated metabolism of co-administered drugs is possible. Imatinib didnot interfere with the biotransformation of 5-fluorouracil, but it inhibited paclitaxel metabolism as aresult of competitive inhibition of CYP2C8 (Ki - 34.7 µM). This Ki value is far higher than theexpected plasma levels of imatinib in patients, consequently no interaction is expected upon co-administration of either 5-fluorouracil or paclitaxel and imatinib.

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). Unchangedimatinib 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 thatonce-daily dosing is appropriate. The increase in mean AUC with increasing dose was linear and doseproportional in the range of 25-1,000 mg imatinib after oral administration. There was no change inthe kinetics of imatinib on repeated dosing, and accumulation was 1.5-2.5-fold at steady state whendosed once daily.

Based on population pharmacokinetic analysis in CML patients, there was a small effect of age on thevolume of distribution (12% increase in patients > 65 years old). This change is not thought to beclinically significant. The effect of bodyweight on the clearance of imatinib is such that for a patientweighing 50 kg the mean clearance is expected to be 8.5 L/h, while for a patient weighing 100 kg theclearance will rise to 11.8 L/h. These changes are not considered sufficient to warrant dose adjustmentbased on kg bodyweight. There is no effect of gender on the kinetics of imatinib.

Pharmacokinetics in paediatric population

As in adult patients, imatinib was rapidly absorbed after oral administration in paediatric patients inboth phase I and phase II studies. Dosing in children at 260 and 340 mg/m2/day achieved the sameexposure, 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 afterrepeated once-daily dosing.

Based on pooled population pharmacokinetic analysis in paediatric patients with haematologicaldisorders (CML, Ph+ALL, or other haematological disorders treated with imatinib), clearance ofimatinib increases with increasing body surface area (BSA). After correcting for the BSA effect, otherdemographics such as age, body weight and body mass index did not have clinically significant effectson the exposure of imatinib. The analysis confirmed that exposure of imatinib in paediatric patientsreceiving 260 mg/m2 once daily (not exceeding 400 mg once daily) or 340 mg/m2 once daily (notexceeding 600 mg once daily) were similar to those in adult patients who received imatinib 400 mg or600 mg once daily.

Organ function impairment

Imatinib and its metabolites are not excreted via the kidney to a significant extent. Patients with mildand moderate impairment of renal function appear to have a higher plasma exposure than patients withnormal renal function. The increase is approximately 1.5- to 2-fold, corresponding to a 1.5-foldelevation of plasma AGP, to which imatinib binds strongly. The free drug clearance of imatinib isprobably similar between patients with renal impairment and those with normal renal function, sincerenal 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-subjectvariation, the mean exposure to imatinib did not increase in patients with varying degrees of liverdysfunction as compared to patients with normal liver function (see sections 4.2, pct. 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 andmonkeys, 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 slightdecreases 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 treatedfor 2 weeks, with elevated liver enzymes, hepatocellular necrosis, bile duct necrosis, and bile ducthyperplasia.

Renal toxicity was observed in monkeys treated for 2 weeks, with focal mineralisation and dilation ofthe renal tubules and tubular nephrosis. Increased blood urea nitrogen (BUN) and creatinine wereobserved in several of these animals. In rats, hyperplasia of the transitional epithelium in the renalpapilla and in the urinary bladder was observed at doses ≥ 6 mg/kg in the 13-week study, withoutchanges in serum or urinary parameters. An increased rate of opportunistic infections was observedwith chronic imatinib treatment.

In a 39-week monkey study, no NOAEL (no observed adverse effect level) was established at thelowest dose of 15 mg/kg, approximately one-third the maximum human dose of 800 mg based onbody surface. Treatment resulted in worsening of normally suppressed malarial infections in theseanimals.

Imatinib was not considered genotoxic when tested in an in vitro bacterial cell assay (Ames test), an invitro mammalian cell assay (mouse lymphoma) and an in vivo rat micronucleus test. Positivegenotoxic effects were obtained for imatinib in an in vitro mammalian cell assay (Chinese hamsterovary) for clastogenicity (chromosome aberration) in the presence of metabolic activation. Twointermediates of the manufacturing process, which are also present in the final product, are positive formutagenesis in the Ames assay. One of these intermediates was also positive in the mouse lymphomaassay.

In a study of fertility, in male rats dosed for 70 days prior to mating, testicular and epididymal weightsand percent motile sperm were decreased at 60 mg/kg, approximately equal to the maximum clinicaldose of 800 mg/day, based on body surface area. This was not seen at doses ≤ 20 mg/kg. A slight tomoderate reduction in spermatogenesis was also observed in the dog at oral doses ≥ 30 mg/kg. Whenfemale rats were dosed 14 days prior to mating and through to gestational day 6, there was no effect onmating 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 the45 mg/kg/day group on either day 14 or day 15 of gestation. At the same dose, the number of stillbornpups as well as those dying between postpartum days 0 and 4 was increased. In the F1 offspring, at thesame dose level, mean body weights were reduced from birth until terminal sacrifice and the numberof litters achieving criterion for preputial separation was slightly decreased. F1 fertility was notaffected, while an increased number of resorptions and a decreased number of viable foetuses wasnoted at 45 mg/kg/day. The no observed effect level (NOEL) for both the maternal animals and the F1generation 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 parietalbones. 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 70postpartum) 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 atapproximately 0.3 to 2 times the average paediatric exposure at the highest recommended dose of340 mg/m2. In addition, mortality was observed in juvenile animals (around weaning phase) atapproximately 2 times the average paediatric exposure at the highest recommended dose of340 mg/m2.

In the 2-year rat carcinogenicity study administration of imatinib at 15, 30 and 60 mg/kg/day resultedin 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 deathor 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/dayor 800 mg/day, respectively, and 0.4 times the daily exposure in children (based on AUC) at340 mg/m2/day. The no observed effect level (NOEL) was 15 mg/kg/day. The renaladenoma/carcinoma, the urinary bladder and urethra papilloma, the small intestine adenocarcinomas,the parathyroid glands adenomas, the benign and malignant medullary tumours of the adrenal glandsand the non-glandular stomach papillomas/carcinomas were noted at 60 mg/kg/day, representingapproximately 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 noobserved effect level (NOEL) was 30 mg/kg/day.

The mechanism and relevance of these findings in the rat carcinogenicity study for humans are not yetclarified.

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 anddilatation, leading to signs of cardiac insufficiency in some animals.

The active substance imatinib demonstrates an environmental risk for sediment organisms.

Imatinib Actavis 50 mg hard capsules

Cellulose microcrystalline

Copovidone

Crospovidone

Sodium stearyl fumarate

Silica, hydrophobic colloidal

Silica, colloidal anhydrous

Hypromellose

Titanium dioxide (E171)

Iron oxide yellow (E172)

Shellac

Black iron oxide (E172)

Ammonia solution

Potassium hydroxide

Imatinib Actavis 100 mg hard capsules

Cellulose microcrystalline

Copovidone

Crospovidone

Sodium stearyl fumarate

Silica, hydrophobic colloidal

Silica, colloidal anhydrous

Hypromellose

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide red (E172)

Shellac

Black iron oxide (E172)

Ammonia solution

Potassium hydroxide

Imatinib Actavis 400 mg hard capsules

Cellulose microcrystalline

Copovidone

Crospovidone

Sodium stearyl fumarate

Silica, hydrophobic colloidal

Silica, colloidal anhydrous

Hypromellose

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide red (E172)

Iron oxide black (E172)

Shellac Glaze-45%

Black iron oxide (E172)

Ammonium Hydroxide 28%

Not applicable.

2 years

Do not store above 25°C.

Store in the original package in order to protect from moisture.

Imatinib Actavis 50 mg hard capsules

Al/PVC/Aclar blister. One blister contains 10 capsules.

Pack containing either 30 or 90 capsules.

Imatinib Actavis 100 mg hard capsules

Al/PVC/Aclar blister. One blister contains either 8 or 10 capsules.

Pack containing either 24, 48, 60, 96, 120 or 180 capsules

Imatinib Actavis 400 mg hard capsules

Al/PVC-PVDC blister. One blister contains 10 capsules.

Pack containing either 10, 30, 60, or 90 capsules.

Not all pack sizes may be marketed.

Handling of opened capsules by women of child-bearing potential

Since studies in animals have shown reproductive toxicity, and the potential risk for the human foetusis unknown, women of child-bearing potential who open capsules should be advised to handle thecontents with caution and avoid skin-eye contact or inhalation (see section 4.6). Hands should bewashed immediately after handling open capsules.

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

Actavis Group PTC ehf.

Reykjavíkurvegur 76-78

IS-220 Hafnarfjörður

Iceland

Imatinib Actavis 50 mg hard capsules

EU/1/13/825/001

EU/1/13/825/002

Imatinib Actavis 100 mg hard capsules

EU/1/13/825/003

EU/1/13/825/004

EU/1/13/825/005

EU/1/13/825/006

EU/1/13/825/007

EU/1/13/825/019

Imatinib Actavis 400 mg hard capsules

EU/1/13/825/020

EU/1/13/825/021

EU/1/13/825/022

EU/1/13/825/023

Date of first authorisation: 17 April 2013

Date of latest renewal: 8 January 2018

Detailed information on this medicinal product is available on the website of the European Medicines

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